Current Diagnosis and Therapy for Head and Neck Malignancies

CURRENT DIAGNOSIS AND THERAPY FOR HEAD AND NECKMALIGNANCIES

CONSULTING EDITOR

NICHOLAS J. PETRELLI, MD, Medical Director, Helen F. Graham Cancer Center,Newark, Delaware; and Professor of Surgery, Jefferson Medical College, Philadelphia,Pennsylvania

GUEST EDITOR

WESLEY L. HICKS, JR, DDS, MD, FACS, Attending Surgeon, Department of Head andNeck Surgery, Roswell Park Cancer Institute; Associate Professor of Otolaryngology,Head and Neck Surgery, and Neurosurgery, School of Medicine and BiomedicalSciences, State University of New York at Buffalo, Buffalo, New York; and Director,Head and Neck Surgical Fellowship Program, Roswell Park Cancer Institute

CONTRIBUTORS

RONALD A. ALBERICO, MD, Associate Professor of Radiology, Assistant ClinicalProfessor of Neurosurgery, School of Medicine and Biomedical Sciences, StateUniversity of New York at Buffalo; Director of Neuroradiology/Head and NeckImaging, Department of Radiology, Roswell Park Cancer Institute, Buffalo, New York;and Acting Director of Pediatric Neuroradiology, Buffalo Children’s Hospital, Buffalo,New York

GARTH R. ANDERSON, PhD, Professor of Cellular and Molecular Biology, Departmentof Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York

JIMMY J. BROWN, DDS, MD, FACS, Assistant Professor, Department ofOtolaryngology–Head and Neck Surgery, Charles R. Drew University of Medicine andScience, Los Angeles, California

AMOS O. DARE, MD, Clinical Instructor, Department of Neurological Surgery, School ofMedicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo,New York

WADE DOUGLAS, MD, Fellow, Department of Head and Neck Surgery, Roswell ParkCancer Institute, Buffalo, New York

KEVIN J. GIBBONS, MD, Program Director and Director of Skull Base Surgery,Department of Neurological Surgery, School of Medicine and Biomedical Sciences,State University of New York at Buffalo, Buffalo, New York

WILLIAM GIESE, MD, JD, Associate Professor, Department of Radiation Oncology,Roswell Park Cancer Institute, Buffalo, New York

iii

RALPH W. GILBERT, MD, FRCSC, Associate Professor, Head and Neck SurgicalOncology; Reconstructive Microsurgery, University Health Network; PrincessMargaret Hospital; and Department of Otolaryngology, University of Toronto,Toronto, Canada

CHRISTINE G. GOURIN, MD, FACS, Assistant Professor, Department ofOtolaryngology–Head and Neck Surgery, Medical College of Georgia, Augusta,Georgia

PATRICK J. GULLANE, MB, FRCSC, FACS, Otolaryngologist-in-Chief, University HealthNetwork; Wharton Chair in Head and Neck Surgery, Princess Margaret Hospital; andProfessor and Chairman, Department of Otolaryngology, University of Toronto,Toronto, Canada

SYED HAMED S. HUSAIN, DO, Radiology Resident, School of Medicine and BiomedicalSciences, State University of New York at Buffalo, Buffalo, New York

DOMINICK LAMONICA, MD, Director of Nuclear Medicine, Division of DiagnosticImaging, Roswell Park Cancer Institute; and Assistant Professor of Radiology andClinical Nuclear Medicine, School of Medicine and Biomedical Sciences, StateUniversity of New York at Buffalo, Buffalo, New York

PABLO MOJICA-MANOSA, MD, Fellow, Department of Head and Neck Surgery,Roswell Park Cancer Institute, Buffalo, New York

JEFFREY N. MYERS, MD, PhD, Associate Professor of Head and Neck Surgery,Department of Head and Neck Surgery, The University of Texas M.D. AndersonCancer Center, Houston, Texas

LARRY L. MYERS, MD, Department of Otolaryngology–Head and Neck Surgery,University of Texas Southwestern Medical Center, Dallas, Texas

RYAN F. OSBORNE, MD, Director, Head and Neck Oncology, Cedars-Sinai MedicalCenter; and Assistant Professor, Department of Otolarynology–Head and NeckSurgery, Charles R. Drew University of Medicine and Science, Los Angeles, California

LANCE E. OXFORD, MD, Department of Otolaryngology–Head and Neck Surgery,University of Texas Southwestern Medical Center, Dallas, Texas

CARSTEN E. PALME, MB BS, FRACS, Clinical Fellow, Oncologic Head and NeckSurgery, Department of Otolaryngology, University of Toronto, Toronto, Canada

JAMES REIDY, DO, Fellow, Department of Head and Neck Surgery, Roswell Park CancerInstitute, Buffalo, New York

NESTOR R. RIGUAL, MD, FACS, Associate Professor of Clinical Otolaryngology, Schoolof Medicine and Biomedical Sciences, State University of New York at Buffalo; andAttending Surgeon, Section of Plastic and Reconstructive Surgery, Department of Headand Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York

JAMES K. SCHWARZ, MD, Assistant Professor, Department of Medicine, Roswell ParkCancer Institute, Buffalo, New York

iv CONTRIBUTORS

IGOR SIROTKIN, MD, Radiology Resident, School of Medicine and Biomedical Sciences,State University of New York at Buffalo, Buffalo, New York

DANIEL L. STOLER, PhD, Assistant Professor, Department of Experimental Pathology,Roswell Park Cancer Institute, Buffalo, New York

MAUREEN SULLIVAN, DDS, Chief, Department of Dentistry and MaxillofacialProsthetics, Roswell Park Cancer Institute, Buffalo, New York

DAVID J. TERRIS, MD, FACS, Porubsky Professor and Chairman, Departmentof Otolaryngology–Head and Neck Surgery, Medical College of Georgia, Augusta,Georgia

KEITH WILSON, MD, Associate Professor, ENT/Head and Neck Surgery, Universityof Cincinnati, Cincinnati, Ohio

SAM M. WISEMAN, MD, FRCS(C), Assistant Professor of Surgery, University of BritishColumbia School of Medicine; and Attending Surgeon, Department of Surgery, St.Paul’s Hospital, Vancouver, British Columbia, Canada

ROBERT L. WITT, MD, Chief, Section of Otolaryngology, Department of Surgery,Christiana Care Health System, Newark, Delaware; and Assistant Professor,Department of Otolaryngology, Jefferson Medical College, Philadelphia, Pennsylvania

MAHER N. YOUNES, MD, Postdoctoral Fellow, Department of Head and Neck Surgery,University of Texas M. D. Anderson Cancer Center, Houston, Texas

CONTRIBUTORS v

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Surg Oncol Clin N Am

13 (2004) xiii–xiv

Foreword

Current diagnosis and therapy for headand neck malignancies

Consulting Editor

Approximately 1,334,100 new cancer cases were diagnosed in 2003. Since1990, over 17 million new cancer cases have been diagnosed. According tothe American Cancer Society, these new cancer cases do not include carci-noma in situ of any site except urinary bladder and do not include basal andsquamous skin cancers. In 2003, approximately 556,500 Americans died ofcancer, which is equivalent to more than 1500 people a day.

Cancers of the oral cavity and pharynx were diagnosed in an estimated27,700 new cases in 2003. These incidence rates are more than twice as highin men as in women and are greatest in men who are over age 50. Neverthe-less, incidence rates for cancers of the oral cavity and pharynx continued todecline in the 1990s in both African American and white males and females.There were an estimated 7200 deaths in 2003 from oral cavity and pharyng-eal cancer. The known risk factors for these cancers are cigarettes, cigars,pipe smoking, and the use of smokeless tobacco. Excessive consumptionof alcohol is also a risk factor.

In this issue of the Surgical Oncology Clinics of North America, under thedirection of Wesley Hicks, Jr., DDS, MD, an outstanding array of authorshas been assembled to discuss many clinical and scientific issues regardingcancers of the head and neck. Dr. Hicks is a member of the Departmentof Head and Neck Surgery at the Roswell Park Cancer Institute in Buffalo,New York, and an Associate Professor of Surgery at the State University ofNew York at Buffalo.

Nicholas J. Petrelli, MD

1055-3207/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.soc.2003.12.010

xiv N.J. Petrelli / Surg Oncol Clin N Am 13 (2004) xiii–xiv

The article by Wiseman, Stoler, and Anderson on the role of genomicinstability in the pathogenesis of squamous cell carcinoma of the head andneck is especially interesting. These researchers are from the Departments ofSurgical Oncology, Experimental Pathology, and Cancer Genetics, respec-tively. Cancer predisposition genes and the genetic heterogeneity of headand neck tumors are discussed in detail.

On the clinical side, the article by Osborne and Brown from the Divisionof Otolaryngology/Head and Neck Surgery at the University of California–Los Angeles Medical Center deals with carcinoma of the oral pharynx withan analysis of subsite treatment heterogeneity. This article provides a cleardiscussion of the clinical treatment modalities in relationship to histopatho-logic characteristics.

As I have stated in previous forewords for the Surgical Oncology Clinicsof North America, this issue is a must-read for trainees in the three majordisciplines of surgery, radiation oncology, and medical oncology. Traineesin pathology and radiology should also make this issue a part of their educa-tional matriculation.

I congratulate Dr. Hicks and his colleagues on an outstanding issue of theSurgical Oncology Clinics of North America.

Nicholas J. Petrelli, MDConsulting Editor

Helen F. Graham Cancer Center4701 Ogletown-Stanton Road

Suite 1212Newark, Delaware 19713, USA

Jefferson Medical CollegePhiladelphia, Pennsylvania

Surg Oncol Clin N Am

13 (2004) xv–xvi

Preface

Current diagnosis and therapy for headand neck malignancies

Guest Editor

Squamous cell carcinoma is the most common histologic malignancy ofthe head and neck region. Despite this monotonous pathologic presentation,there are a plethora of treatment options and clinical outcomes based onboth the site and stage of the primary tumor. The recent movement to com-bined modality therapy has been driven by the clinical need to improve dis-ease-free survival while minimizing functional and cosmetic morbidity. Heremuch more work can and should be done. Advancement in treatmentand survival in head and neck surgery, in our opinion, requires furthertranslational research efforts melding clinical expertise with bench scientificdiscovery.

Oncologic head and neck surgery is one of the most clinically challengingand complex areas of surgical oncology. This issue of the Surgical OncologyClinics of North America presents what we believe is a rational organ-specificapproach to malignancies of this region. This issue is not intended to be anexhaustive explanation regarding the armamentarium or clinical paradigmsfor the treatment of head and neck cancer. We anticipate, however, that itwill serve as a solid foundation for those who wish to pursue a personal clin-ical interest in head and neck surgical oncology.

We anticipate that this issue will give readers a general overview of headand neck cancer and the common surgical/medical approaches to this dis-ease. Each article is a self-contained clinical caveat with a complete explan-ation of how specific subsites within the head and neck region can be

Wesley L. Hicks, Jr, MD


doi:10.1016/j.soc.2003.12.009

xvi W.L. Hicks / Surg Oncol Clin N Am 13 (2004) xv–xvi

evaluated and treated. After reviewing the articles in aggregate, my beliefwas affirmed that an understanding of the clinical nuances pertinent to eachhead and neck subsite must be mastered to obtain effective and improvedclinical outcomes.

I wish to express my sincere gratitude and thanks to the contributingauthors, whose diligent and exacting work made this issue possible.

Wesley L. Hicks Jr, DDS, MD, FACSDepartment of Head and Neck Surgery

Roswell Park Cancer InstituteSchool of Medicine and Biomedical Sciences

State University of New York at BuffaloElm & Carlton Streets

Buffalo, NY 14263, USA

E-mail address: [email protected]

mailto:[email protected]

Surg Oncol Clin N Am 13 (2004) 1–11

The role of genomic instabilityin the pathogenesis of squamous cellcarcinoma of the head and neck

Sam M. Wiseman, MD, FRCS(C)a,1,Daniel L. Stoler, PhDb, Garth R. Anderson, PhDa,c,*

aDepartment of Surgical Oncology, Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY 14263, USAbDepartment of Experimental Pathology, Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY 14263, USAcDepartment of Cancer Genetics, Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY 14263, USA

Human beings are composed of a highly complex community of cells, andeach cell type has its own role that is defined by the genetic instructions itexpresses. For cells to function normally, their genetic instructions must beaccurately transmitted from one generation to the next. The informationcarried by the genetic code must be accurately replicated and efficientlyrepaired to ensure the survival of cells, organisms, and species. In humans,the importance of maintaining the integrity of their genetic blueprint can beappreciated by the approximately 130 genes involved in DNA repair alone[1]. When these cellular self-repair mechanisms break down, or when bathedin an environment of genotoxic compounds, cells become genomicallyunstable. Ultimately, this genomic destabilization, or instability, results inthe natural selection of a genomically heterogeneous cellular mass, orcancer, that threatens the survival of the organism as a whole. The impor-tance of genomic instability in tumorigenesis and tumor evolution may beseen in the work of numerous investigators who have demonstrated thatcells must undergo multiple genetic alterations to become neoplastic. Loeb[2,3] and Jackson and Loeb [4] determined that the normal rate of mutationis insufficient to allow for the observed genetic change in neoplasms to take

1Current address: Department of Surgery, St. Paul’s Hospital, 1081 Burrard Street,

Vancouver, British Columbia, Canada, V6Z 1Y6.

* Corresponding author.

E-mail address: [email protected] (G.R. Anderson).


doi:10.1016/S1055-3207(03)00118-2


2 S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

place. Genomic instability is now seen as an essential enabling componentthat allows tumors to evolve [5].

With a yearly global incidence of 500,000 cases, head and neck squa-mous cell carcinoma (HNSCC) ranks as the sixth most prevalent cancerworldwide [6]. The American Cancer Society estimates that there will be28,900 new cases of oral cavity and pharynx cancers diagnosed and 8900 newcases of larynx cancer diagnosed in 2002 [7]. Despite advancements in medi-cine, surgery, and radiation therapy, the long-term survival of individualsdiagnosed with HNSCC has not increased significantly over the past 20 years,with the 5-year survival rate remaining at 52% in the United States [8]. It isestimated there will be 11,100 deaths from cancer at these head and neck sitesin 2002 [8]. Mortality from this disease correlates with tumor size and thepresence of local nodal or distant metastatic disease [9–11]. This articleprovides an overview of the clinical and experimental evidence, andimplications, of genomic instability as a major force driving HNSCC tumori-genesis and evolution.

Many patients with head and neck cancer are cancer predisposed

HNSCC arises from a complex interaction between the host (geneticfactors) and the environment. Tobacco exposure has long been recognizedas increasing the risk of developing HNSCC between 2- and 20-fold [12].More than 50 years ago, Slaughter et al [13] recognized the ‘‘field can-cerization’’ that occurs in patients with HNSCC as a consequence of pro-longed carcinogenic exposure of the upper aerodigestive tract. It is this‘‘field cancerization’’ that is believed to be responsible for the 2% yearlyincidence of second primary tumors that develop in this patient population.Furthermore, the concurrent consumption of alcohol with tobacco mayhave a multiplicative effect on the risk of developing HNSCC [14–16]. Inaddition to tobacco and alcohol exposure, other environmental factors thatare currently believed to play a role in HNSCC development include viruses,radiation exposure, and certain nutritional deficiencies [17–19].

Epidemiologic and experimental evidence suggests that, because of aninherent inability tomaintain their genomic integrity in the presence of specificenvironmental stressors, certain individuals demonstrate a predisposition todeveloping head and neck tumors. The occurrence of this malignancy, even inthe absence of environmental carcinogen exposure, supports this concept. Thecurrent authors recently described a cohort of 40 nonsmoking, nondrinkingpatients with HNSCC treated at Roswell Park Cancer Institute. Thesepatients tended to be elderly (median age, 60 y), female, andwhite. In addition,they had oral cavity primary tumors and were predisposed to second primarytumor development. Despite a lack of exposure to tobacco and alcohol, 10patients (25% of study population) eventually developed a second primarytumor. The occurrence of second primary tumors in this patient populationsuggests a possible genetic pre11disposition of these individuals to HNSCC

3S.M. Wiseman et al / Surg Oncol Clin N Am 13 (2004) 1–11

development [20]. Information concerningwhether nonsmoking patients withHNSCC have a prognosis different from smoking patients with HNSCC islimited. Koch and McQuone [21] described a cohort of 46 nonsmokers(individuals who never used tobacco on a regular basis) who developedHNSCC, and compared them to a large cohort of smokers who developedHNSCC. Of the 46 nonsmokers in this study, 37 patients (84%) were alsonondrinkers. The overall length of survival of the patients in this study did notvary significantly with either smoking history or drinking history.

Family members of patients with HNSCC also are predisposed to upperaerodigestive tract tumor development. In a study performed in TheNetherlands, Copper et al [22] found that first-degree relatives of patientswith HNSCC had an increased risk of developing upper aerodigestive tracttumors (relative risk [RR], 3.5), with an especially high risk amongst siblings(RR, 14.6). Foulkes et al [23] performed a similar study in southern Braziland found first-degree relatives of patients with HNSCC to have a relativerisk of 3.5 times the general population for developing HNSCC. In thisstudy, siblings had a relative risk of 8.6 for developing the disease. In a studyperformed in the United States, however, Goldstein et al [24] found onlya slight increase in the relative risk of first-degree relatives of patients withHNSCC for developing these tumors themselves (RR, pharynx, 1.7; RR,oral, 1.2). In a study examining 26 individuals with multiple primary upperaerodigestive tract tumors, Foulkes et al [25] demonstrated that the relativerisk of developing HNSCC was significantly higher in relatives of individualswho developed multiple versus single primary tumors (RR, 7.89 versus 3.53,respectively). Only the study by Goldstein et al [24] collected smokingdetails for relatives, and matching was performed according to racial group.Thus, epidemiologic studies suggest the families of patients with HNSCCare themselves genetically predisposed to developing HNSCC, although themagnitude of this predisposition is limited.

There are several rare ‘‘cancer predisposition’’ syndromes that arise fromgenes that maintain genomic integrity. These syndromes have a constellationof associated malignancies, including HNSCC. These cancer predispositionsyndromes include the genomic instability syndromes, Werner’s syndrome,Bloom syndrome, Fanconi’s anemia, and ataxia telangectasia. Patients whohave Bloom syndrome or Werner’s syndrome have deficient RecQ-likeDNA helicases [26,27]. Werner’s syndrome is an autosomal recessive dis-order that has been linked to the WRN locus on chromosome 8p. Homo-zygous individuals age prematurely and are cancer predisposed [26]. Bloomsyndrome is an autosomal recessive disorder that arises from an alterationof the Bloom syndrome gene, which encodes a DNA helicase that interactswith topoisomerase III and plays an important role in DNA repair. Affectedindividuals have impaired fertility, immunodeficiency, dwarfism, and arecancer predisposed [27]. Genomic instability arises in these individuals fromimpaired DNA repair, and consequently, these individuals are vulnerable toDNA damage and subsequent cancer development [26,27].


Fanconi’s anemia is a rare genetic disorder in which affected individualsare predisposed to developing squamous cell carcinoma (SCC) of the gingiva,tongue, and mandible. This disorder is also characterized by developmentalabnormalities and a propensity to develop hematologic disorders and bonemarrow failure. It is currently believed that the protein defects that arise inaffected individuals may result in loss of regulation of DNA repair [28].Ataxia telangiectasia is a rare genetic disorder that arises from a defect in theataxia telangiectasia gene (ATM gene). The ATM gene functions in survey-ing for DNA damage and is responsible for activating DNA repair andapoptosis genes. Individuals homozygous for the defective gene developprogressive neuromuscular degeneration, an unsteady gait, and have facialor conjunctival telangiectasias, and are predisposed to cancer development.Heterozygous individuals also have a cancer predisposition [29].

Hereditary nonpolyposis colorectal cancer is associated with a high fre-quency of microsatellite instability. Mismatches of nucleotides may occurduring DNA replication when DNA polymerase inserts the wrong bases intonewly synthesized DNA. Normally, these DNA mismatches are repaired bymismatch repair enzymes, and individuals with germ-line mutations in thegenes that encode these mismatch repair enzymes have impaired DNAreplication fidelity. The integrity of the mismatch repair enzyme systems ismeasured by microsatellite instability, or a measure of the integrity of short,tandemly repeated DNA sequences (microsatellites) distributed throughoutthe human genome [30]. Individuals diagnosed with hereditary nonpolyposiscolorectal cancer have been reported to be at increased risk of developingHNSCC [31].

Further evidence suggesting patients with HNSCC are cancer predisposedmay be appreciated on experimental studies applying mutagen sensitivitytesting to the HNSCC patient population. Hsu et al [32] developed thebleomycin mutagen sensitivity test as a method of assessing cellular DNArepair capacity. This test is performed by exposing lymphocytes in culture tothe drug bleomycin and quantifying the number of chromosome breaks perlymphocyte in culture. This test has been successfully able to identifyindividuals at high risk for developing head and neck tumors [33,34]. Thehighest rates of chromosomal breakage are observed in individuals witha family history of HNSCC and in those with multiple primary tumors[33,34]. The DNA repair capacity after exposure to the carcinogenbenzo(a)pyrene diol epoxide also is impaired in patients with HNSCC [35].In addition, investigators have found that certain polymorphisms of theDNA repair gene XRCC1 are associated with an increased risk for HNSCCdevelopment [36].

Genomic instability and head and neck cancer

Genomic instability may be broadly considered either chromosomal orintrachromosomal. Intrachromosomal genomic instability, the form most


frequently observed in sporadic disease, consists of amplifications, deletions,inversions, and oligobase or point mutations. These alterations can be readilyassessed by comparative genomic hybridization (CGH) and microsatelliteinstability measurements. Independent measures of intrachromosomalinstability can be assessed by cytogenetic techniques and CGH on orderedBac clone arrays. Chromosomal instability, changes in ploidy status, andchromosomal translocations can be visualized by cytogenetic analytictechniques. Although not all chromosomes are affected in each tumor, allautosomal chromosome arms have been described as being affected in headand neck tumors [17,18,37]. Although clustering aberrations have beendescribed, consistent cyogenetic abnormalities common to all HNSCCs havenot been demonstrated [17,18,37]. CGH analyses performed on HNSCCshave demonstrated multiple chromosomal aberrations found in these tumors[38–40]. Using CGH methodology, Hashimoto et al [40] were able todemonstrate a correlation between specific chromosomal aberrations andpathologic tumor stage in 32 patients with HNSCC.

The literature has been conflicting regarding the role of microsatelliteinstability in head and neck tumor progression. Piccinin et al [41]demonstrated low rates of microsatellite instability in patients who hadHNSCC with a single primary or multiple primary tumors. Both groups hadsimilarly low rates of microsatellite instability. Using makers for 11chromosomal loci, El-Naggar et al [42] examined microsatellite instabilityin peripheral blood, dysplastic tissue, and SCCs. Although microsatelliteinstability was absent in the blood, levels were twice as high in the cancers asin the dysplastic tissue (30% versus 15%, respectively). This finding led theseauthors to conclude that microsatellite instability played an important role inHNSCC progression. Field et al [43], however, were unable to demonstrateany correlation between microsatellite instability and clinicopathologicfeatures (tumor site, tumor grade, nodal metastasis, disease stage, history ofprior treatment, or alcohol consumption) in patients. Thus, whereasmeasurements of microsatellite instability in HNSCC suggest genomicinstability is driving tumor progression, they have been of limited clinicalapplicability.

The study of the fraction of chromosomal arms on which allele loss isobserved, or the fractional allelic loss rate (FAL), has demonstrated howmeasurements of genomic instability in patients with HNSCC may be ofclinical value. By studying 80 HNSCCs, Field et al [44] were able to dem-onstrate a positive correlation between FAL and tumor grade, neck nodalstatus, and overall patient prognosis.

Cancer predisposition genes

Cancer predisposition genes may play an important role in the increasedgenetic susceptibility observed in patients who have HNSCC. Important


cancer predisposition genes that have been found to be mutated in patientswith HNSCC include p16 and TP53 tumor-suppressor genes.

The p16 tumor-suppressor gene is located on chromosome 9p21 andencodes a 16kDa protein that binds to the cyclin-dependent kinases (cdk) 4and 6 and prevents them from complexing with cyclin D1. This inhibition ofD1-cdk 4/6 complex activity does not allow for retinoblastoma phosphory-lation, and thus blocks the cell cycle G1/S transition. Somatic homozygousdeletions andmutations of the 9p21 region are commonly observed in patientswith sporadic HNSCC [45]. Recently, Yu et al [46] performed molecularanalyses of a family with a high incidence of HNSCC and melanoma, andidentified a germ-line p16 tumor-suppressor gene mutation. These results,along with this group’s earlier description of a separate, unrelated familyharboring a p16 germ-line mutation and exhibiting a HNSCC predisposition,suggest a familial HNSCC syndrome may exist [46].

Li-Fraumeni syndrome arises as a consequence of germ-line mutations inthe TP53 gene, which is located on chromosome 17. The affected individualdevelops a sarcoma before age 45, has a first-degree relative with cancerbefore age 45, and has another first- or second-degree relative with a historyof sarcoma at any age or a cancer diagnosed before age 45. Patients whohave Li-Fraumeni syndrome are at increased risk of developing laryngealcancer [47]. The TP53 gene is a well-known tumor-suppressor gene andrepresents one of the most common sites for genetic abnormalities to befound in human tumors [48]. The TP53 gene is frequently mutated in severalhuman cancers, including lung cancer, colon cancer, and breast cancer [49–51]. Multiple investigators have demonstrated that 40% or more of sporadicHNSCC contain TP53 mutations [52–54]. The TP53 gene product, the P53protein, is believed to have a dual role in protecting the cell from cancerdevelopment. The P53 protein causes cell cycle arrest, allowing damagedDNA to be repaired; alternatively, it helps prevent DNA damage from beingpassed on to the next cell generation by causing damaged cells to undergoapoptosis before division. Therefore, cells that lack or only produce abnormalP53 protein are more susceptible to malignant transformation [48].

In sporadic head and neck tumors, TP53 mutation is currently believedto represent a relatively late step in head and neck tumor evolution. Theincidence of TP53 mutation in premalignant head and neck lesions has beenreported to be much lower (19%) than in invasive lesions (43%) [54]. Shinet al [55] reported P53 immunohistologic expression by the adjacent normalepithelium in 6 of 31 (19%) normal epithelium specimens adjacent tosquamous cell carcinomas, in 7 of 24 (29%) hyperplastic lesions, in 12 of 26(46%) dysplastic lesions, and in 28 of 48 (58%) HNSCCs. In a group of 232patients with HNSCC, Koch et al [56] described a much higher incidence ofTP53 mutations in smokers (44%) than in nonsmokers (18%). Field et al[57] correlated tumor TP53 status and the patient’s history of smoking andalcohol consumption, also suggesting both substances may be linked toaberrant P53 expression in HNSCC.


Genetic heterogeneity of head and neck tumors

Despite considerable histologic homogeneity, HNSCCs do not all exhibituniform biologic behavior. Tumors from different head and neck sites displayawide rangeof biologic behaviors, despite often being separatedbyonly a verysmall anatomic distance, and they are not treated in a uniform manner.Recently, investigators have provided evidence that suggests, at the geneticlevel, HNSCCs are actually a heterogeneous group of disease entities. Takeset al [58] studied expression of several proteins (P53, retinoblastoma (Rb),cyclin D1, myc, bcl-2, epidermal growth factor receptor (EGFR), neuro-glioblastoma derived oncogene (neu), E-cadherin, epithelial cellular adhesionmolecule (Ep-CAM), desmoplakin 1, and nonmetastatic protein 23 [nm23])in 33 laryngeal cancers, 31 pharyngeal cancers, and 36 oral cancers. Theseauthors found that cyclinD1 had a very high level of expression in the pharynxcancer (P = 0.0004) and EGFR had a very low level of expression in thelarynx cancer (P\0.0001). Rodrigo et al [59] examined 38 laryngeal cancers,29 oropharyngeal cancers, and 37 hypopharyngeal cancers for the following:amplification of oncogenes at the 11q13 region (CCND1, FGF3, FGF4,EMS1), oncogenesMYC andERBB1, for integration of the human papillomavirus types 6b and 16, loss of heterozygosity at P53 and NAT2, and cellularDNA content. This group found that FGF3 and FGF4 had a significantlyhigher degree of amplification in the hypopharyngeal tumors (P = 0.006 andP = 0.0002, respectively). Aneuploid tumors were found in a significantlylower proportion of larynx tumors than in other sites (P = 0.03). Theseobserved differences in genes and gene expression, at different head and neckdisease sites, provide early evidence suggesting that HNSCC may actuallyrepresent a genetically heterogeneous group of diseases. Furthermore, theremay be different pathways of tumorigenesis and tumor progression that areresponsible for the observed clinical differences in biologic behavior of diseaseoriginating from different sites. The genetic heterogeneity of head and necktumors is not surprising when the genomic instability exhibited by thesetumors is considered. Not only are these tumors genetically heterogeneousfrom one tissue site to the next, however, but they may also exhibitconsiderable intratumoral heterogeneity. Jacob et al [60] evaluated five tumorregions in 12 patients who underwent surgery for oropharyngeal carcinoma.Specimens were each evaluated by immunohistochemical assessment forproliferation markers (Ki67 and proliferating cell nuclear antigen), forquantitative DNA content, and morphologic tumor-front grading. Theirresults demonstrated a considerable variation of proliferation and differen-tiation both intratumorally (within the same tumor) and extratumorally(between different tumors). Consistent with the genomic instability exhibitedby head and neck malignancies, these results suggest that HNSCCs aregenetically heterogeneous tumors. As has been suggested, perhaps head andneck tumors should be studied in amanner similar to how they are viewed andtreated clinically, as separate and distinct disease entities [59].


Summary

Measurements of genomic instability, or identification of genes respon-sible for instability, may potentially be used as molecular markers to predictdisease course and response to therapy. Other possible applications includeuse of genomic instability measurements, or genes, as tools to screen forprimary or recurrent disease. Methodologies for detection of geneticmutations in saliva, blood, and sputum have already been described[61,62]. Brennan et al [63] have described a molecular technique foranalyzing histopathologically negative margins and lymph nodes for thepresence of p53 gene mutation. This study showed that a positive molecularmargin significantly predicted disease recurrence.

The recognition that HNSCC is a genetically heterogeneous disease repre-sents a major step toward developing an understanding of its underlyinggenetic basis. To develop an insight into this genetically heterogeneousdisease, investigators must not only focus their efforts on specific head andneck disease sites. Laser-capture microdissection represents a powerful toolfor isolating very specific cell populations from tumors [64]. Leethanakul et al[65] performed laser-capture microdissection on oral cavity SCC to constructstage-specific cDNA libraries. Sequencing of 96 clones from each of the sixlibraries constructed suggested the existence of 132 novel genes, which mayplay a role in the pathogenesis of HNSCC.

The current literature suggests that many individuals diagnosed withHNSCC are genetically predisposed to developing malignancy because ofsome inherent deficiency of their capacity to maintain their genome in thepresence of environmental stressors. Head and neck cancers are highly het-erogeneous tumors and exhibit a wide variety of forms of genomicinstability. Thus, genomic instability may be viewed as a fundamental forcedriving head and neck tumorigenesis and evolution. Future study of thespecific genetic mechanisms that underlie genomic instability in the HNSCCpatient population is needed. It is only through study of this fundamentalforce that drives the development of these tumors that clinicians may gainthe insight required to develop new diagnostic and therapeutic modalities tobenefit the HNSCC patient population as a whole.

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Imaging in head and neck oncology

Ronald A. Alberico, MDa,b,*

Syed Hamed S. Husain, DOb, Igor Sirotkin, MDb

aDepartment of Radiology, Roswell Park Cancer Institute, Elm and Carlton Streets,

Buffalo, NY 14263, USAbState University of Buffalo School of Medicine and Biomedical Sciences, Buffalo VA

Medical Center 3495 Bailey Avenue, Buffalo, NY 14215, USA

Since the initial description of the pathologic distribution and patterns ofspread of tumors in the head and neck, the pretreatment assessment of thesize, extent, and pattern of spread has been necessary for optimal treatmentplanning. It has subsequently become apparent that decisions, including theoperative approach, possibility of organ preservation or functionalpreservation of tissue, and the appropriateness of an operative role inpatient care, hinge on these important pieces of information. Clinicalexamination alone, however, is limited in its ability to properly assess theextent and size of head and neck tumors, especially for submucosalextension of disease and extent of nodal metastasis.

Modern radiologic imaging has provided the means to maximizeinformation available to clinicians during the treatment-planning pro-cess. The combination of CT, MRI, ultrasound, and positron emissiontomography (PET) has enabled clinicians to obtain a great deal ofinformation about the patient before planning the surgical approach. BothCT and MRI have been shown to be superior to clinical examination inevaluating the size and extent of head and neck tumors and in detailing theextent of nodal metastases [1–4]. Imaging also has added to the cost and, insome cases, the controversy of the preoperative assessment and post-treatment follow-up period. The choice of which imaging modality ispreferred remains controversial and remains part of an ongoing discussion[5]. This article describes a strategy for imaging head and neck neoplasia inan effort to simplify the process and emphasizes the strengths andweaknesses of the available imaging modalities. In addition, the articleemphasizes techniques for imaging and reporting on patients who have head


E-mail address: [email protected] (R.A. Alberico).


doi:10.1016/S1055-3207(03)00124-8


14 R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

and neck cancer in a manner that maximizes the clinician’s ability to makeappropriate treatment plans and avoid unnecessary complications.

The primary goal in imaging of head and neck oncology is to answer thepertinent clinical questions. Too often, the radiologist can get caught up inthe collateral findings and provide information that is confusing orsuperfluous while omitting key points needed for the treatment plan.Although the clinician may feel comfortable filling in the blanks, the scanmay not be optimally designed to answer the clinical question, particularlyin postoperative patients. Frequently, the radiology requests provideinsufficient clinical information to adequately plan the scan, possiblyresulting in exclusion of anatomy crucial to the diagnosis. The solution tothese problems is knowledge and communication. The radiologist must befamiliar with the surgical procedures available and the anatomic criteria thatexclude various procedures from consideration. In addition, the radiologistmust be made aware of the clinical findings and concerns to select theappropriate imaging modality and optimize the imaging technique. Theradiologist’s goal should be not only to answer the questions of size andextent of tumor but to point out potential surgical complications resultingfrom vascular relationships to the tumor, and individual anatomic variantsthat may complicate the procedure. The formation of a differential diagnosisbased on lesion location and imaging characteristics plays an important, butsecondary, role in this process. Even with the best modern imagingavailable, the radiologist is still relegated to the role of gross pathologist,with some limited physiologic data, and, as always, the final answer is in thehistology.

Imaging techniques

The radiology and head/neck surgery literature over the last decade hassupported either CT or MRI as the primary technique for evaluatingpatients who have head and neck cancer. This situation has divided theradiology community into two groups, each of which feels passionatelyabout their respective choices. CT has been shown to be superior to MRI inevaluating necrosis in nodal metastases [6], whereas MRI is better fordetecting perineural extent of disease and disease at the skull base [5,7,8].Other authors have shown improved lymph node detection with MRI [3].Both modalities have advantages and disadvantages in the evaluation ofhead and neck cancer. CT has the advantage of increased speed andavailability and better patient tolerance. The bony framework is betterevaluated with CT and small calcifications are more apparent. CT has thedisadvantage of requiring ionizing radiation and iodinated contrast agents.MRI is more sensitive for subtle spread of disease along nerves and into theskull base. In addition, MRI has higher soft tissue contrast resolution anddirect multiplanar imaging capability. Disadvantages of MRI include lowerpatient tolerance and dangers associated with metallic implants, pacemakers

15R.A. Alberico et al / Surg Oncol Clin N Am 13 (2004) 13–35

and other hardware, and increased expense. MRI is also subject to manyartifacts that can make interpretation more difficult. Patient motion isalways a concern in MRI, particularly in patients who have difficultysuspending swallowing and lying flat.

PET scanning and ultrasound take a definite back seat to CT and MRI inevaluating the head and neck. Ultrasound is useful for image-guided biopsyand can provide the fastest, easiest means to guide the needle to theappropriate target. Doppler sonography has shown some ability to improvethe specificity and sensitivity of nodal staging in clinically N0 neck disease,as has PET imaging, but the clinical criteria for exploring N0 neck diseasefrequently obviates the need to use PET or ultrasound for this purpose [9].

The current authors have found that, for most patients, CT, whenproperly performed, provides a readily available and easily toleratedassessment of head and neck neoplasia. It is easier to interpret for nodalstaging and successfully completed more often than MRI. Multidetector CTobtained with thin images (�2.5 mm) and contrast is able to detectperineural disease and is readily reformatted into multiple imaging planes.The current authors typically assess patients initially with CT and willobtain MRI only if perineural spread of disease is suspected or ambiguouson CT, or to better evaluate cartilage or marrow invasion. MRI is alsouseful in patients who have tumors that are typically lower in attenuation onCT, such as liposarcomas, and may provide additional information inpatients with this type of tumor. The current authors also use MRI forthyroid tumors that may potentially be treated with radio-iodine therapy toavoid the iodine load inherent in CT contrast media. Gadolinium contrastagents, which are usually used in MRI, can be used as an alternative forspecific patients in CT who are allergic to iodinated contrast and who havecontraindications to MRI evaluation. When necessary, the current authorsuse gadolinium as an alternative contrast agent in CT.

All scans are not equal, and to answer the pertinent clinical questions,properly performed scans are needed. The current authors begin all CTimaging for head and neck cancer above the orbit to include the skull baseforamina and pterygopalatine foramen. The authors previously used singledetector helical scanners with 5-mm thick sections at 5 mm intervals with 3mm sections through the larynx. Currently, with multidetector scanners, it ispossible to scan with 2.5 mm section thickness and 2.5 mm section intervalthrough the entire neck without significant time constraints. Multiplanarand three-dimensional models can be readily obtained from these data,including CT angiography as needed to assess vessel–tumor relationships.Artifacts on CT at the oral cavity can limit the evaluation of the intrinsictongue and hard palate; sections angled through the oral pharynx usinga coronal oblique orientation can result in improved visualization of theseareas with a minimum of effort (Fig. 1). It is important to find an imagingcenter that uses techniques such as these, with an effort to guide thetreatment plan of the individual patient in the proper direction.


Imaging the primary tumor

The most important role of imaging in head and neck cancer is toevaluate the primary tumor and its extent. Although T1 lesions are muchmore conspicuous on clinical examination than in images (Fig. 2),submucosal disease and the extent of tumor across tissue planes and along

Fig. 1. (A) Scout image from a CT scan of the neck and skull base for SCC shows dental

hardware and the usual scan section orientation. (B) The axial section from the angle scanned in

A at the level of the oral pharynx has extensive artifact from dental hardware, which obscures

the pharyngeal and parapharyngeal structures (arrow). (C) Scout image with coronal oblique

sections planned to avoid dental artifact through the oral pharynx. (D) The oral pharyngeal

walls and tonsils are now visible with associated left-sided mass (arrow).


nerves is best seen with imaging [10,11]. The findings may affect the choice ofradiation field needed to cover a lesion and can affect the surgical optionsoffered to the patient. The extent of tumors can frequently be observedthrough the submucosal spaces on the images, resulting in higher tumorstaging than is suspected on clinical grounds, whereas in other cases theclinical staging is confirmed. The images are key in defining the final extentof the tumor (Figs. 3 and 4). Invasion of tumor into adjacent structures,such as the mandible, or along perineural pathways may be clinicallyinconspicuous. The sensitivity and specificity of imaging in detecting thesepatterns of disease is well described in the literature; MRI is the preferredmethod for detecting perineural disease and mandibular invasion [10–19].Most reports to date have not accounted for recent advances in CTtechnology, including multidetector scanning. The current authors havefound that perineural spread, although more obvious on a high-quality,motion-free MRI, is detectable on CT, in most cases, by loss of the normalfat signal at the foramen [10,18–19]. Perineural spread of tumor is usuallythe result of squamous cell carcinoma (SCC), although this finding is likelycaused by the prevalence of this tumor in the population. Perineural spreadis also commonly seen in adenoid cystic carcinoma, followed bymucoepidermoid carcinoma [10,18]. Because perineural spread is presentin a higher percentage of cases in these relatively rare tumors, MRI mayprovide a more sensitive assessment of the extent of disease for salivary

Fig. 2. Axial section from a contrast-enhanced CT scan with a subtle high-attenuation lesion

(arrow) that represents a T1 SCC. This finding was much more apparent on clinical

examination.


malignancy. MRI offers advantages in detecting marrow invasion in themandible and the cartilage of the larynx (Figs. 5–9).

SCC, which originates in the mucosa, comprises most head and neckcancer. Imaging can play a roll in the preoperative diagnosis of differenthistologic subtypes by placing tumors in different spaces in the neck. Thesuprahyoid neck is typically divided into muscosal, parapharyngeal, parotid,and masticator spaces, with the parapharyngeal space further divided intopre- and poststyloid components. The mucosal space is composed of themucosal surfaces of the nasal and oral pharynx. Lesions in this space aremost likely SCC with minor salivary tumors, including benign, mixedtumors; mucoepidermoid carcinoma; and possibly adenoid cystic carci-noma. The mucosal spaces of the oral pharynx, specifically the soft palate,may provide perineural pathways of tumor spread along the greater palatineor lesser palatine nerves (Fig. 10). The parotid space includes superficial anddeep lobes of the parotid and involves the space between the styloid processand posterior mandibular ramus (stylomandibular tunnel). Tumors of theparotid include the primary salivary tumors listed previously and metastaticdisease and lymphoma involving intraparotid nodes. The parotid spaceprovides a pathway of perineural spread along cranial nerve VII to thestylomastoid foramen (see Fig. 9). The poststyloid parapharyngeal space(carotid space) is defined by the styloid process and fascia anteriorly,paraspinal musculature posteriorly and medially, and the sternocleidomas-toid (SCM) muscle laterally. Tumors of this space include schwannomas,glomus tumors, metastatic adenopathy or lymphoma, and lipomas orliposarcomas. Perineural spread along the vagus nerve or direct spreadalong the carotid artery or jugular vein can lead into the skull base. A masswithin this space can also result in vocal cord paralysis by means of its effect

Fig. 3. (A) This axial contrast-enhanced CT section reveals a typical-appearing high-

attenuation mass of the right floor of mouth and tongue (arrows). (B) The coronal reformatted

image from the scan in A demonstrates the superior inferior extent of the mass (arrows) and

confirms the lack of extension across the midline.


on the vagus nerve. The prestyloid parapharyngeal space borders themasticator space anteriorly, the mucosal space medially, and the styloidprocess posteriorly. It contains fat and lymphatics and is rarely directlyinvolved as a primary tumor site. Displacement of this fat by large massescan give insight as to which space a large mass is originating from, thusaffecting the differential diagnosis. This space communicates with thepterygopalatine fossa (see Fig. 8) and has access to all perineural routesassociated with the fossa, including spread along the vidian and rotundumcanals and into the inferior orbital fissure. The masticator space is definedby the muscles of mastication and is affected primarily by sarcomas andnerve sheath tumors, including rhabdomyosarcoma, liposarcoma, andschwannomas. Metastatic disease and lymphoma can affect this space as

Fig. 4. (A) Axial contrast-enhanced CT of the neck reveals a high-attenuation mass in the right

pharyngeal tonsil (arrow). (B) A section lower in patient shown in A demonstrates involvement

of the tongue as the tumor spreads anteriorly along the palatoglossus muscle (arrows). (C) A

section higher than that shown in A reveals some early spread to the soft palate as well (between

arrows).


well. Perineural spread from the masticator space usually involves cranialnerve V and specifically its third division (see Figs. 6 and 7).

Imaging of the infrahyoid neck is less complex overall but requiresknowledge of laryngeal anatomy and operative approaches. Most infra-hyoid head and neck tumors are SCC or metastatic disease to the lymphnodes. Three-dimensional and multiplanar modeling of the CT data canprovide the surgeon with a better appreciation of the anatomy pre-operatively, providing a more surgically oriented perspective of thepathology and, in some cases, allowing for production of syntheticprostheses to be prepared preoperatively to fit the patient’s anticipatedsurgical defect [20–22]. The normal distribution of adipose tissue in thelarynx allows clinicians to differentiate the false from the true vocal cords onCT and to see the paraglottic space (see Fig. 10; Fig. 11). The varioussurgical approaches to laryngeal cancer include supraglottic and supra-cricoid laryngectomy and vertical hemilaryngectomy and total laryngecto-my. Diagrams of these procedures can be modeled from modern CT images(see Fig. 11; Figs. 12 and 13). For patients with laryngeal tumors, the imagescan define extension of a primary neoplasm in the paraglottic space acrossthe laryngeal ventricle or across the midline that would render supraglotticor vertical hemilaryngectomy unlikely to provide tumor-free margins. Thisfinding would affect the potential for operative cure in these patients. Withthis information, the head and neck surgeon can have a more informeddiscussion with the patient regarding potential operative options andprognosis. CT provides the best, most rapid, and consistently motion-freeimages in this population. MRI is more sensitive for invasion of the thyroid

Fig. 5. (A) Sagittal T2-weighted MRI image reveals a large intracranial component to this

esthesioneuroblastoma (arrows). Note the cystic and solid components of the mass, which is

a characteristic of these tumors. (B) The coronal T1 fat-saturated gadolinium-enhanced image

reveals the heterogeneous enhancement of this lesion and its sharp demarcation from the brain,

which is not yet invaded (arrows).


cartilage and may be useful in certain patients for evaluation of directcartilage invasion.

The hypopharynx is readily seen on MRI and CT, and patterns of tumorspread to the pyriform sinus and retropharyngeal tissues typically can bedefined by high attenuation on contrast-enhanced CT and enhancement onMRI. Direct invasion of the cervical spine or perivertebral space is bestevaluated with MRI because it is more sensitive for bony invasion than CT.There is currently no well-defined role for PET or ultrasound in evaluatingthe primary tumor site in the infrahyoid neck.

Less common tumors in the infrahyoid neck also include tumors of theperivertebral space, which includes the cervical spine and cord, and theperivertebral muscles. These must include all primary and metastatic bone

Fig. 6. (A) Axial contrast-enhanced fat-saturated T1 image of the suprahyoid neck reveals

a nodule of enhancing tissue (arrow) in the mandibular foramen of this patient who has

a retromolar trigone SCC. (B) Contrast-enhanced axial CT section in the same patient shows

the lack of fat signal typical of perineural spread in the same mandibular foramen imaged 3

weeks earlier (curved arrow). Note the normal fat signal in the foramen of the contralateral side

(straight arrow). (C, D) The invasion of the mandibular marrow space is clearly seen in these

coronal and axial contrast-enhanced T1-weighted MR images from the same patient (arrows).


tumors, and neurofibromas, schwannomas, and other central nervoussystem tumors. Tumors of the thyroid gland include adenomas and thyroidmalignancies of all subtypes. A detailed discussion of thyroid neoplasm isbeyond the scope of this article; however, imaging of the thyroid is bestobtained with a combination of nuclear medicine thyroid scanning,ultrasound, and MRI. CT is excellent as well; however, the iodine loadfrom contrast material can decrease uptake for potential nuclear medicinescanning and result in delayed therapy, so care must be taken to avoidunnecessary iodine loads before diagnosis. The poststyloid parapharyngealspace continues into the infrahyoid neck as the carotid space and is a site formetastatic disease and lymphoma. Glomus tumors and schwannomas alsocan be found in this space.

Nodal staging

Staging of nodal disease in the neck traditionally has been based onclinical examination; however, limitations in the clinical examination resultin relatively low sensitivity and specificity (60%–70%), leading to anunacceptably low negative predictive value [3,4,23]. Improved negativepredictive value is important in defining a population that would benefitfrom surgery without the need for neck dissection and radiation. Imaging,including CT and MRI, uses a threshold size to determine if a node isabnormal. Depending on the reference, this size varies between 1 and 1.5cm. Morphology of the node is also considered in determining the likelihoodof metastasis, including the transverse-to-longitudinal ratio and the

Fig. 7. (A) An axial contrast-enhanced T1-weighted image from an MRI of the neck reveals an

enhancing mass at the top of the right masticator space just below foramen ovale (between

arrows). (B) A coronal contrast-enhanced T1-weighted image reveals the perineural spread of

the tumor into foramen ovale along cranial nerve V3 to involve Meckel’s cave (long arrow).

Compare this to the normal contralateral side (short arrow).


Fig. 8. An axial section from a contrast-enhanced CT of the neck reveals loss of the normal fat

attenuation within the left pterygopalatine fossa (arrow). This finding was confirmed to be

perineural spread from the patient’s left tonsillar fossa SCC.

Fig. 9. An axial section from a contrast-enhanced CT of the neck in a patient with

mucoepidermoid carcinoma of the left parotid gland reveals loss of the normal fat attenuation

in the left stylomastoid foramen (thick arrow). Note the normal low attenuation of the

contralateral side (thin arrow).


attenuation of the node [24,25]. Even with a combined approach, theliterature varies widely on the specificity and sensitivity of nodal stagingwith MRI and CT, with sensitivity varying from 40% to 80% and specificityfrom 90% to 95%. In a large-scale study by Curtin et al [3], attempts weremade to obtain a negative predictive value of 90% with CT and MRI usingsize criteria alone or size criteria in combination with internal morphology.Although CT could achieve this 90% negative predictive value, it requireda size threshold of 5 mm, which decreased positive predictive value to 44%.MRI did not achieve a 90% negative predictive criterion in that study,regardless of size threshold used. Attempts at increasing sensitivity withPET scanning or Doppler sonography to detect malignancy in normal-size

Fig. 10. (A) Axial CT section of the larynx a t the level of the false cords (arrows). Note the low

attenuation of the paraglottic fat. (B) Axial CT section at the level of the paraglottic space

shows the fat within the space to better advantage (arrows). (C) Coronal reformation from the

same scan shows the fatty attenuation in the paraglottic space (long arrow) and false cords (short

arrow) compared with the muscle attenuation of the true vocal cords (curved arrow). (D) Off-

midline sagittal reformat from the same patient clearly shows the air within the laryngeal

ventricle (long arrow). The false cords are above the ventricle with the muscular true cords

below.


nodes have had some success, but the sensitivity is only marginally improvedover that of MRI or CT [25,26]. Combined MRI and CT have approached90% sensitivity for metastatic node detection in one study [1]. It would seemthat, regardless of imaging technique, negative predictive value has notachieved a level that would be clinically useful in excluding clinically N0neck disease without unacceptably low positive predictive values.

Until negative and positive predictive values of nodal disease areimproved, exclusion of patients from treatment of the neck with radiationor neck dissection based on imaging is not appropriate; however, there areother uses for nodal assessment with imaging that can affect patient care andprognosis. The location of nonpalpable adenopathy in the neck in patientswho have disease of any nodal stage can affect the size and extent ofradiation fields and the side and extent of neck dissection. Given theincreased sensitivity of image-based nodal staging compared with clinicalstaging, this is sufficient to warrant nodal evaluation with imaging.

The description of nodal locations in the neck requires precise languageto facilitate communication between the head and neck radiologist, thesurgeon, and the pathologist. Without such a system, patterns of nodaldisease and their relationships to tumor prognosis and location would lackprecision and result in inaccuracies in clinicians’ knowledge of diseaseprognosis and patterns of spread, limiting their ability to treat patients.Various classification systems for nodal disease in the neck therefore havebeen used in the past, including those of the American Academy of

Fig. 11. (A) An axial contrast-enhanced CT scan at the level of the true vocal cords (arrow).

Note the high attenuation (muscle) of the true vocal cords compared with the false cords seen in

Fig. 10. The line delineates the surgical resection for a vertical hemilaryngectomy. Because the

cricoid cartilage is preserved by the surgery, extension of tumor into the cricoid or arytenoid

would contraindicate this type of voice-sparing procedure. (B) A color three-dimensional

diagram of the larynx, again showing the surgical plan for a supracricoid laryngectomy. The

thyroid cartilage is blue, the cricoid cartilage is light blue, the epiglottis is red, and the hyoid

bone is white.


Otolaryngology–Head and Neck Surgery and the American Joint Commit-tee on Cancer. These classification systems did not always precisely definenodal locations, however, and did not account for retropharyngeal nodesdescribed in the original anatomic system proposed by Rouviere [27]. Theprevious nodal classification systems also have been based on anatomiclandmarks that are not necessarily conspicuous in the axial plane. Becausemodern nodal assessment almost always includes imaging, a modernclassification system should refer to anatomic landmarks that are reliablyidentified in the axial plane and at the time of surgery.

In 1999, Som et al [27] undertook this considerable task. They definedlevel I as submental (IA) and submandibular (IB), with both levels anteriorto the posterior margin of the submandibular gland, above the hyoid bone,

Fig. 12. (A) Sagittal CT reformatted image of the neck reveals the resection plan for

a supraglottic laryngectomy. Note the line goes through the laryngeal ventricle and spares the

vocal cords. (B) Coronal section reformatted from the same scan shows the surgical plan

through the laryngeal ventricle between the true and false vocal cords. (C) Color volume–

rendered model of the larynx again reveals the surgical margin. The thyroid cartilage is blue, the

cricoid cartilage light blue, the hyoid bone is white, and the epiglottis is red.


and below the mylohyoid muscle. Level IA is between the anterior bellies ofthe digastric muscles, with level IB lateral to the digastric muscle anteriorbelly. Level II extends from the skull base to the bottom of the hyoid bone,posterior to the back of the submandibular gland, and anterior to the backof the SCM muscle (Fig. 14). Level IIA consists of nodes in the level IIregion that are inseparable from the jugular vein by a fat plane, with levelIIB nodes posterior to the vein and separable from it by a fat plane. Level IIInodes are anterior to the back of the SCM muscle and between the bottomof the hyoid bone and the bottom of the cricoid arch (Fig. 15). Level IVnodes are located below the bottom of the cricoid arch but above theclavicles. They are anterior to the line joining the back of the SCM musclewith the posterolateral margin of the anterior scalene muscle, and lateral tothe common carotid arteries. Level V nodes are posterior to the back of theSCM muscle from the skull base to the bottom of the cricoid arch (level VA)and continue posteriorly to the line connecting the back of the SCM muscleand the posterolateral margin of the anterior scalene muscle to the level ofthe clavicle (level VB). Level VI nodes are between the common carotidarteries from the bottom of the hyoid bone to the top edge of themanubrium, with level VII nodes located between the carotid arteries belowthe top edge of the manubrium to the level of the brachiocephalic vein. Thelevel of the clavicles is defined as the first axial section in which the claviclesare visible. The supraclavicular nodes are at the level of the clavicles lateralto the common carotid arteries. Retropharyngeal nodes are defined asmedial to the internal carotid arteries, within 2 cm of the skull base.

This system provides the precise framework needed to facilitatecommunication among and between surgeons, pathologists, and radiolog-ists. Although all nodal levels may not be commonly used by surgeons in all

Fig. 13. (A) An axial CT reformatted image at the level of the true vocal cords demonstrates the

surgical plan for a supracricoid laryngectomy. Note the cricoid cartilage is spared and only one

arytenoid cartilage is resected. (B) A sagittal section of the same scan shows the two possible

plans for the supracricoid laryngectomy, with and without preservation of the epiglottis.


locations, an effort to adhere to this classification system should improve thequality of surgical–pathologic correlation and result in research in head andneck cancer, which has historically been difficult to study because of lownumbers of patients and inconsistencies in language used in the literatureand pathology and radiology reports.

Other applications of head and neck imaging in malignant disease

Other applications of head and neck imaging include CT or ultrasound-guided biopsy of suspected recurrent or primary disease, evaluation of theneck post treatment, and assessment of anatomic variants that may impactthe surgical approach. CT-guided percutaneous biopsy has been widelystudied in the literature for virtually all potential targets, including thebrain. The application of this technology to head and neck cancer can resultin safe and efficacious tissue sampling of retropharyngeal, parapharyngeal,and other deep or difficult-to-palpate regions of the neck [28,29]. Withproper techniques, nodal biopsy with ultrasound or CT guidance can beperformed with minimal risk to the patient [23]. The current authors’preferred CT technique is to access the face through the buccal space usinga short guide needle to the posterior edge of the pterygoid muscle, allowing

Fig. 14. An axial contrast-enhanced CT section reveals metastatic adenopathy at level IIA on

the right and the left (arrows). Nodes are above the bottom of the hyoid bone, posterior to the

back of the submandibular gland, and anterior to the back of the SCM muscle, inseparable

from the jugular vein. Note that the nodes are enlarged, abnormal in shape (rounded), and

abnormally low in attenuation.


for multiple passes with a 22-guage needle into the substance of the mass,without additional percutaneous passes and with good maintenance of anentry point close to the tumor margin (Fig. 16). From this approach, theguide needle can be angled slightly at the skin surface to obtain samples atdifferent locations within the tumor mass, with minimal additional risk. Thecurrent authors have performed biopsies in 38 patients using this techniqueover the last 4 years without complication. Sufficient tissue for diagnosis wasobtained in 98% of patients who underwent biopsy.

The use of imaging in postoperative patients is perhaps the most difficultpart of head and neck imaging interpretation for the radiologist. MRI in thepostoperative setting frequently proves difficult for patients, because motionand suspension of swallowing can be difficult to control. MRI has beenshown to have a high false-positive rate after radiation, which increases overtime to as high as 58%; CT has a specificity and sensitivity of 80% to 90%[30,31]. Knowledge of the surgical procedure performed and the type orlocation of any operative flap reconstruction, and history of radiationtreatment, will decrease the false-positive rate in MRI. This againemphasizes the need for communication between surgeons and radiologiststo obtain accurate evaluation of the patient and the optimal imagingtechnique [32]. Recognition of the post-treatment appearance of head andneck cancer on CT is an acquired skill that requires practice and readilyavailable follow-up information for the radiologist to become proficient.

Fig. 15. An axial contrast-enhanced CT section reveals an enlarged, rounded hypoattenuating

node at level III on the right (arrow). The node is between the bottom of the hyoid bone and the

bottom of the cricoid cartilage, lateral to the carotid artery, and anterior to the back of the

SCM muscle.


The operative flaps typically contain fat and muscle, with identifiablevascular pedicles. The postradiation density of tumor is intermediatebetween muscle and fat but may maintain the shape of the original neoplasm(Fig. 17). The initial evaluation of PET scanning in recurrent disease and fortumor response to chemotherapy has been promising [33–35], with somearticles stating improved sensitivity of PET over MRI and CT forevaluation of recurrent disease. Overall patient numbers have been low inthese studies, however. Other studies have implied PET has a role duringinitiation of chemotherapy to evaluate initial tumor response using glucosemetabolism as an indicator of tumor response. A lack of metabolic changewith initiation of therapy implies therapy may not be effective [31]. Thisfinding could potentially provide an early indicator that a new therapeuticregimen should be considered.

The role of any radiologist is to provide the clinician with importantanatomic details about the patient that may affect the difficulty or feasibilityof the planned therapeutic approach. This communication is particularlyimportant with head and neck malignancies. The use of three-dimensionaland multiplanar reformatted images in CT or MRI to help define tumorrelationships to vessels and the likelihood of vascular, spinal, perineural, ortracheal invasion is crucial. Controversy still exists as to whether CT orMRI performs these perspective tasks with higher sensitivity, but the well-trained eye, and the clinician who is informed of the planned clinicalprocedure and is aware of the surgical approach and risks, is the best toolfor alerting the surgeon to potential pitfalls related to anatomic variants ina specific patient (Figs. 18 and 19).

Fig. 16. (A) An axial CT section of the neck without contrast reveals a lateral pharyngeal node

on the left (arrow). The section includes part of the biopsy guide needle in the buccal space.

(B) This section shows the biopsy needle piercing the lateral pharyngeal node. Note the initial

scan was obtained with contrast to locate the carotid artery, which was clearly lateral to the

node before biopsy.


Summary

Evaluation of head and neck cancer with imaging is a topic that is farmore extensive than can be covered in this article. The main reason for headand neck imaging is to evaluate the true extent of disease to best determinesurgical and therapeutic options. This process includes evaluation of thesize, location, and extent of tumor infiltration into surrounding vascular andvisceral structures. Important anatomic variants must be pointed out so thesurgeon can avoid potential intraoperative complications. These variantscan be evaluated with the appropriate multiplanar and three-dimensionalimages to provide as much information as possible to the surgeon

Fig. 17. (A) An axial contrast-enhanced CT section through the larynx at the level of the

paraglottic space reveals a high-attenuation mass crossing the laryngeal ventricle through that

space (arrow). (B) The coronal reformatted image from A confirms the paraglottic spread of the

tumor (arrow). This tumor also extended across the midline anteriorly, excluding the patient

from voice-preservation surgery. (C) A follow-up CT scan after radiation therapy in the same

patient reveals the typical low attenuation of treated tumor, which is between muscle and fat

density (arrow). (D) A coronal reformation of C confirms that the paraglottic space also shows

evidence of radiation effect (arrow). Note that the mass effect from the tumor has not yet

subsided and continues to indent the supraglottic airway.


preoperatively. Second, nodal staging should be assessed in an effort toincrease the number of abnormal nodes detected by physical examinationand, more important, to precisely define their location by a standardclassification system that can be understood and consistently applied by theradiologist, surgeon, radiation oncologist, and pathologist. Althoughsecondary to the previously described tasks, imaging frequently enablesa limitation of the diagnostic and histologic possibilities based on lesionlocation and signal-attenuation characteristics, which may lead the clinical

Fig. 18. (A) An axial contrast-enhanced CT section at the level of the hard palate in a patient

with a superficial palatal carcinoma on clinical examination reveals an asymmetry in

attenuation and size of the greater palatine foramen (solid arrow). Compare this to the normal

side (open arrow) in which the attenuation is normal and the foramen is comparatively small.

(B) A bone window of the same section demonstrates the size asymmetry to better advantage

(arrows). (C) Sagittal reformatted image of the mass demonstrates the lack of fatty attenuation

at the opening of the palatine foramen on the left (arrow). (D) Sagittal reformatted image of the

normal side reveals the expected normal fatty attenuation. This finding is consistent with

perineural spread on the CT and changed the surgical plan from intraoral resection to a split

mandible procedure with partial resection of the maxilla. Perineural tumor in the greater

palatine foramen was found pathologically.


investigation along a different path, saving the patient unnecessary risk andshortening the time to diagnosis and ultimate treatment.

This article has attempted to detail the current state of the controversybetween CT, MRI, and other modalities, and has emphasized the constantevolution of this controversy because of the evolving imaging technology.Although CT and MRI are both well suited to evaluation of the deep spacesand submucosal spaces of the head and neck, each has some limitations.MRI has the advantages of higher soft tissue contrast resolution, the lack ofiodine-based contrast agents, and high sensitivity for perineural andintracranial disease. The disadvantages of MRI include lower patienttolerance, contraindications in pacemakers and certain other implantedmetallic devices, and artifacts related to multiple causes, not the least ofwhich is motion. CT is fast, well tolerated, and readily available but has

Fig. 19. (A) A volume-rendered CT laryngoscopy view reveals a posterior bulge in the wall of

the upper hypopharynx (arrows). (B) The cutaway view of the same image reveals a densely

enhancing structure in the submucosa of the retropharyngeal space (arrow). (C) An axial

contrast-enhanced CT section reveals the mass to be secondary to a tortuous carotid artery,

which resulted in a retropharyngeal position of the carotid bifurcation on the right (arrows).

This finding was brought to the attention of the head and neck surgeon.


lower contrast resolution and requires iodinated contrast and ionizingradiation. The current authors’ practice is heavily centered on CT for initialevaluation, preoperative planning, biopsy targeting, and postoperativefollow-up. They reserve MRI for tumors that are suspicious for perineural,cartilaginous, or bony invasion on CT, or for tumors such as adenoid cysticcarcinoma that are highly likely to spread by way of these routes. Forpatients who have head and neck cancer, a radiologist who is educated inthe treatment options, patterns of tumor growth, and important surgicallandmarks, and who has a well-established pattern of communication withthe head and neck clinical services, including surgery, radiation oncology,and pathology, is key in providing accurate and useful image interpretation.

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The expanding role of dental oncologyin head and neck surgery

Maureen Sullivan, DDSDepartment of Dentistry and Maxillofacial Prosthetics, Roswell Park Cancer Institute,


Dental oncology is the discipline within dentistry that combines generaldentistry, maxillofacial prosthetics, oral medicine, and oral pathology. Toprovide state-of-the-art care for patients who have head and neck cancer,the dental oncologist must play an integral role in all facets of treatment,whether surgical or nonsurgical. Historically, the maxillofacial prostho-dontist was the only dental specialist involved in the treatment and reha-bilitation of patients with head and neck cancer; however, it becameapparent that early intervention by a dentist familiar with the complica-tions associated with head and neck malignancies was required. The oralcomplications secondary to the management of head and neck malignan-cies have been well described [1–3]. To maximize the possibility of optimalfunction and cosmesis, and limit the possibility of complications that canlead to significant morbidity, a comprehensive dental screening must beperformed during the pretreatment phase. Close communication betweenthe head and neck surgeon, radiation oncologist, dental oncologist, andmaxillofacial prosthodontist is paramount in achieving function and cure.There are three treatment modalities involved in eradicating head and neckcancer: (1) surgery; (2) radiation therapy, with or without chemotherapy;and (3) combined treatment. Because all of these treatments dramati-cally affect the oral environment, close scrutiny of the dental condition iscrucial.

With a complete understanding of the role of the dental oncology teaminvolved in the pretreatment, treatment, and rehabilitation phases of treat-ing patients with head and neck cancer, the goal of cure with an acceptablequality of life can be obtained.



doi:10.1016/S1055-3207(03)00121-2


38 M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

Dental oncologic assessment

Because radiation therapy is used frequently in the treatment of head andneck malignancies, prompt attention to the dental condition at the time ofdiagnosis can allow time for adequate healing before the onset of radiation,if oral surgery is required. Frequently, the patient will require proceduresunder general anesthesia performed by the head and neck surgeon toformulate an appropriate plan for tumor removal. These assessmentprocedures also provide the dental oncologist an opportunity to performnecessary dental procedures in the operating room setting, which isgenerally preferred by the patient and, more important, allows for longerhealing time if radiation treatment is required.

The oral cavity undergoes monumental insult as a direct result ofradiation therapy to the head and neck. The immediate effects of radiationinclude mucositis, pain, trismus, and hypoguesia. These effects are variable,depending on the type of radiation used, the dose, and the field of involve-ment. Furthermore, these effects can be minimized with close attention tothe dental condition. The long-term effects may include xerostomia,rampant dental caries, trismus, soft tissue necrosis, and, potentially themost devastating effect, osteoradionecrosis (ORN).

Comprehensive evaluation of the dental patient includes Panorex(Orthopantomograph OP 100, Instrumentarium Corp, Tuusala, Finland)radiograph, a full-mouth series of intraoral radiographs, and intraoralexamination, including periodontal probing. All teeth deemed unrestorable,especially those in the field of radiation should be extracted. This procedurehas received much attention in the literature in an attempt to find a formulafor dental extraction requirements before radiation [4,5]. All teeth withadvanced dental decay, with or without pulpal involvement, and advancedperiodontal disease are generally extracted. Partially impacted third molarswith evidence of pericoronitis and any teeth with periapical pathology shouldbe extracted. The time required for adequate healing should be between 2 to 3weeks [6]. If third molars are completely impacted without evidence ofpathology, they are left and simply monitored. Again, if oral surgery is ad-dressed during the head and neck surgeons’ initial treatment-planning phase,there should be adequate time for healing if radiation therapy is required.

After all obvious sources of infection have been eliminated, the need forexisting restorative dental work is evaluated and any necessary restorativedentistry is completed. The specific type of restorative material used inpatients that will become xerostomic has been a consideration [7]. Therehave been a few studies evaluating the efficacy of fluoride-releasing materials,and therefore the type of restoration is not as critical as removing a potentialsource of mechanical irritation during treatment.

If the patient has not had a thorough periodontal scaling and prophylaxiswithin the 3 previous months to diagnosis, these procedures should becompleted. The dental hygienist must be familiar with the secondary

39M. Sullivan / Surg Oncol Clin N Am 13 (2004) 37–46

complications associated with head and neck radiation. At this juncture, theimportance of impeccable oral hygiene can be emphasized. Recently, the useof topical fluoride varnishes containing 5% sodium fluoride (eg, Duraphat,Ivoclan, NA, Amherst, New York) have been shown to be effective inpreventing decay in the xerostomic population [8]. The topical fluoride varnishis applied on the surfaces of all teeth. A daily fluoride delivery system is alsorecommended. Many different means of fluoride delivery have been exploredin the literature [9,10]; these include the fabrication of customfluoride carriers,containing a 0.4% stannous fluoride product, which are worn nightly for 5 to10 minutes. If this process is perceived to be arduous by the patient, the use ofa 1.1% fluoride paste is prescribed. Also at this time, an evaluation forxerostomia is rendered based on the location of the tumor and the type ofsubsequent radiation required. Historically, the radiation oncologist isconsulted regarding the use of a salivary stimulant, such as pilocarpine(Salogen, MGI Pharma, Inc., United Kingdom), in an attempt to maintainsalivary function [11–13]. Pilocarpine (Watson Laboratories, Corona,California) is a parasympathomimetic agent that stimulates exocrine glandtissue. This action promotes salivation and is believed to be most effective ifadministered at the onset of radiation. In a recent study, pilocarpineadministered during and after radiation therapy was found to offer no benefit[14]. Amifostine (Ethyol, Medimmune, Inc., Gaithersburg, Maryland) hasbeen investigated for its use as a chemoprotectant, which reduces the severityof radiation-induced mucositis and maintains salivary function in patientswith head and neck cancer undergoing radiation therapy [15–18]. This agentmust be administered daily throughout radiation therapy, with profoundhydration, to be effective without significant side effects. Although amifostineshows promise, further controlled clinical studies must be performed.

Patients who are at high risk for developing trismus should be giveninstruction for its prevention rather than treatment once it occurs. Patientsrequiring resection of part of the mandible without reconstruction are atconsiderable risk, especially if postoperative radiation is required. Thosepatients who require partial maxillectomy that includes the tuberosity,hamular notch region and the pterygoid fossa area are at risk, especiallyif postoperative radiation is required. For tumors located within thenasopharynx, in which the muscles of mastication and the temporomandib-ular joint are within the field of radiation, trismus therapy must not beoverlooked. Daily opening exercises can be a worthwhile task for minimizingthis debilitating complication. Instructing patients on the use of tongue bladesto use as a lever andmonitoring the range of opening can be useful as well [19].

The use of chemotherapeutic agents in the treatment of head and neckcancer historically has not been as widely used as surgery or radiation.Chemotherapy was reserved for advanced-stage disease or as an adjunctwhen front-line treatment failed. For head and neck malignancies, chemo-therapy can be used before surgery to decrease the possibility of distantmetastases, or it can be used concurrently with radiation therapy.


When chemotherapy is suggested as a course of treatment for head andneck cancer, the timing of the dental assessment is important. The risk ofinfection is great because of a depressed peripheral white blood cell count,which can occur approximately 1 week after infusion. It is critical that thepatient is made aware of oral hygiene measures to limit the possibility ofbacteremia during cycles of chemotherapy. In addition, all possible sourcesof oral infection should be eliminated before the onset of chemotherapy.

In conjunction with the pretreatment dental assessment, a maxillofacialprosthodontist should evaluate the area to be treated, if prostheticrehabilitation is required. The head and neck surgeon should consult withthe maxillofacial prosthodontist before surgery to establish a design forimmediate surgical obturation if resection of the hard palate is unable to bereconstructed by local or regional flap surgery. When large palatal defectsare anticipated, prosthetic rehabilitation is generally preferred, and there-fore presurgical impressions and radiographs are required. The quality ofthe remaining teeth and alveolar bone adjacent to the surgical defect is im-portant when predicting the support for prosthesis. The use of split-thick-ness skin grafts to line the surgical closure of the maxillary defect generallyallows for adequate scar band formation, which provides an optimal sur-face for engaging the eventual prosthesis [20,21].

Presurgical facial impressions are crucial if tumor eradication involvestotal auriculectomy or rhinectomy. Because large facial defects are challeng-ing to reconstruct surgically, prosthetic reconstruction is frequently required.At this stage, osseointegrated implants should be considered; this determina-tion includes CT imaging to evaluate quality and quantity of availablebone. Because the retention of facial prostheses is of great concern, thepossibility of using implants should always be discussed at the pretreatmentphase [22]. The skin overlaying facial implants must be extremely thin andideally free of hair follicles.

Communication between the dental oncologist, maxillofacial prostho-dontist, and the head and neck surgeon is important and should be initiatedat the pretreatment phase to allow for a more predictable reconstructiveoutcome.

Dental considerations during treatment

Head and neck surgery that entails mandibulectomy with immediatereconstruction involving free-tissue grafting is challenging for not only thehead and neck surgical team but the dental team as well. At the time of tumorremoval, the dental oncologist may be required to implement intermaxillaryfixation, with or without occlusal splinting, to ensure appropriate intercus-pation of the remaining mandible. This procedure ensures that the remainingmandible is able to function within the confines of the temporomandibularjoint and provides a template for positioning of the grafted bone. In the


immediate postsurgical period, infection is the greatest risk to the graft;therefore, close observation and meticulous hygiene are required [23].

Osseointegrated implants in free-bone grafts have been used with greatersuccess in recent years. The placement of implants at the time of free-flapsurgery can be achieved, or at a second-stage surgery once graft viability hasbeen confirmed [24–27].

Immediate placement of a surgical obturator for defects of the hardpalate can allow the patient to speak and eat. The use of keratinized skingrafts to line the surgical defect can be beneficial in providing a supportivesurface for a maxillary obturator. After the surgical packing has beenremoved, the immediate obturator can be modified and worn by the patientuntil complete healing has been achieved.

Close scrutiny during radiation therapy of patients who have head andneck cancer is required to monitor toxicity. Mucositis is the thinning andeventual breakdown of the oral mucosa caused by chemotheraputic agentsor head and neck radiation. This condition is first observed within 1 to2 weeks of therapy and continues until therapy is completed. The severityof radiation-induced mucositis depends on the tumor location, type ofradiation, and chemotherapy used, in addition to the patient’s ability tomaintain oral hygiene [28,29]. There is currently no means of preventing oralmucositis, only a means of palliation once it occurs. Patients are at risk ofmany types of infection when tissue breakdown occurs, and should betreated for evidence of bacterial or fungal infections locally to avoid thepossibility of lapse in treatment. Rinsing with topical analgesics, coatingagents, or saliva substitutes can be recommended in addition to systemicpain management. The use of partial and complete dentures should beavoided until the acute effects of therapy have improved. It is during thetreatment phase that trismus therapy should be closely monitored ifradiation involves the muscles of mastication. This step is most significantwhen surgery is combined with radiation therapy.

Long-term dental oncologic considerations

Following treatment, the dental oncology team must closely monitorpatients who have head and neck cancer to minimize the complications oftreatment. Because the treatment for tumors of the mandible, hard and softpalate, tongue, and facial structures can significantly compromise a patient’sability to function, rehabilitation requires immediate attention to assessingthe patient’s post-treatment status. Evaluation for pain, infection, speech,and swallowing, and evaluating the quality of the patient’s oral-care regimenshould be performed weekly following the immediate post-treatment phase.Evaluating the healing of oral tissues before the placement of removableprosthetics is recommended to decrease the possibility of unnecessary tissuetrauma.


For defects of the mandible caused by resections of the floor of mouth,tongue, or mandible itself, fabrication of a mandibular resection prosthesisretained by osseointegrated implants may be required to restore continuity.If the mandible is reconstructed with a microvascular free flap, osseointe-grated implants can provide a more reliable means of rehabilitation. Thesuccess of the prosthesis varies significantly with the amount of hard andsoft tissue affected [30,31]. For patients with significant tongue morbidity,a palatal augmentation prosthesis may provide better tongue contact to thepalate.

The reconstruction of a palatal defect can be extremely challengingdepending on the size of the defect, access to the defect, and the nature ofthe residual dentition. Surgical reconstruction of the hard palate is possible;however, if significant tissue bulk remains, rehabilitation with an intraoralprosthesis is impossible [32]. If prosthetic rehabilitation is required,fabrication of a definitive prosthesis can take place following complete thehealing of the surgical defect, which occurs between 3 to 6 months followingsurgery. This may be delayed even further if radiation therapy is required.

The management of the surgical removal of some or all of the soft palateis challenging. Fabrication of a speech-aid appliance attempts to provideclosure of the oral pharyngeal resection, thereby enabling separation of thenasal and oral cavities. If the patient is edentulous, the retention ofa maxillary speech aid can be difficult; therefore, osseointegrated implantsmay be considered. If the soft palate is present but not functioning, eitherbecause of surgery or radiation, a palatal lift prosthesis may elevate anincompetent soft palate [33].

With initiation of prosthetic rehabilitation, it is important to continuemonitoring patients with head and neck cancer who are at continued risk ofcomplications secondary to radiation therapy. For example, xerostomiainduced by head and neck radiation is well described in the literature [34,35].Because there is currently no means of preventing xerostomia when thesalivary glands are in the field of radiation, attention to patient compliancewith oral hygiene protocol cannot be understated. Rampant tooth decay inpatients who have undergone radiation of the head and neck can lead tosignificant morbidity.

Trismus therapy must be maintained not only during radiation therapybut throughout the life of the patient. Patients’ progress can be monitoredat follow-up examination with the dental hygienist. If there is a lapse ina regular trismus therapy, the ability to wear prostheses, eat, and maintainposterior teeth becomes difficult. Tongue depressors or custom trismusscrews can be used to monitor patients’ compliance with daily openingexercises.

Periodontal management is a challenge, especially for the teeth left in thefield of radiation therapy. It has been suggested that radiation increases theperiodontal attachment loss because of disruption in cellularity andvascularity. It is generally agreed that 3-month recalls are required with


minimal soft tissue trauma, followed by a short duration of chlorhexidinerinsing [36–38].

Despite efforts to maintain adequate oral health following head and neckradiation, soft tissue breakdown, periodontal disease, or rampant decay cannecessitate the extraction of teeth in the field of radiation. This situation hasreceived considerable attention in the literature as a predisposing factorin the development of ORN. ORN is defined as a radiation-inducednonhealing wound rather than an osteomyelitis of irradiated bone [39].ORN can occur spontaneously, from denture trauma, or most often fromtrauma caused by dental extraction. It is generally agreed that the mandibleis at greater risk than the maxilla, and it rarely occurs when the totalradiation dose is less than 6000 cGy. The mandibular molar region isgenerally the most affected area in most clinical studies. ORN can present asa small, isolated area of exposed bone or, in advanced cases, progress topathologic fracture with profound pain [40–42].

There is a significant amount of controversy surrounding dentalextractions following radiation therapy. Some authors suggest that safeoral surgery can be performed with nontraumatic techniques on patientsfollowing radiation therapy [43,44]. Recent studies suggest that the risk ofpostradiation ORN can be dramatically reduced if hyperbaric oxygentreatments are used before dental extractions. Hyperbaric oxygen is believedto promote the revascularization of hypoxic tissues [45,46]. Hyperbaricoxygen therapy is extremely costly, however, and may be contraindicated inthe patient with compromised respiratory function. Most clinicians agreethat in high-risk patients where all attempts at maintaining the dentalcondition have failed, all oral-surgical attempts should be made withextreme caution.

In cases where ORN develops after head and neck radiation, closecommunication between the dental oncologist, radiation oncologist, andhead and neck surgeon is required to determine the best course of treatment.Clearly, conservative treatment involving local wound care is preferred if thearea involved is small and isolated. In cases of advanced necrotic lesions,hyperbaric oxygen therapy can be of benefit in conjunction with surgicalresection of the affected area [47,48].

Summary

A comprehensive dental oncologic screening should be part of thepretreatment workup of patients who have head and neck cancer. Thisscreening should be performed by a dentist who is familiar with thepathologic process of disease and type of treatment being rendered; inaddition, he or she should comprehend the various morbidities associatedwith eradicating head and neck malignancy. The dental oncologist mustprovide the timeline for the surgeon and radiation oncologist in which allnecessary dental treatment will be completed. It is important at this juncture


to educate the patient as to the possible short- and long-term complications,no matter what treatment course they choose.

Osseointegrated implants used in the rehabilitation of patients who haveundergone head and neck surgery have provided a more reliable means ofretaining intraoral and extraoral prostheses. With close communicationbetween the head and neck surgeon and dental oncologist, and carefulpatient selection, better functional outcomes may be provided.

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Current treatment options in squamouscell carcinoma of the oral cavity

Carsten E. Palme, MB BS, FRACS,Patrick J. Gullane, MB, FRCSC, FACS*,

Ralph W. Gilbert, MD, FRCSCDepartment of Otolaryngology, University of Toronto, 610 University Avenue,

Toronto, ON M5G 2M9, Canada

Squamous cell carcinoma (SCC) of the oral cavity is a significant publichealth issue, which uses a wide range of resources. It accounts for 14% ofhead and neck cancers reported to the National Cancer Data Base each year[1]. Approximately 29,000 new cases were diagnosed in the United States in2002, and the mortality rate was approximately 25% [2]. In comparison,France and Hungary have an annual incidence of 40 per 100,000 individuals,with mortality in approximately 12 per 100,000 individuals [3]. The incidenceof this disease is even higher in developing nations where it is the third mostcommon malignancy after both cervical and gastric carcinoma [4].

The anatomic and functional complexity of the oral cavity and becauseSCC is locally invasive and can involve adjacent sites make the diagnosisand management of this disease entity extremely challenging. It is imperativethat physicians adopt a multidisciplinary approach that encompasses bothsurgical and medical expertise. This approach necessitates not only onco-logically sound ablation of the tumor but also timely and state-of-the-artreconstructive techniques. In addition, adjuvant therapy used by bothradiation and medical oncologists is vital to improve disease-specificoutcome. Ancillary medical specialists, including radiologists, anesthesiol-ogists, nurses, and nutritionists experienced in head and neck oncology, areintegral in the multidisciplinary approach. Finally, oral rehabilitation is notcomplete without the expert assistance from speech pathologists, dentists,and prothodontists.


E-mail address: [email protected] (P.J. Gullane).


doi:10.1016/S1055-3207(03)00123-6


48 C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

Etiology

Predisposing factors in the development of oral cavity SCC can bedivided into those that are specific to the patient and those of environmentalorigin. Most patients are men with a median age of 60 years [5]. There is anincreasing trend of this disease in women, however, who now account forapproximately 30% of all cases [6]. A recent Canadian report showed thatthe incidence of oral SCC in women increased by 84% over the periodfrom 1983 to 1997 [7]. In addition, the incidence of oral cavity SCC isapproximately 4% in patients younger than 35 years [6].

The dominant causative environmental factor in the development of oralSCC is smoking. This factor combined with the chronic consumption ofalcohol constitutes a 35-fold greater risk for developing an oral cavitymalignancy [2,8]. A constant and prolonged exposure to these two knowncausative factors results in ‘‘field cancerization’’ of the oral mucosa [9]. Themechanisms are multifactorial and include activation of proto-oncogenesand deactivation of tumor suppressor genes. Genomic instability develops,and this results in a chain of events that ends in the development ofmalignancy with the potential for local destruction and distant spread[10,11].

The culturally specific habits of chewing betel nuts and tobacco andreverse smoking are also implicated in the cause of oral cavity SCC [12,13].Although lip carcinoma is included within the oral cavity, it is important torecognize that it may be caused by excessive exposure to ultravioletradiation and therefore should be classified more appropriately as a skincarcinoma [14]. Other factors, such as poor oral hygiene, significantperiodontal disease, and chronic trauma from ill-fitting dentures or jaggedteeth, also have been proposed as potential causative factors. In additionthere are several other oral pathologic conditions that are potentialprecursors in the development of malignancy, which include erosive lichenplanus, oral submucous fibrosis, erythroplakia, leukoplakia, and possiblychronic hypertrophic candidiasis [2]. An association with Epstein-Barr virusand the human papilloma virus has been suggested, but clear causation hasnot yet been established [15–17].

Pathology

SCC accounts for approximately 90% of all oral cavity malignancies [5].In the differential diagnosis, however, minor salivary gland carcinomas,lymphoma, melanoma, mesenchymal tumors, and tumorlike conditionsmust be considered. Submucosal malignancies arising at the junction of thehard and soft palate often originate in the minor salivary gland and mayinclude adenoid cystic, mucoepidermoid, or acinic cell carcinoma. Mucosalmelanoma needs to be considered in the differential diagnosis of a bluishmass on the alveolus. Other mesenchymal tumors, such as osteosarcoma,

49C.E. Palme et al / Surg Oncol Clin N Am 13 (2004) 47–70

can occur in younger patients. Tumorlike conditions, such as necrotizingsialometaplasia, can involve the hard palate and present a diagnostic andmanagement dilemma. SCC of the oral cavity involves several distinctsubsites, each with its unique diagnostic and management challenges (Fig.1). The most common site involved is the mobile tongue (ie, anterior twothirds of the tongue), which accounts for approximately 30% of all oralcavity SCC [5]. The floor of the mouth is second in frequency, withapproximately 28% of oral cavity SCC, followed by SCC involving theupper (including the hard palate) and lower alveolar ridge, retromolartrigone, buccal mucosa, and the lips. Staging of these tumors is classifiedaccording to the Union Internationale Contre le Cancer and the AmericanJoint Committee on Cancer tumor-node-metastasis (TNM) system (Box 1)[18].

Tumors of the mobile tongue occur most commonly on its lateral andventral surface and tend to spread in both a radial and vertical fashion.Patients who have these lesions present with discomfort on swallowing;

Fig. 1. Oral cavity subsites. (Modified from Sharma PK, Schuller DE, Baker SR. Malignant

neoplasms of the oral cavity. In: Cummings CW, et al, editors. Otolaryngology–head and neck

surgery. Vol. 3, 3rd edition. St. Louis, MO: Mosby; 1998; with permission.)


these lesions are therefore usually diagnosed at an early stage (ie, T1 or T2).Neoplasms that originate in the floor of the mouth and along the loweralveolar ridge tend to invade the mandible early, and patients may presentwith loosening of teeth and ill-fitting dentures. The retromolar trigone isa less common site for oral cavity SCC but deserves special mention. Thesetumors spread early to involve adjacent sites such as the mandible, tongue

Box 1. TNM staging of oral carcinoma

Primary tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor is 2 cm or less in greatest dimensionT2 Tumor is larger than 2 cm but no larger than 4 cm in

greatest dimensionT3 Tumor is larger than 4 cm in greatest dimensionT4 Tumor invades adjacent structures (eg, through

cortical bone, into maxillary sinus, skin, pterygoidmuscle, or deep muscle of tongue)

Nodal involvement (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Single ipsilateral node, 3 cm or less in

greatest dimensionN2a Single ipsilateral node, larger than 3 cm and not

more than 6 cmN2b Multiple ipsilateral nodes, 6 cm or smallerN2c Bilateral or contralateral nodes, 6 cm or smallerN3 Metastasis in a lymph node more than 6 cm in

greatest dimension

Distant metastasis (M)MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis)

Used with the permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for this information isthe AJCC Cancer Staging Manual, 6th edition (2002) published by Springer-VerlagNew York (For more information, visit www.cancerstaging.net). Any citation orquotation of this material must be credited to the AJCC as its primary source.The inclusion of this information herein does not authorize any reuse or furtherdistribution without the expressed written permission of Springer Verlag NewYork, Inc., on behalf of the AJCC.


base, tonsil, and soft palate. Once these lesions have extended beyond theirsite of origin, treatment becomes more complex, with significant ablativeand reconstructive challenges. The hard palate and maxillary alveolus areinvolved in approximately 10% of cases [5]. Aggressive local invasionfrequently occurs with extension to involve the paranasal sinuses,pterygopalatine fossa, infratemporal fossa, orbit, and/or the cranial cavity.SCC of buccal mucosa may occur de novo or become involved by way ofdirect extension from other oral cavity subsites. This site includes all theintraoral lining of the inner surface of the cheeks and lips from the line ofcontact anteriorly to the pterygomandibular raphe posteriorly and attachesto the superior and inferior alveolus. The buccal mucosa is a common site oforigin in India and the southeastern parts of the United States because ofthe high incidence of betel nut chewing in the former and the use of snuff inthe latter [12,13]. SCC of the lip commonly occurs in white individuals whohave a life-long outdoor occupation [2].

Oral cavity SCC presents with regional cervical lymph node involvementin a significant proportion of patients. The incidence of regional metastasesis associated with subsite, stage, and various histopathologic features (eg,depth of invasion, malignancy grading of the tumor front, pattern ofinvasion, growth pattern, and lymphovascular and perineural invasion) [19–22]. For example, neoplasms that are larger than 2 cm, have depth ofinvasion greater then 3 mm, and tend to invade in small groups of tumorcells have been associated with a significant rate of occult nodal metastases[23]. Potential molecular markers (ie, tumor suppressor genes and proto-oncogenes) have been proposed as indicators for regional involvement, buttheir routine application has yet to be proved [11,24].

Management

The management of patients who have oral cavity SCC begins witha comprehensive history and complete head and neck examination, whichincludes an office-based fiberoptic-endoscopic evaluation of the upperaerodigestive tract. In addition, it is vital to confirm any comorbidities,degree of functionality, family support, and understanding and personalwishes of the patient before embarking on any therapeutic path. Treatmentmodalities are divided into surgical and nonsurgical options or a combinationof both. Surgery is further subdivided into ablative and reconstructiveapproaches. Nonsurgical management includes the use of radiotherapy,chemotherapy, and ancillary services aimed at functional rehabilitation (Fig.2). The selection of appropriate therapy depends on certain patient, tumor,and institutional factors. Patient factors have been outlined previously, andthose pertaining to individual tumor sites are discussed later. Institutionalfactors relate to the expertise, resources, and treatment philosophy establishedby the multidisciplinary team. Various therapeutic philosophies exist, andthese need to be considered in the management of each individual patient.


Investigations

Investigations can be divided into those that are general and specific andinclude a complete blood film, biochemistry, ECG, and a chest radiograph.Specific investigations should include imaging of the primary tumor site and

Fig. 2. Management algorithm for oral cavity carcinoma.

Abbreviations: MRND, modified radical neck dissection; RFFF, radial forearm free flap.


regional lymphatics, examination of the upper aerodigestive tract undergeneral anesthesia, and histopathologic verification of the tumor type.Before embarking on surgery, anesthetic fitness needs to be confirmed by theanesthesiologist and other members of the medical team (eg, cardiologist,respiratory specialist). Finally, the patient’s management should be dis-cussed within the setting of a multidisciplinary tumor board.

The goal of imaging is to assist in the staging of the primary tumor,evaluate cervical lymphatics, and detect any bony invasion, which helps inthe planning of the most appropriate therapeutic approach. Pulmonaryimaging in the form of a chest radiograph or CT scan for more advancedtumors is imperative in the evaluation of any underlying lung disease and inthe exclusion of possible metastatic involvement. CT scanning is widely usedin the management of head and neck malignancy. Its many advantagesinclude the clear delineation of the bone–soft tissue interface in theevaluation of the neck and its universal availability. Invasion of the facialskeleton, including the hard palate, paranasal sinuses, and mandible, is bestvisualized using thin slices with bone algorithm (ie, axial and coronal planes)[25]. Dental CT scans have been developed and, if available, offer morechoice in the assessment of mandibular invasion [26]. Panoramic X-ray orocclusal view radiographs of the mandible are simple and cost-effective first-line investigations that have a high specificity but low sensitivity forexcluding mandibular invasion and are therefore useful with gross tumorinvolvement only. They can assist, however, in the planning of tumorresection and in evaluating the remaining dentition [27,28].

MRI is superior in the delineation of soft tissue lesions within the tongueand in the floor of the mouth. In addition, neural involvement andintracranial extension can be accurately evaluated with this modality. MRIallows direct multiplanar evaluation of the pathology and, as an additionalbenefit, avoids the distortion seen in patients with heavily restored dentition[28]. Recent literature has focused on single photon emission CT (SPECT)scanning in evaluating the mandible. Its sensitivity in excluding invasion(95%) was far superior to CT or dental CT scans, or Panorex radiographs[27,28]. Lack of availability, cost, and limited application of this modality,however, demands that further prospective studies be performed before itsuniversally acceptance.

Specific sites

Tongue

Surgery is the mainstay of treatment for early-stage disease of the oraltongue (ie, stages I or II) [29]. Adjuvant radiotherapy improves locoregionalcontrol and disease-specific survival rates in patients with advanced-stagelesions [30]. Chemotherapy in a neoadjuvant setting has been investigatedand shows promise; however, its use is presently limited to institutional trials


[31]. Palliative chemotherapy useful and can be offered to patients for whomdefinitive curative management is no longer an option.

There are several surgical approaches to disease of the oral tongue. Theseinclude the peroral, degloving, mandibular swing (ie, by means of midline,paramedian, or lateral osteotomies), lingual release, or cheek flap approach[32,33]. The approach selected depends on several factors, which include sizeof the primary tumor, mandibular invasion, dentition, extent of cervicallymph node involvement, need for reconstruction, and the expertise andpreference of the individual surgeon. Neoplasms staged T1 or T2 that do notinvade the mandible are best managed using a peroral approach (Fig. 3).More advanced lesions, however, particularly those that have deep tongueinvolvement and extent across the midline require a more radical approach.Both the mandibulotomy and lingual release afford good access, both fortumor ablation and subsequent reconstruction [32,33]. The advantage of thetongue drop is the avoidance of an osteotomy with its associatedcomplications of malunion and/or nonunion [34]. Prior radiotherapy canincrease the rate of complications that occur with a mandibular swing. Inexpert hands, however, complication rates are low, and a recent comparisonof these two approaches showed no significant difference in outcome [35].Patients treated with a mandibulotomy did report superior ability of speech,swallowing, and chewing when compared with the lingual release group,

Fig. 3. (A) Right T2 lateral tongue SCC; (B) transoral resection of lesion; and (C) primary

closure with absorbable suture.


however. The potential negative impact of a facial scar was not borne out inthis analysis [35].

Mandibular swing with either a midline or paramedian osteotomy is thecurrent authors’ preferred approach to the oral cavity (Fig. 4). In patientswith teeth, care needs to be taken in placing the osteotomy site between thetooth roots; however, if there is dental crowding, extraction of one tooth ispreferred. Commercially available plating systems have improved recon-struction and have diminished morbidity. It is important to reduce theprominence of the symphyseal region of the mandible using a high-powerburr to compensate for the thickness of the reconstruction plate. Once thishas been achieved, a thin titanium (eg, 2.3-mm) plate is used to stabilize the

Fig. 4. (A) Lip-split and midline mandibulotomy approach to the oral cavity. (B) Repair with

radial forearm flap and plate.


osteotomy and a tension band splint or circumdental wire help minimizeexcess movement. Alternatively, one or two lag screws can be used toachieve a similar result (Fig. 5) [36].

Floor of the mouth

Tumors in the floor of the mouth are located either anteriorly or laterallyalong the oral tongue. The management of these lesions is challengingbecause of their proximity to the mandible. Edentulous patients seem tohave less resistance to the advancing tumor front, which tends to invade themandible along its occlusal surface at the site of tooth sockets. Onceinvasion of the neurovascular canal occurs, the tumor tends to spread to theskull base along the inferior alveolar nerve. In contrast, dentition does offersome resistance; however, direct tumor invasion through the lingual cortexand tooth roots will eventually occur [37]. The state of dentition thereforeplays a significant role in the selection of appropriate surgical treatment.

Retromolar trigone and lower alveolus

Patients who have tumors located on or near the lower alveolus tend topresent with mandibular invasion and advanced-stage disease. Theseneoplasms frequently involve adjacent sites, including the oropharynx, withdirect invasion of the pterygopalatine and infratemporal fossa. Surgery isthe primary mode of therapy with the need for complex reconstruction,which often necessitates composite free-tissue transfer. In addition, adjuvantradiotherapy is recommended when resection margins are close or involved[38]. This combined therapy frequently results in significant functionaldisability, with resultant dysphagia, lack of speech, xerostomia, and trismus.

Fig. 5. Lag screws for repair of midline mandibular osteotomy.


Upper alveolus and hard palate

Tumors arising from the upper alveolus and hard palate tend to involveimportant adjacent structures at the time of presentation (ie, paranasalsinuses, orbit, or brain). Management frequently requires partial or totalmaxillectomy with, on occasion, orbital exenteration. Reconstruction ischallenging; however, most defects are repaired using a combination of a skingraft and maxillary prosthesis, which provide adequate function and ac-ceptable cosmesis. Alternate options include free-tissue transfer, which is usedin a select number of patients where orbital support and/or repair are ne-cessary. In addition, resection that transgresses the cranial base mandates theuse of free-tissue transfer to minimize potential postoperative complications,such as cerebrospinal fluid leak, meningitis, or intracranial abscess [39].

The lip

Most lip cancers occur on the sun-exposed lower lip; approximately 7%arise from the upper lip and 4% involve the commissure. Simple excisionand primary closure is advocated in defects that involve less than one thirdof the lip. Some form of advancement flap is necessary if the defect exceeds30% of the lip, and the Abbe and Karapandzic flaps are the reconstructiveoptions of choice (Fig. 6) [40]. Total lip replacement, however, usuallyrequires free-tissue transfer, and a combination of the radial forearm free

Fig. 6. (A) Lower lip SCC; (B) excision and outline of bilateral Karapandzic advancement

flaps; (C) flap advancement and closure; and (D) Postoperative result.


flap and the palmaris longus sling has become a popular option [41].Primary radiotherapy is an alternative form of treatment, especially inelderly patients and in those who are medically unfit for prolongedanesthesia and hospitalization. Treatment of the cervical lymphatics (ie,neck levels I to III) should be considered in patients with neoplasms thatinvolve either the upper lip, the oral commissure, or in those with advanced(ie, tumor stage, [T2) or recurrent lesions, because these lesions havea significant incidence of occult metastases [42].

The mandible

Mandibular involvement has significant implications for both prognosisand postoperative rehabilitation. In addition, adjuvant radiotherapy isrecommended in most patients with mandibular invasion. Currently, there isno one diagnostic modality that provides accurate preoperative assessmentof bone invasion. Careful clinical examination is paramount, however, andstudies have shown it to be highly sensitive ([94%) but lacking in specificity(25%) [27]. In certain situations, including those in which lesions are close toand abutting the inferior alveolar ridge, immobile lesions of the floor of themouth and/or in edentulous patients are highly suggestive of bone invasion.A combination of Panorex/occlusal views and CT scanning has a highsensitivity (81%) and specificity (88%) [27]. SPECT and MRI also showpromise, with reported sensitivities of more than 90%, but their limitedavailability curtails their routine use [28]. The current authors’ approach tothe evaluation of the mandible includes a thorough clinical examination,with Panorex/occlusal views, CT scans, and a high index of suspicion.

The goal of resection is to provide a clear margin of more than 1 cm withremoval of all microscopic disease. Where the mandible is involved clinicallyand radiologically, the standard of care is usually segmental mandibulec-tomy (Fig. 7). The reconstructive menu in the current authors’ institutionincludes a vascularized osseous free-tissue transfer, but in select cases, wherethe bony defect is situated posterolaterally in elderly and edentulouspatients, it may be left unreconstructed. The dilemma arises in lesions thatare close to or abut the mandible. A marginal mandibulectomy is a widelyaccepted approach where there is no clear evidence of bone invasion [43].This procedure involves a resection of either the superior half of themandible or the lingual cortex (Fig. 8). Where the resection includes morethan 60% of the height of the mandible, a plate is applied to reduce theincidence of fracture.

The management of the mandible requires a balanced approach, withavoidance of unnecessary, excessive resection of normal, uninvolved tissue.Results support using a marginal mandibulectomy in most patients in whomno gross clinical and radiologic evidence of mandibular invasion exists.Ultimate locoregional control and survival rates compare well with those forsegmental mandibulectomy [44,45].


The neck

The management of the neck in patients who have SCC of the oral cavityis determined by the treatment approach to the primary neoplasm, withmost clinically involved cervical lymph nodes requiring a neck dissection.The standard is a modified radical neck dissection encompassing levels I toV. Recent studies, however, have questioned this approach for small, singlelymph node disease involving the upper neck. Andersen et al [46] in a recentreview reported on 106 patients with clinically positive neck disease. Theprimary sites were varied with approximately half involving the oral cavity.

Fig. 7. (A) T4 right lower alveolar SCC. (B) Composite resection, including lateral segmental

mandibulectomy and radical neck dissection. (C) Repair with free vascularized fibular bone and

overlying skin.


All patients were treated with an appropriate selective neck dissection.Adjuvant radiotherapy was used in 72% of patients, with an overalllocoregional control rate of 94% [46]. Gooris et al [47] evaluated thetherapeutic use of performing a supraomohyoid neck dissection followed byradiotherapy in patients with primary lip SCC and concomitant neck disease(ie, stage N1 or N2) involving only level I. Locoregional control exceeded90%. Although these studies were retrospective and relied heavily onadjuvant radiotherapy, a selective neck dissection as part of a combinationapproach may be adequate treatment of clinically positive neck disease.

The management of clinically negative neck disease provides further con-troversy. There are three accepted treatment approaches: close observation,elective neck surgery, or radiotherapy [48,49]. Physical examination, CTscanning, MRI and positron emission tomography are used in theevaluation of clinically negative neck disease in head and neck carcinoma[50–52]. The combination of clinical examination and CT compares wellwith the ‘‘ gold standard ‘‘ of elective neck dissection (sensitivity, >90%)[50]. A significant number of patients have occult disease, however, and thegoal is to detect those patients who have occult or positive disease to avoidany unnecessary morbidity associated with elective neck surgery.

The technique of sentinel node biopsy as used in the management ofmelanoma has been proposed in an effort to identify those patients withoccult disease [53]. Ionna et al [54] recently reported the use of sentinel nodebiopsy in patients with oral cavity SCC staged T1 or T2. The sentinel node

Fig. 8. (A) Cheek flap approach. (B) Exposure of the lateral oral cavity. (C) Posterior marginal

mandibulectomy.


was identified in 95% of patients, and the overall sensitivity of this approachwas 100%. Ross et al [55] recently presented the results of a multicenter trialon the feasibility of this technique in the management of patients with headand neck SCC and concluded that sentinel node biopsy identified 95% ofsentinel nodes with an overall sensitivity of 90%. The sensitivity droppedsignificantly in centers performing fewer than 10 sentinel node biopsies peryear, however. Although results of this approach are promising, furthermulti-institutional trials need to be performed to evaluate and test thismodality before it can become part of the routine workup in patients whohave clinically N0 neck disease. The management of clinical negative neckdisease therefore continues to be controversial, and the selection oftreatment modality generally depends on the approach to the primarytumor. Treatment of early-stage disease is adequate with single-modalitytherapy. The importance of including the neck in the treatment regime restson the fact that oral cavity SCC has a significant rate of occult metastases.Even T2 lesions have a known incidence of occult disease of more than 15%,necessitating treatment of the N0 neck. Neck dissections encompassinglevels I to III are generally adequate; however, Byers et al [56] reported that‘‘skip metastases’’ involving only levels III or IV exist in up to 15% ofpatients with oral tongue SCC. In addition, midline lesions (eg, anteriorfloor of mouth) usually require bilateral neck treatment. The currentauthors’ approach in the management of clinically N0 neck disease is toperform either unilateral or bilateral selective neck dissections encompassinglevels I to IV. In addition, adjuvant radiotherapy is recommended if occultdisease is identified.

Reconstruction

A wide variety of reconstructive options are currently available to repairsurgical defects of the oral cavity [57]. The simplest approach is to permit thedefect to heal by secondary intention, and this is certainly appropriate forsmall lesions of the tongue, floor of the mouth, or buccal mucosa. Split-thickness skin grafting is an alternative; however, in large defects, thereexists a significant rate of fistula formation, trismus, and graft failure [58].Local mucosal, tongue, or skin flaps (eg, nasolabial) are alternate options,and these are best suited for defects that involve the anterior floor of themouth, especially in edentulous patients [59]. The gold standard in softtissue reconstruction of the oral cavity is the radial forearm free flap [60]. Itprovides significant flexibility to the surgeon because of the size of thepotential skin paddle and adequate length of its vascular pedicle. It is thin,pliable, and potentially sensate and therefore well suited for intraoralreconstruction, with minimal failure rates (Fig. 9) [61].

Three options are available for managing segmental mandibular defects.The first option is to leave posterolateral defects unreconstructed (eg, in


elderly and edentulous patients) and manage these defects with only softtissue replacement (eg, pedicled mycocutaneous or free soft tissue flap).Simple plate reconstruction is another alternative; however, this modality isassociated with high extrusion rates despite adequate soft tissue cover (eg,pedicled mycocutaneous or free soft tissue flap) and therefore is usually notrecommended as a primary reconstructive approach (Fig. 10) [62–64]. Thegold standard approach today is the use of an osseocutaneous free-tissuetransfer (eg, fibula, iliac crest, or scapular free flap) [65].

Radiotherapy and chemotherapy

Radiotherapy is an integral part of the management of oral cavity SCC.In select patients, it may form the primary therapeutic option ifcomorbidities and patients’ wishes preclude the use of surgical excision.Primary radiotherapy is not the treatment of choice for early-stage oralcavity SCC, however, because of significant morbidity, including xerostomiaand dysphagia [66,67]. Furthermore, studies have demonstrated that a returnto normal oral function is achieved more often with primary surgery whencompared with radiotherapy alone [68]. A significant number of patients willdevelop a metachronous neoplasm and therefore it is important to reserveradiotherapy for the treatment of tumor sites that are less amenable tofunction-preserving surgery [69]. In addition, locoregional control andsurvival rates for early-stage oral cavity SCC with surgery alone arecomparable to radiotherapy, and therefore the current authors advocateprimary surgery in these patients [29].

Many patients require postoperative radiotherapy if certain adversefeatures exist. These features may include positive or close margins, sig-nificant perineural/perivascular invasion, bone involvement, multiple nodalinvolvement, and/or extracapsular spread [70]. In addition, patients withadvanced malignancies staged III or IV are best treated with a combinedapproach, and survival rates have been improved in those for whom com-plete surgical resection is possible [30,38].

Fig. 9. (A) Cosmetic result of the lip-split approach. (B) Postoperative appearance of the radial

forearm free flap for the repair of lateral oral tongue defects.


Brachytherapy is an alternative for both primary and recurrent lesions[71]. Marsiglia et al [72] recently published a series of 160 patients with floorof mouth and tongue SCC (ie, T1 or T2) treated with primarybrachytherapy (ie, iridium-192 wires). The survival rates were 88% and74%, respectively, comparing favorably to results obtained with surgeryand/or external beam radiotherapy. Significant local complications, in-cluding soft tissue and bone necrosis occur with this modality, however, andhave resulted in limited application of this form of management.

Chemotherapy for the treatment of oral cavity SCC is presently reservedeither for palliation or within the setting of institutional trials. Licitra et al[31] examined the use of cisplatin and 5-fluorouracil in a neoadjuvantsetting. They compared toxicity and outcome in two treatment arms:chemotherapy and surgery versus surgery alone. Adjuvant radiotherapy wasgiven in those patients with adverse factors (eg, positive margins, soft tissueinvolvement, multiple nodal disease, or extracapsular spread). The results

Fig. 10. Reconstruction plate extrusion 3 years following therapy.


revealed no survival advantage with neoadjuvant chemotherapy. Theauthors reported a decreased need for adjuvant radiotherapy, however,and less need for mandibular resection in those patients who receivedchemotherapy. It may be possible in the future to adopt a less aggressive andorgan-sparing approach if further studies support the findings by theseauthors. Schuller et al [73] reported the use of pre- and postoperativecisplatin concurrently with slightly accelerated hyperfractionated radiother-apy in an attempt to reduce treatment toxicity and improve disease control.The results showed that this combined treatment is well tolerated and mayform part of a future treatment regime for patients with advanced andresectable oral cavity carcinoma. At present, chemotherapy is not part of thefirst-line management of patients who have oral cavity SCC, and itsapplication is reserved for palliative purposes only.

The future may rest on the development of novel treatment strategies thatseek to exploit the molecular characteristics of the tumor. Myers et al [74]recently targeted epidermal growth factor receptor in an experimentalxenograft animal model. Overexpression of this receptor is associated witha poorer prognosis in patients with head and neck cancer, and it waspostulated that blocking this receptor would control the malignant potentialand form the basis of targeted molecular therapy. The results have beenpromising in blocking the growth of human oral cavity SCC, providing hopefor the possible use of this technique in the future.

Chemoprevention is a strategy that aims at preventing the developmentof invasive carcinoma. Certain agents have been isolated that curtail thedevelopment of lower gastrointestinal carcinoma. Among the possibletargets is cyclooxygenase-2 (COX-2), which is expressed in premalignanttissue and certain cancers. This finding probably reflects the action ofvarious oncogenes and growth promoters that induce the expression ofCOX-2. Certain transgenic mouse models have been developed to test therole of COX-2 in tumorigenesis [11]. Celecoxib, a cyclooxygenase inhibitor,has been shown to be effective in the prevention and treatment of coloncancer. It has potent antiangiogenic properties and has been shown toreduce oral cavity SCC tumor volume in vivo. These findings suggest thatthis agent may someday assist in the prevention and treatment of oral cavitycancer [75]. Extensive human trials are required before this agent becomespart of the routine management, however.

Rehabilitation

Post-treatment rehabilitation is vital in patients with oral cavity SCCbecause significant functional morbidity is encountered that affects speech,swallowing, and/or mastication. Oral rehabilitation commences at the timeof initial consultation and is coordinated by a speech pathologist. Inputfrom a dentist and prosthodontist, however, is also vital for successful andexpedient rehabilitation in these patients.


Prognostic factors and outcome

The overall disease-specific survival rate for patients who have oral cavitySCC is approximately 50% [5]. Patients with early-stage tumors (T1 or T2)have survival rates of 70% to 90% [29,38,76,77]. Those with more advancedstage (ie, stage III or IV) of disease have survival rates of less than 25%. Theaddition of radiotherapy has significantly improved disease-specific outcomein these patients, however [78]. The most important factor for prognosis isthe state of the cervical lymphatics, with survival rates halved in the presenceof pathologic nodal involvement [79].

Factors other than those included within the TNM staging system havebeen found to be significant for prognosis. These factors include his-topathologic features, such as grade of tumor, depth of invasion, type oftumor front, extracapsular spread, and the presence of perineural/perivas-cular invasion [19,70]. In a recent analysis, the most important predictivefactor for occult nodal disease in oral tumors staged T1 or T2 was depth ofinvasion in excess of 3 mm [23]. This finding compares well with a pre-vious report by Spiro et al [21], who found that depth of invasion ofgreater then 2 mm was associated with increased regional failure andreduced survival. A recent multivariate analysis found that a high combinedByrne’s invasive front grading score and tumor invasion characterized bysmall groups of dissociated cells were independent, poor prognostic factorsin a group of 102 patients with oral cavity SCC [22]. In addition to thesetumor factors, incomplete surgical resection is significantly associated withan adverse outcome [22]. Young age also has been postulated to affectprognosis; however, recent analysis has not substantiated this. Patients aged40 years or younger had a superior outcome when compared with thoseaged 66 years or older [5,80]. Certain ethnicities seem to have moreaggressive disease. African Americans have a significantly greater risk ofpresenting with advanced-stage disease and therefore have a worse overallsurvival rate when compared with whites (35% versus 51%, respectively).Presentation with advanced-stage disease was associated with low socio-economic status in white patients. This finding was not mirrored in theAfrican American population, however, suggesting features other thanenvironment may be responsible for the poor outcome in this group [5]. Theanswer may lie with molecular markers, such as cyclin D1 and p16. Thesenuclear proteins are important in controlling the cell cycle and over-expression of cyclin D1 and loss of p16 have been found to be commongenetic events in head and neck cancer. Bova et al [24] found that thesefactors were present in 55% to 68% of oral tongue SCC and predictedadvanced neck disease, increased tumor grade, and reduced disease-specificsurvival on multivariate regression analysis [24]. The presence of over-expression of cyclin D1 and loss of p16 were complementary in predictingfor a greater relapse rate and reduced disease-specific survival rate. Theseresults show promise that routine evaluation of these parameters


may become useful in the management of patients who have oral cavitySCC.

Summary

Oral cavity SCC remains a significant health problem and requiresa multidisciplinary approach. Treatment with surgery alone or incombination with adjuvant radiotherapy for more advanced lesions is thestandard of care. Major advances have been made in surgical approaches,reconstructive options, and the rehabilitation of patients who have oralcavity SCC. These advances have significantly improved disease-specificoutcome and quality of life. The future may lie in the development oftreatment regimes that combine early detection with organ preservation andresult in improved cure rates and quality of life.

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Carcinoma of the oral pharynx:an analysis of subsite treatment

heterogeneity

Ryan F. Osborne, MDa,b,Jimmy J. Brown, DDS, MD, FACSb,*

aHead and Neck Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard,

Los Angeles, CA 90048, USAbDepartment of Otolaryngology–Head and Neck Surgery,

Charles R. Drew University of Science and Medicine, 12021 South Wilmington Avenue,

Room 5004, Los Angeles, CA 90059-3051, USA

The treatment of malignant tumors of the oropharynx is far fromstraightforward, and is compounded by the wide variability in treatment tothe different subsites of the oropharynx as shown by reports from the majorcenters that treat this disease. There seems to be no consensus as to the bestmode of primary treatment, and selection of the various treatmentmodalities is largely center driven.

Relevant anatomy

The superior and inferior boundaries of the oropharynx are marked byhorizontal planes at the levels of the hard palate and vallecula or hyoidbone, respectively. The muscular pharyngeal wall between these two planesdefines the posterior limits. The circumvallate papillae and palatoglossalmuscle mark the anterior limits. Most of the lateral wall of the oropharynxis primarily composed of the tonsil and the tonsillar fossa. A smallcontribution comes from the lateral extensions of the posterior pharyngealwall. The oropharynx can be divided into four subsites: (1) the posteriorpharyngeal wall, (2) the soft palate, (3) the tonsil complex (ie, tonsil,tonsillar fossa, and pillars), and (4) the base of tongue. The limits of theoropharynx as a whole can usually be easily appreciated during clinical


E-mail address: [email protected] (J.J. Brown).


doi:10.1016/S1055-3207(03)00117-0


72 R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

examination. In comparison, clearly visualizing the limits of the subsites ofthe oropharynx can be more of a challenge, especially in the presence ofgross disease.

Histopathology

In general, the histopathologic entities seen in the oropharynx representa derivation of tissue normally present there. Because the oropharynx islined with stratified squamous epithelium, 85% to 90% of carcinomas seenare squamous cell in origin. The presence of minor salivary glands,neurovascular and fibromuscular structures, and lymphoid aggregates in theWaldeyer’s ring opens the possibility to a wide variety of mesemchymallyderived sarcomas and carcinomas. A discussion of the management of allmalignancies found in the oropharynx is beyond the scope of this article.Therefore, the remainder of the article pertains to the management ofsquamous cell carcinomas (SCCs) at the various subsites of the oropharynx.

Assigning tumor to subsite of origin

Determining the subsite of origin in oropharyngeal carcinomas can bea daunting task and frequently comes down to an educated guess based onsubjective and objective information. The reason for the great difficulty istwofold. The first factor relates to mucosal continuity between subsites,making it difficult to strictly demarcate one subsite from another. Forexample, the soft palate, which includes the uvula is continous with theanterior tonsillar pillar. Similarly, the lateral extension of the postpharyn-geal wall merges almost imperceptibly with the posterior tonsillar pillar.

The second factor rests with the size and position of a given lesion, whichmay encompass more than one subsite. Lesions located at transition zones,such as between the soft palate and anterior tonsillar pillar, or large lesionsinvolving contiguous subsites may present a diagnostic dilemma.

Some authorities have attempted to use histologic differentiation,imaging studies, or patient symptoms to discern lesion subsite of origin.Approximately 60% of soft palate lesions have been found to be moderatelydifferentiated, 20% poorly differentiated, and 20% well differentiated [1].This distribution is fairly uniform throughout the other subsites of theoropharynx. MRI with gadolinium provides the highest soft tissueresolution but rarely does much better than the examination of anexperienced clinician in positively identifying the subsite of origin. Patientsymptoms are perhaps the least helpful markers of subsite origin, becausedysphagia, odynophagia, and otalgia are common complaints of oropharyn-geal disease in general. It is therefore not unusual for a clinician to beincapable of making a definitive subsite designation.

73R.F. Osborne, J.J. Brown / Surg Oncol Clin N Am 13 (2004) 71–80

Posterior pharyngeal wall

Tumors that are isolated to the posterior pharyngeal wall are veryuncommon. They tend to be asymptomatic unless they become bulky. Theyrarely extend laterally to other subsites of the oropharynx but ratherinfiltrate deeply into the retropharyngeal and prevertebral tissues. They areknown for their early metastases to bilateral jugular and retropharyngealnodes because of their posterior and relatively midline location. The biologiccharacteristics of these tumors are the same as those of tumors of thehypopharynx. As such, the treatment philosophies and approaches are thesame as those used for tumors of the hypopharynx.

Soft palate

The soft palate functions to prevent air escape during phonation andnasal regurgitation during deglutition. Of all the subsites of the oropharynx,it may provide the least challenge to routine examination. Thus, despite therelatively asymptomatic presentation of carcinomas in this region, they areusually identified early and referred for definitive management.

SCC of the soft palate is a relatively uncommon malignancy and remainsvirtually asymptomatic because of its location, until a lesion reachesa substantial size. At first glance, these lesions give the impression that theycan be readily encompassed by a surgical procedure without compromise offunction. Because of the relative infrequency of these lesions, however,many clinicians have limited experience in their management.

The soft palate forms a mucosa-covered muscular bridge from one side ofthe oropharynx to the other. There exists no true barrier to lateral tumorspread, and the aponeurosis of the underlying musculature providesa transient barrier at best. The lymphatic drainage is weighted in anipsilateral direction, yet there are well-recognized lymphatic drainagepatterns that permit contralateral spread. Therefore, even the smallestlesions have the capability of seeding both sides of the neck with metastaticdisease. This possibility becomes more of a reality as lesions approach orcross the midline. The effect of location on prognosis is well documented.The overall 5-year survival rate for patients presenting with unilaterallesions is 70.8% and drops to 51% for patients with midline or bilaterallesions [2]. Approximately 25% of patients treated for a soft palate tumorwill present with a second primary tumor, with the floor of the mouth beingthe most common secondary site [3–8].

Although early-stage soft palate lesions readily lend themselves toprimary surgical treatment, the submucosal nature of the disease demandsthat adequate margins be taken to minimize recurrences. Thus, thetreatment of a small lesion often results in a large defect, which results infunctional difficulties. Modern palatal obturators and surgical reconstruc-tive efforts have reduced the degree of functional deficits; however, these


deficits are not reduced to an appreciable level such that the resultantfunctional status matches that of patients treated with primary irradiation[4]. Because the local control rates for T1 and T2 lesions remains the same at91% to 100% and 70% to 75%, respectively (American Joint Committee onCancer. Manual for Staging Cancer, 5th edition. Philadelphia: Lippincott-Raven, 1997. pp. 29, 37.), for either surgery or radiotherapy [2,3], primaryradiotherapy is considered the treatment of choice for early-stage soft palatelesions [3–6]. Importantly, to achieve similar control rates as radiotherapy,the surgeon must not be conservative with surgical margins out of fear of thefunctional and reconstructive challenges that may present postoperatively.

Advanced soft palate lesions portend a poor prognosis. The 5-yeardisease-free survival rates for T3 and T4 lesions are 39% to 56% and 32% to39%, respectively, for any treatment modality. Studies that have attemptedto analyze the modality which offers the best control rates are limited bysmall numbers and many patient selection biases [9]. Despite theselimitations, there is strong support that surgery combined with radiotherapyprobably offers the best chance for obtaining locoregional control.

Tonsillar complex

Tonsillar carcinoma represents approximately 75% of all carcinomaspresenting in the oropharynx. Among carcinomas of the aerodigestive tract,it ranks second only to laryngeal cancer. Unlike the soft palate, the morecryptic locations of the tonsillar complex places this region at high risk forbeing poorly visualized or overlooked by the casual examiner. This is onereason the source of many unknown primary tumors is ultimately found tooriginate in the tonsil. Furthermore, its relatively ‘‘out of the way’’ laterallocation permits normal speech and swallowing functions to carry on in thepresence of early-stage lesions (T1 and T2). Thus, the asymptomatic nature ofthis disease causes many patients to present with more advanced lesions (T3and T4) after the presence of pain, dysphagia, or dysarthria may prompt themto seek help. Trismus or the restriction of tongue mobility usually indicatesadvanced disease (T4). This symptom is likely caused by disease extensioninto the musculature of the pterygoids or base of tongue, respectively.

In general, lesions involving the anterior tonsillar pillars tend to be lessinvasive and rarely bulky. These lesions spread rapidly across broadmuscosal surfaces and frequently involve adjacent subsites of theoropharynx, such as the soft palate or tongue base. In comparison, tumorsinvolving the posterior pillar or tonsil proper tend to be far more exophyticand invasive but are less likely to spread to adjacent subsites until anadvanced stage of disease.

As with palatal primary tumors, early-stage tonsillar carcinomas (T1 andT2) that remain confined to that subsite can be treated with eitherradiotherapy or surgical modalities, with comparable locoregional controland overall 5-year survival results [10,11].


In these cases, treatment decisions are based on multiple factors: patienthealth profile, patient preferences, availability of adequate radiation orsurgical services, patient compliance, and the presence or absence of nodaldisease.

Despite the single-modality treatment chosen, control rates at theprimary site for T1 lesions approximate 83% to 90% and 70% to 78%for T2 lesions. The overall disease-free 5-year survival rates remainacceptable and similar at 75% to 85% for T1 and 55% to 80% for T2lesions using either surgery or radiation for treatment [10,11].

Because surgical resection of these lesions offers no curative advantage,irradiation largely has become the first-line treatment for early-stagetonsillar carcinomas. Treatment in this manner allows the reservation ofsurgery for salvage, which improves disease-free 5-year survival rates to85% to 100% for T1 tumors and 80% to 92% for T2 tumors, thusminimizing the morbidity associated with treatment of these tumors andmaximizing the locoregional control [12].

The treatment option for advanced (T3 and T4) tonsillar tumors thatprovides the greatest chance of disease control involves both surgery andradiotherapy. Debate continues to revolve around whether surgery shouldbe used up front or for the purposes of salvage, however.

In an effort to spare patients the significant morbidity associated withsurgical resection, especially with large primary tumors, radiotherapy withsurgical salvage has been advocated. The enthusiasm for this treatmentapproach must be tempered with the reality that many of these patients’tumors may not be surgically salvageable after failure of primaryradiotherapy.

The effects of radiation on the soft tissues can alter the sensitivity of theclinical examination to such an extent that a partial response to therapy caneasily be mistaken for a complete response. This situation therefore candecrease the early detection rate of persistent or recurrent disease, leading torecurrences that have extended beyond the scope of surgical resection. Lessthan 25% of patients who fail radiotherapy have tumors that are consideredsurgically salvageable, and only half of patients with salvaged tumorssurvive more than 48 months [13,14].

Patient selection is paramount when considering primary radiotherapyfor advanced cancers of the tonsil. All T3 lesions are not the same. Forinstance, a study from the University of Texas M.D. Anderson CancerCenter attempted to identify patient or tumor factors that may predictpatients’ responsiveness to radiotherapy [15]. The degree of histologicdifferentiation had no influence on locoregional control. Local extension toother oropharyngeal subsites, such as the base of tongue in particular,decreased the curative effects of radiotherapy, however. When lesions werelimited to the tonsillar fossa, radiotherapy controlled 89% of T3N0 lesions.When base of tongue involvement was noted, the control rate dropped to63%. The recurrence rate of tonsil-confined lesions approximated 10%


versus a 47% recurrence rate when there was tongue base invasion. Thesefindings have been mirrored in other studies in the literature [16–18].

Therefore, the mainstay of treatment for T4 and T3 lesions thatdemonstrate ulceroinfiltrative features and involve adjacent subsites of theoropharynx has been combination therapy. The classic composite resectionwith postoperative radiation offers improved locoregional control andsurvival over any single-modality treatment.

A review of the literature showed that combination therapy can decreasethe rate of local recurrence by 25% to 50% when compared withradiotherapy or surgery alone [10,14,18–20]. Perez et al [20] found a 52%recurrence rate when patients with advanced tonsillar lesions were treatedwith single-modality radiotherapy. This rate of recurrence was 33% whencombination therapy was instituted, which further supports the concept ofcombined-modality therapy for advanced tonsillar carcinomas.

Tongue base

Treatment selection for base of tongue carcinomas is institutionallydriven. Some centers primarily use surgery with or without radiotherapy[21–28]; others use primary radiotherapy and reserve surgery for salvage[29–31]. The role of brachytherapy remains controversial. Brachytherapycombined with external beam radiotherapy (EBRT) was initially believed tobe a superior treatment option to EBRT alone for base of tongue lesions. Ithas since fallen out of favor because of the lack of data that supported itsindependent use [15–18]. In addition to unacceptable local control rates,EBRT is time-consuming, costly, requires additional personnel, andincreases the risk of soft tissue necrosis. Interstitial implants, however,may have a role in patients with residual tongue disease who have completeda course of EBRT and are not candidates for surgical salvage.

Centers using primary radiotherapy, such as the University of Florida,are achieving local control rates for T1 and T2 tumors of 75% to 100%[21,22,32,33]. Similarly, centers that approach T1 and T2 tongue basetumors with surgery as a first-line therapy report essentially the same controlrates. Therefore, the approach to these early-stage lesions are primarilybased on the wishes of the patient, health status, institutional resources, andthe morbidities associated with each treatment the patient is willing toaccept. Strong arguments have been made from both sides about whichapproach is less functionally disabling. In general, most centers favor the useof radiotherapy to both the base of tongue and neck, followed by plannedinterval neck dissection for N1 or greater neck disease. The current authorsprefer this approach as well.

Greater controversy exists in the management of advanced (T3 and T4)tongue base tumors. Analysis of the literature to objectively compare theefficacy of surgery with or without postoperative radiotherapy versusprimary radiotherapy is extremely difficult. There seem to be no studies


without significant inherent patient selection bias. To further compound theproblem, these biases vary from one treatment center to another.

At some institutions, patients who have significant comorbidities or havetumors that are deemed unresectable are referred for radiotherapy. Thosepatients with lesions amenable to resection and who are otherwise relativelyhealthy are offered surgery with or without postoperative radiotherapy. Atother centers, patients with large lesions are believed to be unlikely toachieve satisfactory local control with radiotherapy alone and are treatedwith a combined approach, reserving primary radiotherapy for smaller, lessinfiltrative lesions.

Another reason the literature reveals such disparities in treatmentprotocols lies in the inaccurate and varied pretreatment clinical staging ofthese lesions. Foote et al [34] showed that, overall, 16% of patients are up-staged at the time of surgery and 31% are down-staged. Significantly, thegreatest errors in judgment were made in the T1 lesions, in which 46% wereup-staged, and the T3 lesions, in which 58% were down-staged.

Analysis of the 5-year survival rates for patients with T3 and T4 tumorstreated with single-modality radiotherapy shows that these rates equal thoseseen in patients treated with surgery alone, although there seems to be a smallimprovement in locoregional control when a combined modality is used [33].

When treating patients with large T3 and T4 tumors, radiotherapy aloneoffers local control rates of 59% to 73% and 35% to 44%, respectively[33,35]. The range of these control rates reflects tumor differences inradiosensitivity. Despite sophisticated scientific efforts to identify whichtumors are likely to be more radiosensitive, clinicians have yet to trulyachieve this goal. Thus, the clinician must use cruder indications ofresponse, such as gross tumor appearance.

Weber et al [35] showed that T3 and T4 tumor response to radiotherapycould be predicted from morphologic growth patterns of the tumor. Patientswith exophytic tumors had a 5-year local control rate of 84% and a 5-yearsurvival rate of 67%. Those patients with ulceroinfiltrative tumors hada 5-year local control rate of 58% and a 5-year survival rate of 33%.

In general, patients with exophytic lesions, significant comorbid states, orthose who will not accept the functional deficits of large resections, such assubtotal or total glossectomies, are treated with radiotherapy with orwithout chemotherapy, reserving surgery for salvage.

When patients present with tumors that cross the midline, have ulcerativefeatures, or infiltrate into the deep musculature of the tongue, the bestchance for obtaining local control seems to be a combination of radicalsurgery with postoperative radiotherapy.

Approach to management of the neck

Management of the regional lymphatic spread of disease is virtually thesame for all subsites of the oropharynx. The risk of occult cervical


metastases ranges from 15% to 30%; therefore, treatment of N0 necklesions is justified for all T stages of disease. Most early-stage primarylesions are treated with definitive radiotherapy, which is also used to addressclinically negative neck lesions. Elective neck dissections also can be used inthis setting and produce equal control rates with the added advantage ofproviding a histologic specimen for diagnostic and prognostic information.

Clinically positive (N+) neck disease can be managed in several ways.When the primary site is treated with radiation, it is recommended that thenodal disease is concurrently irradiated. If the pretreatment nodal tumorburden is significant, a planned interval neck dissection approximately 6 to 8weeks following radiotherapy is common practice.

When surgery is used as definitive therapy for the primary lesion,however, the cervical adenopathy can be addressed with surgery as well. Inthe presence of extracapsular spread or multiple positive nodes, the use ofpostoperative radiotherapy is recommended.

Chemotherapy

In the past, the role of chemotherapy in the treatment of oropharyngealcarcinoma was generally considered experimental and used for palliation.Most patients being treated with chemotherapy were either enrolled ina study or were receiving treatment at a research-based institution.

There are now many promising cytotoxic agents currently underinvestigation. There exists no way to ascertain from the literature the trueindependent effects of chemotherapy on oropharyngeal carcinomas,however, because there are no studies in which chemotherapy was used asthe sole treatment modality with curative intent. Most studies of merit usedchemotherapy for induction or concomitant therapy. Very little is knownabout its role as an adjuvant therapy.

Cisplastin and 5-fluorouracil continue to be the most commonly usedagents in the treatment of oropharyngeal carcinomas. They have beenshown to improve locoregional control and survival statistics when givenwith concomitant radiotherapy [36,37]. In the treatment of very advancedoropharyngeal lesions, the role of chemotherapy has changed fromexperimental to standard of care. The medical oncologist has a justifiedrole in the team approach to the treatment of advanced oropharyngealcarcinomas.

Summary

The data indicate that SCC of the various subsites of the oropharynx canbe treated successfully with acceptable locoregional control and survivalrates by using either surgery or primary radiotherapy for T1 or T2 primarylesions. Treatment success data for late-stage disease (T3 and T4) are less


encouraging, regardless of which modality is used or which treatment centeris administering treatment. This finding may suggest an intrinsic property ofthese lesions or the patient that may be going unnoticed.

One problem is that the diversity of approaches to these lesions hindersany meaningful comparisons between series from different treatmentcenters. There exists heterogeneity in patient populations and approachesto staging and characterization of these diseases. This situation has ensuredthe same heterogeneity in treatment philosophy, which is largely institu-tionally based.

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Carcinoma of the hypopharynx

Christine G. Gourin, MD, FACS*,David J. Terris, MD, FACS

Department of Otolaryngology–Head and Neck Surgery, Medical College of Georgia,

1120 15th Street, Augusta, GA 30912, USA

Carcinoma of the hypopharynx is uncommon, accounting for 4% of allmalignancies of the head and neck reported by the National Cancer DataBase and 7% of all malignancies of the upper aerodigestive tract [1,2].Squamous cell carcinoma (SCC) accounts for 95% of hypopharyngealpathology. Hypopharyngeal carcinoma is associated with the highest mor-tality of all cancers of the head and neck. Poor survival rates are attributedto a preponderance of late presentations and to the unique behavior oftumors occurring in this location. Tumors of this region typically remainsilent until the disease has reached an advanced stage and causes symptomsfrom airway or digestive tract obstruction or pain from neural invasion.Hypopharyngeal carcinoma is associated with a high incidence of sub-mucosal spread, which can be difficult to detect clinically and can result inunderestimating the extent of disease. Cervical metastases are present in60% to 80% of patients and signify more advanced disease and a poorerprognosis [3–7]. More than 75% of patients who have hypopharyngealtumors have stage III or IV disease at presentation [1]. The overall 5-yeardisease-specific survival rate is approximately 30% to 35% [1,2].

Recent advances in reconstructive techniques and perioperative care haveallowed resection of advanced disease with single-stage reconstruction ofa functional alimentary tract. In addition, improved locoregional controlhas been demonstrated with the use of combined-modality therapy. Overallsurvival rates remain poor and largely unaffected, however, because of a shiftin the pattern of failure from local to distant disease and the development ofsecond primary tumors. Therefore, treatment goals are aimed at eradicatingdisease and restoration of function, while causing the least morbidity andthe most effective palliation of symptoms.


E-mail address: [email protected] (C.G. Gourin).


doi:10.1016/S1055-3207(03)00122-4


82 C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

Clinical behavior

The hypopharynx is described as the region of the pharynx that begins atthe level of the hyoid bone and extends to the inferior border of the cricoidcartilage. Within the hypopharynx are three anatomic subsites: the pairedpyriform sinuses, the postcricoid area, and the posterior hypopharyngealwall. The pyriform sinus is the most commonly involved site, representingmore than 60% of all cases, and the postcricoid region is least commonlyinvolved, accounting for fewer than 5% of cases [2]. Isolated early-stagelesions of the pharyngeal wall or pyriform sinus have the best prognosis andlong-term survival but comprise fewer than 20% of hypopharyngealcarcinomas [3,7–10]. Tumor staging based on the American JointCommittee on Cancer classification system (AJCC Cancer Staging Manual,6th edition; Springer-Verlag: New York, 2003. pp. 33–45.) shows thatcontiguous involvement of adjacent sites portends more advanced disease(Box 1). The proximity of the hypopharynx to the larynx and cervicalesophagus mandates that the extent of disease be accurately determinedbefore embarking on treatment.

Hypopharyngeal carcinoma is unique in demonstrating a high propensityfor extensive submucosal spread. The true extent of disease may be initiallyunderestimated because of submucosal extension and the presence of skiplesions [3]. Using whole organ, serial sectioning studies, Ho et al [11] foundthat submucosal tumor extension was present in 60% of specimens. In onethird of patients, submucosal spread was not detectable on grossexamination, appearing histologically as tongues and islands of tumorinfiltration beneath an intact mucosa. The limits of submucosal extension inthis series were 10 mm superiorly to the oropharynx, 25 mm medially, 20mm laterally, and 20 mm inferiorly toward the esophagus. The incidenceand extent of submucosal spread were higher in patients who had undergoneprevious radiation therapy, with macroscopically undetectable submucosalspread present in 82% of patients [11]. These data provide useful guidelinesfor treatment planning.

The hypopharynx is served by an extensive lymphatic network.Lymphatic drainage proceeds first to the jugular lymphatics and then tothe tracheoesophageal nodes, lateral pharyngeal and retropharyngeal nodes,and the parapharyngeal space. Tumors that involve the posteriorhypopharyngeal wall and the medial wall of the pyriform sinus havebilateral nodal drainage and have a high incidence of involvement of thecontralateral neck. Between 60% and 75% of patients will have clinicallyinvolved neck nodes (node-positive [N+]) at presentation, and more thanone third of patients without clinical evidence of nodal disease will harboroccult metastases [3–8]. In patients with N+ disease, zones II (72%–75%),III (55%–72%), and IV (21%–45%) are most often affected; zones I (1%–10%) and V (11%–15%) are less commonly affected [12,13]. Contralateraloccult metastases are present in 37% of patients with N+ disease [14]. In

Box 1. Staging of hypopharyngeal cancer

Tumor stageTis: Carcinoma in situT1: Tumor limited to one subsite of the hypopharynx and 2 cm or less

in greatest dimensionT2: Tumor invades more than one subsite of hypopharynx or an

adjacent site, or measures[2 cm but not more than 4 cm ingreatest diameter, without fixation of hemi-larynx

T3: Tumor[4 cm in greatest diameter or with fixation of hemi-larynxT4a: Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid

gland, esophagus, or central compartment soft tissue. Note:central compartment soft tissues includes prelaryngeal strapmuscles and subcutaneous fat

T4b: Tumor involves prevertebral fascia, encases carotid artery, orinvolves mediastinal structures

Nodal stageN0: No regional lymph node metastasesN1: Metastasis in a single ipsilateral lymph node, 3 cm or less in

greatest dimensionN2: Metastasis in a single ipsilateral lymph node, more than 3 cm but

not more than 6 cm in greatest dimension; or in multiple ipsilaterallymph nodes or bilateral or contralateral lymph nodes, nonegreater than 6 cm

N2a: Metastasis in single ipsilateral lymph node more than 3 cm butnot more than 6 cm in greatest dimension

N2b: Metastasis in multiple ipsilateral lymph nodes, none more than6 cm in greatest dimension

N2c: Metastasis in bilateral or contralateral lymph nodes, none morethan 6 cm in greatest dimension

N3: Metastasis in a lymph node more than 6 cm in greatest dimension

Distant metastasisM0: No distant metastasisM1: Distant metastasis present

TNM stageStage I: T1, N0, M0Stage II: T2, N0, M0Stage III: T3, N0, M0; T1 or T2 or T3, N1, M0Stage IV: T4, N0 or N1, M0; any T, N2 or N3, M0; any T,

any N, M1

Used with the permission of the American Joint Committee on Cancer (AJCC),Chicago, Illinois. The original and primary source for this information is the AJCCCancer Staging Manual, 6th edition (2002) published by Springer-Verlag New York(For more information, visit www.cancerstaging.net). Any citation or quotation ofthis material must be credited to the AJCC as its primary source. The inclusion ofthis information herein does not authorize any reuse or further distribution with-out the expressed written permission of Springer Verlag New York, Inc., on behalfof the AJCC.


patients who have clinically N0 tumors, 36% harbor occult nodalmetastases in the ipsilateral neck, and 27% have occult disease in thecontralateral neck [14].

Metastatic disease involves the retropharyngeal lymph nodes in at least20% of patients who have hypopharyngeal cancer [15]. The true incidence ofretropharyngeal nodal involvement is probably not known becausedissection of this level is not routinely performed. The incidence of clinicallyinvolved retropharyngeal nodes by imaging criteria in patients withhypopharyngeal cancer is 5% [16]. Imaging studies may underestimateretropharyngeal nodal disease based on the small size (\1.5 cm) of nodes inthis location and will miss occult metastases [17]. A histologic study ofroutinely dissected retropharyngeal nodes showed metastases in 20%of patients with hypopharyngeal carcinoma [15]. The highest incidence ofretropharyngeal node metastases was seen in patients with diseaseinvolvement of the posterior wall of the hypopharynx (57%) or the cervicalesophagus (50%). Retropharyngeal nodes were positive for occultmetastases in 15% of patients with stage N0 disease [15].

Metastases to the thyroid gland and paratracheal lymph nodes occur in30% of patients who have hypopharyngeal tumors [18]. A 20% incidence ofoccult nodal metastases to ipsilateral paratracheal lymph nodes has beenreported in patients with postcricoid lesions and tumors that involve thepyriform fossa apex staged N0 [14]. Occult metastases may involve lymphnodes in the parapharyngeal space, which has been described as a site ofrecurrent disease in 5% of patients when untreated [8]. These data, takentogether, require that both sides of the neck and the retropharyngeal,tracheoesophageal, and parapharyngeal nodes be included in treatmentplanning.

Distant metastases are present in 6% of patients at initial presentation[2,10]. The most common sites of involvement are the lungs, bone, and liver.Between 12% and 32% of patients develop clinically apparent distantmetastases during the course of treatment [3,6–8,11,19–23]. The incidence ofdistant metastases is increased in patients who have stage IV disease,advanced-stage neck disease (N2 or N3), involvement of retropharyngealnodes, extracapsular spread, and lymphovascular invasion [7,8,17,19,23–25].Most mortality in the first 2 years following diagnosis is caused bylocoregional recurrence; after 2 years, distant metastatic disease is re-sponsible for a greater proportion of treatment failures [3,8]. Locoregionalrecurrence may eclipse the appearance of distant metastatic disease, andwith improved locoregional control, distant metastatic disease maysubsequently become apparent. Disease control above the clavicles hasbeen associated with a higher incidence of distant metastases in studies thatreported results of radiation therapy, with or without surgery [7,19]. Others,however, have shown no correlation between the incidence of distantmetastases and locoregional disease control [20,22,25,26]. Salvage of distantmetastatic disease is possible in only 6% of patients, and more than 90% of

85C.G. Gourin, D.J. Terris / Surg Oncol Clin N Am 13 (2004) 81–98

patients die within 2 years of detection of distant metastases [20]. Theincidence of distant metastases may be significantly decreased by theaddition of chemotherapy to radiation therapy according to several reportsand a European Organization for Research and Treatment of Cancer(EORTC) trial specifically evaluating pyriform sinus cancer [27–30].

Most patients who have hypopharyngeal cancers present with advanced-stage disease. Early-stage cancer is considered to be any T1 or T2 lesion withN0 neck disease, whereas T3 or T4 lesions, or any primary lesion associatedwith N+ neck disease, are considered to be advanced cancers (Table 1). Anationwide review of 2939 cases of hypopharyngeal cancer from 1980 to1992 showed that 9% of patients had stage I disease, 11% had stage IIdisease, 22% had stage III disease, and most (56%) had stage IV disease atpresentation [2]. The 5-year disease-specific survival rates by stage was 63%for stage I, 58% for stage II, 42% for stage III, and 22% for stage IVdisease.

Second primary tumors are present in 7% of patients at the time of initialdiagnosis [2]. Between 10% and 17% of patients will subsequently developa second primary tumor, which is a significant cause of mortality in patientswho survive for more than 2 years after the initial diagnosis ofhypopharyngeal cancer [3,7]. A history of previous head and neck canceris present in 16% to 23% of patients, and prior treatment, such as radiationtherapy, may significantly limit treatment options available to the patient[2,7].

Treatment

Currently, several treatment options exist for patients who havehypopharyngeal cancer. Surgery combined with radiation therapy is thestandard treatment for most patients who have hypopharyngeal carcinoma.Radiation therapy alone also may be used and seems to be most useful forsmall (T1 or T2) lesions. Hyperfractionated radiation therapy seems toconfer some advantages over conventional radiation therapy in improvedlocoregional control. Finally, organ preservation therapy using chemo-radiation is being increasingly studied and may result in larynx preservationin one third of patients.

Table 1

American Joint Committee on Cancer TNM staging classification

N0 N1 N2 N3

T1 I III IV IV

T2 II III IV IV

T3 III III IV IV

T4 IV IV IV IV


Surgical treatment

Preoperative evaluation is critical in determining the appropriate surgicalapproach for treatment of hypopharyngeal carcinoma. The location andextent of disease determine the extent of resection required. Accuratestaging is necessary to answer the following questions: Will excision leavea partial or circumferential hypopharyngeal defect, Will total laryngectomybe required, and What is the extent of neck dissection that is required?

The predilection of hypopharyngeal carcinoma for submucosal spreadmust be kept in mind when planning resection of the primary tumor. Wei[18] suggested that, based on measurements of submucosal extension inwhole organ studies, an adequate resection margin in patients who have notreceived previous radiation therapy is 15 mm superiorly, 30 mm inferiorly,and 20 mm laterally. Patients who have undergone previous radiationtherapy require resection margins of 20 mm superiorly, 40 mm inferiorly,and 30 mm laterally. The deep margin in either situation should be greaterthan 1 mm to ensure complete removal of the tumor without leavingresidual disease in the prevertebral musculature [18].

Posterior hypopharyngeal wallPosterior hypopharyngeal wall lesions may be treated with wide local

excision. Endoscopic resection has been described for carefully selectedsmall lesions that are widely accessible endoscopically [31]. The resultingdefect may be left to granulate secondarily. More commonly, thehypopharynx may be approached through either a suprahyoid pharyngot-omy or lateral pharyngotomy; usually a combination of both approaches isrequired for adequate exposure and resection, particularly for midlinedisease. The lesion is excised down to the prevertebral fascia, keeping inmind the extent of resection required to address the possibility ofsubmucosal extension of disease. Prevertebral involvement dooms thisapproach to failure. The resulting partial posterior hypopharyngeal walldefect usually requires coverage with a split-thickness skin graft, local orregional flaps, or free-skin or visceral flaps. Split-thickness skin graftsshould be used whenever possible because of their ease of harvest andminimal morbidity to the patient. The graft is sewn to the prevertebral fasciaand musculature and bolstered for 5 days.

Larger defects can be reconstructed using the deltopectoral skin flap orthe pectoralis major myocutaneous flap. The deltopectoral flap is an axial-pattern skin flap that is based on perforators of the internal mammaryartery. Its use requires a staged procedure. The flap is a medially based skinpaddle from the upper chest and is initially elevated and reset several weeksin advance of its use when possible, to encourage development of a bloodsupply to its most distal tip. Subsequently, the flap is inset into the defectand divided at yet a later stage. Before modern methods of soft tissuereconstruction, the deltopectoral flap was widely used. It has been largely


replaced by the pectoralis major myocutaneous flap. The pectoralis flap isbased on the thoracoacromial artery, which provides an extremely reliableand predictable blood supply. The pectoralis flap may be harvested with orwithout an associated skin paddle: harvest of the overlying skin adds to thebulk of the flap, which, even when used as a muscle-only flap, is significant.The bulk of the pectoralis flap may interfere with swallowing but undergoesatrophy with time. Free flaps are a third option for reconstruction. Theradial forearm and lateral thigh flaps may be harvested as free-skin flaps foruse in hypopharyngeal reconstruction. These require microvascularanastomosis and result in some donor site morbidity but are thin andpliable and well suited for use in the hypopharynx. The use of any free flaprequires suitable recipient vessels. The jejunal free flap may be used asa patch graft and has an advantage of providing lubrication to this area, butit requires a laparotomy for harvest with intestinal anastomosis and thusincreased morbidity.

Pyriform sinusLesions of the pyriform sinus, by virtue of their proximity to the larynx,

require at least a partial resection of the larynx for adequate excision. Early-stage lesions, such as T1 lesions or T2 lesions of less than 2 cm, can betreated by partial laryngopharyngectomy or extended supraglottic partiallaryngectomy. Transoral CO2 laser excision of pyriform sinus tumorsrecently has been reported by one group to be effective, with resultscomparable to transcervical approaches [32]. Regardless of the approachused, aspiration is expected in the postoperative period, and candidates forpartial laryngopharyngectomy must have adequate pulmonary reserve andbe in otherwise good medical condition. Pulmonary function tests mayprovide some objective measure of pulmonary function, but far morephysiologically useful is a determination of an active lifestyle and goodexercise tolerance. The ability to climb two flights of stairs (the ‘‘Ogura stairtest’’) is a reliable test of adequate pulmonary reserve [33].

Contraindications to partial laryngopharyngectomy are severe chronicobstructive pulmonary disease, previous pulmonary resection, an inactive orbed-ridden patient, or extension of the tumor to within 1.5 cm of thepyriform apex. Arytenoidectomy is usually required for adequate excision ofthe pyriform fossa. This procedure is unsafe for any tumor that is largerthan 2 cm; larger tumors require total laryngectomy with partialpharyngectomy, which results in a significant partial pharyngeal defect.Similarly, partial laryngopharyngectomy is unsafe for cancer that involvesthe apex of the pyriform sinus. The proximity of the apex of the pyriform tothe postcricoid mucosa requires total laryngectomy and cervical esoph-agectomy in addition to partial pharyngectomy for removal of the tumorand results in a circumferential pharyngeal defect [3].

Partial pharyngeal defects may be closed primarily if sufficient mucosaremains to give a tension-free closure over a #36 Maloney esophageal


dilator. If insufficient mucosa remains, closure may be achieved with the useof the pectoralis major myocutaneous flap, or free-skin or visceral flaps. Thepectoralis major flap is the preferred method of reconstruction to patchpartial pharyngeal defects because of its ease of harvest, low morbidity, andreliability. For posterior defects, the bulk of the pectoralis major flap mayinterfere with swallowing, but this seems to be less of a problem with lateraldefects after resection of the pyriform fossa. The radial forearm, lateralthigh, and jejunal free flaps may be used to fill the defect but carrysignificantly higher donor site and surgical morbidity.

Circumferential pharyngeal defects require more involved reconstructiveefforts, with a greater potential for stricture formation and anastomoticfailure. Cervical skin flaps, regional flaps, such as the deltopectoral flap andpectoralis major flap, and free-radial forearm, lateral thigh, and jejunal flapsall have been used successfully. Cervical skin-flap reconstruction is a foreignconcept to most recently trained head and neck surgeons, but before thedevelopment of the deltopectoral and pectoralis major flap, medially basedcervical skin flaps were used extensively to reconstruct pharyngoesophagealdefects. Wookey popularized this technique in the 1940s when he developeda method of pharyngoesophageal reconstruction (the so-called ‘‘Wookeyprocedure’’) by elevating a laterally based skin flap to form the newposterior wall of the pharyngoesophageal defect. At a second stagedprocedure several months later, medially based flaps from the original flapwere elevated and closed longitudinally in the midline to create a newpharyngoesophageal segment [34]. The deltopectoral flap is used in a similarfashion, by elevating and transposing the flap and, at a second stagedprocedure, subsequently dividing the pedicle and closing the defect.

Both the Wookey procedure and the deltopectoral flap are associated witha significant incidence of flap complications and, because these are stagedprocedures, there are an average of three procedures before successfulreconstruction is accomplished. The length of hospitalization and the time tooral alimentation is measured in week to months. Flap necrosis, fistulaformation, and stenosis have been reported to occur in 90% of patients whohave undergone surgical reconstruction with cervical skin flaps [35]. Becauselaterally based cervical skin flaps tend to have marginal circulation at the tip,partial flap loss occurs frequently. The incidence of complications has beenreported to be 56% with the deltopectoral flap, likely because of better bloodsupply compared with cervical skin flaps [35]. Staged reconstruction ofpharyngoesophageal defects has been supplanted by newer methods ofreconstruction but may be useful when multiple reconstructive efforts fail.

The pectoralis major myocutaneous flap allows single-stage reconstruc-tion of circumferential defects and is widely used for this purpose today. Thebulk of the pectoralis major flap makes tubing the flap difficult, similar toattempting to roll up a telephone book. Postoperative complications,including stenosis, stricture, and fistula formation, have been reported in41% of patients [36]. In addition, the thickness of the pectoralis flap and its


adynamic properties may impair swallowing function. Functional outcomeseems to be better when the pectoralis major is used to reconstruct a partialdefect as opposed to a circumferential defect: patients with circumferentialdefects have greater difficulty swallowing after pectoralis major reconstruc-tion [37,38].

Free-flap reconstruction of circumferential defects can be accomplishedusing jejunal free flaps or free-skin flaps, such as the radial forearm, lateralthigh, and scapular flaps. Jejunal free flaps have the advantage of beingtubular and match the defect closely in caliber; insetting is relativelystraightforward. Free-skin flaps, like the pectoralis flap, must be tubed toreconstruct a circumferential defect, with a longer suture line resulting andgreater potential for anastomotic complications. The secretory properties ofthe jejunum have been believed to be beneficial, particularly in patientstreated with radiation therapy, but in the current authors’ experience, ex-cessive mucus production often results and interferes with tracheoesoph-ageal voice restoration. The main disadvantage of the jejunal flap is therequirement for laparotomy, with three enteric anastomoses resulting fromharvest. Abdominal complications related to laparotomy occur in 6% ofpatients, and fistula development and swallowing difficulty occur in 18% ofpatients [39]. Jejunal harvesting is contraindicated in patients who haveCrohn’s disease or ascites.

The radial forearm fasciocutaneous flap is based on the radial artery.Because the radial artery in most patients is the dominant vessel to the deeppalmar arch, it must be determined that there is a patent anastomosis acrossthe palmar arch between the radial and ulnar arteries before harvest. Theuse of the radial forearm free flap, compared with the jejunal flap, isassociated with a shorter hospitalization time and decreased time to oralalimentation; in addition, most patients are able to successfully achieve fulloral alimentation without the need for supplemental enteral feedings [40,41].This flap is associated with a somewhat higher incidence of stricture andfistula formation compared with the jejunal flap, however, presumablybecause the suture line is longer in a tubed flap. Donor site morbidity can besignificant, but laparotomy and its attendant risks and longer recovery timeare avoided. The lateral cutaneous thigh flap has gained in popularity as analternative method of reconstruction and, unlike the radial forearm flap, thedonor site defect is smaller and associated with less morbidity.

Postcricoid lesionsPostcricoid tumors are usually advanced at the time of presentation and

require total laryngopharyngectomy and cervical esophagectomy. If diseaseextends below the lower border of the cricoid, total esophagectomy isrequired. The first-line reconstructive technique for the resulting pharyn-goesophageal defect is gastric transposition, or the gastric pull-up. Theprimary advantage of the gastric pull-up is that it allows for reliable single-stage reconstruction with a single anastomosis. Stricture formation is


uncommon, because the only anastomosis is high in the neck where stricturerarely occurs. The entire esophagus is removed and the stomach istransposed through the superior mediastinum into the neck. The maindisadvantage of the gastric pull-up is a significant morbidity and mortalityfrom the procedure. The rate of major perioperative complications is 50%,and the operative mortality is approximately 10% [34]. Organ necrosisoccurs in 3% of patients [38]. In addition, pulmonary complications canoccur from thoracic dissection. The weight of the stomach and gravitationalpull can cause anastomotic tension and suture line disruption. Gastrictransposition entails a complete vagotomy and pyloroplasty, and swallow-ing after a gastric pull-up can be complicated by early satiety, reflux, anddumping syndrome. The most common long-term complication is reflux,which occurs in 20% of patients. Only 30% of patients develop good speechwith available techniques of voice restoration [42]. Gastric pull-up is notwarranted when disease is limited to the cervical esophagus.

Colon transposition is a second-line method of pharyngoesophagealreconstruction when total esophagectomy is required. The right or left colonmay be used, based on the superior mesenteric artery or middle colic artery,respectively. The distal anastomosis is made between the distal colon andstomach. Colon interposition has been associated with a high incidence ofpostoperative infection, and therefore the colon is usually placed ina subcutaneous pocket anterior to the sternum to avoid mediastinalcomplications if necrosis occurs. Colon interposition has fallen out of favorbecause of a 45% incidence of major medical complications; a 25%incidence of reconstructive complications, including necrosis, fistula andstricture; and an overall perioperative mortality rate of 20% [35,43]. Gastrictransposition is considered the reconstructive technique of choice for totalesophageal defects, with colon interposition reserved for patients withcontraindications to gastric surgery or as a salvage technique.

Neck dissectionBecause of the high incidence of nodal metastases, ipsilateral neck

dissection is warranted in all patients who have hypopharyngeal cancer.Selective neck dissection of zones II through IV is recommended for allpatients with clinically N0 neck disease. The scarcity of metastases to zones Iand V supports sparing these zones in this scenario [12,44]. Ipsilateralparatracheal node dissection (zone VI) should be included as part ofselective neck dissection for all patients who have postcricoid tumors andtumors that involve the pyriform fossa apex [14]. Patients with clinicalevidence of neck disease (N+) require modified radical neck dissection orradical neck dissection of zones I through VI.

Contralateral neck dissection is indicated in patients who have midlinelesions of the posterior hypopharyngeal wall and postcricoid tumorsbecause of the increased incidence of occult contralateral metastases.Patients who have laterally situated tumors are usually treated with


ipsilateral neck dissection alone, but T4 lesions may require bilateral neckdissection when involvement of the medial wall of the pyriform sinus orpostcricoid mucosa is suspected. Tumors that involve the medial wall ofthe pyriform sinus have a higher incidence of regional failure in thecontralateral neck compared with lateral wall lesions, and require bilateralneck dissection [6]. Bilateral zone VI dissections are rarely performedbecause of the risk of postoperative hypocalcemia [7].

ResultsLimited data exist regarding the results of surgical treatment alone,

because the combination of surgery and postoperative radiation therapy hasbecome the standard of care for all but very small primary lesions withnegative margins and no histologic evidence of nodal metastases [7].Postoperative radiation therapy is superior to preoperative radiationtherapy, with better locoregional control and fewer surgical complications,and avoids the loss of important prognostic information obtained froma nonirradiated surgical specimen [45]. Most patients who have hypophar-yngeal cancer have histologic indications for adjuvant postoperativeradiation therapy, such as perineural invasion, lymphovascular invasion,more than two lymph nodes with metastatic disease, extracapsular spread,or close or positive margins. For most patients, surgery alone does notprovide sufficient disease control. Retrospective reviews comparing surgicaltreatment alone with surgery plus postoperative radiation therapy haveshown decreased locoregional recurrence rates (11%–14% versus 39%–57%, respectively) and improved 5-year disease-specific survival rates(40%–48% versus 18%–25%, respectively) with the addition of post-operative radiation therapy [8,46].

Surgery with postoperative radiation therapy is associated with localrecurrence rates of 4% to 18% and regional recurrence rates of 17% to 47%[3,6,7,11,46]. Locoregional recurrence has been reported to be higher inpatients with postcricoid lesions compared with those who have lesions inother sites [2]. No significant difference has been shown in local or regionalcontrol rates between pyriform lesions and posterior wall lesions, with theexception that T4 lesions of the posterior wall seem to have a higherincidence of local recurrence when compared with lateral lesions, probablybecause of prevertebral muscle involvement [23]. Within subsites, medialwall pyriform sinus lesions have a higher incidence of failure in thecontralateral neck when compared with lateral pyriform lesions but haveequivalent local and regional recurrence rates [6].

Advanced-stage neck disease is significantly associated with increasedlocoregional recurrence rates and poorer 5-year disease-specific survivalrates. N2 or N3 neck disease is associated with 5-year disease-specificsurvival rates of 0% to 20% compared with 28% to 57% in patients with N0or N1 disease [3,7]. The presence of extracapsular spread is associated with


poorer survival rates among patients with nodal disease [8]. In patients withindications for elective treatment of the neck, the combination of surgeryand radiation therapy seems to result in better regional control ratescompared with reliance on postoperative radiation therapy alone to sterilizeN0 neck disease [6,7]. In patients who have clinically staged N0 disease, thepresence of occult metastatic disease results in poorer 5-year disease-specificsurvival rates compared with patients who have N0 disease without occultnodal disease (32% versus 50%, respectively) [7].

Surgical resection results in loss of the larynx in 56% to 79% of patientsand pharyngoesophagectomy in 27% to 44% of patients [2,7,10,27,47].These numbers have driven the search for effective organ-sparing methodsof treatment.

Primary radiation therapy

The results of treatment with primary radiation therapy for curingpatients who have hypopharyngeal cancer are not as favorable as they arefor those who have tumors in other sites. Locoregional control has beenreported to occur in 35% to 40% of patients in several nonrandomizedsingle-institution trials [8,9,21–23,27,48]. Early-stage T1 or T2 lesions havethe best prognosis for locoregional control with radiation therapy alone,with rates comparable to those obtained with combined surgery andradiation therapy [9,49]. Local control rates for early-stage disease havebeen reported to range from 77% to 89%, with 5-year disease-specificsurvival rates as high as 69% [2,3,7–10]. Advanced-stage primary disease(T3 and T4) and advanced-stage nodal disease (N2 or N3) are associatedwith dismal rates of laryngeal preservation and 5-year disease-specificsurvival rates of 0% to 12%. Surgical salvage after failure of radiationtherapy is successful in less than 10% of patients, and larynx preservation israrely possible [50,51]. Fewer than one third of patients are alive at 5 yearswith a functional larynx [48]. Because of the prevalence of nodal disease andthe poor results of surgical salvage, primary radiation therapy is notconsidered a first-line treatment for most patients with advanced-stagehypopharyngeal cancer. Some of these studies, however, suffer from aninherent selection bias by including patients referred for radiation therapybecause of inoperable disease or poor patient condition, thus contra-indicating surgery or chemotherapy [21].

The addition of a neck dissection following radiation therapy for patientswho have N2 or N3 disease improves regional control rates and may curea subset of patients with residual microscopic regional disease [23,52–56].More than 30% of patients who have N2 or N3 disease harbor residualoccult microscopic disease in cervical lymph nodes after definitive radiationtherapy. Neck dissection following radiation therapy may provideprognostic information, because residual disease may be more likely torecur locally [56]. Most surgeons believe postradiation neck dissection is


indicated for residual neck disease and for patients with N2 and N3 neckdisease who seem to have had a complete response to treatment [57].

Several nonrandomized studies have reported that hyperfractionatedradiation therapy provides a 15% to 25% improvement in local controlrates for larger tumors [9,23,27]. It has been suggested that doses of 7680 to7920 cGy administered by twice-daily fractionation are required todemonstrate benefit: the larynx must be shielded at doses greater than7440 cGy to prevent laryngeal complications from treatment [23]. There isan increased incidence of treatment-related complications on this schedulewhen compared with conventional radiation therapy and these seem to bedose related [9,23]. Hyperfractionated radiation therapy seems to improvelocal control rates but incurs socioeconomic and time constraints and doesnot seem to result in improved survival when compared with conventionalradiation therapy [9,23]. Prospective randomized studies are needed toseparate out selection bias to determine the efficacy of radiation therapyalone in patients who have hypopharyngeal cancer compared with othermodalities of therapy.

Chemoradiation therapy

Chemotherapy sometimes yields impressive initial tumor responses, but itis not a curative modality and does not improve survival rates in patientswho have head and neck cancer. Multiple chemotherapeutic agents havebeen tried in combination with surgical therapy or radiation therapy. Theresponse of SCC to cisplatin, particularly in combination with 5-fluorouracil(5-FU), has resulted in more widespread interest in chemotherapy asadjunctive treatment. Patients who respond to chemotherapy show a sub-sequent response to definitive radiation therapy, suggesting that tumors thatare sensitive to chemotherapy are radiosensitive. Induction chemotherapyconsists of the administration of two or three cycles of chemotherapyinitially, to distinguish between responders who are likely to benefit fromradiation therapy and nonresponders who are more likely to fail and requiresurgery. In 1990, the use of chemoradiation for organ preservationwas established by the Department of Veterans Affairs Laryngeal CancerStudy Group in a landmark prospective randomized trial [58]. Inductionchemotherapy with cisplatin and 5-FU, followed by definitive full-courseradiation therapy in responders, resulted in larynx preservation in two thirdsof patients who otherwise would have required total laryngectomy, withoutcompromising survival. These findings resulted in the acceptance of organpreservation therapy in the treatment of laryngeal cancer and have led tointerest in determining whether these findings hold true for other sites in thehead and neck.

The only randomized, prospective phase 3 trial to date investigatingchemoradiation in patients who have hypopharyngeal cancer was conductedby the EORTC Head and Neck Cancer Cooperative Group [29]. Patients


with T2 to T4 lesions who required total laryngectomy as part of definitivesurgical treatment were randomized to receive either induction chemother-apy with cisplatin and 5-FU followed by definitive radiation therapy, or tosurgery with postoperative radiation therapy. This trial found no significantdifference between the chemoradiation arm and the surgery arm in local(12% and 17%, respectively) or regional (19% and 23%) recurrence ratesand 5-year disease-free survival rates. A decreased incidence of distantmetastases was identified in the organ preservation group compared with thesurgery group (25% versus 36%, respectively). The 5-year estimate ofretaining a functional larynx for the chemoradiation group was 35% [29]. Asimilar incidence of laryngeal preservation with the use of platinum-basedchemotherapy and radiation therapy has been reported by other institutions[27,28,59–61]. These data suggest that larynx preservation with chemo-radiation is far less likely for hypopharyngeal cancer than for laryngealcancer but can be attempted without compromising survival.

More recently, concurrent chemoradiation, the simultaneous administra-tion of chemotherapywith radiation therapy, has been used to take advantageof the effects of simultaneously administered chemotherapy as a radiationenhancer. The administration of chemotherapy and radiation therapyconcurrentlymay result in a synergistic effect,which is suggested by impressiveinitial complete response rates [62]. Concurrent treatment with chemotherapypotentially treats distant disease and locoregional disease and may improvesurvival rates [63]. Prospective randomized trials to test this hypothesis are inprogress. Acute side effects of treatment, particularly mucositis, seem to bemore severe with concurrent regimes compared with induction chemotherapyand subsequent radiation therapy; however, there seems to be no difference inlong-term side effects between either modality of chemotherapy delivery [30].

Although larynx preservation is possible with chemoradiation, the pre-served organ is not always functional. Significant laryngeal and pharyn-geal dysfunction has been reported following chemoradiation [64–68].Dysphagia may have a slow onset during treatment and a prolongedrecovery period: at 1 year after chemoradiation, 60% of patients treated withthis modality have moderate to severe impairment in swallowing ability anda restricted diet caused by pharyngeal dysfunction [64–66]. Pretreatment vocalcord fixation seems to be the strongest predictor of a poor functional outcome,with more than 50% of patients requiring a feeding tube or tracheostomy 6months after the completion of therapy compared with patients without vocalcord fixation [69]. Patients who present with a fixed vocal cord should becounseled accordingly as to expectations about treatment and results.

When surgical salvage is required after treatment with organ-preservingtechniques, the postoperative complication rate is significant. Neckdissection after chemoradiation is associated with a complication rate of38% [70]. Primary resection without free-flap reconstruction is associatedwith a 77% incidence of postoperative complications, including woundbreakdown and fistulas [71]. When free flaps are used for reconstruction, the


incidence of wound complications following chemoradiation has beenreported to be 20%, and less severe with an average hospital stay of 8 days[72]. These data suggest that free-flap reconstruction should be performedwhen salvage surgery of the primary site is required.

Summary

Despite advances in surgical and nonsurgical treatment, overall survivalrates for patients who have hypopharyngeal carcinoma have not improved,and this disease still has a poor prognosis. The best results are obtained withmultimodality therapy, but at best, two thirds of patients are palliated ratherthan cured of disease. Radical surgery with postoperative radiation therapyremains the standard of care. Organ preservation strategies have not been assuccessful in hypopharyngeal cancer as for cancers of other head and necksites. Chemoradiation is an effective alternative method of aggressivetreatment but may be associated with significant dysfunction of the endorgan when preservation is possible. Because of poor long-term survivalrates, local control remains the most important factor in planningtreatment, to provide meaningful palliation and best possible quality of life.

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Larynx squamous cell carcinoma: conceptsand future directions

Pablo Mojica-Manosa, MDa,*, James Reidy, DOa,Keith Wilson, MDb, Wade Douglas, MDa

aDepartment of Head and Neck Surgery, Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY 14263, USAbUniversity of Cincinnati, Medical Science Building, P.O. Box 670528, Cincinnati,

OH 45267, USA

The larynx is a sphincter and is therefore one of the most importantstructures in the upper aerodigestive tract. Functional impairment of thelarynx is a burden to patients who suffer from laryngeal carcinoma, thesecondmost common cancer of the head and neck region after the oral cavity.

The American Cancer Society estimated that there would be 8900 casesof laryngeal carcinoma in 2002, with 3700 deaths. Spain has one of the highestrates in the world—some regions reach a rate of 20 cases per 100,000 persons.Other countries with high incidence are France, Italy, and Poland. Men areaffected four times more frequently than women [1]. The male/female ratio isgreater in glottic carcinoma than supraglottic carcinoma, and is often adiseaseof the elderly. The peak incidence is in the sixth and seventh decade of life.Less than 1% of the cases developed in patients under 30 years of age [2].

As with most tumors, multiple factors contribute to the developmentof this cancer, tobacco being the single most important risk factor. Thereare more than 30 known carcinogens in tobacco. The most well-knownare polycystic aromatic hydrocarbons and nitrosamines [3]. Cessation ofsmoking for more than 15 years decreases the risk to nearly that of non-smokers [4,5]. Another risk factor for developing larynx carcinoma isalcohol use. The relationship to alcohol and larynx carcinoma is unclear,but most studies show that it has a synergistic effect with tobacco use [6,7].

In addition, certain occupations and exposures increase the risk ofdeveloping carcinoma of the larynx, such as: painters; metal-workingand plastic-working machine operators; construction workers; and those


E-mail address: [email protected] (P. Mojica-Manosa).


doi:10.1016/S1055-3207(03)00130-3


100 P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

exposed to diesel and gasoline fumes, therapeutic radiation, wood dust,or asbestos [8]. Dietary factors that predispose an individual to laryngealcarcinoma include intake of salt-preserved meat and high dietary fats andchronic gastric reflux disease.

Anatomy

The larynx is divided anatomically and clinically into three areas: supra-glottic, glottic, and subglottic. This section describes how the anatomy re-lates to cancer origin and spread. Treatment options are often based onthe anatomic site of laryngeal cancer.

Larynx

The supraglottic larynx extends from the epiglottis down to the lateralangle of the ventricles. This includes the epiglottis, pre-epiglottic space, thehyoid bone and arytenoids cartilage mucosa. The supraglottis is derivedfrom midline wedge-shape structures and ultimately has bilateral bloodsupply and lymphatic drainage.

The hyoid bone is the most superior structure of the supraglottic larynx.It is the point of attachment of numerous muscles and ligaments. It iscomposed of the greater cornu laterally and lesser cornu medially.

The epiglottis is composed of elastic cartilage. It is widest at the top andtapers down to the petiole. There is a suprahyoid, infrahyoid, and petioleportion. The suprahyoid portion is covered by mucosa in both sides. Theinfrahyoid portion is covered by mucosa posteriorly and abuts the fat ofthe preepiglottic space anteriorly. It is a fenestrated structure that pro-vides a pathway for the extension of normal structures like lymphatics,submucosal glands, blood vessels, and nerves. In addition, these perfo-rations provide a route of spread for supraglottic carcinoma from the mu-cosa to the pre-epiglottic space [9]. The most inferior aspect is the petiole,which is attached to the thyroid cartilage by way of the thyroepiglotticligament. The hyoepiglottic ligament is the roof of both the paraepiglotticand preepiglottic spaces. It provides a formidable barrier for carcinomainvasion to the base of the tongue [9].

The pre-epiglottic space is surrounded by the hyoepiglottic membranesuperiorly, the epliglottis posteriorly, the thyrohyoid membrane anteriorly,and the thyroepiglottic ligament inferiorly. This space is continuous laterallywith the para-epiglottic space. This space is bounded anterolaterally withthe thyroid cartilage and thyrohyoid membrane and medially with the quad-rangular membrane. These spaces are important because they provide theroute for superior and inferior spread in the larynx [9].

The glottic larynx extends from the lateral angle of the ventricle down toone centimeter below the apex of the ventricles. It contains the true vocalcords, the posterior and anterior commissure. It arises from lateral cell massesthat come together, and the lymphatic drainage tends to be ipsilateral.

101P. Mojica-Manosa et al / Surg Oncol Clin N Am 13 (2004) 99–112

The lamina propia of the true vocal cords has a superficial layer com-posed of loose fibrous tissues that makes up Reinke’s space. An interme-diate and deep layer consisting of elastic and collagenous fibers forms thevocal ligament. Blood vessels and lymphatics are almost absent in this space,which creates resistance to tumor invasion [9].

The true vocal cords meet anteriorly in the anterior commissure tendon,which is attached to the thyroid cartilage. This area is devoid of peri-chondrium, which is a pathway of less resistance to tumor progression. Thiscommisure extends superiorly from the thyroepliglottic ligament.

Another structure that makes tumor invasion more resistant is the conuselasticus. This membrane extends from the true vocal cord down to theupper border of the cricoid cartilage. The most anterior aspect is the crico-thyroid membrane. This area contains the paraglottic space, which is apathway for tumor progression through the larynx [9].

The subglottic larynx extends from the bottom of the glottic to the inferioraspect of the cricoid cartilage. It is a rare site for primary tumor origin, but ismore commonly associatedwith subglottic extension from the glottis. Becauseof the proximity of the cricothyroid membrane and the rich postcricoid,lymphatics have a higher propensity for extralaryngeal extension.

Lymphatic and distant spread

Lymphatic spread from the primary tumor of the larynx is of greatimportance because of its impact on treatment options and survival. Theoverall metastatic rate to cervical lymph nodes for larynx squamous cellcarcinoma in general for all subsites is: T1, 6% to 25%; T2, 30% to 70%; T3and T4, 65% to 80% [10–12]. The occult metastasis ranges from 20% to50% base on the T stage.

The lymph nodes that are more commonly involved are levels II, III, andIV [13,14]. Past studies have shown that levels I and V have been involved in6% and 1%, respectively, with most of the patients also presenting nodalinvolvement at levels II to IV [15].

The lymphatic spread has also been studied by site. In the supraglotticlarynx, the rate of nodal involment depends on the T stage. For T1/T2the rate for clinical or occult metastasis is 30% to 70%, having 50% ofthose with contralateral disease. The rate of lymph nodes metastasis isalso influence by the subsite in the supraglottis. The incidence of clinical oroccult node metastasis in tumors presenting at the marginal zone or largesize tumors is greater when compared with centrally located or transglottictumors. However, the rate of bilaterally disease in the neck is higher incentrally located and large tumors [16].

In glottic tumors, the rate of node metastasis differs from that of thesupraglottic. The rate of neck metastasis overall is less than 5% for T1, 5%to 10% for T2, 10% to 20% for T3, and 25% to 40% for T4 tumors [12].Bilateral and contralateral neck metastasis is rare except in subglottis and


supraglottis extension of the tumor. In addition, with this type of extensiondelphian node involvement and thyroid invasion are evident [12].

Little is known about primary subglottis tumors, because their incidenceis less than 1% of all larynx tumors. One important aspect to consider withthis type of tumor is the high rate of paratracheal node involvement (65%)and low rate of cervical node involvement (20%) [17]. Mediastinal nodeinvolvement has also been described [17].

The clinical development of distant metastasis for larynx tumors of thesupraglottis and glottis are 15% and 3%, respectively, after a follow-up of2 years [18]. The most common affected organ is the lung, followed by themediastinum, bone, and liver. The incidence of distant metastasis withoutlocal recurrence is greater for supraglottis tumors than for glottis tumors.Second primary malignancies develop in 11% to 19% of patients, usuallywithin the first 5 years after treatment [19].

Staging and prognosis

In the United States, larynx tumors are classified using the AmericanJoint Committee for Cancer guidelines. They are staged according to thetumor size (T stage), presence of cervical lymph node metastasis (N stage),and presence of distant metastasis (M stage) (Table 1) [20].

Factors that portend a poor prognosis include: increasing T stage, pre-sence of cervical nodal metastasis, extracapsular spread of the cancer, andpresence of distant metastasis [21–24].

With an increased understanding of the molecular biology of cancer, muchresearch has been directed in characterizing this tumor type. There have beenstudies pointing to DNA aneuploidy as a factor for increased recurrencewhen compared with diploidy tumors [25,26]. Overexpression of the c-myconcogene has been correlatedwith a resistance to radiation and chemotherapyand increasedmetastatic potential [27]. Expressionof int-2has been associatedwith decreased survival [28]. Mutations in p53 and ras genes have beenassociated with high-grade tumors and increased metastatic potential [29].

Diagnosis

The diagnosis of laryngeal cancer should be suspected when hoarsenessis present for more than 2 to 3 weeks. Tumors in the glottic usually presentearly because of vocal cord involvement; tumors of the supraglottis usuallypresent later because of a lack of symptoms in the early stages. Othersymptoms associated with laryngeal tumors are hemoptysis, airway insuffi-ciency upon exertion, halitosis, and the so-called ‘‘hot potato’’ voice. Dys-phagia, airway compromise, stridor, and neck mass are more common inadvance disease.

Accurate examination by way of indirect or direct laryngoscopy isof most importance to staging and treatment planning [30]. A critical


Table 1

TNM staging of larynx carcinoma

Primary tumor (T)

Tx Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

Supraglottis

T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility

T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis, glottis,

or region outside the supraglottis (eg, mucosa of base of tongue, valleculla,

medial wall of pyriform sinus) without fixation of the larynx

T3 Tumor limited to larynx with vocal cord fixation or invades any of the following:

postcricoid area, pre-epiglottic tissues, paraglottic space, or minor thyroid

cartilage erosion (eg, inner cortex)

T4a Tumor invades through the thyroid cartilage or invades tissues beyond the larynx

(eg trachea, soft tissues of neck including deep extrinsic muscle of the tongue,

strap muscle, thyroid, or esophagus)

T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal

sturctures

Glottis

T1 Tumor limited to the vocal cords (may involve anterior or posterior commissure)

with normal vocal cord mobility

T1a Tumor limited to one vocal cord

T1b Tumor involves both vocal cords

T2 Tumor extends to supraglottis or subglottis, or there is impaired vocal cordmobility

T3 Tumor limited to the larynx with vocal cord fixation or invades paraglottic space,

or minor thyroid cartilage erosion (eg, inner cortex)

T4a Tumor invades through the thyroid cartilage or invades tissues beyond the

larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of

the tongue, strap muscles, thyroid, or esophagus)

T4b Tumor invades prevertebral space, encases carotid artery, or invades

mediastinal structures

Subglottis

T1 Tumor limited to the subglottis

T2 Tumor extends to vocal cords with normal or impaired mobility

T3 Tumor limited to larynx with vocal cord fixation

T4a Tumor invades through the thyroid cartilage or invades tissues beyond the

larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of the

tongue, strap muscles, thyroid, or esophagus)

T4b Tumor invades prevertebral space, encases carotid artery, or invades mediastinal

structures

Regional lymph nodes (N)

Nx Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Single ipsilateral node, 3 cm or less in greatest dimension

N2a Single ipsilateral node, greater than 3 cm and less than 6 cm

N2b Multiple ipsilateral nodes less than 6 cm

N2c Bilateral or contralateral nodes less than 6 cm

N3 Metastasis in a lymph node more than 6 cm in greatest dimensions

(continued on next page)


component of evaluation is an assessment of the size and location of thetumor, vocal cord involvement, extralaryngeal spread, and regional lymphnode in the neck.

Adjunct to the history and physical examination is the use of radiologicstudies to ascertain the depth of the tumor involvement. These studies helpevaluate the presence of pre-epiglottic space extension, paraglottic spaceextension, cartilage involvement, and extralaryngeal involvement. Both CTand MRI provide adequate assessment. Involvement of the soft tissue,subglottis extension, and early cartilaginous invasion is better evaluated withMRI, while invasion of bony or cervical lymph nodes is better evaluatedwith CT [31,32]. PET imaging can be used to differentiate postchemotherapyand radiation changes of sterilized tumor and fibrosis from recurrence incomparison with CT and MRI in those nonsurgical or organ-preservingpatients. It is also helpful for surveillance for second primary malignancies[33,34].

Operative endoscopy is the gold standard for pretreatment staging.Direct visualization can assess the size, location, and mucosal extent of thetumor. Under general anesthesia, digital palpation of the base of the tongueand vallecula may reveal areas of extensive submucosal spread. A biopsy ofthe lesion should be performed in this case. With a suction catheter tip,areas of friable mucosa and submucosal firmness—which may representsubmucosal extension—may be identified. The status of laryngeal ventriclesand the subglottic extend of the tumor are the two most challenging aspectsof direct laryngoscopy, especially with bulky tumors. The esophagous,trachea, and bronchial tree should be evaluated to rule out any synchronoustumors in the upper aerodigestive tracts. A chest X ray and liver functiontest is sufficient for a metastatic survey in the absence of systemiccomplaints [35]. The true extent of the tumor is fully evaluated duringsurgical exploration, which could reveal the need for a total laryngectomy;patients must be warned of this possibility when conservation surgery iscontemplated.

Table 1 (continued )

Distant metastasis (M)

Mx Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

Data from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original

and primary source for this information is the AJCC Cancer Staging Manual, 6th edition (2002)

published by Springer-Verlag New York (For more information, visit www.cancerstaging.net).

Any citation or quotation of this material must be credited to the AJCC as its primary source.

The inclusion of this information herein does not authorize any reuse or further distribution

without the expressed written permission of Springer Verlag New York, Inc., on behalf of the

AJCC.


Pathology

Only 1% of all laryngeal tumors are of the nonsquamous type. The mostcommon tumor types include cystic adenoid (adenocarcinoma), neuroen-docrine, and carcinoid. Sarcomas have been reported, of which chondro-sarcomas predominate. Other tumor types include pseudosarcoma, fibroushistiocytoma, leiomyosarcoma, liposarcoma, synovial sarcoma, and giantcell tumors. The vast majority of laryngeal tumors are squamous cell car-cinomas. This article concentrates on the management of this type of tumor.

Treatment

Treatment of this type of tumor should focus on providing an ade-quate oncologic chance of cure while attempting to minimize morbidity.Important secondary goals of treatment include a serviceable voice and theability to swallow without aspiration.

Several factors may affect treatment. For example, exophytic tumorstend to respond better to radiation than endophytic tumors, and poorlydifferentiated tumors tend to metastasize more readily than well-differen-tiated ones [36]. Tumor location and extent and the patient’s general medicalcondition may also dictate the treatment option.

Supraglottic carcinoma

Treatment options for carcinoma of the supraglottis varies widely forlocal control, cure rates, and 2- to 5-year survival rates for surgery, radia-tion, or combination therapy, depending on the stage.

For early (T1, T2) tumors, surgery and radiation treatment are equivalentin terms of locoregional control and survival. The control rates for surgeryand radiation in T1 tumors are 90% to 95% and 80% to 90%, respectively;in T2 tumors, they are 80% to 90% and 70% to 80%, respectively [37–40].Surgical salvage for radiation failure equalizes locoregional control for bothmodalities.

It is important to consider the patient’s age and general medical condition.The most common approaches to stage I and II are vertical partial laryng-ectomy, supraglottic laryngectomy, supracricoid subtotal laryngectomy, andtotal laryngectomy. The type of procedure is influenced by the site of thetumor, extension, nodal status, and surgeon’s expertise. Although conserva-tion surgery may be planned, is important to inform the patient that it mayultimately change to a total laryngectomy if the tumor extension goes beyondthe previous examination studies.

Cure rates are lower for advanced tumors (T3, T4), with stage III at40% and stage IV at 20% [8]. The mainstay of treatment for advanced supra-glottic carcinoma is combination modality therapy that includes surgeryand radiation. Chemotherapy and radiation is an alternative that is under


evaluation. Many factors can influence the decision regarding optimaltreatment. Clinical consideradtions include endophytic versus exophytic,extensive cartilage invasion, involvement of soft tissue in the neck, presenceof cervical node metastasis, and involvement of the airway. The mostcommon surgical treatment is total laryngectomy. In rare cases, conservationsurgery may be attempted. If a nonsurgical approach is chosen, thecombination of chemotherapy with radiation is an effective treatment andwill conserve the larynx 60% of the time. For cases in which nonsurgicaltreatment yields a response of less than 50%, salvage with surgery may beindicated [41].

Glottic caricinoma

Locoregional control in glottic carcinoma differs from the supraglotticcarcinoma because of its embryology. Locoregional control after surgery orradiation for T1 is 98% and 85% to 95%, respectively; for T2 it is 82% and65% to 75%, respectively [8]. Treatment options will be affected bydecreased vocal cord mobility, anterior commissure involvement, subglotticextension, and total size of the tumor. Vocal cord impairment will decreaselocal control from 77% to 50% in 3 years, especially if both cords arediseased. Radiation therapy is less effective with vocal cord mobilityimpairment [42]. Anterior commissure invasion may change the T stagefrom T1 to T4 in a few millimeters. Subglottic extension may increaserecurrence from 12% to 32% if extension is greater than 5 mm posteriorlyor 10 mm anteriorly [43].

For advanced glottic cancer (T3, T4), the local control rates for radiationtherapy range from 40% to 60%. Local control rates for surgery are greater,ranging from 84% to 96%, and the 2-year disease-free survival is 79% forT3 and 58% for T4 [8]. The ultimate decision to treat advanced glotticcarcinoma depends on the tumor specifics and the patient’s desires andgeneral medical condition. Combined modality therapy is considered supe-rior to either surgery or radiation alone. Total laryngectomy is usually per-formed, while near total laryngectomy or supracricoid laryngectomy maybe used in certain cases. Laryngeal preservation can be achieved with thecombination of chemotherapy and radiation 60% of the time [41].

Subglottic carcinoma

Primary subglottic carcinoma is rare. Most cases are a subglottic exten-sion from glottic carcinoma. Involvement of the subglottic space increasesthe risk of extralaryngeal spread. Treatment usually involves the combina-tion of surgery and radiation therapy. It is recommended that surgeryinclude laryngectomy, thyroidectomy, and paratracheal node dissection.Radiation therapy is recommended for advance cases. Elective neck dis-section is recommended when the risk of cervical nodal metastases is greaterthan 25%.


For the supraglottis, the location of the tumor influences the incidenceof nodal metastasis. In the clinically negative neck, the risk of pathologicmetastatic node involvement ranges from 15% to 48% depending on the siteand size of the tumor [8]. For lesions in the marginal zone, the rate is higherwhen compared with more centrally located tumors. One important aspectof supraglottic carcinoma is the fact that as the tumor size increases, so doesthe risk of bilateral neck spread. For T2 tumors, the risk of pathologicalor clinically involved nodes is between 30% and 70%, with contralateraldisease occurring 50% of the time. With this in mind, it is recommendedthat both sides of the neck be included in the treatment planning for tumorsT2 or higher, whether with surgery or radiation.

Because of the embryology of glottic carcinoma, the incidence of nodalspread differs and the rate of contralateral disease is lower. Because the rateof occult metastases for T1 and T2 lesions is between 1% to 8%, there islittle role for elective neck treatment [44,45]. The rate of occult disease isapproximately 15% for T3 and approximately 30% for T4 [46]. Electiveneck treatment in the form of surgery or radiation is recommended for T3or T4 glottic lesions. Bilateral or contralateral disease will be seen withsubglottic and supraglottic extension of the tumor.

These nodal patterns support the removal of levels II, III, and IV in theclinically negative neck. If there is extension beyond the subglottis, level IVshould be included in the dissection [47–49]. A comprehensive neck dis-section should be performed for the clinically positive neck. For cases inwhich there is pathologic node involvement of only one node, selective nodedissection can be adequate treatment.

Radiation can be considered for definitive treatment of cervical nodalmetastases in patients presenting with N0 or N1 disease [50]. Postoperativeradiation to the neck should be considered for patients who present withmultinodal disease or extracapsular spread [51].

Radiotherapy and chemotherapy in the treatment of laryngeal cancer

Radiation therapy may be used in the treatment of laryngeal cancerin a variety of ways. Radiation can be used as primary, adjuvant, orneoadjuvant modality. In the last decade, chemotherapy has played a moreimportant role as neoadjuvant therapy in combination with radiation totreat advanced laryngeal carcinoma. The goal of this approach is to preservethe larynx in those patients who would otherwise need a total laryngectomy.Many study protocols using chemotherapy and radiation to preservelaryngeal function have demonstrated that the larynx can be preservedwithout compromising survival. The most significant of these protocolscomes from the multi-institutional trail performed by the Departmentof Veterans Affairs Laryngeal Cancer Study Group [41]. In this study,induction chemotherapy was administered with cisplatin and 5-FU, fol-lowed by radiation. The experimental arm consisted of two initial cycles


of chemotherapy; if the tumor responded with more than 50% reduction,the patient completed a third cycle of chemotherapy followed by radiation.If the tumor had less than 50% reduction or progression of the disease,a total laryngectomy was performed with adjuvant radiation. The survivaland locoregional control was equivalent between both arms, and 64% of thepatients retained their larynx in the chemotherapy/radiation therapy arm.

Studies that followed that of the Department of Veterans AffairsLaryngeal Cancer Study Group have tried to identify the combination andsequence schedule that will yield the best responses for organ preservationandmorbidity without compromising survival.More recent studies show thatcomplete clinical response has been seen 59% to 68% of the time [52–54].There have been studies investigating the differences between sequentialand concomitant chemotherapy/radiation therapy, different chemotherapycombinations (most cisplatin-based), and conventional fractionation versusaccelerated fraction radiotherapy. Some studies suggest that concomitantchemotherapy and radiation therapy may provide better locoregional controlwhen compared with sequential chemotherapy/radiation therapy [55]. Atpresent, no study has demonstrated conclusively that either concomitantchemotherapy/radiation therapy or accelerated fractionation is better thanstandard sequential chemotherapy followed with conventional fractionationradiation therapy in demonstrating a difference in overall survival.

The major drawback for the induction concurrent chemotherapy/radiation therapy is the substantial morbidity, particularly if radiation isadministered in the therapeutic range. Protocols have decreased totalradiation dosages in an attempt to minimize this. Toxicities include mu-cositis, diarrhea, dermatitis, renal failure, and myelosuppression. This ap-proach has prevented 7% to 18% of patients from completing a full course ofneoadjuvant therapy [56,57]. In addition, mortality has been reported withchemotherapy and radiation in the range of 0.6% to 6% [58,59]. Neverthe-less, it should be mentioned that preservation does not translate into functionautomatically. Problems in function after chemotherapy and radiation havebeen reported, such as reduced laryngeal closure, reduced laryngealelevation, and reduced posterior tongue base movement [60].

Complications, outcomes, and future directions

Complications after surgery can be classified as acute or chronic. Acutecomplications include wound infection, hematoma, seroma, pneumonia,and pharyngocutaneous fistula (PCF) formation (5% to 15%) [61,62].Complications increase when radiation therapy is used preoperatively; themost troublesome is PCF, with incidence rates increasing to 20% to 30%.Conservation management with appropriate wound care, early detection,and cessation of oral intake will promote fistula closure most of the time. Inthose cases where PCF persists despite conservative therapy, local, regional,or free flaps may be used to correct the defect [63–65].


The most common chronic complication after total laryngectomy is stric-ture formation. If a stricture is identified, it can be treated with dilation. Indilation failures, consideration of tissue transfer is recommended to correctthe stricture [66].

Acute radiation reactions characteristically present as skin dermatitis andmucositis. These are managed symptomatically with adequate oral hygiene.Late complications include xerostomia, skin dermatitis, and osteoradionec-rosis [66]. For xerostomia, patients should be instructed to take adequateamounts of fluids orally to maintain humidification of the oral cavity.Osteoradionecrosis sometimes can present severe enough to cause impairswallowing. Aggressive debridement is recommended occasionally.

Laryngeal cancer historically has been treated with surgery or radiationalone for early disease and combination therapy with surgery followed byadjuvant radiation reserved for advance disease [22]. Location of the tumor,determination of its size, and nodal involvement are important consi-derations for optimal treatment. Of these, nodal involvement is the mostimportant prognostic factor for recurrence and long-term survival [24,67,68].

Future directions focus on optimizing locoregional control and survivalwhile preserving the organ. Protocol modalities, including combinationchemotherapy and radiation treatment, are under intense investigation toachieve this goal. The approach of multimodal treatment with incorporationof biological markers and novel biologic and genetic techniques may in thefuture increase long-term survival and organ preservation for this population.

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Major salivary gland cancer

Robert L. Witt, MDa,b,*aSection of Otolaryngology, Department of Surgery, Christiana Health Care Systems,

Newark, DE, USAbDepartment of Otolaryngology, Jefferson Medical College, Philadelphia, PA, USA

Salivary gland tumors represent 3% of head and neck tumors and 0.6%of all tumors in the body. Parotid gland tumors constitute 70% to 80% oftumors of the salivary gland, and 20% of parotid gland tumors aremalignant. Four fifths of the parenchyma of the gland lies lateral to thefacial nerve, in the superficial lobe, and 90% of parotid neoplasms present inthe superficial lobe. Approximately 80% of parotid tumors occur in thelower part of the gland. Parotid pleomorphic adenoma is the most commonparotid neoplasm, accounting for 60% to 70% of parotid tumors.

Malignant salivary gland tumors have an incidence of less than 1 per100,000 individuals. Most malignant salivary gland tumors arise from theexcretory or intercalated duct reserve cells [1]. Their origin is largelyunknown. Genetic alterations, including allelic loss, chromosomal trans-locations, and absence or addition of a chromosome, may be factors in somecases. A heightened risk after radiation exposure [2] is not uniformlyreported [3]. Malignant parotid tumors are slightly more common inwomen, with a peak incidence in the fifth through seventh decades of life.

Malignant salivary gland tumors generally present as painless, slow-growing tumors that are indistinguishable from benign tumors. The overalldetection rate for salivary gland malignancy based on clinical features isapproximately 30%; palpable cervical lymph nodes, facial nerve palsy, anddeep fixation and rapid enlargement of the tumor are significant parametersfor parotid gland tumors [4]. Both benign and malignant tumors can presentwith pain in a small percentage of patients. Approximately 10% of patientswho have parotid gland malignancies present with facial paralysis, which isassociated with a poor prognosis. Patients who have deep-lobe parotidtumors may present with distortion of the lateral pharyngeal wall on intraoralexamination. Trismus may represent infratemporal fossa involvement.

* 2401 Pennsylvania Avenue, Suite 112, Wilmington, DE 19806.



doi:10.1016/S1055-3207(03)00126-1


114 R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

Cervical lymph node metastasis is observed in 10% to 20% of malignantcases. Most parotid cancers are high-grade tumors, with a global 5-yearsurvival rate of 45% to 50%.

Submandibular gland tumors are malignant in 50% of cases, constituting10% of all salivary gland malignancies. Fixation to the mandible or skininfiltration suggest extraparenchymal extension. Weakness or numbness ofthe tongue indicates perineural involvement of the hypoglossal or lingualnerve. The 5-year survival rate has recently been reported to be as high as50% [5], but generally, submandibular gland cancers are regarded as moreaggressive and are associated with a lower survival rate compared withparotid gland tumors of the same histologic type. Sublingual gland tumorsare very rare; approximately 80% are malignant. They present asa submucosal mass on the anterior floor of the mouth, and survival ratesare similar to those in patients who have submandibular gland tumors of thesame histologic type.

The American Joint Commission on Cancer 2002 classification of majormalignant salivary gland tumors follows the tumor-node-metastasis (TNM)system of staging (AJCCCancer StagingManual, American Joint Committeeon Cancer, 6th edition. Springer-Verlag: New York; 2002.) (Box 1).

Imaging and fine-needle aspiration

Preoperative CT, MRI, or ultrasonography rarely alters the clinicalcourse for small tumors of the superficial parotid lobe. Management ofparotid tumors with fixation, facial nerve dysfunction and cervical lymphnode metastasis, and deep-lobe tumors with parapharyngeal extension isenhanced with imaging. Imaging is helpful for submandibular and sublingualgland tumors. MRI provides superior resolution of soft tissue structures andis the preferred modality for evaluating a parotid tumor and neck metastasis.MRI may indicate an inferior tail of parotid mass, when clinical presentationwould suggest an upper cervical nonparotid neck mass. Infiltration of thetumor into muscle or bone on MRI is predictive of malignant disease. High-resolution MRI may detect perineural involvement. Positron emissiontomography categorizes only 69% of parotid tumors correctly whenattempting to distinguish benign from malignant parotid masses [6].

Fine-needle aspiration (FNA) for a small, mobile mass of the tail of theparotid gland is not mandatory. The breadth of histologic subtypes inparotid tumors makes cytologic diagnosis a formidable goal. Furthermore,histologic patterns of pleomorphic adenoma are variable, and they can bemistaken for mucoepidermoid carcinoma or adenoid cystic carcinoma [7,8].There is difficulty in distinguishing a benign oncocytic tumor from an aciniccell carcinoma, and a Warthin’s tumor (adenolymphoma) from a low-grademucoepidermoid carcinoma [8]. The accuracy of FNA in broadly distin-guishing benign and malignant tumors, however, is more than 90% in mostseries [7]. In elderly, debilitated patients with a parotid neoplasm, such as

115R.L. Witt / Surg Oncol Clin N Am 13 (2004) 113–127

a Warthin’s tumor, FNA may obviate the need for surgery. In addition, theuse of FNA may avoid parotid gland surgery in sarcoidosis, tuberculosis,histoplasmosis, lymphoma, and benign cervical adenopathy in patients withHIV and in children. FNA can distinguish an upper cervical neck mass froma low tail of parotid tumor. It also is helpful in patients who have

Box 1. TNM staging system for salivary gland tumors

T: tumorT1 tumor smaller than 2 cmT2 tumor 2 to 4 cmT3 tumor 4 to 6 cm or tumor with extraparenchymal extensionT4a tumor invading skin, mandible, ear canal, or facial nerveT4b tumor invading skull base or pterygoid plates or encasing

carotid artery

N: regional lymph nodesN1 single ipsilateral node smaller than 3 cmN2a single ipsilateral node 3 to 6 cmN2b multiple ipsilateral nodes smaller than 6 cmN2c bilateral or contralateral node smaller than 6 cmN3 node larger than 6 cm

M: distant metastasesM0 no distant metastasesM1 distant metastases present

StagingStage I T1 N0 M0Stage II T2 N0 M0Stage III T3,

T1/T2/T3 N0, N1 M0, M0Stage IVa T4a,

T1/T2/T3 N0/N1/N2 M0, M0N2

Stage IVb T4b,any T N3, any N M0, M0

Stage IVc any T any N M1

Data from the American Joint Committee on Cancer (AJCC), Chicago,Illinois. The original and primary source for this information is the AJCC CancerStaging Manual, 6th edition (2002) published by Springer-Verlag New York (Formore information, visit www.cancerstaging.net). Any citation or quotation ofthis material must be credited to the AJCC as its primary source. The inclusionof this information herein does not authorize any reuse or further distributionwithout the expressed written permission of Springer Verlag New York, Inc.,on behalf of the AJCC.


submandibular neoplasms, and can distinguish a salivary gland neoplasmfrom a metastatic occult upper respiratory tract primary tumor in a patientwho has a painless mass that does not enlarge with oral intake. Preoperativediagnosis is helpful to advise patients about the extent of surgery that maybe required or that operative findings may dictate sacrifice of the facialnerve.More rigorous attention to the operative margin may be required whenresults of preoperative cytologic tests reveal malignancy. The type ofmalignant tumor is much more difficult to classify correctly by FNA. Finally,there have been no reports of seeding of tumor along the needle tract.

Histology, immunohistochemistry, and molecular biology

In 2002, the World Health Organization suggested the histologic typingof malignant salivary gland tumors listed in Box 2.

Mucoepidermoid carcinoma

Mucoepidermoid carcinoma is the most common malignant tumor of theparotid gland and the second most common malignant tumor of the

Box 2. Histologic typing of malignant salivary gland tumorsa

Acinic cell carcinomaMucoepidermoid carcinomaAdenoid cystic carcinomaPolymorphous low-grade adenocarcinomaEpithelial-myoepithelial carcinomaBasal cell adenocarcinomaSebaceous carcinomaPapillary cystadenocarcinomaMucinous adenocarcinomaOncocytic carcinomaSalivary duct carcinomaAdenocarcinomaMyoepithelial carcinomaCarcinoma ex pleomorphic adenomaSquamous cell carcinomaSmall cell carcinomaOther carcinomas

Data from: Seifert G in collaboration with Sobin LH, and pathologists in6 countries. World Health Organization international histological classificationof tumors. Histological typing of salivary gland tumors, 2nd edition.Springer-Verlag: Berlin, 1991.

a World Health Organization, 2002.


submandibular and sublingual glands. There is a slight female predilection.Mucoepidermoid carcinoma is located in the parotid gland in 80% to 90% ofpatients, comprising approximately one third of parotid malignancies.Mucoepidermoid carcinomas contain mucin-producing cells and epithelialcells. Differentiation between high-grade mucoepidermoid carcinoma andpoorly differentiated squamous cell carcinoma (SCC) may require specialstaining with periodic acid–Schiff stain for the presence of glycogen in themucin or positive staining for mucicarmine in the mucous cells. Sub-classification includes low-grade, intermediate-grade, and high-grade tumors.Low-grade tumors are circumscribed but not encapsulated and havea predominance of mucin cells (Fig. 1), whereas high-grade tumors aredominated by poorly differentiated squamous cells with poorly definedmargins, high mitotic activity, neural invasion, and tumor necrosis. Mostmucoepidermoid carcinomas are low grade, with less than 10% of patientspresenting with facial nerve dysfunction. Wide excision without radiationtherapy results in 5-year survival rates for low-grade tumors that approach75%. High-grade mucoepidermoid carcinoma presents with facial nerve

Fig. 1. Photomicrograph of low-grade mucoepidermoid carcinoma (magnification 40� with

H&E stain). (From Ellis GL, Auclair PL. Tumors of the salivary gland. In: Rosai J, editor. Atlas

of tumor pathology. Washington, DC: Armed Forces Institute of Pathology; 1996. p. 164; with

permission.)


dysfunction in 25% of patients and has a propensity for locoregional anddistant recurrence. Recommended treatment is surgery and radiation therapy,which yields a 5-year survival rate of 50%. Grading is not as successful inpredicting clinical outcome in submandibular mucoepidermoid carcinoma.

Adenoid cystic carcinoma

Adenoid cystic carcinoma is the second most common salivary glandmalignancy, representing 10% to 20% of major salivary gland cancers.Women are more commonly affected. It is the most common malignancy ofthe submandibular gland and sublingual glands: half of all sublingualtumors are adenoid cystic carcinomas. Perineural involvement by directinvasion is the hallmark of adenoid cystic carcinoma, allowing distantspread, including the skull base in 42% of patients [8]. Invasion into salivarygland parenchyma and soft tissues is common. The incidence of facial nervedysfunction in adenoid cystic carcinoma is 20%, although most of thesetumors present as an asymptomatic mass. Lymphatic spread is less commonthan distant metastasis to bone and lung. Histologic subtypes include themost common ‘‘Swiss cheese–appearing’’ cribriform pattern (Fig. 2). Thetubular subtype, with a more glandular histology, has the best prognosis.The solid subtype has sheets of cells and is associated with a grim prognosis.Most tumors display more than one histologic subtype, with the classi-fication depending on the predominant subtype. Recurrences generally de-velop within 5 years, but late recurrences develop 10 to 20 years later. Thefactors with the greatest impact on survival are the stage of the disease andhistologic grade; other significant factors include the site of origin, surgical

Fig. 2. Photomicrograph of the cribriform type of adenoid cystic carcinoma demonstrating the

‘‘Swiss cheese’’ appearance (magnification 100� with H&E stain). Arrows show pseudolumens

that are in continuity with the stroma of the tumor. (From Ellis GL, Auclair PL. Tumors of the

salivary gland. In: Rosai J, editor. Atlas of tumor pathology. Washington, DC: Armed Forces

Institute of Pathology; 1996. p. 206; with permission.)


margin, and previous radiation therapy. The 10-year survival rates for thesolid and cribriform subtypes have been reported as 0% and 62%,respectively [9]. Many patients survive for several years after recurrence,but up to 80% ultimately succumb to this malignancy.

Acinic cell carcinoma

Acinic cell carcinoma constitutes 10% to 15% of malignant salivarygland tumors. Two thirds of the patients are female. Approximately 3% ofacinic cell carcinomas occur bilaterally, making this tumor second only toWarthin’s tumor for bilateral presentation [10]. This low-grade tumoroccurs primarily in the parotid gland and rarely presents with facial nervedysfunction (Fig. 3). Regional lymph nodes are the most likely site ofmetastasis. There are numerous subtypes, including solid, papillary cystic,follicular, medullary, and microcystic, which do not correlate with

Fig. 3. Photomicrograph of acinic cell carcinoma (magnification 200� with H&E stain). (From

Ellis GL, Auclair PL. Tumors of the salivary gland. In: Rosai J, editor. Atlas of tumor pathology.

Washington, DC: Armed Forces Institute of Pathology; 1996. p. 186; with permission.)


prognosis. Surgery without radiation is recommended for this well-circum-scribed tumor. Five-year survival rates of 75% are achieved but these ratesdecrease with longer follow-up periods. Local recurrences are treated withfurther surgery. Acinic cell carcinoma is the second most common pediatricsalivary gland malignancy after mucoepidermoid carcinoma.

Malignant mixed tumors

Malignant mixed tumors comprise 5% to 10% of salivary glandmalignancies, with most occurring in the parotid gland. Gender is nota factor in presentation. The most common of the three types of malignantmixed tumors, carcinoma ex pleomorphic adenoma (CEPA), arises froma pleomorphic adenoma that has been untreated for many years or froma previously treated pleomorphic adenoma that has recurred. Suddenenlargement may represent malignant transformation. Clinical findings andhistologic features at the initial diagnosis that indicate a greater likelihoodof malignant transformation are as follows: older patient age, large tumorsize, submandibular gland location, and prominent zones of hyalinization orat least moderate mitotic activity [11]. The rate of malignant transformationapproaches 10% in tumors that have been present for 15 years [12]. Only theepithelial component metastasizes, typically presenting as an adenocarci-noma. A noninvasive subtype with either complete encapsulation or onlylimited microscopic invasion has an excellent prognosis, but the invasivesubtype is associated with regional and distant metastasis [13]. Immunohis-tochemistry has demonstrated that activation of c-myc and ras p21 proto-oncogenes and the involvement of the p53 mutation may play an importantrole in the malignant transformation of pleomorphic adenoma [14]. Ploidyresults do not predict tumor behavior inCEPA.Cervical neck nodemetastasisoccurs in 25% of patients. Surgery and postoperative radiation therapy arerecommended and lead to an overall 5-year survival rate of 40%. In addition,the degree of invasion and histologic grade have an impact on survival.

The malignant mixed tumor also can present as a true carcinosarcomafrom the beginning, with both epithelial and mesenchymal metastasizingcomponents. The most common epithelial types are SCC and adenocarci-noma, and the most common mesenchymal tumor is chondrosarcoma,a lethal tumor with few survivors. Finally under this category is the rarehistologic curiosity known as benign metastasizing pleomorphic adenoma.These tumors have an absence of cytologic atypia, and they arehistologically indistinguishable from pleomorphic adenoma; however, thesetumors are associated with a mortality rate of 22% [15].

Adenocarcinoma and related classifications

Adenocarcinoma is a shrinking category (as is undifferentiated carcinoma).These tumors have been reclassified into subtypes with similar histopathology


and biologic behavior based on electron microscopy and immunohistochem-istry. Carcinomaswith ductal features without other distinguishing character-istics are termed ‘‘adenocarcinoma, not otherwise specified.’’ Adeno-carcinoma is generally an aggressive tumor. Approximately 20% of patientspresent with facial nerve dysfunction, with frequent regional and distantmetastasis. Treatment consists of wide excision and postoperative radiationtherapy. A 5-year survival rate of less than 50% is generally predicted.

Immunoreactivity of smooth muscle–specific proteins helps differentiateadenocarcinoma from the high-grade salivary duct carcinoma. Salivary ductcarcinoma, which originates from the excretory duct reserve cell andresembles intraductal carcinoma of the breast, is an extremely aggressivetumor with low survival rates [16].

Differentiating salivary duct carcinoma from the more indolent poly-morphous low-grade adenocarcinoma (PLGA) is important. PLGA hasa female predominance (2:1) and arises primarily from intraoral minorsalivary glands. PLGA has a varied histologic (polymorphic) appearance ofpapillae, glandular structures, and solid aggregates. Local and regionalspread is limited, and this tumor is associated with low recurrence rates anda high rate of expected survival. Perineural involvement can makedistinction from the more aggressive adenoid cystic carcinoma difficult.The immunoreactivity of smooth muscle–specific proteins also helpsdifferentiate adenoid cystic carcinoma from PLGA [16]. Invasion helpsdistinguish PLGA from the benign pleomorphic adenoma, for which it canalso be mistaken. Before histologic refinements, salivary duct carcinoma andPLGA were classified as adenocarcinoma.

Squamous cell carcinoma

Primary SCC of the parotid gland is rare, representing 1% of cases. Thereis a 2-to-1 male preponderance. Metastatic disease to an intraparotid lymphnode from a skin primary tumor, contiguous spread of SCC from anadjacent skin primary tumor, poorly differentiated mucoepidermoidcarcinoma (mucin stains must be negative to exclude mucoepidermoidcarcinoma), and squamous metaplasia must be excluded. Primary SCCarises from metaplastic parotid duct epithelium. These tumors often act inan aggressive fashion, widely infiltrating the parotid gland. Up to 60% ofpatients who have this SCC present with cervical lymph node metastasis andfacial nerve dysfunction. With advanced-stage disease, survival rates are lessthan 50%. Radical surgery and postoperative radiation therapy are requiredfor this highly malignant tumor.

Melanoma

Most malignant melanomas arise from cutaneous primary sites, with theparotid gland being a frequent metastatic location. The prognosis isgenerally poor. Mucosal and ocular primary sites also must be considered.


Identifying the primary tumor of a parotid metastasis can be exceptionallydifficult when the rare spontaneous regression of the primary tumor occurs.The complex lymphatic drainage of the head and neck has slowed the use ofsentinel node biopsy. Many patients have multiple positive nodes, andprimary melanomas may be near or overlap the nodal basin in the head andneck. Preoperative lymphoscintigraphy using intradermal injections oftechnetium Tc 99m antimony trisulfide colloid, followed within 4 hours byintraoperative handheld gamma-probe localization, has been used toimprove sentinel node biopsy. This procedure can be coupled withintraoperative injection of 1% isosulfan blue dye. Technical success rateshave risen to 95%. The routine elective use of superficial parotidectomy forpatients who have primary melanoma of the scalp, auricle, and face has beenquestioned. Sentinel node biopsy in the parotid gland has been performedwithout facial nerve dissection, with a 2.6% rate of facial nerve dysfunction(and one case of temporary facial nerve paresis) [17]. Further study to definethe role of sentinel neck nodes in the parotid gland and the surgicalprocedures to address them is required.

Lymphoma

Lymphoma of the parotid gland represents 1% to 2% of parotidmalignancy presenting either primarily or as part of disseminated disease.The incidence is equal in men and women, and this tumor rarely occurs beforethe age of 50. Patients with Sjogren’s syndrome have a 40-fold greater risk fora parotid lymphoma than the general population. Most are B-cell, non-Hodgkin’s lymphomas, with 80%of patients presenting in stage I or II disease[18]. Primary lymphomas are usually low grade; however, even intermediate-and high-grade lymphomas of the parotid gland can have a satisfactoryprognosis with chemotherapy and radiation therapy. Immunohistochemicalanalysis can help differentiate the low-grade mucosa-associated lymphoidtissue lymphoma from myoepithelial sialadenitis. In many cases, lymphomacan be diagnosed with FNA using immunohistochemistry.

Undifferentiated carcinoma

Undifferentiated carcinomas include large cell undifferentiated carci-noma, small cell undifferentiated carcinoma, and lymphoepithelial carci-noma. Primary lymphoepithelial carcinomamay arise fromabenign epitheliallesion. It has been reported in Asians and Greenland Eskimos, with anassociated Epstein-Barr virus infection [19].

Molecular biology

DNA flow cytometry can assist in the characterization and diagnosis ofsalivary gland malignancies, which can be difficult to diagnose. Bang et al[20] reported that 43% of salivary gland tumors were reclassified after DNA


flow cytometry. The development and progression of cancer are regulatedby various oncogenes and tumor-suppressor genes. Genetic alterations, suchas those involving p53 and c-erbB-2, play an important role in theprogression of malignant salivary gland tumors, specifically adenocarci-noma, CEPA, and salivary duct carcinoma [21]. The p53 tumor-suppressorgene may be involved in salivary gland carcinogenesis, and its oncoproteinexpression is an independent indicator of clinical aggressiveness in parotidcancer [22]. Collagen IV and tenascin are extracellular matrix constituents.Weak immunoreactivity for collagen and intense staining of tenascin aredeterminants of recurrent disease. Tenascin immunoreactivity is intimatelyassociated with c-erbB-2 positivity and weak staining of collagen IV [23].DNA aneuploidy noted in undifferentiated adenocarcinoma or squamouscarcinomas is associated with reduced survival times compared with those ofpredominantly diploid tumors, such as mucoepidermoid, acinic cell, andadenoid cystic carcinomas [20].

Treatment

Salivary gland surgery

Surgery is the primary treatment for salivary gland malignancy. Theminimal operation for a parotid mass is superficial parotidectomy with facialnerve dissection. Enucleationwill result in higher rates of recurrence and facialnerve dysfunction. Low-grade parotid tumors may be treated with superficialparotidectomy. Facial nerve monitoring for a mobile tumor of the superficiallobe will not decrease the rate of facial nerve dysfunction [24]. Deep-lobetumors, facial nerve dysfunction, recurrent tumors, fixed tumors, tumorslarger than 4 cm, and nodal metastasis are indications for nerve monitoring.

The incision in the preauricular skin curves gently 2 mm below the earlobule to prevent distortion of the ear lobule, and subsequently 3 cm belowthe mandible so as not to traumatize the marginal mandibular branch of thefacial nerve. Electrosurgical dissection is eschewed. The sternocleidomastoidmuscle is separated from the parotid gland. The facial nerve trunkemanating from the stylomastoid foramen is superior to the cephalicmargin of the digastric muscle. The cartilaginous tragal pointer leads to thetympanomastoid suture. The pes anserinus of the facial nerve is invariablylocated 2 mm to 4 mm inferior to this most important anatomic landmark.Facial nerve dissection can be performed atraumatically with a finehemostat, bipolar coagulation, and plastic scissors. Bipolar scissors, theharmonic scalpel, and hemostat/stimulator probes with a dedicated nervemonitor have been advocated.

Deep-lobe dissection or total parotidectomy is indicated for deep-lobetumors, superficial tumors that extend to the deep lobe, high-grade tumors,and tumors involving the parapharyngeal space. After completion of thesuperficial parotidectomy, the facial nerve branches are elevated fromsurrounding parotid tissue or tumor, and the deep lobe is separated from the


masseter and other muscles. Parapharyngeal parotid tumors can present asan oropharyngeal submucosal mass and can pass posteroinferiorly orposterosuperiorly to the stylomandibular ligament. The cervical-parotidapproach is successful for most cases. Anterior or lateral mandibulotomy isrequired more commonly for malignant tumors approaching the skull base.Suction drainage will minimize the risk of hematoma and allow the woundto be readily observed without a dressing. Infrequently, retrogradeidentification of peripheral nerve branches is required for large, bulkytumors or for surgical procedures for recurrent tumors. Cortical mastoid-ectomy can be used to identify the intratemporal course of the facial nerveand to follow it to the stylomastoid foramen. Involvement of the middlecranial fossa and medial neurovascular structures of the jugular foramenmay require subtotal petrosectomy.

A balance between eradicating the tumor and preserving the facial nerve iswarranted. Facial nerve branches should be spared unless they are involvedwith tumor. In cases in which the tumor extends close to the nerve, the tumorpotentially can be peeled off the nerve and treated with postoperativeradiation therapy. Although this procedure transgresses the classic oncologicprinciple that malignant tumors should be resected with a wide margin, highrates of survival confirm the efficacy of postoperative radiation therapy ineradicating microscopic remnants of tumor after surgery. Preoperative facialnerve weakness suggests a very high likelihood of facial nerve sacrificeintraoperatively. A facial nerve surrounded by tumor is best treated withresection. If direct neurorrhaphy is not possible, cable nerve graft re-construction is performed, most commonly with the greater auricular or suralnerve. Facial skin involvement requires reconstruction with local or regionalflaps or free-tissue transfer. Complications include facial nerve dysfunction,Frey’s syndrome, ear numbness, hematoma, and salivary fistula.

Submandibular gland tumor resection calls attention to the followinganatomic sites: themarginal mandibular branch of the facial nerve deep to theplatysma (ligation of the facial vein and upward traction protects this branch);the lingual nerve, identified by its looping course along the hyoglossusmuscle;and the hypoglossal nerve deep to the posterior belly of the digastric muscle.En bloc excisionmay require resection of the floor of themouth ormarginal orsegmental mandibulectomy. Sublingual gland resection should proceed withcannulation ofWharton’s duct using a lacrimal probe and identification of thelingual nerve. These structures, the mucosa of the floor of the mouth, and theassociated alveolar mandible may require resection if sublingual gland canceris present. Complications of submandibular and sublingual gland surgeryrevolve around the cranial nerves dissected.

Neck dissection

Neck metastases are present in 10% to 20% of parotid glandmalignancies. These generally occur in levels II and III. The survival rate


for parotid gland malignancies without metastasis is 75%. Nodal metastasisreduces the survival rate by 50%. Clinically positive neck metastases aretreated with neck dissection. In N0 neck disease, the odds of neck micro-metastasis being present are increased in adenocarcinoma, SCC, high-grademucoepidermoid carcinoma, CEPA, high-grade tumors (excluding adenoidcystic carcinoma, in which lymph node metastasis is rare), facial nerveinvolvement, and extraglandular tumor extension. T1 and T2 tumors havea reported 12% risk of metastasis, and T3 and T4 tumors have a 27% risk ofnodal metastasis [25]. Selective neck dissection at levels IB, II, III, and theupper part of level V should be considered in patients who have high-riskN0 disease. Selective neck dissection may assist in determining the need forpostoperative radiation therapy. The risk of neck recurrence is higher inpatients with node-positive disease [25].

Immunohistochemistry, molecular analysis, cell culture techniques, andserial sectioning of lymph nodes have increased the rate of reportedmicrometastasis. Neck dissection for N0 neck disease remains a debatedtopic. In a reported series of N0 parotid gland malignancies treated withparotidectomy and radiation therapy without neck dissection, the risk ofsubsequent nodal metastasis was only 4% (7 of 164 cases) [26].

Radiation therapy

Patients who have advanced-stage disease, positive margins, nodal me-tastasis, preoperative facial nerve dysfunction, and high-grade tumors arecandidates for postoperative radiation therapy. Combined therapy withsurgery followed by radiation therapy has resulted in improved 5-yeardisease-free survival rates as high as 77%, with few sequelae from radiation[27]. Retrospective reviews have not defined a radiation dose–responserelationship, and treatment has ranged from 50 to 70 Gy. Radiation therapyas the primary treatment may be appropriate for patients with unresectabletumors or those with overwhelming comorbidities. Postoperative radiationtherapy for patients with positive surgical margins was reported to beeffective for T1 and T2 disease but not for advanced-stage disease [28].Chemotherapy or combined radiation therapy and chemotherapy have notimproved survival (excluding lymphoma), although chemotherapy has beenused in palliative settings.

Recurrence

The pattern of recurrence for most parotid gland malignancies, in orderof frequency, is local recurrence, cervical neck metastasis, and distantmetastasis [26]. Significant factors for survival are as follows: advanced age,tumor stage, positive nodal disease, facial nerve involvement, high-gradetumors, extraparenchymal spread, and positive margins.


Recurrence in submandibular gland cancer is most significantly related tothe initial stage at presentation, with most deaths caused by metastaticdisease. Other factors include clinical skin or soft tissue invasion, lymphnode metastasis, and perineural growth. Lower recurrence rates withpositive margins can be achieved with postoperative radiation therapy.Survival rates for sublingual gland cancer are similar to those forsubmandibular gland malignancy. All salivary gland malignancies requirefollow-up periods of 20 years for true measures of clinical outcomes.

Summary

Major salivary gland cancers are rare, with many histologic types andsubtypes. The tumor stage at presentation will dictate the need for imaging,FNA, and facial nerve monitoring. Immunohistochemistry has enhanceddiagnosis. In addition, precise attention to surgical landmarks and techniquewill reduce complications. Tumor stage, histologic type, tumor grade,surgical margin, facial nerve dysfunction, perineural involvement, extra-parenchymal spread, and nodal metastasis are factors influencing the indi-cation for neck dissection, postoperative radiation therapy, and survival rate.

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Iodine 131 (131I) as adjuvant therapyof differentiated thyroid cancer

Dominick Lamonica, MDa,b,*aDepartment of Nuclear Medicine, School of Medicine and Biomedical Sciences,

State University of New York at Buffalo, Parker Hall, Room 105, 3435 Main Street,

Building 10, Buffalo, NY 14214-3007, USAbDepartment of Nuclear Medicine, Division of Diagnostic Imaging, Roswell Park Cancer

Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA

Thyroid carcinoma is the most common endocrine malignancy in theUnited States, with 22,000 new cases and 1400 deaths projected for 2003 [1].For unclear reasons, the annual incidence of thyroid carcinoma has risenover the last quarter century [2]. In the management of patients who havethyroid cancer, nuclear medicine and surgical oncology often interface. Thediscovery and use of radioactive iodine are major reasons that nuclearmedicine originally achieved its specialty standing and central role in themanagement of thyroid disease.

Nearly 90% of malignant tumors involving the thyroid are differentiatedthyroid carcinomas (DTCs). Approximately 75% to 80%of these carcinomascan be categorized as papillary and 15% to 20% as follicular [3]. DTCtypically has a low incidence and a good prognosis. Nevertheless, somefactors separate patients into low and high risk for recurrence and adverseoutcome, and numerous classification systems have been proposed to assessoverall risk. Fig. 1 summarizes cumulative mortality rates over a 20-yearperiod for Mayo Clinic patients with papillary carcinoma that is judged to behigh (25%–40%) or low risk (1%–�2%) using four of these scoring systems:European Organization of Research and Treatment of Cancer (EORTC) [4],Union Internationale Contre le Cancer (UICC) [5], AGES a staging systemwith origins at the Mayo Clinic that stands for Age, Grade, Extent and Size[6], and AMES a staging system originating in the Lahey Clinic which is anacronym for Age,Metastases, Extent and Size [7,8]. Cumulative survival ratesat 20 years are even more impressive forMayo Clinic patients at low (survival

* Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.



doi:10.1016/S1055-3207(03)00129-7


130 D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

rate, 88%–90%) versus high (survival rate,\10%) risk from follicular tumorsin a system incorporating age and the presence of vascular invasion anddistant metastases at diagnosis [9]. Although follicular carcinomas aretypically smaller when discovered, they are usually found later in life and aremore advanced, with a propensity for hematogenous dissemination anddistant metastasis. Survival statistics for equally staged papillary tumors arealso poor. A recent large-scale retrospective analysis comprising patientsfrom the Ohio State University (OSU) and US Air Force (USAF) who hadboth papillary and follicular cancers focused principally on tumor-specificfactors associated with disease recurrence and cancer-specific mortality [10].As a part of this study, tumor variables alone were used in a system for theclinical staging of thyroidmalignancies. In addition to age at diagnosis and, toa lesser degree, patient gender, tumor features, such as size, extrathyroidalextension, multifocality, and the presence of distant metastases were allshown to affect outcomes. From a clinical standpoint, all of the previouslymentioned factors warrant review at the time of initial consultation. Froma nuclear medicine perspective, we believe that it is most important to basedecisions regarding adjuvant 131I therapy on anatomic staging at the time ofdiagnosis.

Patient-specific prognostic factors

For reasons that are poorly understood, both the age and gender of thepatient at diagnosis influence disease behavior and outcome to initialtherapies.

Fig. 1. Mayo Clinic patients with papillary carcinoma judged to be at high (25%–40%) or low

(1%–2%) risk for mortality using EORTC (upper left), UICC (upper right), AGES (lower left),

and AMES (lower right) classification systems. (From Hay ID. Papillary thyroid carcinoma.

J Endocrinol Metab Clin North Am 1990;19:561; with permission.)

131D. Lamonica / Surg Oncol Clin N Am 13 (2004) 129–149

Age at diagnosis is included in nearly all series as a factor influencingmortality in DTC. Thyroid carcinoma is more often a fatal illness in patientsolder than 40 years when first diagnosed. Mortality further increases when itis diagnosed over subsequent decades [11,12].

A different overall pattern emerges when disease recurrence is examinedrelative to age. Although the incidence of tumor recurrence from midlife onis high, it is even more frequent among children (Fig. 2), despite the morefavorable outcomes in this age group. Long-term survival statistics for thepediatric population are usually good, although children more often presentwith advanced-stage tumors, which typically recur [13–15]. Some risk ofrecurrence and cancer-specific mortality remains well beyond 20 years frominitial diagnosis for all patients (Fig. 3), emphasizing the need for adequateearly treatment and careful follow-up examinations.

A second patient-specific factor that is believed to affect outcome isgender. Although gender holds variable statistical weight in different studypopulations, there is evidence throughout the literature that the prognosisfrom thyroid carcinoma is less favorable among male patients. Two large-scale studies have reported that male gender has an overall negative effect onsurvival [4,10]. Most physicians therefore agree that these patients warrantcareful attention, particularly when lesions are diagnosed in midlife andbeyond.

Fig. 2. Recurrence and cancer death based on age at diagnosis. (From Mazzaferri EL, Jhiang

SM. Long-term impact of initial surgical and medical therapy on papillary and follicular cancer.

Am J Med 1994;97:422.)


Tumor-specific prognostic factors

The size and extent of the tumor at diagnosis have been shown repeatedlyin series both in the United States and abroad to have statistical bearing onoutcome in DTC.

The size of the primary tumor is a major factor affecting disease controlin both papillary and follicular tumors. It is included in seven of the ninescoring systems compiled in Table 1. Most small carcinomas containedwithin the thyroid gland rarely recur. This finding is particularly true forlesions located below the limits of palpation (\1.0 cm). The OSU/USAFseries described the 30-year recurrence rate for lesions smaller than 1.5 cm tobe one third that of larger tumors, with a cancer-specific mortality rate of0.4% compared with 7.0% for tumors larger than 1.5 cm (P > 0.001) [10].Papillary microcarcinomas are often uncovered as a result of surgery forbenign conditions, and these almost never recur. Although they are lesscommon, more aggressive forms of microcarcinoma do exist [19]. Thesemicrocarcinomas can be a source of locoregional and distant metastatictumor [20]. They are usually multifocal tumors at presentation, however,and it is most often the spread of disease that first brings them to clinicalattention [21].

The invasion of perithyroidal tissues by tumor also has a clear statisticalbearing on recurrence and mortality from DTC. Gross or microscopic

Fig. 3. Recurrence and cancer death based on time from initial diagnosis. (From Mazzaferri

EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and

follicular cancer. Am J Med 1994;97:421.)


evidence of direct extension to local tissues signals an increased risk forrecurrence. All recognized scoring systems list direct tumor invasion beyondthe gland capsule as a major risk factor for cancer-related death (see Table 1).

More controversy exists concerning the relevance of locoregional lymphnode metastases in DTC. More than one third of patients (35%) who havepapillary carcinoma present with locoregional lymph node metastases, anda lower percentage (13%) of patients with follicular tumors [3]. A majorclinical and pathologic feature of DTC in children is spread to regionallymph nodes [13]. Some series have reported the incidence of cervicalmetastases in children with DTC to be as high as 90% [15]. Someinvestigators claim that regional lymph node metastases have little impacton overall outcome [7,22,23]. Others, however, consider this finding a riskfactor for both disease recurrence and cancer-specific mortality [10,24,25].This pattern of spread is considered even more worrisome when disease hasextended to contralateral or bilateral neck nodes, or to mediastinal nodes[10]. The spread of metastatic tumor beyond the lymph node capsule is anespecially worrisome finding, as is extension of the primary tumor to tissuesoutside of the thyroid gland [26].

Finally, there is little debate over the impact of distant metastatic tumoron overall survival rates. One large-scale review of 13 series comprising 1231

Table 1

Risk stratification systems for differentiated thyroid carcinoma

Recognized risk factors

Scoring system Patient-specific Tumor-specific

United States

AMES [7] (Lahey Clinic) Age Metastasesa, extentb, sizec

AGES [6] (Mayo Clinic) Age Graded, extent, size

MACIS [23] (Mayo Clinic) Age, completeness

of resection

Metastases, extent (invasion

beyond gland), size

University of Chicago [16] — Metastases, lymph node statuse,

extent

OSU/USA [10] — Metastases, lymph node status,

extent, size

MSKCC [17] Age Metastases, extent, size

AJCC [18] Age Metastases, extent, size

Europe

EORTC [4] Age, sex Metastases, lymph node status,

cell typef, extent

UICC [5] Age Metastases, extent, size

Abbreviations: AJCC, American Joint Committee on Cancer; MACIS, Metastases, Age,

Completeness of resection, Invasion, Size.a Metastases, distant tumor in sites outside of neck (ie, lung, bone, brain).b Extent invasion, extension of tumor to extrathyroidal soft tissues.c Size, size of primary tumor.d Grade, histologic grade of primary tumor.e Lymph node status, tumor-positive cervical lymph nodes.f Cell type, medullary, poorly differentiated follicular, anaplastic, all other.


patients estimated that 5% of papillary carcinomas and 13% of follicularcarcinomas have extended beyond the neck at diagnosis. This distant spreadof tumor was most common within the lung (49%), which was followed inorder of frequency by metastases in bone (25%), lung and bone (15%), andthe central nervous system (CNS) or other tissues (10%). Overall, close to50% of these patients die of their disease within 5 years [27]. Although someforms of pulmonary spread may be compatible with long-term survival andeven ‘‘cure,’’ macroscopic tumor within the lung, skeleton, or brain istypically difficult to treat and often fatal [28,29].

In summary, although differences exist in the various staging andprognostic scoring systems used at clinics in the United States and inEurope, these are outweighed by similarities. Emphasis is given to tumorsize, local soft tissue invasion, and the presence of distant metastases. All ofthese characteristics have a clear bearing on the risk of tumor recurrence andcancer-specific mortality. Furthermore, these same factors can be used totailor therapy to individual disease risk both in the operating room and inthe clinic following surgery. Although age is weighted by many physicians,the current author does not include it in treatment decisions for theindividual patient. Although young patients often demonstrate morefavorable outcomes to treatment, the reasons are not well understood.The current author does not believe that age alone should override the redflags of anatomic staging. Improved mortality figures are not sufficient causeto ignore data that clearly point to an increased incidence of tumorrecurrence and associated morbidity.

Postsurgical131

I remnant ablation

When the surgical team intends to perform total or near-totalthyroidectomy, patients are typically referred for a postoperative 131I scanfor assessment for remnant thyroid tissue and adjuvant administration ofradioactive iodine. Total resection of the thyroid is a difficult proposition,and attention to critical structures within the neck usually interferes withcomplete surgical removal of glandular tissues. The term ‘‘radioiodineablation’’ refers to the use of 131INa to destroy what is presumed to benormal thyroid tissue remaining within the neck following operation. Thecurrent author has found that more than 90% of patients referred forradioiodine scan in the weeks following surgery show uptake within the neckindicative of some thyroid remnant. Radioiodine ablation of residualthyroid tissue in the setting of intermediate-stage tumor is advised for thefollowing reasons:

1. It has been shown to reduce the risk of tumor recurrence and therebylessen the chances of adverse outcome relating to treatment failure [10,30].

2. It clearly increases the sensitivity of diagnostic 131I scans and the efficacyof further 131I treatments. DTC is typically less iodine-avid than is the


normal glandular epithelium. The radioiodine localization that enablesboth tumor detection and effective therapy is enhanced by thyroid-stimulating hormone (TSH) release, which can be difficult to stimulatewith significant postsurgical remnant in place.

3. Finally, postoperative 131I ablation greatly improves disease monitoringby facilitating the use of serum thyroglobulin (Tg) as a tumor markerand eliminating the variable ‘‘background’’ Tg levels that persist withnormal thyroid remnant and often confound accurate interpretation oflaboratory results.

The current author’s initial postoperative ablation doses of radioactiveiodine for papillary or follicular tumors usually follow a regimen comprisingtwo levels, provided there has been surgical removal of all gross andmicroscopic evidence of tumor.

1. Fixed ‘‘low-dose’’ ablation, 1850 to 4625 MBq (50–125 mCi), isperformed following surgery for solitary tumors smaller than 4.0 cmin diameter without pre- or postsurgical evidence of spread tolocoregional lymph nodes or extension to extrathyroidal soft tissue.(Dosing is based on age, patient size, tumor characteristics, and uptakewithin thyroid remnant.)

2. Fixed ‘‘high-dose’’ ablation, 5550 MBq (150 mCi), is reserved forpatients with lesions larger than 4.0 cm or with any of the following inthe operative specimen: multifocal tumor, spread to locoregional lymphnodes, prominent vascular invasion, or extension of tumor toextrathyroidal soft tissue.

Radioiodine ablation is ordinarily performed following a 131I diagnosticsurvey demonstrating persistent radioiodine concentration within thesurgical bed 6 to 8 weeks after the operation. Following surgery,levothyroxine sodium (T4) is withheld in preparation for 131I scanning andablation. To postpone and alleviate the effects of a T4 deficit, liothyroninesodium (T3) is given for 3 to 4 weeks. T3 has a much shorter half-life andmay be discontinued 10 to 14 days before 131I dosing. At the same time,a low-iodine diet is initiated, which is intended to further enhance uptake ofthe radioisotope. Pre- or postsurgical findings that suggest persistent tumor(local or distant) have clear therapeutic relevance and such patients warrantsafe augmentation of the 131I dose.

131I therapy of differentiated thyroid carcinoma

The approach to radioiodine therapy of metastases from DTC varies inmany clinics within the United States. The demonstration of iodine-concentrating tumor outside the operative bed on preablation 131I imagingoften calls for an increase in the 131I doses typically used for the ablation ofnormal postsurgical thyroid remnant. Persistent or recurrent tumor seen on


postablation imaging may also be most effectively addressed with additional131I. Dose augmentation for treatment can take one of three forms:

1. Fixed dosing: This is an approach that was first introduced andeffectively applied to the management of patients with DTC by a teamof physicians at the University of Michigan, and it may be the treatmentsystem most commonly used in clinics throughout the United Statestoday [31]. Fixed-dose augmentation does not involve measurement ofradiation dose to thyroid remnant or to functioning metastatic lesionsbut instead focuses on the empiric dosing of radioiodine based onknowledge of the extent and location of tumor. A sliding scale is used inaccordance with the operative report and visualization of disease ondiagnostic scans within limits determined to be safe for most adultpatients. A documented tumor that is limited to lymph nodes within theneck that are not obviously involved by disease or that are beyond thereach of the surgeon’s knife is usually treated with 5500 to 6475 MBq(150–175 mCi) of 131I. Tumor invading soft tissues within the neck thatmay have been incompletely excised is most often addressed with 131Idoses in the range of 5500 to 7400 MBq (175–200 mCi). Finally, patientswho have clear evidence of distant metastatic disease are usually safelyadministered doses in the 7400 to 9250 MBq (200–250 mCi) range. Dosereduction may be warranted for unusually large remnants or extensivediffuse lung tumor that strongly retains 131I to avoid prolonged countreductions or possible lung injury.

2. Type I (remnant/tumor) dosimetry: Investigators who have looked atsome of the issues surrounding effective radioiodine therapy of DTChave determined that normal glandular remnant requires a radiation-absorbed dose of at least 300 Gy for likely ablation (80%) and thatiodine-concentrating tumor limited to lymph nodes within the neckshould receive at least 80 to 100 Gy for similar efficacy [32]. Although itis necessary to measure the volume of larger lesions treated with 131I toaccurately estimate the absorbed dose from systemic radiotherapy, thecurrent author has found that many of the lymph nodes first detected ona postoperative radioiodine scan are at or below the radiographic sizecriterion (1 cm) for characterization as abnormal. This is a fact thatincreases the likelihood of effective treatment with radioiodine. Inaddition to some anatomic estimate of lesion dimension, a calculation ofthe radiation dose delivered to a glandular remnant or metastatic lesionrequires serial measurement of the uptake of 131I at 2 or optimally 3times over a 1-week period. There is evidence to suggest thata radioiodine dose that is not sufficient to deliver at least 35 Gy willbe ineffective and that such lesions should be addressed surgically or byexternal beam radiotherapy [33,34].

3. Type II (blood-based) dosimetry: It is frequently difficult, if notimpossible, to estimate radiation delivery to sites of metastatic tumor.


Iodine-avid metastatic disease may be distributed in such a way thatvolume cannot be measured. To increase the likelihood of effectivedelivery of 131I, systems have been developed for maximum delivery oftargeted systemic radiotherapy within limits that will protect what hasbeen determined to be the dose-limiting organ for most patients, thebone marrow [35]. This system requires serial blood sampling andmeasurement of retained activity over a 1-week period. The system wasoriginally proposed and validated by Benua et al [35] and Leeper andShimoaka [36] of the Memorial Sloan-Kettering Cancer Center(MSKCC). Serious complications from dose maximization were avoidedby using this approach and limiting blood exposure to 200 cGy whilekeeping whole body retention under 4440 MBq (120 mCi) at 48 hours orunder 2960 MBq (80 mCi) in patients with diffuse lung disease.

Enhanced radioiodine uptake outside the confines of the surgical bed onpostoperative examination often indicates metastases from DTC. If thispattern is first evident on the initial postoperative survey, the currentauthor’s approach is to maximize the ablative dose within the previouslynoted fixed-dose guidelines for 131I therapy. The patient is then reimaged in6 to 12 months with formal blood-based dosimetry, which will allow safeadministration of a maximum permissible dose of 131INa for therapy ofmetastatic tumor. Prior knowledge of distant metastases or of persistenttumor within the neck will prompt the physician to include dosimetry in theinitial postoperative evaluation. Post-therapy imaging is included for allpatients undergoing ‘‘high-dose’’ remnant ablation or therapy for locore-gional or distant metastases. Imaging is done not only to document effectiveuptake within thyroid remnant and tumor but to gain added informationabout the extent of disease. It has been estimated that as many as 20% to25% of patients will demonstrate lesions not evident on pretreatment studies[37]. This finding is more frequent in cases where patients with negativepretreatment imaging are treated empirically with 131I based on rising serumTg levels. There are probably few situations where the results willsignificantly alter treatment plans [38].

Acute and long-term effects of 131I therapy

Early effects

Although 131I is lethal to the cells most able to concentrate it, it is notwithout immediate and long-term effects on background tissues free ofdisease.

Mild, acute radiation symptoms have been described in the immediatepost-treatment period in close to two thirds of patients receiving 131I therapy[39,40]. These symptoms are usually reported for doses in excess of 5550MBq(150 mCi), and this post-treatment period is often marked by fatigue, loss of


appetite, headache, nausea, and occasional vomiting. The gastrointestinalcomponent that is often described also may reflect the direct effect ofphysiologic localization of radioiodine within normal salivary tissues andgastric mucosa. This symptom constellation usually resolves over a 48-hourperiod.

Radiation thyroiditis, characterized by throat discomfort, cervicalswelling, and difficulty swallowing, can result when high doses of radiationare delivered to large gland remnants [41]. Patients also may experiencesymptoms of transient hyperthyroidism caused by release of stored hormonefrom large remnants or from extensive functioning follicular tumor [42].Physicians should be wary of this effect, particularly in patients withdocumented coronary artery disease or compromised cardiovascularfunction. All such patients should be made euthyroid before treatmentand should be observed carefully for signs of thyroid storm within 10 daysof 131I therapy, because this situation requires prompt attention [43]. Rarely,local swelling may be sufficient to precipitate vocal cord dysfunction [44].Such effects are usually limited to patients who have an invasive tumorinvolving the vocal cords or who have large thyroid remnants adjacent tothe recurrent laryngeal nerves. These are situations that call for carefulmonitoring, and treatment will likely involve the systemic administration ofcorticosteroids. It is important to appreciate that large gland remnants willcompete for finite doses of administered 131I. Such competition is believed tointerfere with the detection and effective treatment of a tumor that may havebeen incompletely excised [45,46]. The current author therefore recommendsre-operation for patients known to have large gland remnants and residualtumor that requires the upfront, effective delivery of 131I.

Cytopenias are frequently observed following high-dose radioiodinetherapies for DTC. A reduction in platelet and white blood cell counts maybe witnessed over the weeks following 131I therapy based largely on the doseadministered and on the effective half-life of radioiodine in the individualpatient. A University of Michigan study reported anemia (35%), leucopenia(10%), and thrombocytopenia (3%) in 157 patients treated with an averagedose of 207 mCi. Count reductions can be expected to resolve by 1 year,with red cell declines persisting slightly longer than white cell and plateleteffects [47]. Weekly monitoring of counts over an 8- to 12-week period isadvocated, particularly for patients receiving doses in excess of 9250 MBq(250 mCi) for treatment of widespread disease. Long-term hematologiceffects are not likely if the red marrow dose is kept within theaforementioned 200 cGy exposure limit.

Finally, the salivary effects from 131I treatment can sometimes beprominent. Tenderness and swelling may result from radiation effect on thelingual, parotid, and submandibular salivary glands following 131Iadministration. These effects have been reported to occur in up to onethird of individuals treated with 131I doses, with a direct correlation to theradiation dose received [48]. Symptoms usually become evident over a 24- to


48-hour period following administration of therapy and have been describedas reflecting the radiation effect of large 131I doses in patients with minimalthyroid remnant. Transient alteration or loss of taste sensation can result,most often resolving spontaneously over an 8- to 12-week period.Emphasizing hydration and encouraging salivary flow through use oflemon drops or chewing gum over the early post-treatment period mayreduce these symptoms. Despite these measures, longstanding adverseeffects are possible, particularly in patients receiving repeated high-dose 131Itreatments for refractory tumor. These effects include dry mouth, alteredtaste and conjunctival irritation, and ear and jaw pain caused byintermittent salivary obstruction from desquamation of glandular epithe-lium [49]. The latter symptom complex is often precipitated by eating andmay persist for some months.

Late effects of 131I treatment

Although most of the immediate effects described previously resolveduring the weeks following 131I therapy, the chances of long-term organ ortissue injury increase with the cumulative dose of radioactivity required fortreatment.

Female reproductive function is usually unaffected by single admin-istrations of 131I. Permanent reproductive organ impairment may resultfrom repeated therapies for this disease, however. One study noted that themiscarriage rate after 131I ablation that used doses in excess of 100 mCi wasnearly double the increase observed following thyroidectomy alone [50]. Thereasons for this finding are not entirely clear, although this observationsuggests a possible relation to irradiation of the ovaries. It seems that thereis no increase in risk of birth defects from treatment of children or women ofchildbearing age. This same study of women and pregnancy before and after131I therapy for thyroid carcinoma revealed no evidence for increased risk ofcongenital malformation, stillbirth, or prematurity following treatment ofthis disease. Long-term studies suggest that fertility is unaffected for womenyounger than 30 years at the time of therapy [51]. Such statistics are usuallydirectly correlated to cumulative radiation dose, however. Althoughpermanent sterility has not been recorded for premenopausal womenreceiving less than 11,100 MBq (300 mCi) of 131I, it has been reported innearly 60% of women receiving 131I doses in excess of 29,600 MBq (800mCi) [10,52]. Patients should be aware of this finding. Women treated in thecurrent author’s clinic are advised to avoid pregnancy during the 12 monthsfollowing 131I therapy.

A different situation exists for men undergoing 131I therapy for thyroidcancer, because the testes are especially vulnerable to the effects of radiation.A single 131I treatment involving only moderate doses of radioiodine (1850–3700 MBq [50–100 mCi]) is sufficient to cause reduction in sperm count [53].The testicular effects described from 131I therapy in men are proportional to


the total dose of radioactivity received over the course of treatment [54].Permanent sterility has been described in men receiving cumulative dosesgreater than 29,600 MBq (800 mCi) [55]. Sperm banking should beconsidered for young men who have extensive disease.

Lung fibrosis is often a concern for physicians treating patients who havediffuse pulmonary spread of iodine-avid thyroid tumor; however, it isuncommon. Lung fibrosis was originally reported in the early experience ofthe MSKCC group [32]. Based on five events in 59 patients, dosimetryguidelines were adjusted to ensure retained activities were kept under 4440MBq (120 mCi) at 48 hours in all patients and under 2960 MBq (80 mCi) at48 hours in those who had diffuse lung metastases [56]. It is the currentauthor’s experience that, on average, 30% to 50% of the administered 131Idose is excreted within 24 hours in athyrotic patients who have normal renalfunction. Exceptions to this are patients with large thyroid remnants orthose with an overwhelming mass of persistent, functioning tumor. Thestandard fixed-schedule dose of 7400 MBq (200 mCi) usually advocated fortreatment of lung metastases is therefore safe for treatment of pulmonarydisease in the overwhelming majority of patients. An approach that usesdosimetry would safely permit the upfront augmentation of therapy, whichis particularly needed for disease outside the neck. It would also be recom-mended in therapies for those patients who have compromised renal function.

Radiation-induced malignancy is probably the most serious among thepotential late effects of 131I treatment. Permanent count reductions and whitecell and platelet abnormalities are sometimes seen in patients receiving morethan 37 GBq of 131I for treatment of thyroid cancers. A large-scale meta-analysis comprising 13 series and 2753 patients reported a slight increase inprevalence of acute myelogenous leukemia (AML) for patients who hadreceived 131I therapy for thyroid cancer [57]. Many of the patients receivedhigh doses of radioiodine over short time intervals, a fact that only enhancesthe mutagenic properties of ionizing radiation for both normal and diseasedtissues. A small increase in deaths from bladder cancer and leukemia hasbeen reported with cumulative 131I doses in excess of 37 GBq [51]. Again, therisk is proportional to cumulative dose of radioactivity and underscores theneed for attention to bowel and bladder function in the days followingtherapy. In view of these effects, 131I treatments are normally spaced at 12-month intervals and are usually not repeated any sooner than 6 months forthe more aggressive tumor variants. Placed in perspective, the lifetime risk ofleukemia is small enough so that, even with the added radiation exposurefrom 131I treatment, this risk does not exceed the risk of dying frommetastatic thyroid cancer [2].

131I imaging and follow-up

Following radioiodine ablation of thyroid remnant or treatment ofiodine-concentrating thyroid tumor, the current author recommends


a minimum of one follow-up 131I study to assess the efficacy of theradioiodine dose. For reasons described previously, once normal thyroidremnant has been eliminated, unrecognized areas of disease may becomeapparent on whole body survey. The initial postoperative radioiodine surveyis done to assess the presence of normal thyroid remnant following total ornear-total thyroidectomy. Uptake in the neck is likely in this setting, andthis study is therefore performed using only a small 37-MBq (1-mCi) dose of131I. Once remnant ablation is achieved, patients are re-imaged to detect anypersistent or recurrent tumor. Diagnostic scans for this application areacquired with 74-MBq (2-mCi) doses of 131INa. The tracer dose is doubledbut is kept below 111 MBq (3 mCi) because of a concern that the diagnosticdose of 131I might interfere with radioiodine concentration for subsequenttherapy, a concept termed ‘‘stunning’’ [58,59]. 131I studies in the currentauthor’s clinic are accompanied by stimulated serum Tg assays, allowingserial comparison of this tumor marker in the assessment of a patient’sdisease as well. Serum Tg is usually undetectable (\0.5 ng/mL) in patientsfree of disease following successful postsurgical 131I remnant ablation.

In patients who are at increased risk for recurrence, the current authorordinarily advocates obtaining at least two negative 131I scans over the first 5years following initial 131I administration to increase the chances of earlydetection and prompt treatment of recurrent tumor at a time when it is mostlikely to be discovered. This imaging schedule is accompanied by regularfollow-up examinations within the clinic, with a physical examination every3 to 6 months for the first 2 to 3 years, thyroid function testing at 3 monthsand 6 months, then annually, and serum Tg assay at 6 and 12 months andannually thereafter. Once two negative 131I surveys have been documented,the current author believes it is appropriate for patients to enter long-termfollow-up, with clinic visits every 6 to 12 months and further diagnosticstudies based on the results of serial examination and laboratory testing.Recently, it has been suggested that regularly repeating the 131I whole bodyscan adds little to the DTC workup in this setting. In place of serial 131Iscans at 3- to 5-year intervals used in the past for disease monitoring,recombinant human thyroid-stimulating hormone (rhTSH) -stimulated Tgtesting has been suggested as an even more sensitive indicator of diseaserecurrence, highlighting a need for further workup to determine the mosteffective and appropriate therapy [60]. Although in the past eligibility for131I therapy was principally determined by uptake on radioiodine scansalone, this paradigm has recently changed. Several investigators havedemonstrated post-treatment evidence of tumor uptake in more than onehalf of patients with negative diagnostic 131I studies when they were treatedempirically with 3700 MBq to 5550 MBq (100–150 mCi) of 131I based onlyon elevated serum Tg [61,62]. A lowering of serum Tg levels also has beenrecorded in 30% to 50% of such patients in response to treatment [62].The current author has also seen benefit from the empiric administration of131I, both in terms of lowering of tumor marker and resolution of


anatomic findings on CT without clear evidence of uptake on pretreatmentimages.

If a surgically treatable lesion cannot be identified on diagnostic studies(eg, CT,MRI, or ultrasound) that are done for rising Tg levels, one might stillconsider moving ahead with additional empiric 131I therapy based on a risingtumor marker alone. This is an approach further strengthened by concernsover lesion stunning. In this situation, the post-treatment surveys acquired 7to 10 days following 131I therapy often provide the image evidence of DTCmissing from the interim diagnostic studies. The Tg thresholds forconsideration of additional 131I therapy of DTC are in evolution. SerumTg levels of more than 10 ng/mL in patients who are off thyroid hormonereplacement or levels greater than 5 ng/mL in patients undergoing T4

treatment are currently used by some clinicians to determine the need foradditional 131I therapy [37]. An rhTSH-stimulated Tg level of more than 2 ng/mL recently has been described as having a sensitivity of 100% for thedetection of recurrent disease [60,63].

131I therapy of differentiated thyroid carcinoma: outcomes

A beneficial effect has been demonstrated from the use of 131I for thepostoperative ablation of thyroid remnant in patients at intermediate riskfor disease recurrence [10,30]. Patients who have disease outside the neckwho respond to 131I therapy have significantly longer survival times thanthose who do not [11]. There can be considerable impact for the 131Itreatment of distant metastases within the lung. The 10-year survival rate forpatients treated with 131I for lung metastases evident only on post-treatmentwhole body survey has been reported to be 100%. The numbers are lowerbut still impressive for disease seen either on pretherapy 131I imaging alone(91%) and/or with an accompanying micronodular pattern on radiographicstudy (63%) [64]. Macronodular lung tumor is considerably more difficult totreat with 131I, and bone metastases represent an even greater challenge.Dominant or solitary skeletal sites optimally require a multidisciplinaryteam approach centering on surgery or external beam radiotherapy [65].Here as well, however, 131I can have a role for the treatment of residualdisease (Fig. 4). A similar application for 131I is anticipated for rareindividuals with isolated CNS lesions [66].

Further management

L-thyroxine therapy

Following surgery and initial radioiodine therapy for DTC, patients arebegun on T4 replacement and enter a regular schedule of clinical follow-upbased largely on surgical findings and results of post-therapy imaging.


Fig. 4. (A) Skeletal metastases (arrowheads) from papillary thyroid carcinoma on initial

postoperative 131I scan. (B) Positive post-treatment images 1 week after 131I therapy. (C)

Negative follow-up 131I images 1 year post therapy.


Studies have suggested that the recurrence rate of DTC is reduced by theaugmented administration of T4. The degree of TSH suppression requiredremains controversial, however. A retrospective European investigationshowed degree of TSH suppression as an independent predictor of diseaserecurrence [67]. A more recent prospective study in the United States,however, reported that, when it was measured against other variables, thedegree of TSH suppression taken alone did not predict those individuals atgreater risk for recurrent disease [68]. Despite ongoing debate, it isrecommended that intermediate-stage patients be started on a dose of T4

sufficient to maintain serum TSH levels just below the lower limit of thenormal range 0.1–0.4 micro-International Units per mililiter (uIU/mL) [69].If there is documentation of residual neck disease or distant metastatic

Fig. 4 (continued)


tumor following initial therapy, the replacement dose of T4 is usually furtheraugmented to limit or remove evidence of circulating TSH (\0.02 uIU/mL)from serum samples on second-generation assays. Here, as elsewhere, it isimportant to stress that patient management must be individualized, andthat there may be patients who cannot tolerate such dose augmentation. Aninitial TSH assay is usually obtained at 12 weeks or on the first follow-upvisit following postoperative 131I ablation and initiation of hormonereplacement. Using these results, the T4 dose is further adjusted.

Serum Tg testing and rhTSH

It is the current author’s practice to perform a stimulated Tg assay at thetime of the initial postoperative 131I scans. This assay is repeated at 6 monthson hormone replacement and again at 12 months, both on and offsupplementation at the usual time of the first follow-up 131I imaging.Laboratory testing and 131I scans are obtained to determine the efficacy ofthe ablative or therapeutic dose. These are both done in the TSH-stimulatedstate either following hormone withdrawal or rhTSH administration.Although the current author attempts to lessen the ill effects of hormonewithdrawal by routinely using T3 during T4 withdrawal for imaging andtherapy, he still cannot downplay the morbidity associated with the cessationof thyroid hormone. At present, the current author does not use rhTSHstimulation for patients who are expected to receive therapeutic doses of 131I,because this approach has not been proved equally effective. Thus, the choiceof scan preparation is based largely on risk and on the probability thata patient will require additional treatment with 131I. Moreover, there areother factors that need consideration in the decision to substitute rhTSH forthe standard imaging preparation. Two large-scale studies of rhTSH showthat less disease may be detected on 131I scans following rhTSH injectionversus with T4/T3 withdrawal [70,71]. A more recent investigation showedthe difference between the two techniques to be less marked, provided greaterattention was paid to scanning technique [63]. The proposed technicalmodification involved a doubling of the tracer dose of 131I from 74 MBq to148 MBq (2 mCi to 4 mCi) to account for the increased renal clearance offree iodide in the rhTSH-stimulated patient. This is a change that someclinicians are reluctant to make because of considerations regarding possiblestunning of iodine-concentrating tumor and a potential for reduction inefficacy of subsequent radioiodine therapy. The more important point of thisstudy was that the addition of a stimulated Tg level to rhTSH-simulatedimaging allowed detection of all patients who had recurrent tumor withoutthe negative effects of hormone withdrawal. Serum Tg should be undetect-able when persistent thyroid tissue or thyroid carcinoma is not present.

From these results, the current author believes that using this combinedmethod for the follow-up of DTC is worthwhile to reduce morbidity forpatients at relatively low risk for tumor recurrence requiring therapy.


Moreover, rhTSH is a welcome and necessary option for those who cannotmount a TSH response to hormone withdrawal (ie, functioning tumor,pituitary insufficiency) and a needed, although as yet unproven, alternativefor treatment of patients unable to tolerate the prolonged effects ofprofound hypothyroidism (ie, CNS critical lesions, cardiac insufficiency). Asituation that would not allow use of this dual approach using rhTSHimaging and Tg would be the patient with autoantibodies to Tg, becausethese would likely invalidate the added information obtained with thislaboratory assay.

Summary

The importance of the optimization of the upfront management of DTCcannot be underestimated. An aggressive approach is advocated, except insituations widely accepted to be low risk (ie, female patients \40 y, withtumors \1.0 cm confined to the gland). Distant tumor greatly reduces thechances for survival in all patients. The loss of iodine-concentrating abilityremoves systemic radioiodine from the therapeutic equation and therebyvirtually eliminates chances for cure. The role of chemotherapy in noniodineresponsive DTC is still in question, and a benefit in advanced disease has notbeen established. For non–iodine-concentrating tumor that cannot beapproached surgically, external beam therapy remains an option, bothwithin the neck and for dominant foci of distant metastatic tumor (ie, brainand bone). Any distant lesion demonstrating the capacity for radioiodineuptake also should be addressed with 131I, because this will potentially treattumor not evident on diagnostic survey.

In conclusion, 131I has demonstrated efficacy for the postsurgicalmanagement of DTC. Although its acute and long-term side-effect profileis not especially worrisome relative to other forms of systemic cancertherapy, the administration of 131I is not entirely without risk. Taking intoaccount many of the issues described in this article, the administration of131I should in every case be optimized. It also should be applied carefullyand judiciously to patients expected to derive benefit.

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Neck dissection: current conceptsand future directions

Nestor R. Rigual, MD, FACSa,b,*,Sam M. Wiseman, MD, FRCS(C)c,1

aSchool of Medical and Biological Sciences, State University of New York at Buffalo,

Buffalo, NY 14263, USAbSection of Plastic and Reconstructive Surgery, Department of Head and Neck Surgery,

Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USAcDepartment of Surgical Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets,

Buffalo, NY 14263, USA

This article discusses the classification, rationale, and future directionspertaining to neck dissections in the management of cancers of the head andneck. Most head and neck cancers arise from the squamous epithelium ofthe upper aerodigestive tract. In this article, the term ‘‘head and neckcancer’’ refers to squamous cell carcinoma (SCC) of the upper aerodigestivetract.

The development of lymph node metastasis is a critical factor in guidingthe treatment and determining the prognosis of individuals diagnosed withhead and neck carcinoma. The presence of lymphatic metastases is asso-ciated with a decrease in the survival rate of up to 50% of patients [1,2].Radical neck dissection (RND), first described by Crile [3] in 1906, andpopularized by Martin et al [4], has remained the cornerstone of the surgicaltreatment of cervical lymph node metastasis throughout most of the 20thcentury. The classic RND requires en bloc resection of the cervical lymphnodes, internal jugular vein, sternocleidomastoid muscle (SCM), and spi-nal accessory nerve. This operative procedure has significant long-termmorbidity, including shoulder dysfunction, cosmetic deformity, cutaneousparesthesia, and chronic neck and shoulder pain syndrome. These morbid-ities are exacerbated when postoperative radiotherapy is added. For thesereasons, and because of a lack of rationale for removing all cervical lymph

1 Current address: Department of Surgery, St. Paul’s Hospital, 1081 Burrard Street,

Vancouver, British Columbia, Canada, V6Z 1Y6.


E-mail address: [email protected] (N.R. Rigual).


doi:10.1016/S1055-3207(03)00119-4


152 N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

nodes, a change in the surgical approach to managing cervical metastasiswas initiated by Suarez [5] in the late 1950s. In anatomic studies, Suarezdemonstrated that cervical lymphatics are contained within well-definedfascial compartments, separate from muscles, nerves, blood vessels, andother visceral structures of the neck. Thus, he proposed that muscles, bloodvessels, and nerves that were routinely removed during an RND could bepreserved without compromising regional disease control in patients whohad limited neck disease. Bocca et al [6] subsequently popularized this‘‘functional neck dissection’’ concept, or neck dissection with the pre-servation of vital structures. The development of a better understanding oflymph node drainage patterns [7,8], the discovery of fascial compartmentsseparating cervical lymph nodes from neck structures commonly removed inRND, and an improved understanding of the role of adjuvant radiationtherapy [9,10] have been the impetus for the development of current modi-fications of the RND.

In response to a need for an organized approach for describing andclassifying neck dissection, the Committee for Head and Neck Surgery andOncology of the American Academy of Otolaryngology/Head and NeckSurgery standardized neck dissection terminology in 1991 [11], and a morerecent update was published in 2002 [12]. Neck dissection classificationcategories are shown in Box 1.

In the current classification schema, the location of cervical lymph nodegroups is delineated by the level system [11]. This system is easy to rememberand has become widely accepted (Fig. 1).

Recently, the concept of neck sublevels has been introduced into theclassification schema, because areas have been identified within the six necklevels that seem to have independent oncologic significance [12]. Thesesublevels include level IA (submental nodes), level IB (submandibularnodes), levels IIA and B (upper jugular nodes), level VA (spinal accessorynodes), and level VB (supraclavicular nodes). The lymph node groupscontained in these levels and the anatomic boundaries of the six neck levelsare shown in Table 1. Lymph node groups not located within these regionsshould be referred to by their specific nodal group name. Examples includeretropharyngeal, periparotid, and suboccipital nodal groups.

The structures defining the anatomic boundaries of the neck levels andsublevels are depicted in Fig. 2. Most of these anatomic boundaries are

Box 1. Neck dissection classification

� Radical neck dissection� Modified radical neck dissection� Selective neck dissection� Extended neck dissection

153N.R. Rigual, S.M. Wiseman / Surg Oncol Clin N Am 13 (2004) 151–166

familiar and well-defined anatomic structures, with few exceptions. Theposterior boundary of levels II through IV is delineated by the posteriorborder of the SCM or by the sensory branches of the cervical plexus. Thesecervical plexus sensory nerve branches also define the anterior boundary oflevel V. The anterior border of level IIA is defined by the stylohyoid muscle(see Table 1).

Imaging-based classification of cervical lymph node groups

Imaging studies were not used in the initial neck dissection classificationscheme in 1991 [11].

Radiologists therefore have recently identified landmarks that accuratelydefine the location of lymph nodes and have devised an imaging-basedclassification scheme for the cervical lymph node groups [13]. Thisradiologic classification was designed as an adjunct to the clinically basednodal classifications. Using imaging landmarks, level IA includes the lymphnodes that are located between the medial margin of the anterior belly ofthe digastric muscles, superior to the body of the hyoid bone, and belowthe mylohyoid muscle. Level IB includes nodes that also lie below the

Fig. 1. The levels of the neck. (Drawing by Paul Tomljanovich, MD, medical illustrator.)

Table 1

Neck level ana

Level Sup edial (anterior) Lateral (posterior)

IA Ma ontralateral digastric muscle,

anterior belly

Ipsilateral digastric muscle,

anterior belly

IB Ma nterior belly of digastric

muscle

Stylohyoid muscle

IIA Bas tylohyoid muscle Plane (vertical) defined by

spinal accessory nerve

IIB Bas lane (vertical) defined by

spinal accessory nerve

Sternocleidomastoid muscle,

lateral border

III Pla

d

o

ternohyoid muscle,

lateral border


lateral border, or cervical

plexus sensory branches

IV Pla

b

c

ternohyoid muscle, lateral

border


lateral border, or cervical


VA Ap

o

s

ternocleidomastoid muscle,

posterior border, or cervical


Trapezius muscle,

anterior border

VB Pla

in

o

ternocleidomastoid muscle,

posterior border, or cervical


Trapezius muscle,

anterior border

VI Hy ommon carotid artery Common carotid artery

154

N.R.Rigual,S.M

.Wisem

an/Surg

OncolClin

NAm

13(2004)151–166

tomic landmarks

erior Inferior M

ndibular symphysis Hyoid bone body C

ndibular body Posterior belly of digastric

muscle

A

e of skull Plane (horizontal) defined by

inferior border of hyoid bone

S

e of skull Plane (horizontal) defined by

inferior border of hyoid bone

P

ne (horizontal)

efined by inferior border

f body of hyoid

Plane (horizontal) defined by

inferior border of cricoid

cartilage

S

ne (horizontal) defined

y inferior border of cricoid

artilage

Clavicle S

ex of the point of convergence

f the trapezius and

ternocleidomastoid muscles

Plane (horizontal) defined

by inferior aspect

of cricoid cartilage

S

ne (horizontal) defined by

ferior border

f cricoid cartilage

Clavicle S

oid bone Sternum C


mylohyoid muscle and above the hyoid bone but are posterior and lateral tothe anterior belly of the digastric muscles and anterior to the posteriorborder of the submandibular gland. Level II nodes are contained in thespace defined superiorly by the skull base, inferiorly by the hyoid bone,anteriorly by the posterior border of the submandibular gland, andposterior to a transverse line drawn on each axial image through theposterior edge of the SCM. The deep border of level II is defined by theinternal carotid artery in that any nodes lying medially to this vessel areconsidered to belong to the retropharyngeal nodal group. Level III nodesare located between the lower border of the hyoid bone and the lowermargin of the cricoid cartilage. These nodes lie laterally to the commoncarotid artery. On both sides of the neck, the medial margin of the carotidarteries separates the level III nodes, which are located laterally to level IVnodes, which lie medially to the vessels. Level IV nodes lie inferiorly to thelower border of the cricoid cartilage and superiorly to the clavicle. Theboundaries of levels V and VI are the same as in the clinical classification.

Neck dissection classification

The neck dissection classification system has arisen because radical neckdissection remains the standard procedure for cervical lymphadenectomy,

Fig. 2. The sublevels of the neck. (Drawing by Paul Tomljanovich, MD, medical illustrator.)


with other operations representing alterations of this classic operation (seeBox 1). The term ‘‘modified radical neck dissection’’ (mRND) is used whenone or more nonlymphatic structures routinely removed in an RND ispreserved. In general, currently preserved structures include the SCM, theaccessory nerve, and the internal jugular vein. If one or more lymph nodelevels that are routinely removed in an RND are preserved, the procedure istermed a ‘‘selective neck dissection’’ (SND). Finally, if the procedure includesremoval of additional nonlymphatic structures or lymph node groups(relative to the RND), the operation is termed an ‘‘extended neck dissection.’’

The anatomic boundaries of the RND include the following: superiorly,the inferior border of the mandible; inferiorly, the clavicle; medially, themidline; and posteriorly, the anterior border of the trapeziusmuscle. Includedwithin these boundaries are lymph node levels I through V, the SCM, theinternal jugular vein (IJ), and accessory spinal nerve (cranial nerve XI), whichare removed at surgery (Fig. 3).

An mRND refers to the removal of lymph node levels I through V, withpreservation of one or more nonlymphatic structures that are routinelyremoved during the course of an RND. In describing an mRND, theanatomic structure or structures preserved should be clearly specified (eg,mRND with preservation of the internal jugular vein).

SNDs are commonly used in the staging and treatment of the clinicallyundetectable (or N0) neck tumor. In this type of neck dissection, one or

Fig. 3. Radical neck dissection. (Drawing by Paul Tomljanovich, MD, medical illustrator.)


more lymph node levels are preserved. The lymph node levels removedare based on the location of the primary tumor because the clinicalpatterns of cervical lymphatic metastasis from head and neck tumors havebeen shown to be predictable in multiple, large-scale, retrospective studies[8,14,15].

The lymph nodes at risk for laryngeal, hypopharyngeal, and oropharyn-geal carcinomas are usually found within levels II, III, and IV. For thyroidcancer and subglottic cancers, the nodes in level VI are at greatest risk ofharboring metastatic disease. Lymph nodes in levels I, II, and III are atgreatest risk of harboring microscopic metastatic disease in patients whohave oral cavity primary cancers. Skip metastasis to level IV may potentiallyrepresent a problem in patients who have oral tongue carcinoma [16].

The most significant paradigm shift in the management of cervical lymphnode disease over the past decade has been the selective removal of lymphnode groups that are at greatest risk of harboring metastases. Although thischange in treatment philosophy has been applied mostly to patients with N0nodal disease, SND also has a role in the treatment of N-positive necktumors [17,18].

Selective neck dissection for oropharyngeal, laryngeal,

and hypopharyngeal cancer

The lymphadenectomy of choice in the treatment of cancers affectingthese anatomic sites includes the removal of lymph node groups in levels II,III, and IV (SND II–IV). Patients who have SCC of the larynx rarelypresent with metastases at the submandibular triangle (level I) [19]. Datafrom two recent studies support the use of SND II–IV for the treatmentof N0 laryngeal and hypopharyngeal carcinomas [20] and transglotticcarcinomas (supraglottic tumors that cross the laryngeal ventricle andinvade the glottis) [21]. The anatomic limits of this lymphadenectomy are asfollows: the clavicle inferiorly, the skull base superiorly, the lateral border ofthe sternohyoid muscle medially, and the posterior border of the SCM andcutaneous sensory branches of the cervical plexus posteriorly (Fig. 4).

With the exception of the glottic larynx, cancers of the oropharynx,hypopharynx, and larynx have bilateral lymphatic drainage patterns. Thus,the procedure of choice for patients withN0 primary tumors in these locationsis a bilateral SND II–IV in cases where the neck is managed surgically. Incancers involving the walls of the hypopharynx and oropharynx, theretropharyngeal nodes may harbor metastatic disease. Therefore, in thiscircumstance, removal of this nodal group should be considered. Theprocedure would be termed SND II–IV, retropharyngeal nodes. In laryngealand hypopharyngeal carcinomas extending below the glottic larynx, level VIlymph nodes are usually included in the neck dissection (SND II–IV, VI),because they are at risk [21].


Selective neck dissection for cancer of the oral cavity

In oral cavity cancer, the nodal groups at risk are located in levels I, II,and III [8]. The procedure of choice is SND I–III (Fig. 5). Some evidencesuggests that, in cancer of the anterior tongue, level IV nodes may containmetastatic disease [16]. Therefore, it is recommended that lymph nodes inlevel IV be removed in patients who have cancer of the tongue (Fig. 6). Incancers involving midline structures, including the floor of the mouth, theindicated procedure is a bilateral SND I–III, because the lymph nodes onboth sides of the neck are at risk for containing metastases. The adequacyof SND I–III for treating clinically negative neck tumors in patients whohave oral carcinomas has been examined thoroughly [9,10,22]. In addition,investigators have demonstrated that, in patients with pathologically posi-tive lymph nodes, the addition of postoperative radiotherapy following SNDI–III can achieve regional control comparable to that of level I–V dissectionand postoperative radiotherapy [9].

Anterior neck dissection (selective neck dissection VI)

Level VI, central compartment neck dissection refers to the removal ofbilateral, paratracheal, delphian, and perithyroiidal lymph nodes, including

Fig. 4. Selective neck dissection II–IV. (Drawing by Paul Tomljanovich, MD, medical

illustrator.)


Fig. 5. Selective neck dissection I–III. (Drawing by Paul Tomljanovich, MD, medical

illustrator.)

Fig. 6. Selective neck dissection I–IV for oral tongue cancer. (Drawing by Paul Tomljanovich,

MD, medical illustrator.)


nodes adjacent to the recurrent laryngeal nerves [7]. The superior boundaryof the dissection is the body of the hyoid bone, and the inferior margin is thesuprasternal notch. The lateral margins are defined by the common carotidarteries. SND VI is most commonly indicated in the treatment of thyroidcancer, advanced laryngeal cancer with subglottic extension, and cervicalesophageal carcinoma (Fig. 7). In thyroid cancer where there is clinicalevidence of nodal metastases in the neck, either preoperatively orintraoperatively, the procedure of choice also would include levels II to V,and is designated SND II–VI.

Extended neck dissection

Extended neck dissection is by definition more extensive than an RND.Extended neck dissection involves the removal of additional lymph nodegroups or nonlymphatic structures not included in an RND. The anatomicstructures and lymph node groups removed during the course of this oper-ation must be documented. Examples of such lymph node groups includethe retropharyngeal, suboccipital, and paratracheal nodes. Examples ofnonlymphatic structures that may be removed include the vagus nerve,carotid artery, and the strap muscle (Fig. 8).

Fig. 7. Selective neck dissection VI, or central compartment neck dissection. (Drawing by Paul

Tomljanovich, MD, medical illustrator.)


Posterolateral neck dissection

Posterolateral neck dissection is an SND that involves removal of thesuboccipital lymph nodes, postauricular lymph nodes, and lymph nodes inlevels II through V (Fig. 9). SND II–V (postauricular, suboccipital) is theprocedure of choice to treat the neck in patients with cutaneous carcinomasof the posterior scalp and neck [23].

The superior limit of the dissection is the base of skull and the nuchalline. The inferior limit of the dissection is the clavicle. The anterior (medial)limit of the dissection is the lateral border of the sternohyoid muscle. Thelateral (posterior) limit is the anterior border of the trapezius muscleinferiorly and the midline of the neck superiorly [24,25].

Sentinel lymph node biopsy: a new paradigm for staging N0 neck tumors

Sentinel lymph node biopsy (SLNBX) has become an accepted techniquefor staging the first extratumoral echelon of draining lymph nodes inindividuals diagnosed with melanoma or breast cancer. Similar to SND,SLNBX is based on the principle that lymphatic metastases do not occur ina random manner, but rather predictably, in accordance with preexistinglymphatic anatomy. As discussed, the practice of Staging SND, performed

Fig. 8. Extended neck dissection (common carotid artery, digastric muscle, hypoglossal nerve).

(Drawing by Paul Tomljanovich, MD, medical illustrator.)


by removing nodal levels with the highest probability of harboring metastaticdisease, is based on studies examining the pattern and incidence of metastasesin large patient cohorts. Unlike SND, however, SLNBX is a lymphaticmapping technique that allows for the direct evaluation of the lymph node ornodes that initially receives metastatic disease, in a specific individual, witha tumor at a specific location.

Patients who have N0 head and neck cancer may benefit most fromSLNBX. Approximately 20% to 40% of patients who have N0 diseaseharbor microscopic tumor foci [26–28]. Thus, approximately two thirds ofpatients who have N0 head and neck cancer will have no pathologicevidence of metastatic disease [26,29]. Taking a ‘‘wait and see’’ approach inpatients with N0 cancer has been associated with disease recurrence anda worsened prognosis [26]. SLNBX has the potential of avoiding eitherovertreatment or undertreatment of the neck. In addition, SLNBX has theadded benefit of improved disease staging by directing the pathologist to the‘‘highest risk’’ lymph node or nodes, which may be more extensively eval-uated by either immunohistochemical or molecular techniques. Hamakawaet al [30] determined that routine histologic evaluation of neck dissectionspecimens miss micrometastatic disease in up to 28% of patients. It is thisgroup of ‘‘understaged’’ patients with head and neck cancer that may espe-cially benefit from SLNBX.

Recently, Wiseman et al [31] presented the results of a pilot study usingan isosulfan blue dye technique to carry out SLNBX in patients with early-

Fig. 9. Selective neck dissection II–V (postauricular, suboccipital), or posterolateral neck

dissection. (Drawing by Paul Tomljanovich, MD, medical illustrator.)


stage N0 oral cavity head and neck cancer. Although SLNBX wastechnically feasible, and no adverse effects were observed in the authors’patient population, the sentinel node identification rate was only 57%, andwhen identified, the sentinel node accurately predicted the pathologic statusof the neck in 75% of patients. The negative predictive value for the absenceof cervical metastases was 67% [31]. The authors’ experience was similarto that of other investigators who found that a vital dye technique alonehad a low rate of sentinel node identification (0%–67%), and even whenidentified, the sentinel node often did not accurately predict the pathologicstatus of the neck (0%–75%) [32,33]. The poor clinical utility of the vitaldye methodology is a sharp contrast to the high rate of sentinel nodeidentification reported when a radiotracer technique is used (in most series,100% of sentinel nodes were identified) [34–44]. In addition, using theradiotracer technique, the sentinel node almost always accurately reflectedthe pathologic status of the neck. Other investigators have used a combinedvital dye/radiotracer technique and have reported that these methodologiescomplement one another and also have high rates of sentinel node iden-tification (90%–100%) and accurate nodal staging (97%–100%) [43–45].

Recently, Ross et al [46] reported pooled results, from 22 centers, ofSLNBX being performed on 316 patients who had N0 head and neckcancer. Although this study was not prospective, and the study populationwas treated heterogeneously, these investigators reported a 95% rate ofsentinel node identification and an overall sensitivity of 90% for thisprocedure. At centers that performed 10 or fewer procedures, the sensitivitywas 57%; centers that performed more than 10 procedures had a sensitivityof 92% [46].

Although the data reported by Ross et al [46] are provocative, they mustbe interpreted with caution because this study was performed in a patientcohort that was nonrandomized, uncontrolled, retrospectively collected, andheterogeneous. The results reported in the current literature are encourag-ing, however. SLNBX does seem to be a technically feasible and accuratemethod for staging N0 neck cancer. There remain many issues that mustbe addressed before SLNBX becomes integrated into the managementalgorithm of N0 neck cancer. Critical unresolved issues include the identi-fication of patient/tumor characteristics appropriate for this methodology(eg, stage, site, subsite) and a determination of the technique (eg, radio-tracer, vital dye, or combination technique) most appropriately applied tothese individuals.

Summary

For individuals diagnosed with head and neck cancer, neck dissectionmay be performed for therapy or disease staging. The classification of neckdissection and the definition of precise anatomic landmarks have allowed


for this operation, and its many variations, to become standardized world-wide. SLNBX shows promise in its ability to accurately stage N0 head andneck cancer and may allow patients with no micrometastatic disease toavoid neck dissection. Before this technique becomes adopted into routineclinical practice, however, it must first be prospectively scrutinized in largepatient populations. Regardless of the future role of SLNBX in the man-agement of head and neck cancer, currently it is only through a completeunderstanding of the clinical, theoretic, and technical aspects of neck dis-section that surgeons may benefit individual patients and the head and neckcancer patient population as a whole.

Acknowledgment

The authors thank Paul Tomljanovich, MD, for his excellent artwork.

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Differential diagnosis and treatmentoptions in paranasal sinus cancers

Larry L. Myers, MD*, Lance E. Oxford, MDDepartment of Otolaryngology–Head and Neck Surgery, University of Texas Southwestern

Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9035, USA

Despite major advances in the diagnosis and treatment of paranasal sinuscancers, these rare malignancies remain a complex and difficult problem.Improved surgical techniques, including the ability to safely reconstructlarge, complex defects with free-tissue transfers, multimodality therapiesand radiation therapy and chemotherapy protocols have had little impact onimproving the traditionally poor prognosis. Paranasal sinuses are in-accessible on routine examination and cancers of this region typically do notbecome manifest until critical adjacent structures are involved. The pooroverall and disease-free survival rate is commonly attributed to theadvanced stage at presentation of most tumors. This article presents thediagnosis, staging, treatment options, and outcomes for these heterogeneousneoplasms arising from the anatomically complex region of the paranasalsinuses, with an emphasis on epithelium-derived malignancies.

Anatomy

A fundamental knowledge of the anatomy of the paranasal sinuses iscrucial in any discussion of malignancies of this region. The paranasalsinuses consist of the paired maxillary, ethmoid, sphenoid, and frontalsinuses (Figs. 1 and 2). Each sinus is named according to the bone that itpneumatizes. The frontal sinus is located between the outer and inner tablesof the frontal bone. Each frontal sinus drains inferiorly by way of thenasofrontal duct, which continues inferiorly to drain into the medial meatusof the lateral nasal wall. The middle meatus is the area found inferior to themiddle turbinate and superior to the inferior turbinate. The dura of the


E-mail address: [email protected] (L.L. Myers).


doi:10.1016/S1055-3207(03)00115-7


168 L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

anterior cranial fossa is located immediately posterior to the sinus. Theethmoid sinuses consist of 3 to 18 thin-walled air cells. The lateral border isformed by the lamina papyracea of the medial orbital wall. The ethmoidsinuses are divided into anterior and posterior ethmoid cells by the basallamella, a bony structure that supports the middle turbinate by attachmentto the lamina papyracea and anterior skull base. The anterior cranial baseforms the superior border of the ethmoids, and the nasal cavity is locatedmedially. The sphenoid sinus is the most posterior of the paranasal sinuses. Itis surrounded by numerous vital structures. The internal carotid artery andoptic nerve are located along its lateral wall. Its superior surface forms thesella turcica and contains the pituitary gland. Each of the sphenoid ostia islocated on the anterior wall of the sphenoid sinus, which also forms theposterior wall of the nasal cavity superior to the choanae. The sphenoid sinusand posterior ethmoid cells drain into the sphenoethmoid recess in theposterior superior lateral nasal cavity. The maxillary sinuses are the largestsinuses and are the only ones separated from the skull base. Each maxillarysinus is shaped similar to a pyramid, with a base formed by the lateral nasalwall and an apex projecting toward the zygomatic arch. The superiorboundary is formed by the orbital floor, and the inferior boundary is formedby the alveolar and palatine process of the maxilla. The pterygopalatinefissure is located immediately posterior to the sinus. The soft tissues of the face

Fig. 1. Sagittal section of head, depicting position of paranasal sinuses and sectioning planes

1 and 2 of Fig. 2. AE, anterior ethmoid; ME, middle ethmoid ostium; OB, olfactory bulb; PE,

posterior ethmoid; SO, sphenoid ostium.

169L.L. Myers, L.E. Oxford / Surg Oncol Clin N Am 13 (2004) 167–186

are located anteriorly and laterally to the sinus. The maxillary sinuses and theanterior ethmoid cells drain into the middle meatus [1,2]. The normally air-filled sinuses surround the nasal cavity and are lined by ectodermally derivedrespiratory epithelium, consisting of ciliated, pseudostratified, columnarepithelial cells and interspersed mucus producing goblet cells. The lining ofthe sinuses is continuous with the mucosa of the nasal cavity. The sinusmucosa is thinner, however, and more adherent to the surrounding bone [1].

Incidence

Paranasal sinus cancers account for less than 1% of all malignancies andcomprise 3% of all head and neck malignancies [3]. The incidence rate is 0.3to 1.0 case per 100,000 people per year in Western populations [4–6]. Theincidence is 2 to 3 times higher in Japan [7]. In the United States, the overallmale-to-female incidence is 3 to 2, with a strong predilection for whites. Theincidence rate of sinonasal cancer progressively increases after age 35.Epithelium-derived neoplasms are almost nonexistent in children [5,6].

Etiology

The precise cause of paranasal sinus malignancies is unknown. Knownrisk factors for the development of cancer in this region, however, include

Fig. 2. Coronal section of head to illustrate relationships of paranasal sinuses (see Fig. 1 for

planes of sections 1 and 2).


wood and leather dust, smoke, and heavy metals, including nickel. Mostpatients have a history of exposure to carcinogens for more than 10 years [8].

Pathology

The paranasal sinuses contain diverse components: schneiderian mucosa,minor salivary glands, neural tissue, lymphatics, vessels, and bone. Aneoplasm may arise from any type of tissue present in the paranasal sinuses.This article discusses epithelium-derived malignant neoplasms, includinglymphomas.

Epithelium-derived malignancies

Squamous cell carcinomaNon–squamous cell carcinomaAdenocarcinomaAdenoid cystic carcinomaMucoepidermoid carcinomaMelanomaOlfactory neuroblastomaSinonasal undifferentiated carcinoma

Presenting symptoms/history

Patients typically present after symptoms have been present for severalmonths and the tumor has involved adjacent structures. Small tumors areoften asymptomatic but may present with nasal obstruction, epistaxis, orsymptoms consistent with chronic sinusitis, such as headache or rhinorrhea.With involvement of surrounding structures, patients may experiencediplopia or vision changes, infraorbital nerve deficits, maxillary dentalsymptoms, or possibly neurologic deficits secondary to intracranialextension.

Evaluation

A suspected paranasal sinus malignancy requires a thorough head andneck examination complemented by imaging studies. Office nasal endoscopyunder topical anesthesia allows assessment of the extent of a mass and itsfixation to surrounding structures. A biopsy can usually be performed in theoffice setting. If there is concern for bleeding or the lesion is not easilyaccessible, then endoscopic or open biopsy is best performed in theoperating room. A complete cranial nerve examination may disclose skullbase or direct nerve involvement by the tumor. A formal ophthalmologicevaluation is recommended if there is concern for orbital involvement.


CT imaging, with at least 3-mm cuts, allows the best assessment ofinvolvement of surrounding bone. Coronal imaging readily demonstratesthe anatomy of the paranasal sinuses, including fine bony structures such asthe lamina papyracea, orbital floor, and cribiform plate. The extension ofa paranasal sinus malignancy through the skull base is best evaluated withfine-cut coronal imaging. Contrast infusion may help demonstrate regionsof enhancement containing neoplasm. Often on CT scans, it is difficult todetermine the soft tissue extent of a malignancy. Sinus opacification on CTimages may be secondary to tumor infiltration or the result of accumu-lations of mucus from obstruction of the sinus. MRI with gadolinium issuperior in delineating soft tissue detail, both intra- and extracranially. Thismodality provides the best assessment of tumor extent and can easilydifferentiate between tumor and inspissated mucus (Fig. 3). In addition,MRI has the advantage of avoiding dental filling artifacts, imaging in thesagittal plane, and not exposing the patient to ionizing radiation. Plainradiographs are generally not useful in assessing a sinus malignancy. A 6-ftCaldwell view is occasionally used to create a template of the outline of thefrontal sinus to guide frontal bone osteotomies.

Staging

Staging paranasal sinus malignancies as a whole is imprecise andcontroversial. A formal staging system has been developed only for maxillarysinus carcinomas. In 1933, Ohngren [9] differentiated maxillary sinus tumorsbased on whether they primarily involved the suprastructure or theinfrastructure of the maxillary sinus. Ohngren’s line runs from the medialcanthus inferiorly and laterally to the angle of the mandible. Theinfrastructure of the maxillary sinus lies anterior and inferior to the line andthe suprastructure lies posterior and superior. Tumors of the infrastructureare associated with a better prognosis because of decreased involvement of theorbit and cranial base. In 1997, the American Joint Committee on Cancerrevised its 1977 criteria to more accurately correlate tumor stage and survival[10]. The 1997 staging system is described in the following sections [11].

Tumor classification

T1: Tumors limited to antral mucosa, without bone erosion or destructionT2: Tumor causing bone erosion or destruction, except for the posterior

wall, including extension into the hard palate or middle nasal meatusT3: Tumors invading any of the following: posterior wall, subcutaneous

tissue, skin of the cheek, floor, or medial wall of the orbit,infratemporal fossa, pterygoid plate, or ethmoid sinuses

T4: Tumors invading orbital contents beyond the floor or medial wall,including any of the following: orbital apex, cribiform plate, base ofskull, nasopharynx, and sphenoid and frontal sinuses


Node classification

N0: No regional node metastasisN1: Metastasis to single ipsilateral node, less than 3 cm in greatest

dimensionN2a: Metastasis to single ipsilateral node, more than 3 cm and less than 6

cm in greatest dimension, or in multiple ipsilateral lymph nodes,none more than 6 cm in greatest dimension

N2b: Metastasis to multiple ipsilateral nodes, all less than 6 cm in greatestdimension

N2c: Metastasis to bilateral or contralateral nodes, all less than 6 cm ingreatest dimension

N3: Metastasis of more than 6 cm

Metastasis classification

M0: No distant metastasisM1: Distant metastasis present

Fig. 3. Axial contrast-enhanced MRI depicting actual extent of left posterior ethmoid sinus

adenocarcinoma. Black arrow indicates actual tumor. White arrow indicates inspissated mucus.


Disease stage

Stage I: T1N0Stage II: T2N0Stage III: T3N0 or T1-3N1 in greatest dimensionStage IV: T4N0 or T1-4N2-3

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most common paranasal sinusneoplasm, accounting for 58% to 73%ofmalignancies [12–14]. Themaxillarysinus is the most common location for paranasal sinus SCC, followed by theethmoid sinuses. The frontal and sphenoid sinuses each account for 1% ofSCC [1,12]. The neoplasmmore commonly affects men and typically presentsin the sixth and seventh decades of life [1]. Reported risk factors includea history of inverted papilloma and exposure to radioactive thorium dioxide(thorotrast) contrast and nickel [1]. SCC typically presents at an advancedstage; more than 80% of patients present with stage III or IV tumors[10,12,13]. Lymph node or distant metastases are rare on presentation [15].

SCC arises from the respiratory ciliated columnar epithelium of theparanasal sinuses. Histologically, 80% of cases demonstrate keratinizationand the remainder are the nonkeratinizing subtype. The tumors may exhibiteither papillary, exophytic, or inverted growth patterns [1].

The standard treatment of paranasal sinus SCC is combined therapyinvolving resection and radiation [10,13]. Tiwari et al [13] reviewed 35 casesof SCC of the maxillary sinus. Twenty-six patients were treated with surgeryand postoperative radiation and nine were treated with chemotherapy andradiation therapy. Resections included 12 maxillectomies, 7 infrastructuremaxillectomies with preservation of the orbital floor, 6 radical maxillec-tomies with orbital exenteration, and 1 craniofacial resection. The surgicalgroup demonstrated a significantly higher 5-year disease survival rate of64%, compared with the chemotherapy/radiation therapy group; however,22.5% of patients treated with resection developed a local recurrence, mostcommonly in the infratemporal fossa. Duelguerov et al [12] reported a 58%5-year survival rate for 126 patients treated at the University of California–Los Angeles and Geneva University Hospital. The most common treatmentapproach used was surgery and radiation therapy. The authors reviewed theliterature and demonstrated a significant improvement in survival comparedwith previous publications. The reported survival rates in articles publishedin the 1960s through 1990s were 25%, 34%, 45%, and 50%, for each decaderespectively.

The favorable response of head and neck SCCs to the chemotherapeuticagents 5-fluorouracil (5-FU) and cisplatin recently has been reported, and theuse of these agents may be an effective adjuvant treatment for paranasal sinusSCC. Nibu et al [15] reported an overall 5-year survival rate of 86% in 33patients with maxillary sinus SCC. Even with skull base involvement, a 60%


survival rate was achieved. Multimodality treatment included preoperativecisplatin, 5-FU, and radiation therapy, surgical resection; and postoperativeradiation therapy. Orbital contents were preserved in 67% of patients. Ninepatients developed a local recurrence; three of these recurrences weresalvaged with repeat resection [15]. In addition, a University of Chicagostudy reported 11 of 12 patients with no evidence of disease at a medianfollow-up period of 55 months after preoperative chemotherapy, surgicalresection, and postoperative radiation therapy [16].

Adenocarcinoma

Paranasal sinus adenocarcinomas differ from SCC in risk factors andtypical location. Chronic exposure to wood or leather dust has been cited asa risk factor for the development of sinonasal adenocarcinoma in numerousstudies. Woodworkers in England have greater than a 1000-fold increasedincidence of ethmoid adenocarcinoma [17–24]. Adenocarcinomas accountfor 17% to 90% of ethmoid malignancies, depending on geographic locationand occupational risk factors [25–27].

Sinus adenocarcinomas may develop from either minor salivary glandtissue or the epithelium. Histologically, adenocarcinomas are classified aslow grade, high grade, or intestinal type. Low-grade adenocarcinomascontain numerous glands lined by a single layer of cuboidal to columnar cellswith uniform nuclei. Papillary formations or large, irregular cystic spacesmay be present. High-grade lesions may demonstrate glandular structuresbut are characterized by a solid growth pattern containing pleomorphismand increased mitotic activity. Intestinal- or colonic-type adenocarcinomaresembles intestinal adenocarcinoma and may contain goblet or signet ringcells. All intestinal types are considered to be high-grade lesions [1].

Ethmoid adenocarcinoma typically requires a craniofacial approach forresection. Postoperative radiation therapy is recommended for positivemargins, dural or cribiform plate invasion, and high-grade lesions adjacentto the cribiform plate [28]. Wax et al [27] reported on eight patients withadenocarcinoma of the ethmoid sinuses who were treated with craniofacialresection, with follow-up periods ranging from 9 months to 5 years. Fourpatients received postoperative radiation therapy. Seven patients have noevidence of disease, including five patients who were observed for more than3 years. Only one patient had positive margins secondary to braininvolvement and died of local recurrence at 8 months. The 5-year survivalrates after craniofacial resection ranged from 39% to 57% [29–31]. Knegtet al [32] reported a 5-year survival rate of 87% in 70 patients treated withsurgical debulking and topical chemotherapy with 5-FU. The patientsreceived biweekly packing changes, removal of necrotic tissue, and topicalchemotherapy for 4 weeks. Selection bias likely contributed to the highsurvival rate, however, because advanced tumors with invasion of dura orthe orbit were excluded from the protocol.


Adenoid cystic carcinoma

Adenoid cystic carcinoma (ACC) most commonly develops in the majorsalivary glands. It may arise from minor salivary gland tissue locatedthroughout the upper respiratory tract, however, including the paranasalsinuses. ACC is the second most common malignancy of the paranasalsinuses in some series [33,34]. It is an aggressive neoplasm characterized byearly neural invasion and a high incidence of local recurrence and distantmetastases, which may develop years after initial resection. Although the 5-year survival rate of ACC of all head and neck sites is 75%, the 20-yearsurvival rate is only 13% [1]. ACC of the paranasal sinuses has the highestincidence of local recurrence, likely secondary to its advanced stage atpresentation and vicinity to cranial nerves and the skull base [35,36]. Themost common location of ACC of the sinonasal tract is the maxillary sinus,accounting for 66% of cases [36].

Histologically, ACC is characterized by varied growth patterns, includingcribiform, tubular, and solid arrangements of hyperchromatic cells withindistinct cell borders. The neoplastic cells may form nests of ducts ortubules, which are sharply demarcated from the surrounding myxoid orhyalinized interstitial stroma [1].

The standard treatment for ACC of the paranasal sinuses is combinedtherapy with resection and radiation therapy [36–38]. Pitman et al [36]reviewed 35 patients with ACC of the sinonasal tract and reported a 46%disease-free survival rate with a median follow-up of 40 months. Approx-imately 71% of patients developed a recurrence, however, including 21%with distant metastases. Salvage therapy yielded no evidence of disease for atleast 2 years in only 1 of 17 patients with a local recurrence. Craniofacialresection in 23 patients allowed a similar rate of control of advanced tumorscompared with patients treated with a maxillectomy for limited tumorextension. In a longer-term follow-up period of 22 patients with ACC of themaxillary antrum, Kim et al [37] reported a 10-year survival rate of 37.6%and a 10-year disease-free survival rate of 13.6%. All 12 of the patientstreated with a single modality developed local recurrence, compared witha local recurrence rate of 40% in patients receiving resection and radiationtherapy. With a median follow-up period of 8 years, the median survival timefor all patients was 7.5 years. Negative predictors for survival were perineuralinvasion and single-modality treatment. Patients with unresectable ACC orresidual disease after resection should be evaluated for neutron radiotherapy.Neutron therapy delivers a higher linear energy transfer compared withconventional radiotherapy. Five-year survival rates of approximately 50%have been reported for advanced cases of ACC [39,40].

Melanoma

Sinonasal melanomas are rare neoplasms characterized by a poorerprognosis than cutaneous melanomas. Malignant melanoma occurs in the


sinonasal tract in less than 1% of cases [41], and sinonasal melanomaaccounts for less than 4% of sinonasal malignancies [42]. The incidence ofsinonasal melanoma is much higher in certain populations. It accounts formore than 25% of melanoma cases in Japan and 7% to 11% of sinonasalneoplasms [43–45]. There is an equal male-to-female incidence, and mostpatients present in their sixth or seventh decade of life [46]. Sinonasalmelanoma most commonly develops in the nasal cavity, especially the lateralnasal wall. The ethmoid and maxillary sinuses are the most commonlocation for paranasal sinus melanomas [47].

Sinonasal melanomas develop from neural crest–derived melanocytesfound in the lamina propria of respiratory epithelium and around sinonasalminor salivary glands [48]. Histologically, melanomas may exhibit variousgrowth patterns, including epithelioid and spindle cell formations, withvariable melanin deposition [1]. Immunohistochemical staining for S-100protein and HMB45 allows the diagnosis to be made with amelanoticmelanomas [1,49].

Surgical resection is the standard treatment for sinonasal melanomas. Ina review of 72 cases of sinonasal melanoma, Lund et al [47] reported a 5-yearsurvival rate of 28%. There was no improvement in local control or survivalrates with the addition of radiotherapy or chemotherapy compared withsurgical resection. Brandwein et al [46] reviewed 25 cases from Mount SinaiHospital and performed a meta-analysis of 163 reported cases. The overall5-year survival rate was 36%. Despite advances in chemotherapy andradiation therapy, there was no improvement in survival in patients reportedbefore 1980 compared with patients from 1980 to 1995. Despite initialresection with negative margins, patients may develop local recurrences ordistal metastases years later [50,51]. Recurrences amenable to surgery shouldbe resected to help prolong survival [46].

Olfactory neuroblastoma (esthesioneuroblastoma)

Olfactory neuroblastomas, also known as esthesioneuroblastomas, areaggressive, rare neoplasms derived from the olfactory mucosa present on thesuperior septum, cribiform plate, and upper surface of the superiorturbinate [52]. The ethmoid sinuses are the most common paranasal sinusesto be affected by this neoplasm. The tumor displays a bimodal distributionfor patient age, with peaks in the second and sixth decades of life. Olfactoryneuroblastomas commonly extend intracranially and are associated witha high local recurrence and metastatic incidence. The cervical lymphatics arethe most common site of metastasis, but distant spread may involve thebrain, bones, viscera, and lungs [53].

On histology, low-grade olfactory neuroblastomas exhibit lobulararchitecture with pseudorosette formations, prominent neurofibrillarymaterial, variable calcification, and well-differentiated cells. Higher-gradeneoplasms are characterized by anaplastic tumor cells with increased mitotic


activity. High-grade olfactory neuroblastomas may retain a lobular con-figuration with rosette formation [1].

Standard treatment consists of combined therapy with surgical resectionand postoperative radiation therapy. Craniofacial resection is frequentlynecessary because of the high incidence of anterior cranial fossa involvement.Broich et al [54] reported a 5-year survival rate of 72.5% with combinedtherapy. The survival rates with surgery or radiation alone were 62.5% and53.85%, respectively. Chao et al [55], at Washington University MedicalCenter, observed a 5-year local control rate of 87.4% for combined therapyand51.2% for irradiation alone.Others proposed that craniofacial resection issufficient treatment when negative margins are obtained with limited tumors.Resto et al [53], at Johns Hopkins, obtained complete surgical resection in62% of patients with craniofacial resection. Approximately 80% of patientswith negativemargins had no evidence of disease at amedian follow-up periodof 5.6 years. In patientswith unresectable tumors, chemotherapymay be givenin conjunction with radiation therapy for palliation.

Sinonasal undifferentiated carcinoma

Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressiveneoplasm, which was not described until 1986 [56]. The mean age ofpresentation is the sixth decade of life, and there is a male-to-femaleincidence of approximately 2.5 to 1 [57,58]. Patients present with rapid onsetof symptoms, such as epistaxis, nasal obstruction, cranial nerve deficits, orproptosis. The tumor typically presents with involvement of multiple sinusesand extension through the skull base and into the orbit. The most commonlocations are the ethmoid sinuses and the nasal cavity. Proposed risk factorsinclude smoking and prior radiation therapy [56–58]. Histologically, SNUCis characterized by nests of small- to medium-sized cells with extensivenecrosis. Cells contain numerous mitotic figures, a high nuclear-to-cytoplasmic ratio, and moderate pleomorphic, hyperchromatic nuclei [57].

In a recent review of 36 cases of SNUC, Jeng et al [57] reported a highincidence of metastasis. Approximately 17% of patients had cervical nodeinvolvement and 31% had distant metastasis, most commonly to the liver,lungs, or bone. Various protocols, including surgery, chemotherapy, andradiation therapy, yielded only a 10-month median survival time. All five ofthe patients with no evidence of disease at a median follow-up time of 31months received surgical resection as part of their treatment. Despiteadvances in craniofacial resection, radiation therapy, and chemotherapy,there has not been an improvement in survival times. Duelguerov et al [12]reviewed 30 cases and reported a 10-year survival rate of 33%. The authorsperformed a meta-analysis of cases reported since 1960 and demonstratedno significant improvement in survival rates during the past 40 years. Thesurvival rates for articles from the 1960s through the 1990s were 23%, 42%,30%, and 28%, for each decade respectively.


Lymphoma

Lymphomas of the paranasal sinuses are rare but are the most commonnon–epithelial-derived neoplasm of the sinuses. Lymphomas of thesinonasal tract account for less than 0.2% to 2% of extranodal lymphomasin Western populations [59,60]. There is significant geographic diversity inthe incidence and histology of paranasal sinus lymphomas. In Asianpopulations and in Peru, most cases are T-cell derived neoplasms affectingyoung men. Most Western cases, however, are large B-cell–type lymphomasdiagnosed in elderly men [59–66]. The maxillary sinus is the most commonsite of involvement. Orbital extension is more often associated with diffuse,large B-cell lymphomas, whereas T-cell lymphomas more commonly involvethe nasal cavity [62].

If lymphoma is suspected, it is necessary to send biopsy specimens informalin and in saline to allow permanent section analysis and flowcytometry. A combined modality approach with chemotherapy andradiation therapy is the treatment of choice. A review of 70 patients whohad sinonasal lymphoma and who were treated at M.D. Anderson CancerCenter reported improved prognosis with combined therapy versusradiotherapy alone, yielding a 67% overall survival rate [61]. Cuadra-Garcia et al [62] reported a significantly improved prognosis with patientswho had T-cell/natural killer cell lymphomas treated at MassachusettsGeneral Hospital compared with Eastern reviews. Approximately 11 of 15patients were alive at a median follow-up period of 10 years, compared witha median survival time of 6 to 25 months in Asian populations [67–69].Because T-cell–derived lymphomas are associated with Epstein-Barr virus,diversity of Epstein-Barr strains in the different populations may contributeto the marked difference in disease course [62].

Treatment

Surgical treatment

Amultidisciplinary approach is often used before resection of a paranasalsinus cancer. Patients are presented to a tumor board consisting ofspecialists in head and neck oncologic surgery, medical oncology, andradiation therapy. Imaging studies are reviewed by a neuroradiologist. Aneurosurgeon is consulted if there is skull base involvement anda craniofacial resection is anticipated. Formal ophthalmologic evaluationis helpful when there is concern for orbital involvement. If a patient isexpected to require radiation therapy, the patient is referred to an oralsurgeon so that any needed dental extractions may be performed at the timeof surgery.

The goal of surgical resection is to remove the cancer en bloc, withmargins clear of neoplastic cells. For maxillary sinus neoplasms, maxillec-


tomy is the standard surgical procedure. Numerous modifications, such asmedial maxillectomy, subtotal maxillectomy, infrastructure maxillectomy,suprastructure maxillectomy, and radical maxillectomy, may be useddepending on tumor extent. Neoplasms involving the ethmoid, frontal, orsphenoid sinuses usually require a craniofacial approach because of skullbase involvement.

Before beginning surgical resection, patients receive broad-spectrumintravenous antibiotics. Cefuroxime and metronidazole are most commonlygiven upon entering the operating room and every 8 hours for at least 24hours postoperatively. In addition, 2 to 4 units of blood are made availablefor the patient. After general endotracheal anesthesia, the extent of thetumor is assessed with rigid telescopes and indirect mirror examination ofthe nasopharynx.

The two most commonly used incisions for approaches to the midface andanterior skull base are the lateral rhinotomy and the facial deglovingtechnique. The lateral rhinotomy technique provides access to the nasalcavity, medial third of the maxilla, and the ethmoid sinuses. The incisionbegins in the inferior hairs of themedial one third of the eyebrow. The incisioncurves downward midway between the nasion and the medial canthus. Itcontinues slightly on the nasal side of the nasofacial groove until it curvesaround the ala and into the floor of the nose. The incision is carried deepthrough the periosteum. The medial canthal ligaments may be detached fromthe lacrimal crest in the subperiosteal plane. After periosteal elevation,a curved osteotome is used to make low lateral osteotomies through thefrontal process of themaxilla. The lateral nasal wallmay then be out-fracturedand retracted medially. If a total maxillectomy is required, aWeber-Fergusonincision may be made, which combines the lateral rhinotomy incision with anupper lip–splitting incision. Placing the vertical component of the incision onthe philtral crest minimizes the visibility of the subsequent scar [70–72].

The midfacial degloving technique offers the advantage of avoiding facialincisions. Exposure is compromised, however, in patients with decreaseddistance between the oral commissures [73]. This technique provides accessto the midfacial skeleton, nasal cavity, sinuses, and clivus. Bilateralintranasal incisions include a transfixion, an intercartilaginous incisionalong the cephalic border of the lower lateral cartilage, and an incision alongthe nasal floor. The medial nasal floor incision may include a small Z-plastyor triangular incision to decrease postoperative stenosis. The hemitrans-fixion incisions are connected, and the nasal tip and dorsal nasal soft tissuesare elevated as with a rhinoplasty. The mucosa of the gingivobuccal sulcus isincised between the maxillary tuberosities. The maxillary soft tissues maythen be elevated in a subperiosteal plane to the orbital rims, with exposureof the pterygopalatine fissure. The infraorbital neurovascular bundle ispreserved, if possible, and may be freed with osteotomies [74].

Anterior craniofacial resection is most commonly used for resection oftumors originating in the sinonasal tract with invasion of the floor of the


antezrior cranial fossa. This approach combines a bifrontal craniotomy withtransfacial exposure of the nasal cavity, ethmoid, maxillary, and orbitalregions. If a total maxillectomy is also planned, an upper lip incision isincluded with the lateral rhinotomy incision. The periosteum is elevatedfrom the maxilla, nasal bones, and medial and inferior orbital rims. Acontralateral Lynch incision facilitates elevation of the contralateralperiorbita, control of anterior and posterior ethmoid vessels, and exposurefor osteotomies.

Once transfacial exposure has been obtained, a neurosurgeon performsthe bifrontal craniotomy. An osteoplastic frontal sinus flap may be used inpatients with large frontal sinuses to avoid cosmetic deformity from theplacement of burr holes in the forehead region. A diamond burr may then beused to remove the posterior table to expose the dura. In patients with smallfrontal sinuses, a guarded osteotome is introduced by means of burr holesabove the hairline or in the temporal regions to create the frontal boneflap. Cutting the anterior horizontal bone inferiorly within 1 cm of thesupraorbital rims minimizes the amount of subsequent brain retractionrequired. In the midline, care is taken to separate the superior sagittal sinuscontained in the dural folds from the frontal bone before making the lowerhorizontal bone cut. Once the bone flap is removed, the frontal lobe is thenelevated from the cranial base. The olfactory nerves are severed at thecribiform plate. The dura is then elevated to expose the planum sphenoidale,fovea ethmoidales, orbital roofs, and the base of the anterior clinoidprocesses. If the posterior limit of resection involves the planumsphenoidale, the optic nerve should be decompressed. Removing the opticcanal allows an osteotomy to be made in the planum sphenoidale withdecreased risk of injury to the optic nerve. Optic nerve decompression is notrequired if the posterior limit of resection is limited to the cribiform region.Osteotomies of the zygoma and palate are included if a total maxillectomy isrequired.

Once margins have been cleared and the dura is closed, attention isdirected at reconstruction of the anterior skull base defect. A vascularized,anterior-based pericranial flap is placed over the defect, and the distal endmay be sutured to dura. Because the pericranial flap traverses the frontalsinus, the frontonasal duct should be obliterated. The frontal sinus mayeither be obliterated or cranialized. During closure of the facial wound, themedial canthal ligaments are resuspended to the medial orbital wall. Stentsmay be placed in the canalicular system to help prevent dacrostenosis [75,76].

A less aggressive approach toward orbital exenteration with resection ofsinonasal malignancies has developed during the past century. In the early1900s, all resections for maxillary sinus carcinomas included an orbitalexenteration [77]. With the realization that the entire orbit is lined by aperiosteum (periorbita), which is resistant to tumor infiltration [78], orbitalpreservation became more accepted. Traditionally, if the tumor involves theperiorbita or other intraorbital structures, orbital exenteration is indicated


[79]. Recent articles report similar local control rates with orbitalpreservation in selected cases of infiltration of the periorbita. At theUniversity of Virginia, the invaded periorbita is resected, and the defect isclosed primarily or with temporalis fascia, without reconstruction of thebony orbital wall [80].

Radiation therapy

Radiation therapy is often used with combination therapy, includingsurgical resection. Multiple studies have demonstrated improved survivalwith paranasal sinus malignancies with combined therapy compared withsingle-modality treatment. Patients who have advanced lesions, positivemargins of resection, or regional metastasis should be evaluated forradiation therapy. Before referral for radiation therapy, patients areevaluated by an oral surgeon for extractions of diseased dentition todecrease the risk of osteoradionecrosis. Patients are counseled regardingpotential adverse effects, such as xerostomia, hypothyroidism, middle eareffusions, and blindness. Radiation therapy is typically started approxi-mately 4 weeks after surgical resection.

Chemotherapy

In general, chemotherapy is of limited use for most sinus malignancies.Chemotherapy regimens may be used with radiation therapy for palliationof unresectable neoplasms. Chemotherapy is the primary treatment forparanasal sinus lymphomas, however. Recent studies for aggressive cancers,such as SNUC, have included chemotherapy, in addition to surgery andradiation therapy. Thus far, however, no improvement in overall survivalrates has been demonstrated with such regimens compared with surgery andradiation therapy.

Management of cervical nodes

Regional metastasis to cervical nodes is less common with paranasalsinus malignancies compared with other head and neck sites, such as thenasopharynx, oral cavity, oropharynx, and hypopharynx. Approximately10% of paranasal sinus cancers are found to have regional spread at thetime of diagnosis. The most common locations for cervical involvement arethe submandibular and jugulodigastric nodes [81,82]. Nodal metastasisshould be treated with neck dissection at time of surgical resection of theprimary cancer. The neck should be included in the postoperative radiationfield if there are two or more pathologic nodes or if one node exhibitsextracapsular spread. There are no standard criteria for the treatment of N0neck tumors. The 5-year incidence of post-treatment regional nodal failurewith N0 disease is reported to range from 12% to 29% [81–83]. The risk ofregional failure is higher with SCCs and undifferentiated carcinomas. Jiang


et al [84] reported a regional recurrence rate of 38% with SCC and SNUC atthe M.D. Anderson Cancer Center. Several centers have reported improvedregional control with elective neck irradiation. Patients presenting with T3or T4 maxillary sinus carcinomas routinely receive cervical radiationtherapy [81], whereas physicians at Loyal University of Chicago MedicalCenter use radiation therapy with all maxillary sinus carcinomas [82].Jeremic et al [85] achieved a 10-year regional control rate of 97% withelective radiation and surgical salvage in 44 patients.

Prognosis/outcome

The overall survival prognosis for paranasal sinus malignancies remainspoor. Five-year survival rates range from 35% to 40% [12,86,87]. In Myerset al’s [14] series of 141 patients with paranasal sinus malignancies, an ad-vanced stage, nodal metastasis, and distant metastasis negatively influencedsurvival. Survival rates are higher for maxillary sinus neoplasms comparedwith other paranasal sinuses because of decreased incidence of skull base in-volvement. There is a wide variety in the clinical courses of paranasal sinusmalignancies depending on the histopathologic type. Melanoma and SNUCsare both aggressive neoplasms associated with a dismal prognosis, charac-terized by local recurrence and metastatic spread. In contrast, patients whohave ACC often seem to have no evidence of disease during the first 5 yearsafter treatment. With a long-term follow-up period of 20 years, the most ofthese patients develop a local recurrence or a metastasis.

Summary

Paranasal sinus malignancies are challenging to treat. Most patientspresent with advanced lesions, often with intracranial or intraorbitalextension, and have a poor overall prognosis. Given the low incidenceand diverse pathologies of paranasal sinus cancers, it is extremely difficult toperform prospective, randomized clinical trials to compare differenttreatment approaches. Improving the prognosis of these cancers continuesto be a difficult task, even in light of advances in surgical techniques,radiation delivery techniques, and new chemotherapeutic agents. Cranio-facial resection techniques developed in the past few decades have curedmany patients with skull base invasion, who would have been consideredunresectable in the past. Furthermore, improvements in radiation therapycan allow more accurate administration to the desired region, withdecreased damage to surrounding structures such as the orbit and brain.Aggressive and oncologically sound surgical resection combined withradiation therapy remains the treatment of choice for most patients.Finally, advances in the diagnosis and staging by use of molecular or DNAmarkers of tumor behavior may allow for more directed therapy.


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Organ preservation in patients withsquamous cancers of the head and neck

James K. Schwarz, MDa,*, William Giese, MD, JDb

aDepartment of Medicine, Roswell Park Cancer Institute,

Elm and Carlton Streets, Buffalo, NY 14263, USAbDepartment of Radiation Oncology, Roswell Park Cancer Institute,


In recent years, significant progress has been made in improving survivalin some types of malignancies. In many cancers, survival times have notincreased significantly, but progress has been made in lessening the nega-tive impact that cancer treatments may have on patients. Examples ofthis progress include preoperative chemotherapy and radiation followed bysphincter-sparing surgery for rectal cancer, and multimodality therapy andlimb-sparing surgery for sarcoma. This article addresses issues of organpreservation in the treatment of patients who have head and neck cancers.

The issue of organ preservation in patients who have head and neckcancers often is centered on the larynx. This article, however, adapts abroader perspective to include several head and neck functions that are im-pacted significantly in patients who undergo treatment for head and neckcancer. Box 1 lists physiologic functions that can be altered significantly byeither head and neck cancer or its treatment. This article addresses onlya subset of these issues.

Anatomic organ preservation does not necessarily equate to functionalpreservation. This situation is fairly obvious in the case of radiation-inducedxerostomia, in which the salivary glands are anatomically intact, yetfunctionally impaired. It is less clear in the case of a patient with persis-tent swallowing or speech difficulties after treatment with radiation andchemotherapy.

Furthermore, issues of organ preservation are inexorably linked withquality of life, and this is the impetus for development of treatment regimensthat result in maximum functional organ preservation. Therefore, this article


E-mail address: [email protected] (J.K. Schwarz).


doi:10.1016/S1055-3207(03)00120-0


188 J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

briefly addresses the issue of quality of life in patients who have head andneck cancer before discussing specific functions.

Finally, an article of this type should be able to make recommendationsas to what treatment regimens would be most appropriate for a givensituation. For organ preservation for head and neck cancer, this is a difficulttask. Some reasons for this difficulty include the following: the number ofrandomized trials (particularly trials of surgery versus a nonsurgical modal-ity) are limited, specific functional assessment (subjective and objective) isnot routinely performed in treatment trials, different assessment tools havebeen used in different studies, patients have been assessed at different inter-vals in different studies, and new technical changes in modalities of treat-ment (ie, new surgical techniques, new radiation techniques) have not beencompared with each other.

Radiation as an alternative to surgery: the nature of side effects

and complications

Head and neck irradiation, whether adjuvant or definitive, has certainside effects and complications. Irradiation does result in anatomic organpreservation; however, the larger issue of whether that preserved organremains functional is tainted by patient perception. Although the patientmay be seduced by an alternative that does not include the surgical extir-pation of their tongue or larynx, the risks of full-course head and neck ir-radiation are not trivial. It is therefore important that the advising physicianbe cognizant of the potential temporary and permanent side effects andcomplications of radiation, and that they be fully disclosed.

First, it is necessary to realize that although irradiation may eradicate theprimary tumor and sterilize nodal metastases, it often will not restorefunction of an organ destroyed by tumor. In addition, radiation can havesignificant, long-term detrimental effects on speech and swallowing. Among

Box 1. Functions impacted by head and neck cancers andtheir treatment

SpeechSwallowingSalivary functionHearingDental functionNeuromuscular functionTasteCosmetic function

189J.K. Schwarz, W. Giese / Surg Oncol Clin N Am 13 (2004) 187–199

the other significant radiation-associated factors that affect a patient’squality of life are acute mucositis and acute and long-term xerostomia.

Acute oral mucositis is painful. Good oral hygiene seems to help reducethe temporal appearance and severity of the reaction. Treatment has beenlargely based on patient symptoms, using salt and baking soda gargles/rinsesand antifungal and antibiotic therapy. Preventative measures under inves-tigation include systemic or topical prostaglandins, growth factors, amifos-tine, certain amino acids (glutamine), and photodynamic therapy. The issueis important, because severe mucositis can result in breaks in treatment thatmay translate into a reduced cure rate.

Quality of life in patients with head and neck cancer

Numerous articles have been published on quality of life in patients whohave head and neck cancer [1]. It is difficult to draw definitive conclusionsfrom much of this work, however, for the following reasons: the patientpopulations and their treatments are varied, the tools (subjective andobjective) are varied, and often the patient groups studied are selected froma single institution. In addition, treatment trials (randomized and non-randomized) rarely include prospective and ongoing assessment of organfunction. What is clear is that the quality of life of patients who have headand neck cancer is profoundly impacted by the disease and its treatment,and that treatment choices made by patients and providers are influenced byperceptions of the impact of treatments on the patients’ quality of life [1–4].

Speech

In the early 1980s, the most aggressive treatment option (in terms ofsurvival) for patients with advanced larynx cancers was total laryngectomy,possibly followed by adjuvant radiation therapy. Several phase 2 trialsdemonstrated that some patients with advanced larynx and hypopharynxcancer who responded to induction chemotherapy could be subsequentlytreated successfully with radiation therapy and avoid a total laryngectomy[5–7]. These studies provided the rationale for three trials in which patientswere randomized between initial surgery or induction chemotherapy fol-lowed by radiation for those patients who responded to chemotherapy.

The Veterans’ Administration (VA) trial was initiated in 1985 andrandomized 332 patients with larynx cancer to primary laryngectomy ora nonsurgical approach [8]. The nonsurgical approach started with twocycles of cisplatin and 5-fluorouracil (5-FU) chemotherapy. Patients whodid not have a 50% or greater decrease in the primary lesion after twocycles of chemotherapy underwent surgery. Patients with a 50% or greaterresponse (and no progression in neck disease) received a third cycle ofchemotherapy followed by definitive radiation. Approximately 64% of the


patients assigned to the induction chemotherapy arm had an anatomicallyintact larynx at a median follow-up time of 33 months. There was a slightlydecreased overall survival rate in the induction chemotherapy group, butthis was not statistically significant.

A second randomized trial of similar design was performed by theEuropean Organization for Research and Treatment of Cancer in 194patients who had resectable cancers of the aryepiglottic fold or pyriformsinus [9]. A complete clinical response to two to three cycles of cisplatin and5-FU chemotherapy was required for patients randomized to the nonsurgicalarm to proceed to radiation. Approximately 54% of the patients assigned tothe induction chemotherapy arm achieved a complete response. The 3- and5-year estimates of having an intact larynx in the patients assigned toinduction chemotherapy were 42% and 35%, respectively. Again, there wasno statistical difference in survival between groups assigned to surgery orinduction chemotherapy.

A third trial randomized 68 patients who had laryngeal cancers to eitherinduction chemotherapy followed by radiation or upfront surgery [10].Larynx preservation was achieved in 41% of the 36 patients randomized toinduction chemotherapy, but there was a decreased survival rate for patientsrandomized to the nonsurgical arm. This trial has been criticized for itssmall size, lack of CT scan assessment of the tumor extent at the beginningof the trial, and less stringent evaluation of response after chemotherapy andafter radiation.

A meta-analysis that pooled updated survival data from these three trialsconcluded that there was not a statistically significant difference in thesurvival rates of patients randomized to the two different arms in each ofthese studies [11]. The conclusion from these trials was that, for patientswith large, resectable cancers of the hypopharynx or larynx, a strategy ofinduction chemotherapy followed by radiation for those patients whorespond to chemotherapy is a reasonable treatment option. This strategymay provide comparable survival rates to a strategy of upfront surgery andresult in rates of anatomic larynx sparing of approximately 50%.

Given that these trials were performed to provide support for a larynx-sparing approach, it is important to confirm the benefits of anatomic larynxpreservation in the patients whose larynx was spared versus those whounderwent laryngectomy. The VA trial assessed patients periodically for2 years after treatment for parameters related to speech, swallowing, andemployment [12]. There were no significant differences in swallowing andemployment in the two groups. There was a difference in parameters forspeech and voice, however, favoring the group that received inductionchemotherapy.

Long-term (mean, 10.5 y) follow-up of 46 patients from the VA trial alsohas been reported [13]. Twenty-five of the patients had been randomizedto initial surgery and 21 to induction chemotherapy. In addition, 8 of the21 patients had undergone laryngectomy at some point. The 21 patients


randomized to the induction chemotherapy arm had significantly betterquality of life scores for mental health and pain compared with thoserandomized to surgery. This finding was also true of the 13 patients withanatomically preserved larynges. Furthermore, patient-reported assessmentof speech was not significantly different between any of the groups. Thus,although the self-reported quality of life was better in those patients ran-domized to initial chemotherapy, this could not be attributed to speech.Two things are worth mentioning: (1) the laryngectomy patients may havelearned to adapt well to their state and (2) differences in the domain scoresfor speech were partly minimized because the speech scores for patients withan intact larynx were well below that of healthy control subjects.

Induction chemotherapy followed by radiation (in those who respond tochemotherapy) is currently considered a reasonable treatment option forpatients with larynx and hypopharynx sinus cancers who would otherwiserequire total laryngectomy. Close monitoring of these patients by a headand neck surgeon (particularly during the assessment of response to chemo-therapy) is an intrinsic part of this strategy.

Technical improvements and larynx-preservation strategies

Numerous advances in treatment modalities have been made since thepreviously discussed randomized trials were initiated. With respect to sur-gery, the use of hemilaryngectomy, supraglottic laryngectomy, or supracri-coid laryngectomy may allow for laryngeal voice preservation while stillproviding a sound oncologic operation [14].

Radiation therapy has evolved to include altered fractionation schedulesand powerful new planning techniques, such as intensity-modulatedradiation therapy (IMRT). In addition, the use of chemotherapy concurrentwith radiation has been demonstrated to be superior to radiation alone inseveral randomized trials. The Intergroup Trial R91-11 randomized 547patients with larynx cancers to radiation alone, induction chemotherapy fol-lowed by radiation, or concurrent chemotherapy and radiation [15]. Pre-liminary analysis suggests that concurrent chemotherapy may be superiorto induction chemotherapy followed by radiation or radiation alone forlarynx preservation. It is too early to tell if concurrent chemotherapy andradiation should be considered a standard larynx-sparing approach.

Comparing voice quality in patients treated with different modalities

Numerous studies have been performed documenting quality of speechand voice in patients after treatment for larynx cancers. Few studies haveassessed speech prospectively, however, and measurement of vocal functionis generally not part of treatment trials. It is generally assumed that patientswith an intact larynx will have more favorable speech function than patients


who have undergone a total laryngectomy. This assumption has not beenclearly documented, however. As noted previously, in long-term follow-upfrom the VA trial, patient-reported speech quality of life was similar inpatients with and without an intact larynx [13].

Whether radiation therapy can have adverse effects on larynx function isnot clearly known. Poor vocal function after radiation for larynx cancercould be caused by the treatment or by irreversible damage from the cancer.In patients who have small- to moderate-sized larynx cancers, improvementin self-assessed speech has been shown to occur at 6 months after treatmentwith radiation [16].

As mentioned previously, newer surgical techniques involving less thana total laryngectomy may allow for reasonable voice production [14]. Thistype of surgery can also obviate a permanent tracheostomy. Because atracheostomy contributes significantly to negative quality of life [17], sur-gical options that avoid this procedure will result in improved quality of life,regardless of vocal function.

Options for speech rehabilitation in patients who have undergone a totallaryngectomy include an electrolarynx, esophageal voice, and esophagealvoice with augmentation by a tracheoesophageal prosthesis (TEP) [18].

Voice function in patients who have larnyx cancer treated with radiationhas been compared with voice function in patients who have had a totallaryngectomy and speech rehabilitation with a TEP [19,20]. The perceptionof speech by trained and untrained listeners was higher in patients who hadreceived radiation, but the difference was not large. In addition, there wereclear differences in patients who had received radiation compared withcontrol subjects who did not have larynx cancer. Most of the poor voicequality in the patients who received radiation is likely caused by irreversibledamage from the cancer rather than the radiation, but this is not knownwith certainty [21]. Furthermore, although a TEP can result in good voicequality, this approach has not been successful in some patients.

Patients who have advanced larynx cancer, in whom a total laryngectomytraditionally would be considered, often have significant impairment ofvoice before treatment. Oncologically successful treatment of this popula-tion with radiation should not be expected to restore excellent vocalfunction in most of these patients. Surgical procedures that preserve someform of laryngeal voice and avoid a permanent tracheostomy have thepotential to be associated with quality of life that might equal that asso-ciated with nonsurgical treatments.

Swallowing

There are at least two basic considerations when evaluating swallowingfunction in patients who have head and neck cancer: (1) the ability toswallow itself and (2) whether there is aspiration.


Patients who have head and neck cancer often have abnormal swallowingbefore treatment. In one study using videofluoroscopy, 11 of 27 patientswith advanced head and neck cancers were found to have aspiration [22].Impairment of swallowing was more closely associated with hypopharynxand larynx cancers in another study [23], whereas in a third series, patientswith larynx cancers did not have the worst swallowing function [24]. Thus,patients who have advanced head and neck cancers often have abnor-mal swallowing function before treatment, and a nonsurgical treatment ap-proach may not result in restoration of function, even if the treatment iseffective.

Swallowing after surgery for patients with head and neck cancers

Much of the literature concerning swallowing function after surgery hasfocused on patients who have base of tongue cancer. Harrison et al [25]reported that, in patients with base of tongue cancer, swallowing functionwas better in those patients treated with radiation rather than surgery. Alater series from the same institution noted that patients treated surgicallymay have swallowing function that is more comparable to patients treatedwith radiation [26]. The extent of surgical resection for the base of thetongue is hard to quantify, however, and the experience and opinion of theconsulting surgeon is invaluable in estimating the degree of swallowing func-tion to be expected after surgery.

Surgery for head and neck cancer in sites other than the tongue of headand neck cancer surgery can result in difficulty swallowing, but modernmethods of reconstruction have had reasonable functional outcomes [27–30].

Radiation can have detrimental effects on swallowing function (discussedlater), and patients treated with postoperative radiation have had swal-lowing function that is inferior to patients treated by either surgery or radia-tion alone [31].

Radiation effects on swallowing

Swallowing symptoms after radiation in patients who have head andneck cancercan been separated into those symptoms that are caused byxerostomia versus a mechanical problem with the tongue or pharyngealfunction [32,33]. Patients with xerostomia may or may not have difficultieswith the mechanical act of swallowing.

Swallowing abnormalities after radiation have been documented [34–36].Swallowing changes have been attributed to decreased compliance in tissuesafter radiation.

Several randomized trials have demonstrated that administration ofchemotherapy concurrent with radiation has been associated with morefavorable outcomes for control of disease and survival compared withradiation alone. This type of treatment also has been clearly associated with


more severe short-term toxicity, particularly mucositis. It is possible thatlong-term swallowing problems are more prevalent in patients treated withconcurrent chemotherapy and radiation.

Severe, long-term swallowing problems also have been noted in severalphase 2 trials of concurrent chemotherapy and radiation [35,37–41]. In someof these trials, the chemotherapy regimens are experimental and may re-sult in greater toxicity than more commonly used regimens. For example,in a trial in which gemcitabine was used concurrent with radiation (in pa-tients with mostly oropharynx and nasopharynx cancers), 14% of patientsaspirated pretreatment versus 62% post treatment.

The randomized trials of concurrent chemotherapy and radiation versusradiation alone did not report long-term swallowing function, however.Thus, although the results of concurrent chemotherapy and radiation areattractive from a survival standpoint, quality of life and swallowing in par-ticular need to be carefully evaluated in these patients [42].

Salivary function

Radioprotective agents

The concept that certain agents taken systemically might render a pro-tective effect against ionizing radiation is not new [43]. WR-2721 (com-monly known as amifostine; trade name, Ethyol) was developed circa WorldWar II by the US Army at the Walter Reed facilities with the hope it mightprove protective to troops in the field when and if they became exposed toatomic fallout. The prodrug form becomes dephosphorylated to form anactivated free thiol, WR-1065 [44]. This free-radical scavenger is concen-trated preferentially by normal rather than tumor cells [45]. The precisereasons for this behavior is unclear, but may be because of the lower con-centration of alkaline phosphatase in tumor tissue [46].

Data from randomized trials have concluded that amifostine reducesboth acute and chronic xerostomia in patients who have head and neckcancer, with no evident tumor protection [47]. The drug has received Foodand Drug Administration approval to be marketed for that purpose, but islimited to intravenous administration at 200 mg/m2 daily, given just beforeirradiation. The drug may be useful for radiation-induced mucositis as well.Practically, the drug seems to be tolerable for some patients, althoughhypotension, nausea, and rash (both in and outside the irradiated portals)limit its use in others. Pretreatment hydration and antiemetic agents seem tobe helpful.

Another agent with a differing mode of action touted as potentially usefulin the prevention or treatment of radiation-induced xerostomia is pilocarpinehydrochloride. This parasympathomimetic agent stimulates secretion fromsalivary glands. The theory is that stimulation of output from those acinithat remain functional translates into a reduction in the sensation of dry-


ness. A recent phase 3 placebo-controlled trial failed to demonstrate a benefitwith respect to subjective parameters of swallowing and taste. This wasdespite statistically significant presence of salivary output in the pilocarpinearm [38]. This study limited eligibility to a planned dose of more than 50 Gyto at least 50% of both parotid glands. The output of major salivary glandsdecreases with doses of 10 Gy and worsens with dose escalation. If IMRT canbe used to limit a significant portion of the total volume of major salivarygland tissue to below this dose, this output stimulation may prove beneficial.

Limiting salivary gland exposure to radiation

Another avenue for the reduction of the xerostomia inherent to head andneck irradiation is to limit the dose that the salivary gland receives. It hasbeen theorized that this may be accomplished through the use of computer-generated three-dimensional dose distributions that conform to the tumorand tissues deemed at risk, while limiting dose to a sufficient volume of thesaliva-producing organs. Although research has largely focused on themajor salivary glands (parotids and submandibular/sublingual complex),the sparing of minor salivary gland–rich tissues is also protective.

IMRT uses sophisticated computer algorithms to design a treatmentbeam array. It is the intersection of multiple noncoplaner beams that resultsin the dose delivered to any one point. The physician must first define theacceptable radiation exposure to all tissues, both those that are normal andthose at risk. The computer modulates fluence as a function of entry anglefor each defined point and simply ‘‘grinds out’’ a plan by shear power ofrepetition in a trial-and-error format, a function uniquely suited to this tool.

Cheng et al [48] compared the fractional volume of parotid gland receiv-ing 30 Gy by conventional versus other techniques and showed that IMRTnearly reduced this volume by half (from 93% to 48%). Chao et al [49]noted that, whereas limiting parotid gland dose resulted in both an objective(stimulated and unstimulated salivary flow rate) and subjective improve-ment of quality of life scores (by quality of life questionnaire), both currentIMRT and non-IMRT techniques could achieve this.

There exist logistical constraints to these approaches, however. Perhapsmost important, it remains unclear just what daily and overall dose isappropriate for closely juxtaposed structures heretofore similarly exposed.Although the appropriate doses should become clearer with the test of timeand analysis of failure patterns, close follow-up and frequent reimagingare mandatory. Physicians need to weigh the risk of locoregional failure,a potentially life-threatening event, to the possible benefit of some degree ofsalivary gland sparing that, although uncomfortable, remains tolerable.

A current technique to reduce xerostomia is to physically transfer thesubmandibular gland to a region of the head and neck outside theanticipated irradiation portal. Surgical relocation of this gland to the sub-mental space is technically feasible; however, it applies to those patients


deemed surgical candidates and, perhaps more significantly, is limited tothose in which the submental space can safely be shielded. In general,eligibility criteria limit applicability to squamous cell carcinomas of theoropharynx, hypopharynx, and larynx, with either no or unilateral necknode involvement [50]. This technique is also limited to those surgeonsfamiliar with how to move the particular gland with limited trauma to thegland duct. In experienced hands, this technique seems to be useful.

Neuromuscular function

Neck function can be significantly altered by surgery and radiation.Radiation can result in long-term decreased mobility of the neck tissues [51].Surgical morbidity associated with neck dissection depends largely on theextent of surgery; sparing of the spinal accessory nerve, sternocleidomastoidmuscle, and internal jugular vein are associated with improved function[52–55].

In patients who have advanced head and neck cancers (ie, the patients forwhom the question of organ preservation is an issue), treatment decisionsconcerning the neck often necessitate using both surgery and radiation.Thus, the development of treatment strategies that result in improvedoutcomes in neck function have lagged behind that of the primary sites.For example, a clinically complete response to primary radiation alone inpatients with N2 or N3 disease in the neck would typically require a neckdissection. It is not known if a neck dissection is required after a completeresponse following concurrent chemotherapy and radiation for patients withN2 or N3 nodal disease [56].

Summary

Treatment strategies that have the potential to improve functional organpreservation in patients who have head and neck cancer are emerging. Clin-ical research in this field, however, has been limited by the lack of stan-dardized, objective criteria of organ function post treatment and by lack ofprospective assessment of organ function in treatment trials [56]. Advancesin surgical techniques, radiation techniques, radiation protectants, andcombined-modality therapies are promising, but well-planned and executedclinical trials are necessary to determine how best to apply these techniquesto patient care.

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Melanoma of the head and neck: currentconcepts in staging, diagnosis, and

management

Maher N. Younes, MD, Jeffrey N. Myers, MD, PhD*Department of Head and Neck Surgery, University of Texas M.D.

Anderson Cancer Center, Box 441, 1515 Holcombe Boulevard,

Houston, TX 77030-4009, USA

Cutaneous malignant melanoma (CMM) is an aggressive malignantneoplasm of the melanocytes. CMM is less common than basal cell andsquamous cell carcinoma (SCC), but far more fatal. Therefore, earlydetection is paramount and is associated with a high chance of cure. Incontrast, late-stage disease has a dismal chance for cure. Because as many asone third of CMMs arise from the skin of the head and neck region, it iscritical that head and neck surgeons have a thorough understanding of thenatural history, diagnosis, staging, and treatment of CMM. It is alsoimportant that clinicians are aware of the less common types of melanomaarising in the head and neck, including mucosal melanoma and desmoplasticmelanoma.

Epidemiology

It is estimated that cutaneous melanoma of the skin comprised 5% and4% of all new cancer cases in the United States among men and women,respectively, in 2002 [1]. This statistic makes CMM the fifth and the sixthmost common cancer in the United States among men and women,respectively [1]. In 2002, it was estimated that 53,600 new cases of CMM andabout 34,300 new cases of melanoma in situ were diagnosed. In the UnitedStates, the lifetime risk for developing CMM is 1.72% (1 in 58) for men and1.22% (1 in 82) for women. This lifetime risk increases with age (0.13%at birth, up to 0.97% at 60–79 y for men; 0.19% at birth, up to 0.49% at


E-mail address: [email protected] (J.N. Myers).


doi:10.1016/S1055-3207(03)00125-X


202 M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

60–79 y for women) [1]. The overall incidence of CMM is increasing at adisturbing rate of 5% per year. In 1935, the estimated lifetime risk of develop-ing CMM was 1 in 1500. In 2001, it was estimated that 1 in 75 Americansdeveloped CMM (Fig. 1) [2].

Primary melanoma of the head and neck accounts for approximately25% to 35% of all melanomas, although the head and neck region accountsfor a mere 9% of the total body surface area [3]. There are many reasons forthat predilection to the head and neck area, including sun exposure and theregional variation in the skin distribution of melanocytes, because themelanocytic content in the head and neck is 2 to 3 times higher than it iselsewhere in the body [4].

There are different sites in the head and neck region where CMM can befound. The most common sites in decreasing order are the skin of the cheek(46%), neck (20%), scalp (18%), external ear (125), nose (2%), and eyelids

Fig. 1. Incidence and mortality rates by gender. (From Ries LAG, Eisner MP, Kosary CL,

Hankey BF, Miller BA, Clegg LX, Edwards BK. The Surveillance, Epidemiology, and End

Results [SEER] Cancer Statistics Review 1973-1997; National Cancer Institute: Bethesda, MD,

2000. NIE pub. no. 00-2789; with permission.)

203M.N. Younes, J.N. Myers / Surg Oncol Clin N Am 13 (2004) 201–229

(1%) [5]. In addition, the survival rates differ depending on the specificlocation of the melanoma in the head and neck, with the skin of the scalptumors with the worst rate, followed by those of the temple, ear, cheek, andneck (Fig. 2) [6].

Mortality

The number of deaths attributed to melanoma was projected to beapproximately 7400 persons in the United States for 2002 [1]. Thisrepresents a 2% annual surge in total mortality since 1960. The explanationfor this increase in mortality is a parallel increase in incidence. Despite of theincrease of melanoma, the 5-year survival rates for all ethnic groups inthe United States for CMM is on the rise: from 80% for 1974 to 1978, to

Fig. 2. Actuarial survival rates by site of primary tumor for patients with melanoma of the head

and neck. (From Ames FC, Sugarbaker EJ, Ballantyne AJ. Analysis of survival and disease

control in stage I melanoma of the head and neck. Am J Surg 1976;132:484–89; with

permission.)


85% for 1983 to 1995, to 89% for 1992 to 1997 [1]. These rates can beattributed to an increase in earlier detection of the disease, allowing moreeffective treatment in the earliest stages, rather than to a true improvementin treatment.

Causes and risk factors

Sun exposure

The most important predisposing factor in the development of CMM isexposure to sunlight. Studies have shown that excessive lifetime exposure tosunlight, intermittent exposure to sunlight, and a history of sunburns arerisk factors for developing CMM later in life. Whether cumulative exposureversus early exposure is more important is still a debatable issue. Manyinvestigators believe that intermittent, acute exposure during childhood andadolescence is more damaging to the skin [7].

Ultraviolet (UV) B radiation (280–320 nm) has long been believed to bethe most critical factor in the pathogenesis of CMM; however, recentevidence shows that UV-A (320–400 nm), and even visible light radiation,may also play a role [8].

Because of the pivotal role of sunlight exposure in the development ofCMM, much interest has been focused on prevention strategies, includingthe use of sunscreens. Although there is an expanding body of epidemiologicevidence for the effectiveness of sunscreens in the prevention of CMM [9],there is also evidence for their inefficiency. The conclusions drawn froma European case control study [10] and one animal study [11] suggest thatsunscreens may not be protective. There are several reasons behind thiscounterintuitive finding. First, sunscreens help in preventing or, at leastdelaying, the development of sunburns, the body’s alarm system againstsunlight overexposure. This in turn induces a ‘‘safe’’ feeling among users,which results in longer time exposures to sunlight. Second, most sunscreensare effective against UV-B, not UV-A or the visible light spectrum, both ofwhich have been implicated in the pathogenesis of CMM.

Despite the conflicting data, there is a consensus that sun protection in itsdifferent forms: sunscreens, protective clothing [12] and hats, and a decreasein daily exposure to sunlight, particularly between 10 AM and 2 PM, is anintegral part of an overall sun protection regimen [13,14]. These practiceshave been tested in Australia, where it has been shown that the incidence ofCMM can be decreased and the melanomas that develop can be diagnosedearlier by raising public awareness through education [15].

Precursor lesions

Most patients who have head and neck melanoma have a history of a pre-existing lesion. One report found that one third of melanomas arise from


congenital nevi, one third arise in nevi present for more than 5 years, andone third arise in newly acquired nevi (nevi present for\5 y) [16].

Three types of lesions are known to be precursors to CMM. Congenitalnevi are usually present at birth. Patients with large congenital nevi (>20cm) have a lifetime risk between 5% and 20% for developing CMM [17].Dysplastic nevi may either occur sporadically or as a part of a familialsyndrome called dysplastic nevus syndrome (DNS). The lifetime risk forCMM in the sporadic form is unknown, but the lifetime risk of CMM in theDNS is believed to be close to 100% [18]. Lentigo maligna is considered tobe a preinvasive lesion of lentigo maligna melanoma and frequently occurson the head and neck region. The rate of progression of lentigo maligna tomelanoma is between 5% and 33% [18].

Patient characteristics

Certain phenotypic characteristics increase the risk for developing CMM.These characteristics include blue or green eyes, blonde or red hair, a faircomplexion, a freckling pattern, and an inability to tan [19]. Rigel [20] usedmultivariant analysis to identify six independent risk factors for CMM:family history, freckling of upper back, blonde or red hair, history of 3 ormore years at an outdoor job as a teenager, history of 3 or more blisteringsunburns before the age of 20 years, and presence of actinic keratosis.Individuals with one or two of these risk factors had a fivefold increased riskof developing CMM, whereas those with three or more factors hasa twentyfold increased risk [20].

Genetics

Familial melanoma/dysplastic nevus syndromeMembers of familial melanoma and DNS families have a lifetime risk for

developing CMM approaching 100% [21]. Linkage analysis has shown theinvolvement of several genes. An early, unconfirmed study that showed alinkage of familial melanoma to chromosome 1p36 was followed by multiplestudies that demonstrated linkage to chromosome 9p21 [22–25]. Subsequentinvestigations showed that the gene of interest at 9p21 was the previouslydescribed p16 gene [26].

Xeroderma pigmentosumXeroderma pigmentosum (XP) is a hereditary syndrome that predisposes

individuals to the development of skin cancers. This rare autosomal-recessivedisease increases the risk of skin cancer in individuals with this syndrome by1000 times more than that of the general public. Clinical features of XPinclude early onset of freckling (by age 2 y) and multiple skin cancers,including SCC, basal cell carcinoma, and melanoma. The onset of skincancers often occurs in individuals younger than 10 years who are affectedwith this syndrome [27].


Patients with XP are hypersensitive to the sun, and skin cells in thesepatients exhibit decreased survival and increased mutagenesis after UVradiation because of defects in nucleotide excision repair [28]. Thepathogenesis of skin cancers in XP patients highlights the important rolefor UV-induced DNA damage in the development of all three types of skincancer.

Pathology

Lentigo maligna melanoma

Lentigo maligna melanoma is the least common subtype of melanoma,comprising 5% to 10% of all cases. Its main characteristics includea prolonged radial growth phase, which may last for decades. Therefore,these tumors are fairly slow to invade. The neoplastic melanocytes remain atthe dermoepidermal junction, and the intraepithelial growth is along hairfollicles and sweat ducts. A differentiating feature of lentigo malignamelanoma from lentigo maligna lies in the requirement of this melanoma toinvade into the papillary dermis.

Superficial spreading melanoma

Superficial spreading melanoma is the most common subtype, accountingfor 75% of cases. It is marked by an initial radial growth spread that iseventually followed by a vertical growth, which can be heralded by ulcerationand bleeding. The melanocytic neoplastic cells are uniform, formingaggregates in all levels of the epidermis. The hallmark feature of this formof melanoma is that all tumor cells, although atypical, maintain a uniformappearance throughout the epidermis.

Nodular melanoma

Nodular melanoma accounts for 10% to 15% of all melanoma cases. It ischaracterized by a lack of radial growth and early vertical growth. It isinvasive almost from the onset.

Desmoplastic melanoma

This subtype of melanoma is characterized by a dermal population ofspindle cells among a fibrous stroma, a pattern that has been likened toa ‘‘school of fish.’’ These lesions are often not pigmented. These lesions alsohave been found to infiltrate and expand nerves and may show neural-likedifferentiation. When this occurs, the term ‘‘neurotropic melanoma’’ is oftenused. This affinity for perineural spread is crucial to consider duringevaluation and treatment [29].


Diagnostic evaluation

History

The key to effective treatment of malignant melanoma lies in earlyrecognition and diagnosis. Either the patient or a family member detectsapproximately 75% of the cases, with the remaining 25% detected byphysicians [30]. The most common presenting signs are color change orgrowth of a pre-existing lesion. In addition, other signs may include itching,bleeding, ulceration, paresthesis, and pain. These signs usually are ominous,late signs, which occur more often in thick melanomas rather than thin ones.Physicians need to ask patients about overall sun exposure, family history ofmelanoma, and about their history of sunburns.

Physical examination

A comprehensive assessment of the total number and types of molespresent is required. Physicians should look for congenital nevi, dysplasticnevi, and lentigo malignas. On examination, a bright light and a magnifyinglens are needed to assess the size, color, border, and surface characteristics(irregularly raised) of moles. Hallmarks of melanoma include the following:(1) variation in color, (2) irregularly raised surface, (3) an irregular border,and (4) ulceration. These features are what characterize benign frommalignant lesions.

ABCD checklist

The ABCD checklist is used by clinicians to identify potentiallymalignant lesions [31]. The following clinical factors are included:

Assymetry. Assymetric growth patterns are caused by uneven growthrates.

Border irregularities. Lesions that show border irregularities are likely tobe melanoma.

Color variegation. Differential coloring and shading indicates malignantpotential, especially red, white, and blue [32].

Diameter. Any increase in the size of a lesion, or a diameter greater than6 mm, is suspicious.

All these factors have been found to predict malignant lesions to a varyingdegree, with border irregularity being the strongest predictor [33].

Biopsy

All suspicious lesions should undergo biopsy to confirm the diagnosis ofmelanoma and for accurate staging once the diagnosis is established. Inaddition, the biopsy method of choice should not interfere with subsequent


resection and reconstruction efforts if needed later on. Several methods ofbiopsy are available to clinicians to choose from.

If the lesion is small and the location is amenable, excisional biopsy with1- to 2-mm margins is recommended. Patients who underwent excisionalbiopsy have had better overall survival rates [34]. Furthermore, excisionalbiopsy does not interfere with or affect subsequent staging procedures, suchas lymphoscintigraphy, compared with wide local excision (WLE). WLEbefore lymphscintigraphy makes it difficult to accurately access sentinellymph nodes (SLNs) and drainage basins [35].

For lesions that are either large or inaccessible to excisional biopsywithout significant disfiguration, incisional biopsy through the thickest partof the tumor is recommended. Punch biopsies, if they encompass the entirethickness of the tumor, are sufficient and easy to perform in the office or theclinic. Needle and shave biopsies of the primary tumor are stronglydiscouraged because they do not properly assess the thickness, which iscritically important for further treatment options. Needle biopsies are usefulto assess suspicious lymph nodes or distant metastasis, however.

Staging

Anatomic location of the primary tumor

Numerous studies have shown the prognostic significance of anatomicsite of the primary tumor on survival rates. In an analysis of prognosticfactors in 8500 patients with CMM, Balch et al [36] showed that patientswith head and neck primary tumors are believed to have a worse prognosisthan patients with extremity tumors. Although controversial, several studieshave revealed that patients with tumors arising in the so-called ‘‘BANS’’region (upper back, upper arm, posterior neck, and scalp) have lowersurvival rates than those individuals with tumors arising in non-BANSregions [37,38].

A review from the M.D. Anderson Cancer Center revealed thatmelanoma lesions on the scalp do significantly worse than lesions on theear, face, and neck (see Fig. 2) [39]. This finding has been confirmed by otherstudies [40,41].

Depth of invasion

During the 1960s, the landmark histologic staging of Clark [42], whodefined the levels of invasion, was set. The depth of invasion became themost important prognostic factor for stage I and stage II melanoma tumors.Breslow [43], however, demonstrated the importance of tumor thickness.Currently, Breslow thickness represents a more powerful prognostic toolthan do Clark’s levels, although both remain widely used in the literatureand in clinical practice (Table 1).


American Joint Committee on Cancer

First published in 1978, the American Joint Committee on Cancer(AJCC) staging system of CMM has undergone several changes in an effortto incorporate current knowledge into each version. It is based on thetumor-node-metastasis (TNM) classification and incorporates the Breslowsystem into the primary tumor stages.

In 2002, the AJCC published a new staging system for CMM (Box 1) [44].This new melanoma staging system includes five major changes from the1997 version as follows [45]:

1. Level of invasion (Clark’s level) is replaced by tumor thickness, withcutoff levels of 1 mm, 2 mm, and 4 mm, as the prognostic variable ofprimary tumor invasion that best predicts survival.

2. Ulceration of the primary tumor is included in this system, and patientswith ulceration in each T-stage subgroup are upstaged accordingly.

3. The number of lymph nodes involved in staging replaces the size oflymph nodes.

4. Patients are categorized into clinical and pathologic staging toincorporate lymphatic mapping data and micrometastatic disease.

5. Subcategorization of stage IVmetastatic disease is based on anatomic siteand inclusion of an elevated serum lactate dehydrogenase (LDH) [46,47].

6. Distinct definitions for clinical and pathologic staging incorporate thenew staging information gained from intraoperative lymphatic mappingand SLN biopsy [48].

Staging: clinical versus pathologic

In the past, the TNM classification system of melanoma had beenbroadly based on a clinical staging system that recognized three generalcategories: (1) localized melanoma (stages I and II), (2) regional disease

Table 1

Histopathologic staging systems—Clark’s levels and Breslow thickness

Classification Characteristics

Clark’s levels

I Lesions involving only the epidermis (in situ melanoma); not an

invasive lesion

II Invasion of the papillary dermis but does not reach the papillary-

reticular dermal interface

III Invasion fills and expands the papillary dermis but does not penetrate

the reticular dermis

IV Invasion into the reticular dermis but not into the subcutaneous tissue

V Invasion through the reticular dermis into the subcutaneous tissue

Breslow thickness stage

I �0.75 mm

II 0.76–1.50 mm

III 1.51–4.0 mm

IV �4.0 mm


Box 1. Revised AJCC TNM classification

T classificationT1: 1.0 mm or less

(a) without ulceration(b) with ulceration or level IV or V

T2: 1.01 to 2.0 mm(a) without ulceration(b) with ulceration

T3: 2.01 to 4.0 mm(a) without ulceration(b) with ulceration

T4: greater than 4.0 mm(a) without ulceration(b) with ulceration

N classificationN1: one lymph node

(a) micrometastasisa

(b) macrometastasisb

N2: two to three lymph nodes(a) micrometastasis(b) macrometastasis(c) in-transit metastasis/satellites without metastatic lymph

nodesN3: four or more lymph nodes, matted lymph nodes, or

combinations of in-transit metastasis/satellites andmetastatic lymph nodes

M classificationM1: distant skin, subcutaneous, or lymph node metastasis;

normal LDH levelsM2: lung metastasis, normal LDH levelsM3: all other visceral or any distant metastasis, elevated LDH

levels

a Micrometastases are diagnosed after sentinel or elective lymphadenectomy.b Macrometastases are defined as clinically detectable lymph nodemetastases

confirmed by therapeutic lymphadenectomy or when any lymph nodemetastasis exhibits gross extracapsular extension.

From Balch CM, Buzaid AC, Atkins MB, Cascinelli N, Coit DG, Fleming ID,Houghton A Jr, et al. A new American Joint Committee on cancer staging systemfor cutaneous melanoma. Cancer 2000;88(6):1484–91; with permission.


(stage III), and (3) distant disease (stage IV) [49]. Because of major advancesin the diagnosis and staging of CMM brought about primarily by thedevelopment of SLN mapping and/or biopsy for the identification ofmicrometastases, however, the new AJCC staging system incorporatesclinical and pathologic staging (Table 2).

The AJCC melanoma staging committee recommends that, whenpossible, nodal staging should be performed and that, for clinical trials,nodal staging is particularly important. Early-stage (I and II) localizedmelanoma is a primary tumor without evidence of lymph node metastasis.Ulceration of the primary tumor up-stages each T stage [50]. A new stagingcategory of IIC was designed for ulcerated T4 lesions. The IIC patients havean equivalent prognosis as those with multiple metastatic lymph nodes [51].The hallmark of stage III is the involvement of regional lymph nodes. Thepresence of micrometastasis in the lymph nodes using SLN biopsy isdifferentiated by the pathologic staging [52]. Patients with multiple lymphnode metastases and ulcerated primary tumors do worse are categorized ashaving stage IIIC disease. Similarly, satellite or intransient metastases havea poor prognosis and are up-staged to IIIB. Stage IV is defined by distantmetastasis and remains the same in the new system.

Pretreatment evaluation by stage

Although there are general stage-specific guidelines, each patient’sevaluation and treatment should be individualized. The general guidelinesfollowed at the M.D. Anderson Cancer Center are summarized in Table 3and are available at www.mdanderson.org. Similar guidelines are availablefrom the National Comprehensive Cancer Network at www.nccn.org andthe National Cancer Institute at www.nci.nih.gov.

In situ and/or Clark’s level I lesions are effectively treated with WLE andrequire no further workup. In asymptomatic patients with primarymelanoma (stage I or II), a chest radiograph and an evaluation of LDHlevels is recommended [50]. For patients with lesions of intermediatethickness (1–4 mm) and thin lesions that are either ulcerated or extend intoClark’s level IV, preoperative lymphoscintigraphy is warranted, especially ifelective lymph node dissectionmay be part of the treatment plan. For patientswith thick lesions (>4 mm) or those who have regional metastatic orrecurrent locoregional disease, a more comprehensive workup is recom-mended. For this patient population, there is a high risk for distantmetastasis, and therefore consideration should be given to a metastaticworkup (complete blood count; liver function tests, including alkalinephosphatase and LDH levels; a CT of the chest, abdomen, and pelvis; andMRI of the brain). All patients with clinically evident regional disease (stageIII) must undergo imaging of the cervical lymphatics andmetastatic screening(CT or ultrasound of the head and neck, chest radiograph, and LDH). Forpatients with signs or symptoms of metastatic disease, selective metastatic


imaging should be performed. Finally, patients with known systemic disease(stage IV) should be more comprehensively evaluated. Accordingly, theyrequire a full metastatic workup, including the following: chest radiograph;LDH levels; CT or ultrasound of the head and neck; CT of the chest,abdomen, and pelvis; and MRI of the brain. Other studies (eg, gastrointes-tinal series, bone scan) are performed according to symptoms [53].

Newer modalities, including positron emission tomography (PET), andtheir role in the detection of melanoma of the head and neck are currentlybeing investigated. PET is one of the new modalities that has shown promisein detecting regional andmetastatic lesions; however, its role in the evaluationand follow-up of patients with CMM awaits further studies [54–56].

Table 2

New stage groupings for cutaneous melanoma

Clinical staginga Pathologic stagingb

Stage T N M T N M

0 Tis N0 M0 Tis N0 M0

1A T1a N0 M0 T1a N0 M0

1B T1b N0 M0 T1b N0 M0

T2a N0 M0 T2a N0 M0

IIA T2b N0 M0 T2b N0 M0

T3a N0 M0 T3a N0 M0

IIB T3b N0 M0 T3b N0 M0

T4a N0 M0 T4a N0 M0

IIC T4b N0 M0 T4b N0 M0

IIIc Any T N1 M0 — — —

— N2 — — — —

— N3 — — — —

IIIA — — — T1–4a N1a M0

— — — T1–4a N2a M0

IIIB — — — T1–4b N1a M0

— — — T1–4b N2a M0

— — — T1–4a N1b M0

— — — T1–4a N2b M0

— — — T1–4a/b N2c M0

IIIC — — — T1–4b N1b M0

— — — T1–4b N2b M0

— — — Any T N3 M0

IV Any T Any N Any M1 Any T Any N Any M1

a Clinical staging includes microstaging of the primary melanoma and clinical/radiologic

evaluation for metastases. By convection, it should be used after complete excision of the

primary melanoma with clinical assessment for regional and distant metastases.b Pathologic staging includes microstaging of the primary melanoma and pathologic

information about the regional lymph nodes after partial or complete lymphadenopathy, except

for pathologic stage 0 or stage 1A patients, who do not need pathologic evaluation of their

lymph nodes.c There are no stage III subgroups for clinical staging.

Data from Balch CM, Buzaid AC, Atkins MB, Cascinelli N, Coit DG, Fleming ID,

Houghton A, Jr, et al. A new American Joint Committee on Cancer staging system for

cutaneous melanoma. Cancer 2000;88(6):1484–91.


Management

General treatment options

SurgerySurgery is well accepted as the primary treatment modality for CMM.

Complete surgical excision is recommended in most patients who have localor regional disease in the absence of systemic disease. Recent studies haveindicated that a 2-cm margin around the primary tumor for intermediate-thickness melanoma is sufficient [57]. For thinner lesions, 1-cm marginsprovide equivalent local control and survival [58]. A crucial reminder is thatthese recommendations are derived from studies of truncal and extremitymelanoma and that, in the head and neck, the surgeon may not have theluxury of being able to take 1- to 2-cm margins without running the risk ofsignificant functional disability or cosmetic deformity.

A sound knowledge of the anatomy of the pathways of lymphatic spreadfor CMM of the head and neck is essential. It is generally accepted thatclinically positive neck disease requires surgical treatment. In these patients,it is important to address all the intervening lymphatics between the primarytumor and the positive node or nodes. The type of neck dissection must betailored to the disease.

The treatment for clinically N0 neck disease is less definite. Patients withstage I disease have a low rate of occult metastasis and thus may not needsurgical treatment of the neck. In contrast, a substantial number of patients

Table 3

Recommendations for workup based on stage

Stage Workup

Melanoma in situ None

Stage I or II CXR, LDH

Stage I or II with ulceration or T3 CXR, LDH; consider lymphoscintigraphy

T4 or recurrent primary melanoma CXR, LDH

Consider metastatic imaging (CT of chest, abdomen,

pelvis, MRI of brain)

Stage III CXR, LDH (CT or US of the neck for regional

lymphatics); consider metastatic imaging for patients

with signs and symptoms of metastatic disease

Stage IV CXR, LDH, metastatic imaging (CT or US of

the head and neck, CT of abdomen, pelvis, chest,

MRI of brain)

Abbreviations: CXR, chest X ray; US, ultrasound.







AJCC.


with stage II disease harbor an occult regional metastasis and need to beconsidered for elective treatment. To date, there are no prospective data tosupport the use of any elective neck dissection for N0 neck disease toimprove either locoregional control or overall survival.

The most commonly used elective treatment is elective neck dissection(END). If END is undertaken, it should be guided by a comprehensiveknowledge of the pathways of lymphatic spread (Fig. 3). In general, tumorsarising on the scalp and the forehead anterior to a line drawn through theexternal auditory canal most commonly spread to the parotid/periparotidlymph nodes and upper jugular lymph nodes; thus, a parotidectomy andlateral neck dissection are recommended. Tumors arising on the scalp andocciput posterior to a line drawn through the external auditory canal mostcommonly spread to postauricular, suboccipital, and posterior trianglelymph nodes; therefore, a posterolateral neck dissection is recommended[59]. Tumors located anteriorly on the face and neck tend to spread to thefacial, submental, submandibular, and deep cervical nodes; consequently,a supraomohyoid neck dissection is advocated.

A newer option for elective treatment of the neck is sentinel lymph nodebiopsy (SLNB). The rationale behind SLNB is as follows. There existsa limited set of regional lymph nodes as a first stop along the route of

Fig. 3. Predicted patterns of lymphatic drainage from primary sites in the head and neck.

Location of nodes: A, submental; B, submandibular; C, preauricular; D, jugular chain; E,

occipital; F, posterior cervical; G, retroauricular; H, jugulodigastric; and I, supraclavicular.

(From Byers RM. Cervical and parotid node dissection. In: Balch CM, Houghton AN, Milton

GW, et al, editors. Cutaneous melanoma. 2nd edition. Philadelphia: JB Lippincott; 1992. p. 377;

with permission.)


lymphatic drainage. Using dyes, radiographic contrasts agents, or radioactivetracers, these ‘‘sentinel’’ lymph nodes can be localized and surgically removed.Based on the result, a decision can be made as to whether to perform a moreextensive lymphadenectomy or provide systemic adjuvant therapy.

SLNB has proved to be a well-accepted method in the treatment oftruncal and extremity melanoma. It provides accurate staging and impor-tant prognostic information [60]. In a multi-institutional study, Gershen-wald et al [61] showed the status of SLNs was the strongest predictor ofdisease-free survival in patients who have stage I and II disease (Fig. 4). Thesame group of investigators also has shown that among the benefits ofthis method is that it allows the pathologist to focus on fewer lymphnodes than found in an END, which allows for a more comprehensive

Fig. 4. Disease-free survival and disease-specific survival according to sentinel lymph node

status. Kaplan-Meier survival for patients undergoing sentinel lymph node biopsy. (A) Disease-

free survival. (B) Disease-specific survival. (From Gershenwald JD, Thompson W, Mansfield

PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of

sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999;17:976–83;

with permission.)


search for metastasis by applying molecular methods to increase thesensitivity of detection [62,63].

Despite its promise in truncal and extremity melanoma, the role of SLNBin the management of CMM of the head and neck has yet to be defined. Thissituation is attributed to many factors: (1) the complexity of the lymphaticdrainage patterns in the head and neck; and (2) the frequent need for theremoval of the SLN from the parotid gland, thus placing the facial nerve atrisk of injury. Currently, the data from head and neck studies concerningSLNB are conflicting. Most studies have reported that SLNs can beidentified in almost 95% of cases and that false-negative results are low[63,64]. Also, CMMs of the head and neck were found to metastasize toclinically predicted nodal groups in 92% of patients, and that postauricularand contralateral metastatic node involvement was uncommon [65]. Otherstudies, however, have shown disturbingly high rates of regional recurrencein patients with negative SLNB results [66]. Moreover, there seems to bea steep learning curve associated with the technique and potential risks tothe facial nerve and other cranial nerves during the biopsy procedure.

To properly assess the accuracy and applicability of the SLNB in themanagement of CMM of the head and neck, investigators at M.D.Anderson Cancer Center designed a prospective trial of intraoperativelymphatic mapping and SLN identification in 43 patients who had head andneck CMM. This trial showed that intraoperative lymphatic mappingaccurately depicts the SLN and that false-negative results were 0% (nopatient who had a negative SLN had a positive nonsentinel lymph node [67].The multiplicity of the nodes, their widespread distribution (42% withnoncontiguous nodal basins), and their frequent location within the parotidgland (44%), however, may preclude SLNB in many patients. Thus, therecommendations from that study are that selective lymphadenectomy ofthe SLN basins allows histologic staging of the regional lymphatics withlimited morbidity. More studies are warranted to establish the role of SLNBin the management of head and neck CMM [67].

RadiotherapyIn the past, melanoma was believed to be a radioresistant tumor. The

past 20 years, however, have shown that different dosimetric andfractionation schemes are needed for CMM treatment than those used totreat other tumors. For example, significant improvements in locoregionalcontrol have been noted with the use of adjuvant radiotherapy [68].

At M.D. Anderson Cancer Center, data reveal the possibility of attaininga locoregional control rate of 88% in patients with stages II and III diseasewhen postoperative radiotherapy is used at a dose of 30 Gy given in 5fractions [69]. In this trial, three groups of patients were investigated: (1)those who underwent excision of stage III primary tumors, (2) those withpalpable lymphadenopathy who underwent WLE and neck dissection, and(3) those with nodal relapse who underwent neck dissection. The locore-


gional control rates in all three groups were higher than in historical controlsubjects. Moreover, the overall survival rate in patients with stage II diseasewas higher than in historical control subjects (Fig. 5) [69].

In a more recent study, a retrospective analysis of 338 patients with lymphnode involvement who underwent complete lymph node dissection (LND) ofthe nodal basin, which had pathologically involved lymph nodes, wasperformed. The study showed that patients who have malignant melanomawith nodal involvement have significant risk of nodal basin failure after LNDif they have cervical involvement, extracapsular extension, more than threepositive lymph nodes, clinically involved nodes, or any node that is largerthan 3 cm. Overall and disease-specific survival rates for all patients at 10years was 30% and 36%, respectively. The rate of cervical nodal basinrecurrence at 10 years was 43%. This study concluded that patients with suchrisk factors should be considered for adjuvant radiotherapy to the lymphnode basins to reduce the incidence of recurrence [70].

The M.D. Anderson Cancer Center recommends postoperative radio-therapy for all patients with stage II lesions in which regional lymph nodesare not treated surgically and in patients with pathologically proven nodaldisease or nodal recurrence, after nodal dissection has been performed.Clinicians should bear in mind, however, that dosimetry is harmful tonervous tissues and cannot be used for lesions near the eyes or centralnervous system.

ChemotherapyTraditionally, chemotherapy served two main purposes: (1) as a palliative

therapy for patients with stage IV disease and (2) as an adjuvant therapy inhigh-risk patients. The use of chemotherapy as an adjuvant therapy forCMM still needs to be substantiated by prospective randomized trials.Three major randomized trials have been performed using adjuvantchemotherapy postoperatively [71–73]. In two of these studies, there wasno difference in disease-free interval or overall survival rates withchemotherapy [71,72], and in the third study, worse overall survival rateswere found with chemotherapy [73]. Currently, the single most effectivechemotherapeutic agent approved for the treatment of advanced melanomais decarbazine. Response rates to decarbazine alone are 10% to 20%,however. Using combination chemotherapy leads to a small, insignificantimprovement in response rates.

ImmunotherapyBecause melanoma is the most immunogenic type of solid tumor, it serves

as a primary model for immunotherapy, both in animal models and in theclinic. The approaches used to boost the body’s immune system include thefollowing: (1) biologic response modifiers (interleukins and interferons),(2) immunostimulants, and (3) vaccines. All three approaches, thoughpromising, remain investigational. As in chemotherapy, the use of

Fig. 5 apy. (A) All patients. (B) Group 1, treated with elective

irrad 3, treated with irradiation after nodal recurrence. (From

Ang head and neck region. Int J Radiat Oncol Biol Phys

1994;

218

M.N

.Younes,

J.N

.Myers

/Surg

OncolClin

NAm

13(2004)201–229

. Locoregional control and survival rates of patients treated with elective or adjuvant radiother

iation. (C) Group 2, treated with adjuvant irradiation after WLE plus neck dissection. (D) Group

KK, Peters LH, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the

30:296–8; with permission.)


immunotherapy has been primarily in the form of adjuvant therapy forhigh-risk patients or for patients with metastasis or recurrent disease.

Biologic response modifiers have been extensively studied; interferon a2b(IFN-a2b) is the most promising of these agents [74]. The EasternCooperative Oncology Group (ECOG) trial E1684 is a prospectiverandomized trial that revealed significant improvements in relapse-freeand overall survival rates in patients who had node-positive disease treatedwith high-dose IFN-a2b as a postoperative adjuvant drug [74]. A morerecent ECOG trial (number 1690) aimed at verifying these results andassessing the efficacy of low-dose IFN-a2b [75]. This study confirmed theimprovement in the relapse-free survival rate in patients given the high-doseINF-a2b; however, the difference was not as significant as was found in theECOG 1690 trial. Moreover, low-dose IFN-a2b showed no efficacy. Thelack of difference in the overall survival rate, however, was because ofa significant increase in the survival rate in the trial’s observation group:patients in this group who had experienced a relapse had been given INF-a2b as salvage therapy. Thus, the effect of adjuvant INF-a2b therapy onoverall survival rate awaits further investigation.

Other immunostimulants include Calmette-Guerin bacillus [76], Co-rynebacterium parvum [77], and levamisole [78], although their use hasyielded either negative or conflicting data. These agents do not yet play a rolein the treatment of melanoma [79].

Melanoma vaccines seem to be promising. Furthermore, many advancesin melanoma vaccination have been made during the past 15 years.Consequently, many clinical trials of melanoma vaccines are now underwayand include carbohydrate-based vaccines, antibody-based vaccines, DNAvaccines, dendritic cell–based vaccines, peptide vaccines, and heat-shockprotein vaccines [80]. Several phase 2 trials have shown feasibility andsuggested efficacy; however, no phase 3 trial has yet established any im-provements in disease-free survival or overall survival rates in vaccinatedpatients [80,81].

BiochemotherapyBiochemotherapy is the combination of two modalities of treatment:

immunotherapy and chemotherapy. This form of therapy attempts toachieve responses higher than those achieved when either treatment is usedalone. At the M.D. Anderson Cancer Center, trials have usually combinedcisplatin, vinblastine, and decarbazine with interleuken 2 and IFN-a2b[82]. The few prospective randomized trials showed similar survival rates,higher response rates, and increased toxicity as compared with immuno-therapy and chemotherapy alone [83–85]. Several large-scale trialsare currently underway to further evaluate the potential role of biochemo-therapy, both as a postoperative adjuvant treatment and for treatment ofsystemic disease.


Treatment by stage

Three different aspects need to be addressed in the management of CMMof the head and neck: the primary tumor, the regional lymphatics, anddistant metastasis. Although an acceptably high rate of locoregional controlhas been established, many patients who have stage II disease and highereventually die of distant disease. The recommendations for treatment on thebasis of stage are presented in Table 4.

Melanoma in situFor patients with melanoma in situ, the treatment of choice is surgical

excision with conservative margins (0.5–1cm) because the risk of metastasisis essentially zero. No regional or metastatic workup is required.

Stage IThe recommended treatment in patients with stage I melanoma is WLE

[6]. Margins of 1 cm are generally acceptable. The defect can be closedprimarily or reconstructed using local flaps or skin grafts. Delayedreconstruction is often advisable, given the limitations of frozen sectionanalysis of margins for pigmented lesions. As in melanoma in situ, noregional or metastasis workup is needed because of the low risk ofmetastasis in this group.

Table 4

Recommendations for treatment based on stage

Stage Treatment

I Primary tumor: WLE

II Primary tumor: WLE

Regional lymphatics: observation vs, END vs SLNB vs ENI

III Primary tumor: WLE

Regional lymphatics: neck dissection +/� parotidectomy

Consider postoperative radiotherapy

IV Primary tumor: WLE

Regional lymphatics: neck dissection +/� parotidectomy if node-positive

Metastasis site–directed surgery or radiotherapy

Consider systemic adjuvant therapy trials

Supportive care

Abbreviations: END, elective neck dissection; SLNB, sentinel lymph node biopsy; WLE,

wide local excision.







AJCC.


Stage IIThe adopted treatment in patients with stage II melanoma is WLE. If

possible, 2-cm margins are taken. If 1-cm or smaller margins are obtained,adjuvant radiotherapy should be contemplated. As in stage I lesions, thedefect can be closed either primarily or reconstructed using local flaps or skingrafts.

Given the substantial percentage of patients with stage II diseaseharboring occult regional metastasis, elective neck treatment is oftenconsidered. There are, however, no prospective trials to support the use ofany type of elective neck treatment for improving the locoregional controland the overall survival rates. Once elective neck treatment is decided on,there are several options to choose from.

END is the most widely adopted treatment option. The nodes of interestare those considered to be at risk. A major advantage to END is theprognostic information it provides. If occult metastasis is present, thenpatients can be up-staged and are eligible for adjuvant systemic treatment(immunotherapy, chemotherapy, or biochemotherapy).

Elective neck irradiation constitutes the second option. Locoregionalcontrol rate is achieved in 85% of stage III patients who were givenirradiation to the primary site after WLE [68].

Finally, SLNB is still under investigation as a possible modality for theevaluation of patients who have stage II melanoma.

Stage IIIThe recommendations for stage III disease include treating the primary

tumor by WLE and obtaining, if possible, a 2-cm margin. In addition, toattain locoregional control, regional disease can be addressed by neckdissection. If the disease allows, a selective or modified radical neckdissection is advised rather than a classic radical neck dissection. Inaddition, postoperative radiotherapy seems to increase locoregional control.Unlike with stage I and stage II disease, systemic therapy, in the form ofchemotherapy, immunotherapy, or biochemotherapy, should be contem-plated in patients with stage III disease because of the high risk for distantmetastasis.

Stage IVDespite the dismal prognosis in this subgroup of patients, locoregional

control remains an important consideration because of the devastatingeffects of uncontrolled locoregional disease. The overall treatment approachin the treatment of stage IV metastatic melanoma is best determined bya multidisciplinary team, including a surgeon, radiation oncologist, andmedical oncologist, and is often best performed in the context ofa prospective clinical trial. Palliative and supportive care is also animportant issue to address in these patients.


Recurrent disease

Recurrent disease is usually associated with a poor prognosis. Therecurrence can be locoregional or distant. For locoregional recurrence, re-excision [86], if possible, and adjuvant radiotherapy (if it has not beenadministered before) are indicated. If surgery is not an option, radiotherapyand systemic therapy are secondary options, but they can only be palliativeat this stage. Distant metastases that are surgically resectable shouldbe aggressively treated because, in rare instances, a cure or long-termprogression-free interval can be achieved. Sometimes, however, isolateddistant metastases are kept in place to initially ‘‘monitor’’ the response tosystemic treatment, and then depending on the result, excised later on. Theprognosis for pulmonary metastasis is better than brain and liver metastasis,which carries with it a dismal expected survival time of 2 to 4 months [87].Even in the context of recurrent disease, every effort should be made toachieve locoregional control, if only to improve the patients’ quality of life.

Follow-up

Because CMM is a disease of young people (average age, 45 y), both theclinical and financial aspects of the patient’s follow-up are important andneed to be addressed. Weiss et al [88] reported that intensive follow-up in thepost-treatment phase (5 y) costs around $421,000 for laboratory tests alone[88]. Thus, the need arises to establish equilibrium between what can becalled an ‘‘adequate’’ surveillance and fiscal responsibility. An estimated28% to 56% of recurrences are usually detected by physicians [89,90].Therefore, physical examination when supplemented with periodic labora-tory testing and radiologic assessment is a good basis for follow-up. At theM.D. Anderson Cancer Center, the follow-up depends on the stage of thedisease at diagnosis (Table 5).

Special issues in melanoma

Mucosal melanoma

Mucosal melanoma of the head and neck is rare (1%–2% of melanomas).In the head and neck, the most common sites of occurrence include the nose,paranasal sinuses, oral cavity, and nasopharynx. If located in the sinonasalcavity, mucosal melanoma typically presents with symptoms of nasalobstruction, epistaxis, pain, visual disturbances, or facial deformity. Patientswho have mucosal melanomas of the oral cavity most often present withasymptomatic masses; however, symptoms of dysphagia are not un-common. Because most of these symptoms are indolent and nonspecific,there is often a delay in presentation and a worse prognosis.

Mucosal melanoma tumors may lack melanin, making the diagnosisdifficult from the histopathologic standpoint. The 5-year disease-specific


survival rates depend on the anatomic site of the primary lesion [91] and are40% for oral lesions and 47% for sinonasal lesions [93]. In addition, most ofthe staging criteria for CMM, including depth of invasion and regionallymphadenopathy, fail to impact or affect the prognosis in mucosalmelanoma. The only significant and independent predictors of thedevelopment of distant failure and death in patients who have mucosalmelanoma of the head and neck are as follows: the clinical stage atpresentation, whether the tumor thickness is greater than 5 mm, whetherthere is vascular invasion on histologic studies, and the development ofdistant failure [92,93].

As a group, mucosal melanomas of the head and neck are highlyaggressive and rapidly fatal [91]. Radical surgery with aggressive resection ofthe primary tumor is the primary treatment used to achieve locoregionalcontrol [93]. Adjuvant radiotherapy does improve locoregional control;however, it probably does not affect overall survival rates because of thehigh rates of distant metastasis at the time of initial presentation [94].Overall 5-year survival rates are usually between 15% and 20%, althoughrates as high as 40% have been reported [92,95].

Desmoplastic melanoma

Desmoplastic melanoma (DM) was first described by Conley et al [29], in1971, as a rare variant of spindle cell melanoma. These lesions are oftennonpigmented and may appear only slightly abnormal or harmless whenactually an aggressive malignant lesion is present. The seemingly benignappearance of this tumor can be misleading to patients and physicians alike,causing a delay in proper therapy. Previous studies have noted that DM was

Table 5

Recommendations for follow-up based on stage

Stage Physical examination Radiology Labs

Melanoma in situ Every 6 mo�4 y, then annually None None

Stage 1 or II (no ulceration,

thickness\1.0 mm)

Every 6 mo�4 y, then annually CXR LDH

Stage I or II (with ulceration

or thickness >1.0 mm)

Every 6 mo�2 y, then every

6 mo�2 y, then annually

CXR LDH

Stage III or recurrent primary

melanoma

Every 3 mo�2 y, then every

6 mo�3 y, then annually

CXR LDH, CBC

Stage IV Individualize Individualize Individualize

Abbreviations: CBC, complete blood count; CXR, chest X-ray.







AJCC.


more commonly diagnosed in elderly men [91,96] and more frequentlyreported in the head and neck region [97,98]. At presentation, the lesions areusually thicker (median tumor thickness, 2.5 mm; Clark’s level IV or V)[103] than other forms of melanoma; however, the thickness of DM lesionsis not as useful a predictor of prognosis as it is in other forms of melanomas.This subtype of melanoma is characterized by its neurotropism. This trait isof critical importance in the head and neck because even small DM lesionscan spread to cranial nerves, causing palsies and leading to intracranialspread. The particularly high rate of local recurrence with these tumors hasbeen attributed to this propensity for perineural spread [99], which isa strong adverse factor for prognosis [100,101]. WLE with a 2-cm margin, ifpossible [96], and a meticulous analysis of the specimen for evidence ofperineural spread are important. Adjuvant radiotherapy is also recom-mended for patients with this pathologic finding. Finally, the rate ofregional lymph node metastasis in DM (15.4%) is lower than for otherforms of CMM [101], regardless of tumor thickness. The overall survivalrates, however, tend to be similar to other forms of CMM [102].

Metastatic melanoma of unknown origin

In rare cases, melanoma is discovered in the cervical and parotid lymphnodes without evidence of a primary tumor. The hypothesis is that, in mostcases, these metastases result from primary melanomas that have regressedspontaneously. Clinicians must first rule out mucosal or ocular melanoma,however. The treatment of choice is appropriate lymphadenectomy andpostoperative radiotherapy. These patients also need to be considered forclinical trials of adjuvant systemic therapy. The prognosis for this group ofpatients is similar to that for other patients who have stage III disease [104].

Summary

Major advances in the understanding of the causes and risk factors formelanoma and for the prevention and management of this tumor have takenplace since the beginning of the past century, when the diagnosis ofmelanoma was synonymous with death. As many as 80% of earlymelanomas can be cured, and a high rate of locoregional control for evenfar-advanced melanoma is plausible. The major challenge for the years tocome lies in curtailing the steady rise in the incidence of melanoma byincreasing patient education and adopting measures to prevent theincreasing mortality rates associated with this disease. Cure rates can beimproved by early diagnosis by physicians and instant referral to ex-perienced oncologists. Finally, new advances in diagnostic and treatmentstrategies carry the hope for further improvements in locoregional controland survival rates.


Acknowledgments

The authors thank Bradley A. Schiff, MD, for his review and critique andMs. Yolanda Luna for her administrative assistance.

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The integration of neurosurgicaltechniques in current head and neck

skull base surgery

Kevin J. Gibbons, MD*, Amos O. Dare, MDDepartment of Neurological Surgery, School of Medicine and Biomedical Sciences,

State University of New York–Buffalo, 3 Gates Circle, Buffalo, NY 14209, USA

Skull base surgery requires integrating surgeons of differing specialties,and appropriate techniques specific to each specialty, to complete atechnically difficult surgery without complication. Neurosurgical techniqueshave evolved over the past 60 years, from a point in time when any cranialsurgery involved great uncertainty and risk, to surgery in the modern era inwhich complex operations are routinely performed to treat lesions that were,until recently, considered inoperable.

This article initially focuses on the avoidance and management ofcerebrospinal fluid (CSF) leak and wound reconstruction. These problemsgreatly limited early efforts in cranial base surgery, with complication ratesapproaching 40% to 50% in some early series, and remain pertinent forskull base surgeons today.

Malignant disease involving the internal carotid artery (ICA) limits theresectability of disease; even if the ICA is not invaded directly, proximity bypreoperative imaging or by direct operative inspection prevents adequateoncologic margins. A significant number of patients, particularly those whohave recurrent, advanced head and neck malignancies, are not consideredcandidates for resection because of concerns about stroke or residualdisease. This article reviews current protocols for assessment and man-agement of these patients.

The major advance in cranial base surgery, and neurosurgery in general,is the integration of imaging into the operative suite for surgical planning,localization, and real-time image acquisition. This apparent revolution intechnique application is actually more of an evolving step, albeit a large one,


E-mail address: [email protected] (K.J. Gibbons).


doi:10.1016/S1055-3207(03)00116-9


232 K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

in the neurosurgical challenge of localization. Most patients who have skullbase malignancies now undergo multimodality multiplanar preoperativeimaging to aid in surgical planning. Select cases undergo intraoperativelocalization, with a combination of preoperative images and intraopera-tive localization with computer-assisted navigation (frameless stereotaxy).In many centers, intraoperative imaging is available, with real-time dataacquisition, using MRI obtained in the operative theater and updated asneeded to demonstrate location and extent of residual disease.

Cerebrospinal fluid leaks

In most patients, skull base surgeons link the intracranial subdural spacewith the nasapharyngeal compartment. CSF leaks seemed to be a near-insurmountable problem early in the development of the specialty, however.These leaks resulted in, or may have presaged, serious wound complications,such as dehiscence and infection. The development of CSF diversion,multilayered closures, and fibrin sealant has resulted in significant im-provement in avoiding this problem.

Cerebrospinal fluid diversion

The first step in prevention and treatment of fistula formation iselimination of any pressure gradient between compartments. In skull basesurgery, this step generally involves temporary lumbar CSF diversion. Incases of persistent hydrocephalus, permanent diversion may be required, butthis is generally delayed until any question of perioperative contaminationor postoperative infection has been resolved.

A series describing the role of lumbar CSF diversion was reported byShapiro and Scully [1] in 1992. The authors reported a 94% success rate,with a 5% infection rate and a 3% rate of temporary decline fromoverdrainage. Lumbar root irritation, again only temporary in this series,was reported in 14% of patients. Subgroups included 25 patients withdocumented postcraniotomy fistulae, with an 87% success rate, and 38patients who experienced successful augmentation of ‘‘tenuous duralclosure.’’. Similar results were subsequently reported by McCutcheon et al[2] in 1996, with a 4% rate of transient CSF leak, an overall 7% rate ofpneumocephalus, and a 4% incidence of symptomatic pneumocephalusrequiring intervention. All patients were treated with primary dural closureor cadaveric dural reconstruction, pericranial flap base reconstruction, and4 days of lumbar drainage.

The role, risk, and benefit of postoperative CSF diversion remainscontroversial, however. Complications of overdrainage include pneumo-cephalus, acute foramen magnum syndrome, and uncal and other herniationsyndromes. A report by Dagnew et al [3] described three cases of acuteforamen magnum syndrome with arrest and quadriplegia secondary to

233K.J. Gibbons, A.O. Dare / Surg Oncol Clin N Am 13 (2004) 231–239

lumbar drainage. The authors also reviewed the syndrome and itsmanagement, the theory of cranial spinal pressure gradients, and thepractical details of successful lumbar drainage (eg, minimal duration;volume drainage targets; and careful frequent nursing care, ideally in anICU setting).. An important practical point is the need to clamp the catheterat the first sign of neurologic decompensation, as opposed to removing thecatheter, which could result in uncontrolled drainage into the soft tissues ofthe back and further herniation.

Another study reported two patients with coma associated withoverdrainage from a lumbar catheter, with the recommendation to attemptcranial catheter placement, either subarachnoid or intraventricular, to avoidthe pressure gradient across the foramen magnum when possible [4]. Uncalor transtentorial herniation syndromes occur in the setting of temporal lobeedema or hemorrhage and lumbar drainage, with potentially devastatingresults. Ventriculostomy placement is not without risk, however. Risksinclude intraparenchymal hemorrhage and, in particular, serious centralnervous system (CNS) infection, which is uncommon with lumbar drains. Arecent review of ventriculostomy-related infection and specific risk factorswas published by Lozier et al [5].

The decision to place a lumbar drain is usually made before surgery, incases where significant dural reconstruction is likely to be required. Theplacement of a catheter into the subarachnoid space before craniotomy,after induction of general anesthesia, is advantageous for the followingreasons:

1. The lumbar subarachnoid space is easily and safely entered beforedrainage of large amounts of CSF at the primary surgical site (dry tapsare more likely to result in root injury or irritation).

2. Controlled drainage during surgery facilitates exposure and minimizesbrain retraction.

3. Large-bore (14- or 16-gauge) Tuohy needles are more comfortablyplaced in patients under general anesthesia (from both the patient’s andsurgeon’s perspective).

4. Securing the catheter at multiple sites by suture fixation of the loopedcatheter is often essential to maintain a working catheter for 5 days ormore; this procedure is easier to perform under general anesthesia.

5. The most tenuous cranial/dural base repairs can be disrupted by evenbrief periods of intracranial hypertension associated with Valsalva’smaneuvers and other events during emergence from anesthesia; CSFdrainage may avoid these periods of intracranial hypertension.

Dural repair and multilayered closure

Adequate resection of lesions extensively involving the skull base requiresmeticulous wound closure and repair for several reasons, including the


avoidance of CNS infection, CSF leaks, cosmetic deformity, and structuralsupport of the CNS and important end organs. Numerous techniques havebeen developed to optimize closure and repair. Although the findings atsurgery may require a deviation from the planned approach and procedure,in most cases with proper preoperative imaging and planning, techniques ofrepair and tissue acquisition for repair are determined in advance of surgery.Preparing the closure during the exposure is a hallmark of the successfulsurgeon.

Most of the literature regarding closure of complex wounds after skullbase surgery, and the predominance of cases in most surgeons’ personalseries, involves anterior cranial fossa surgery. In this location, a watertightdural closure and a viable tissue barrier providing separation from the upperrespiratory tract are essential. Temporal bone and lateral skull base casesare less likely to involve difficult or impossible dural repairs in directconnection with a sinus. Posterior fossa cases are usually neurosurgicalcases, with complex repair schemes rarely necessary.

The goal, when possible, is primary dural closure. Primary dural closureis possible in limited situations in skull base surgery, when the opening islimited and the adjacent dura is substantial and able to be mobilized: anexample is primary closure or oversewing of the subfrontal dura afterdivision of an olfactory tract involved with a small esthesioneuroblastoma.More extensive defects can be repaired primarily with mobilization ofsurrounding dura, if viable. Viability in this instance describes dura that is ofadequate thickness and has been kept hydrated during the procedure upuntil closure. The dura should be kept moist during any lengthy procedure,a practice aided by well-positioned irrigation catheters, a moist collagensponge over exposed dural surfaces, and general attention to detail.

When dural grafting is required because of an extensive defect, the nextissue is to determine whether a margin of native dura exists circumferentiallyaround the defect such that a graft can be sewn in a watertight fashion. If so,the next question is which type of graft to place. When available, autogenouspericranium is ideal. It may be harvested early on in the procedure and keptmoist on the table as a free devascularized graft. The current authors’preference is to mobilize as large a pericranial flap as possible, maintainingattachment and vascular supply during the procedure. This method allowsthe alteration of the size of both the free graft used for dural closure and thevascularized graft used as a sling for floor reconstruction. The grafts aresecured with 4-0 silk or polyglactin 910 (Vicryl) sutures for the dural patch,and 3-0 and 4-0 silk for attachment of the sling to the surrounding bone ofthe defect (usually the orbital roofs for anterior craniofacial resections).Drill holes are placed with a 2-mm round bit in the adjacent bone. A recentreport described a sutureless fixation, using autologous fascia or peri-cranium, and anchoring it with titanium screws, with or without titaniummesh. The repair is reinforced with fibrin glue [6]. This method may be usefulwhen the dural margin is inadequate to place or hold a suture.


Dural substitutes and allogenic cadaveric dura may be used, particularlyif native tissue is not available because of prior surgery or radiation.Although these substitutes are acceptable for dural closure in limitedcircumstances, they should not be used, even as a dural patch, if there is notenough vascularized native tissue to provide a viable barrier between theairway and the subdural compartment. Vascularized muscle flaps may beused if rotated in (temporalis, latissimus) with adequate tissue and length. Incertain instances, the use of vascularized free flaps is increasing. Radialforearm free flaps are used for smaller defects, and rectus abdominis freeflaps, with or without subcutaneous fat and/r skin, are placed for largerdefects.

Carotid artery assessment, preservation, sacrifice, and bypass

Tumor involving the ICA presents a major surgical management issue.Traditionally, tumor involvement of the ICA relegated the patient topalliative care for malignancies in which surgical resection was the maintherapy. Considerable work in the past 10 years has reported on thepreoperative assessment of adequate collateral circulation, assessment ofadequate cerebral vascular reserve, and the safety of elective carotidocclusion and sacrifice.

Carotid involvement seen on preoperative imaging limits intervention tothe following options: debulking without oncologic margins (peeling tumoroff the ICA), resection with carotid sacrifice (preoperative with endovascularballoon occlusion or intraoperative), resection after revascularization(bypass), and delegation to nonoperative therapy (often palliative care)[7]. For squamous carcinoma of the head and neck nonoperative treatmentis associated with a dismal prognosis of 1-year survival time.

The decision process is aided in many centers with preoperativeassessment of collaterals and reserve. Collaterals are located by means ofthe circle of Willis and the external carotid branch anastomosis to theintracranial vasculature. Although identification of an isolated hemisphereor middle cerebral artery (ie, those without apparent collaterals by means ofthe circle of Willis) may be obtained with conventional angiography with theaddition of simple cross compression tests (further testing has beenadvocated and used) [7,8]. Balloon test occlusion with hypotensive challengeis an accepted means of assessing cerebrovascular reserve and is used by theauthors in selected patients.

This technique and subsequent ICA sacrifice has been used successfullyfor more than a decade. Before routine incorporation into a surgical headand neck oncology practice, however, there are several key issues tounderstand. First, the series that have reported testing and carotid sacrificewere primarily in patients before elective ICA occlusion for aneurysms:vascular complications in patients who have skull base tumor occur ata higher rate (eg, 22%, in one large-scale series) than in aneurysm patients


after a simple hunterian ligation [9]. Second, establishing the presence ofadequate collaterals does not eliminate the risk of embolic stroke. Stumpemboli occur at a higher rate during and following extensive tumorresection, likely from a transient hypercoagulable state. The current authorshave reported a single case of a stump embolus resulting in a fatal dominanthemisphere stroke, which occurred after permanent balloon occlusion, aftersuccessful test occlusion with hypotensive challenge, before a scheduledtumor resection [7].

The routine use of bypass surgery to prevent ischemic complications ofcarotid sacrifice is intuitively attractive. This practice does not seem toreduce or eliminate the risk of stroke, however. In a series reported byAbruzzo et al [10], 7 of 15 patients undergoing bypass suffered an ischemicevent. Anticoagulation may have lessened the risk of stroke in carotidsacrifice with or without bypass; antiplatelet agents were not protective. Inpatients who have head and neck cancer, prior radiation and surgery arelikely to impair and, in many cases, eliminate the donor and recipientvasculature. Crossover bypass from the contralateral side (bonnet bypass)may be an option in selected cases.

Despite careful assessment of collaterals and cerebrovascular reserves,and the use of extensive revascularization procedures, cerebral ischemia ofvarying degrees of severity may affect 20% to 50% of patients undergoingelective ICA occlusion and represents a major ongoing area of concern inthe treatment of patients with head and neck cancer.

In view of these results, a novel approach for carotid artery managementhas been proposed and tested in animal models. Endoluminal stenting of theICA, followed by a delay to allow in-stent endothelialization, followed by‘‘exarterectomy’’ has been tested [11]. This method involves the removal ofthe diseased ICA around the endothelialized stent. The stent itself may beremoved. Before routine application, the risks of pseudoaneurysmformation, carotid blowout, and occlusion need to be determined, and thedurability of this construct needs to be established.

Imaging

Neurosurgeons relied on clinical acumen and knowledge of neurologyand anatomy to guide surgery for the first 70 years of the specialty, from thedays of Harvey Cushing until the advent of CT in the 1970s. Until CTbecame available, neurodiagnostic testing included air ventriculograms,pneumoencephalograms, and contrast angiography, with toxic agentsdelivered by direct carotid puncture. With the introduction of CT andsubsequently MRI, the location and extent of lesions were no longer indoubt. Neurosurgery as a specialty was reborn based on modern neuro-imaging. Standard CT acquisition was slow, however, with thick (5–10 mm)slices, significant volume averaging, and very limited nonaxial slice imagingor reconstruction capability. MRI provided better views of nonosseous


structures in three standard planes but required lengthy scan times anda cooperative patient, and often included significant artifacts.

The introduction of improved hardware and software in both CT andMRI modalities greatly aids modern-day skull base surgeons. Thin-slicehigh-resolution CT with multiplanar reconstruction and workstationcapabilities allows the surgeon to rotate, magnify, and adjust windowsand plan approaches before incision. CT had been relegated to a distantsecond place in terms of value to the surgeon; however, improved computercapabilities has returned the modality to equal footing with MRI,particularly in cranial base surgery.

CT and MRI have advanced the specialty of neurosurgery in general andskull base surgery in particular. Those images initially were only pre-operative, however, and although of great use to the surgeon, were onlyimages on a light box in the operating room, not always readily oraccurately transferable in the surgeon’s mind to the three-dimensional fieldin which he or she must work. Now, imaging is available with three-dimensional reconstruction, thin-slice multiplanar imaging, intraoperativelocalization (frameless stereotaxy), and intraoperative MRI.

Framed stereotactic techniques in neurosurgery involve the application ofa head frame and localizer ring, image acquisition in the ring, and transfer tothe operating suite with frame attached. Image fusion permits accuratelocalization and target identification, as described later. Operativelocalization of a predetermined target is useful; however, framed stereotacticsurgery did not allow for reorienting the surgeon. In addition, operatingaround a frame is difficult for extensive or lengthy procedures. The conceptof frameless stereotaxy involves preoperative imaging with fixed referencepoints, either anatomic structures or fiducials, which are then referenced inthe operating room with a system that allows the surgeon to reorient thelocation of a probe or any surgical instrument to a three-dimensionaldisplay in the operating suite. The use of frameless systems for intra-operative navigation is increasing in neurosurgery and otolaryngology, andnumerous systems are available [12,13]. These systems include those withreference points with fixed arcs attached to typical neurosurgical headframes; those with localized skull pins, dental stents, or reference blocks andless invasive localizing points; and, in surgery, those with tool localizationbased on ultrasound, optics, and articulated arms that allow the surgeon toknow where in three-dimensional space he or she is working.

Combining these modalities in overlaid sections and rendered three-dimensional images is the result of image fusion. The use of fusiontechniques in preoperative frameless guidance combines the submillimetricaccuracy of CT with the tissue-imaging capabilities of MRI, and moreaccurately displays the information than either modality alone [14]. Thisfusion technique, with accurate three-dimensional renderings, providesbetter depiction of individual anatomic structures and key structuralrelationships (eg, tumor–bone and tumor–vessel) [15].


Incorporating frameless image–guided surgical technique involves in-creased cost initially, from equipment and prolonged setup and operativetime; these disadvantages are generally eliminated with routine use, withseveral studies documenting no increases or actual decrease in operative time,and hospital length of stay [16,17]. The use of frameless guidance clearly ismore surgeon-friendly and quicker than framed stereotactic systems, with thepossible exceptions of simple biopsy, in which framed systems are bothaccurate and quick, and uncomplicated primary transphenoidal surgery, inwhich image guidance is likely to prolong surgery [16,18]. The authors’practice is to use frameless guidance in cases of repeat operation and tumorsinvolving multiple anatomic compartments. Frameless guidance is particu-larly useful in repeat operations in which normal, adjoining anatomicreference points are distorted or destroyed. In intradural, intraparenchymalsurgery of primary brain tumors, brain shift is a particular problem. Thishindrance is far less likely to occur in skull base surgery [19].

Intraoperative MRI

The latest and potentially most useful imaging modality in the surgicalsuite is real-time intraoperative image acquisition that demonstrates thesurgical anatomy and remaining pathology as the procedure evolves.Intraoperative MRI is now available, with intraoperative magnets of 0.12-to 1.5-T field strengths now available. MRI surgical suites and compatibleoperating equipment, consisting of anesthetic and surgical instruments, arenow available [20]. The transition period from research tool to widespreadclinical applications is now upon us. The use of updated images eliminatesthe concern of brain shift and should reduce the occurrence of unsuspectedtumor remnants and the need for return trips to the operating room. In thefuture, the routine use of intraoperative MRI may provide intraoperativequality assurance in neurosurgery and skull base surgical procedures.

Summary

The recent advances in neurosurgery, applied to the growing field of skullbase surgery, provide surgeons with new techniques to avoid the devastatingcomplication of CSF leak, to improve patient selection by reducing the riskof stroke while expanding the operative options available to patients withhead and neck malignancies, and to aid operative care through improvedsurgical planning and intraoperative localization.

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[9] Origitano TC, Al-Mefty O, Leonetti JP, DeMonte F, Reichman OH. Vascular

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Index

Note: Page numbers of article titles are in boldface type.

A

Acinic cell carcinoma, salivary gland, 119

Adenocarcinoma, of paranasal sinuses, 174salivary gland, 120–121

Adenoid cystic carcinoma, of paranasalsinuses, 175salivary gland, 118

Adjuvant therapy, iodine 131 for well-differentiated thyroid cancer, 129–149

Alveolus, squamous cell carcinoma of,surgical treatment of, lower, 56

upper, 56–57

Amifostine, to protect salivary functionduring radiation therapy of head andneck cancer patients, 194–195

Anatomic landmarks, for identification ofcervical lymph nodes, 153–154

Anatomy, of paranasal sinuses, 168–169

B

Biochemotherapy, of cutaneous melanomasof head and neck, 219

Biopsy, imaging-guided, in head and neckoncology, 28–29of cutaneous melanomas of head and

neck, 207–208sentinel lymph node, for staging N0

neck tumors, 161–163

C

Cancer predisposition, in patients withsquamous cell carcinoma of head andneck, 2–4

genes for, 5–6genomic instability and, 4–5

Carotid artery, assessment, preservation,sacrifice, and bypass of, in skull basesurgery for head and neck cancer,235–236

1055-3207/04/$ - see front matter � 2004 Elsev

doi:10.1016/S1055-3207(03)00146-7

Cerebrospinal fluid leaks, integration ofneurosurgical techniques into skullbase surgery for head and neck cancer,232–233

Cervical lymph nodes, anatomic landmarksfor identification of, 153–154

Chemoradiation therapy, forhypopharyngeal carcinoma, 93–94

Chemotherapy, dental oncology and, inhead and neck cancer, 39–40for laryngeal carcinoma, 107–108for oropharyngeal carcinoma, 78in management of oral cavity

squamous cell carcinoma,63–64

of cutaneous melanomas of head andneck, 218

Chermotherapy, for paranasal sinuscancers, 181

Complications, of laryngeal carcinoma,108–109of radiation therapy, as alternative to

surgery for head and neckcancers, 188–189

Computed tomography (CT), imaging inhead and neck oncology, 13–35

in skull base surgery, 236–237

Cutaneous malignant melanoma. SeeMelanoma.

D

Dental oncology, expanding role in headand neck surgery, 37–46

assessment, 38–40considerations during treatment,

40–41long-term considerations, 41–43

Desmoplastic melanoma, 206, 223

Differentiated thyroid carcinoma. SeeThyroid carcinoma.

ier Inc. All rights reserved.

242 Index / Surg Oncol Clin N Am 13 (2004) 241–247

Dysplastic nevus syndrome, as risk factorfor cutaneous malignant melanoma,205–206

E

Esthesioneuroblastoma, of paranasalsinuses, 176–177

F

Familial melanoma/dysplastic nevussyndrome, as risk factor for cutaneousmalignant melanoma, 205–206

Fine-needle aspiration, of salivary glandtumors, 114–116

Floor of mouth, squamous cell carcinomaof, surgical treatment of, 55–56

Function, preservation of, in head and neckcancer patients, 187–199

neuromuscular function, 196salivary function, 194–196speech, 189–192swallowing, 192–194

G

Genes, for cancer predisposition, in patientswith squamous cell carcinoma of headand neck, 5–6

Genetics, risk factors for cutaneousmalignant melanoma, 205–206

familial melanoma/dysplasticnevus syndrome, 205

xeroderma pigmentosum,205–206

Genomic instability, role in pathogenesis ofsquamous cell carcinoma of head andneck, 1–11

Glottic carcinoma, surgical treatment of,105–106

H

Hard palate, squamous cell carcinoma of,surgical treatment of, 56–57

Head and neck cancer, 1–239dental oncology, expanding role of,

37–46

assessment, 38–40considerations during treatment,

40–41long-term considerations, 41–43

imaging in, 13–35nodal staging, 22–28of primary tumor, 16–22

other applications, 28–31techniques, 14–16

melanoma, 201–229neck dissection, 151–166neurosurgical techniques in skull base

surgery, 231–239paranasal sinus cancers, 167–186salivary gland cancer, major, 113–127squamous cell carcinoma, genomic

instability, role in pathogenesisof, 1–11of hypopharynx, 81–98of larynx, 99–112of oral cavity, current treatment

options, 47–70of oral pharynx, subsite

treatment heterogeneity,71–80

organ preservation in patientswith, 187–199

thyroid cancer, iodine 131 as adjuvanttherapy for well-differentiated,129–149

Hypopharyngeal wall, posterior, surgery forcarcinoma of, 86–87

Hypopharynx, carcinoma of, 81–98chemoradiation therapy, 93–94clinical behavior, 82–85primary radiation therapy, 92–93selective neck dissection for, 157surgical treatment, 85–92

I

Imaging, in head and neck oncology, 13–35anatomic landmarks for

identification of cervicallymph nodes, 153–154

integration of neurosurgicaltechniques into skull basesurgery in, 236–238

nodal staging, 22–28of primary tumor, 16–22of salivary gland tumors,

114–116other applications, 28–31techniques, 14–16with iodine 131, as follow-up to

radioiodine ablation ofthyroid remnant or tumor,140–142

Immunotherapy, of cutaneous melanomasof head and neck, 218–219

Internal carotid artery. See Carotid artery.

Intraoperative magnetic resonance imaging(MRI), in skull base surgery for headand neck cancers, 238

243Index / Surg Oncol Clin N Am 13 (2004) 241–247

Iodine 131, for adjuvant therapy ofwell-differentiated thyroid carcinoma,129–149

acute and long-term effects oftherapy, 137–140

further management, L-thyroxinetherapy, 142–144serum Tg testing and

rhTSH, 145imaging and follow-up,

140–142outcomes, 142postsurgical remnant ablation,

134–135therapy of metastases from,

135–137

L

L-Thyroxine, therapy with, after iodine 131therapy for differentiated thyroidcarcinoma, 142–144

Larynx, squamous cell carcinoma of,99–112

anatomy, 100–101complications and outcomes,

108–109diagnosis, 102–104lymphatic and distant spread,

101–102pathology, 104preserving speech in patients

with, 189–192radiotherapy and chemotherapy

in treatment of, 107–108selective neck dissection for, 157staging and prognosis, 102surgical treatment, 104–107

Lentigo maligna melanoma, 206

Lip, squamous cell carcinoma of, surgicaltreatment of, 57–58

Lymph nodes, cervical, anatomic landmarksfor identification of, 153–154sentinel, biopsy of for staging N0 neck

tumors, 161–163

Lymphoma, of paranasal sinuses, 178of parotid salivary gland, 122

M

Magnetic resonance imaging (MRI),imaging in head and neck oncology,13–35

in skull base surgery, 236–238intraoperative, 238

Malignant melanoma. See Melanoma.

Mandible, squamous cell carcinoma of,surgical treatment of, 58

Maxillofacial prosthodontics, dentaloncology in head and neck cancer, 40

Melanoma, of head and neck, 201–229causes and risk factors,

204–206diagnostic evaluation, 207–208epidemiology, 201–203follow-up, 222management, 213–222

biochemotherapy, 219by stage, 219–221chemotherapy, 218immunotherapy, 218–219radiotherapy, 216–218surgery, 213–216

mortality, 203of paranasal sinuses, 175–176pathology, 206recurrent disease, 221salivary gland, 121–122special issues, 222–224

desmoplastic melanoma,223

metastatic melanoma ofunknown origin,223–224

mucosal melanoma,222–223

staging, 208–213

Metastases, imaging of nodal disease inhead and neck oncology, 16–22metastatic melanoma of unknown

origin, 223–224of paranasal sinus cancers, 181–182to neck, of hypopharyngeal

carcinoma, 90to neck, of oropharyngeal carcinoma,

77–78

Molecular biology, of salivary glandcancers, 122–123

Mortality, due to melanoma of head andneck, 203–204

Mucoepidermoid carcinoma, salivary gland,116–117

Mucosal melanoma, 222–223

N

Neck, cancer of. See Head and neck cancerdissection of. See Neck dissection.levels of, 152–153squamous cell carcinoma of, surgical

treatment of, 58–61


Neck dissection, current concepts andfuture directions, 151–166

anterior (selective VI), 158–160classification systems, 152–157

imaging-based, 153–155extended, 160for cancer of oral cavity,

157–158for oropharyngeal, laryngeal, and

hypopharyngeal cancer, 157posterolateral, 160–161sentinel lymph node biopsy for

staging N0 neck tumors,161–163

for salivary gland cancers, 124–125

Neuroblastoma, olfactory, of paranasalsinuses, 176–177

Neuromuscular function, preservation of, inhead and neck cancer patients, 196

Neurosurgical techniques, integration of incurrent head and neck skull basesurgery, 231–239

carotid artery assessment,preservation, sacrifice, andbypass, 235–236

cerebrospinal fluid leaks, 232–233imaging in, 236–238wound closure, 233–235

Nodal disease, imaging of, in head and neckoncology, 16–22

Nodular melanoma, 206

O

Olfactory neuroblastoma, of paranasalsinuses, 176–177

Oral cavity, squamous cell carcinoma of,47–70

etiology, 48management, 51–66

diagnostic investigations,51–53

prognostic factors andoutcome, 65–66

radiotherapy andchemotherapy, 62–64

reconstruction, 61–62rehabilitation, 64selective neck dissection for,

157–158specific sites, 53–61

pathology, 48–51

Oral pharynx. See Oropharynx.

Organ preservation, in patients withsquamous cancers of head and neck,187–199

Oropharynx, carcinoma of, analysis ofsubsite treatment heterogeneity,71–80

assigning tumor to subset oforigin, 72

chemotherapy, 78histopathology, 72management of regional spread

to neck, 77–78posterior pharyngeal wall, 73relevant anatomy, 71–72selective neck dissection for, 157soft palate, 73–74tongue base, 76–77tonsillar complex, 74–76

Osteoradionecrosis, dental oncology in headand neck cancer, 43

Outcome, in laryngeal carcinoma,108–109in oral cavity squamous cell

carcinoma, 65–66of paranasal sinus cancers, 182with iodine 131 therapy of

differentiated thyroid carcinoma,142

P

Palate, hard, squamous cell carcinoma of,surgical treatment of, 56–57

Palate, soft, carcinoma of, 73–74

Paranasal sinus cancers, differentialdiagnosis and treatment options,167–186

anatomy, 167–169epithelium-derived malignancies,

170–178etiology, 169–170incidence, 169lymphomas, 178pathology, 170prognosis and outcome, 182treatment, 178–182

chemotherapy, 181management of cervical

nodes, 181–182radiation therapy, 181surgical, 178–181

Pharyngeal wall, posterior, carcinomaof, 73

Pharynx, hypopharynx, see Hypopharynxoral, see Oropharynx


Pilocarpine hydrochloride, to protectsalivary function during radiationtherapy of head and neck cancerpatients, 194–195

Positron emission tomography (PET),imaging in head and neck oncology,13–35

Postcricoid tumors, surgery for, 89–90

Postoperative evaluation, in head and neckoncology, use of imaging in, 29

Precursor lesions, risk factor for cutaneousmalignant melanoma, 204–205

Predisposition, to cancer, in patients withsquamous cell carcinoma of head andneck, 2–4

genes for, 5–6genomic instability and, 4–5

Primary tumor, imaging of, in head andneck oncology, 16–22

Prognostic factors, in oral cavity squamouscell carcinoma, 65–66in well-differentiated thyroid

carcinoma, patient-specific,130–131tumor-specific, 131–134

Prosthodontics, dental oncology in headand neck cancer, 40

Pyriform sinus, surgery for carcinoma of,87–89

Q

Quality of life, in patients with head andneck cancers, 189

R

Radiation therapy, dental oncology and, inhead and neck cancer, 38for laryngeal carcinoma, 107–108for paranasal sinus cancers, 181for salivary gland cancers, 125in management of oral cavity

squamous cell carcinoma, 62–63of cutaneous melanomas of head and

neck, 216–218primary, for hypopharyngeal

carcinoma, 92–93side effects of, as alternative to surgery

for head and neck cancers,188–189

xerostomia induced by, strategies toreduce, 194–196

Radical neck dissection. See Neck dissection.

Radioiodine ablation. See Iodine 131

Reconstruction, after surgery for squamouscell carcinoma of oral cavity, 61–62

Recurrence, of salivary gland cancers,125–126

Rehabilitation, after treatment of oralcavity squamous cell carcinoma, 64

Retromolar trigone, squamous cellcarcinoma of, surgical treatment of, 56

Risk factors, for cutaneous malignantmelanoma, 204–206

S

Salivary function, preservation of, inpatients with head and neck cancers,194–196

limiting salivary gland exposure,195–196

radioprotective agents, 194–195

Salivary gland tumors, major, 113–127acinic cell carcinoma, 119adenocarcinoma and related

classification, 120–121adenoid cystic carcinoma, 117imaging and fine-needle aspiration,

114–116lymphoma, 122malignant mixed tumors, 120melanoma, 121–122molecular biology, 122–123mucoepidermoid carcinoma, 116–117recurrence, 125–126squamous cell carcinoma, 121treatment, 123–125

neck dissection, 124–125radiation therapy, 125salivary gland surgery, 123–124

undifferentiated carcinomas, 122

Selective neck dissection. See Neckdissection.

Sentinel lymph node biopsy, for staging N0neck tumors, 161–163

Side effects, of radiation therapy, asalternative to surgery for head andneck cancers, 188–189

Sinonasal undifferentiated carcinoma, 177

Sinus cancers. See Paranasal sinus cancers.

Skull base surgery, for head and neckcancer, integration of neurosurgicaltechniques in, 231–239


Skull (continued)carotid artery assessment,

preservation, sacrifice, andbypass, 235–236

cerebrospinal fluid leaks, 232–233imaging in, 236–238wound closure, 233–235

Soft palate, carcinoma of, 73–74

Speech, preservation of, in patients withhead and neck cancers, 189–192

technical improvements in, 191voice quality with different

treatment modalities,191–192

Squamous cell carcinoma, of head and neck,genomic instability, role inpathogenesis of, 1–11

of hypopharynx, 81–98of larynx, 99–112of oral cavity, current treatment

options, 47–70of oral pharynx, subsite

treatment heterogeneity,71–80

of paranasal sinuses, 173–174of salivary gland, 121organ preservation in patients

with, 187–199

Staging, of cutaneous melanomas of headand neck, 208–213

Subglottic carcinoma, surgical treatment of,106–107

Sun exposure, risk factor for cutaneousmalignant melanoma, 204

Superficial spreading melanoma, 206

Supraglottic carcinoma, surgical treatmentof, 105

Surgical treatment, dental oncology and,40–41for hypopharyngeal carcinoma,

85–92for laryngeal squamous cell

carcinoma, 104–107for oropharyngeal carcinoma,

according to subsite, 71–80for salivary gland cancers, 123–125for squamous cell carcinoma of oral

cavity, 53–62neck dissection in head and neck

cancers, 151–166of cutaneous melanomas of head and

neck, 213–216of paranasal sinus cancers,

178–181

skull base surgery for head and neckcancer, integration ofneurosurgical techniques in,231–239

carotid artery assessment,preservation, sacrifice, andbypass, 235–236

cerebrospinal fluid leaks,232–233

imaging in, 236–238wound closure, 233–235

Swallowing, preservation of, in patientswith head and neck cancer, 192–194

after radiation, 193–194after surgery, 193

T

Thyroglobulin assay, after postoperativeiodine 131 therapy for differentiatedthyroid carcinoma, 145

Thyroid carcinoma, iodine 131 as adjuvanttherapy of well-differentiated, 129–149

acute and long-term effects oftherapy, 137–140

further management, L-thyroxinetherapy, 142–144serum Tg testing and

rhTSH, 145imaging and follow-up, 140–142outcomes, 142postsurgical remnant ablation,

134–135therapy of metastases from,

135–137prognostic factors, patient-specific,

130–131tumor-specific, 131–134

Thyrotropin administration, afterpostoperative iodine 131 therapy fordifferentiated thyroid carcinoma, 145

Thyroxine, L-, therapy with, after iodine131 therapy for differentiated thyroidcarcinoma, 142–144

Tongue, squamous cell carcinoma of,surgical treatment of, 53–54

Tongue base, carcinoma of, 76–77

Tonsillar complex, carcinoma of, 74–76

U

Undifferentiated carcinoma, of salivarygland, 122sinonasal, 177


V

Voice, preservation of. See Speech.

W

Wound closure, integration of neurosurgicaltechniques into skull base surgery forhead and neck cancer, 233–235

X

Xeroderma pigmentosum, as risk factor forcutaneous malignant melanoma,205–206

Xerostomia, preservation of salivaryfunction in patients with head andneck cancer, 194–196

Documents

Current Diagnosis and Therapy for Head and Neck Malignancies