Review- Surgical Pathology of Salivary Gland Tumors for Practicing Pathologists- Richard Zarbo- Modern Path 2002

Salivary Gland Neoplasia: A Review for the PracticingPathologistRichard J. Zarbo, M.D., D.M.D.

Henry Ford Hospital, Detroit, Michigan

The purpose of this review is to identify advances insalivary gland tumor pathology that have takenplace over the past 30 years. In addition, selectedtumor entities likely to be encountered or topresent diagnostic difficulty in general practice willbe addressed in detail.

EpidemiologyOver the years there has been some progress in

clarifying specific causes of salivary gland cancer.The best known risk factor is that of radiation ex-posure as evident in the increased risk in atomicbomb survivors and in patients receiving therapeu-tic radiation. An increased occurrence in childrenwith leukemias treated with multiagent chemother-apy and prophylactic cranial irradiation has alsobeen noted (1). A dose response effect for low doseirradiation has been shown with a mean latencyperiod of tumor development of 11 years for malig-nant tumors and 21.5 years for benign tumors (2).However, no increased risk is noted for exposure toUVB radiation.

Of potential viral etiologies, only EBV infection isimplicated in the pathogenesis of salivarylymphoepithelioma-like carcinomas that are morecommonly encountered in Eskimo and Chineserather than Western populations. However, no in-creased risk is documented for infections with her-pes, papilloma or HIV viruses (3, 4). Contrary to oneprevious study (5), it is acknowledged now thatthere is no increased risk of a second primary breastcancer in women who have had previous salivarygland cancer. However, there is some increased riskfor the development of second primary cancers ofthe oropharynx, thyroid gland and lung, especiallyfor those whose salivary gland cancers were treatedwith radiotherapy (6). Unlike other head and neckcancers, alcohol and smoking abuse are not asso-

ciated with increased risk for developing salivarygland neoplasms with the exception of a greatlyincreased risk and association of smoking withWarthin’s tumor (7–9). One interesting finding, un-confirmed by others, is an elevated risk of salivarygland cancer in women employed as hairdressersand those working in beauty salons (10).

GeneticsObviously, there are abnormalities based in the

genome that underlie salivary gland neoplasia. Thisis evident in the rare familial autosomal dominantTurban Tumor (Brooke-Spiegler) syndrome, local-ized to a tumor suppressor gene on chromosome16q12-q13. In this condition individuals developnumerous cutaneous dermal cylindromas, tricho-epitheliomas and eccrine spiradenomas with occa-sional similar appearing (dermal analogue) salivarymembranous type basal cell adenomas (11–13).Other salivary tumors known to have a familialoccurrence include pleomorphic adenoma, aciniccell carcinoma (14), Warthin’s tumor and lympho-epithelial carcinoma (15). The latter has also beennoted in association with dominantly inherited tri-choepitheliomas in a Finnish family (16).

Cytogenetic analyses of benign tumors showcommon abnormalities like trisomy 8 or transloca-tions, often reciprocal, that involve activation ofoncogenes HMGIC located on chromosome 12q13and PLAG1 found on chromosome 8q12 (17). Re-cent evidence shows that PLAG1 is a nuclear pro-tein that activates transcription of human insulingrowth factor II (IGF-II) by binding to the promotor3 site. Deregulation of this IGF-II target gene, inac-tive in adult salivary glands, is a recent molecularclue in salivary gland tumorigenesis (18). However,this does not appear to be specific to salivary glandas lipoblastomas also exhibit chromosome 8q12 re-arrangements resulting in PLAG1 activation (19).Moreover, not all adenomas exhibit abnormalPLAG-1 expression leaving much about the role ofoncogenes in tumor development and progressionpresently undefined.

Copyright © 2002 by The United States and Canadian Academy ofPathology, Inc.VOL. 15, NO. 3, P. 298, 2002 Printed in the U.S.A.Date of acceptance: September 27, 2001.Address reprint requests to: Richard J. Zarbo, M.D., Department of Pa-thology, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, Michigan48202; e-mail: [email protected].

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Genetic abnormalities common to the malignan-cies include trisomy 8 but also loss of genetic ma-terial like Y chromosome and deletion 6q21–23.3and 6q27. It is hypothesized that these chromo-somal abnormalities reflect inactivation of morethan one tumor suppressor gene. Specific histologictumor types are also associated with specific abnor-malities – carcinoma ex pleomorphic adenoma[8q12–13 & 12q13–15 rearrangements], adenoidcystic carcinoma (t[6;9][q21–24;p13–23]), and mu-coepidermoid carcinoma (t[11;19][q14 –21;p12–13])(17). Interestingly, the latter rearrangement is iden-tical to that encountered in Warthin’s tumor. Withthe advent of gene and protein expression profiling,future molecular and genetic insights are bound toinfluence current understanding of salivary glandtumorigenesis and its classification.

Histogenesis versus MorphogenesisMuch of the early years of salivary gland tumor

pathology focused on relating histologic tumortypes to cell of origin. The most popular histoge-netic hypothesis championed by Batsakis and col-leagues theorized two stem cell progenitors in prox-imal and distal regions of the duct system. A morehypothetical distal intercalated duct reserve cellwas proposed as the progenitor of tumors withterminal ductal, myoepithelial and acinar differen-tiation whereas an excretory duct reserve cell wasthe proposed cell of origin for tumors with largeduct, squamous or mucous cell differentiation (20,21). A more recent progression in conceptualizingand classifying salivary gland tumors is a morpho-genetic one, championed by Dardick (22), whichrelates morphology to cell differentiation derivedfrom differential gene expression of a stem cell inconjunction with tumor matrix production ratherthan to a specific proposed cell of origin.

ClassificationIn the second half of the 20th century, the field of

salivary gland tumor pathology proved fertileground for the identification of a considerablenumber of new entities (Table 1). This is evidencedby the 16 salivary tumor entities listed in the 1954AFIP fascicle classification of Foote and Frazell (23)compared with 36 entities in the 1996 AFIP fascicleauthored by Ellis and Auclair (24). Since 1954 therehas been a doubling in tumor categories of bothbenign (6 now 13) and malignant (10 expanded to23). Classification schemes are dynamic, continu-ing to evolve as new light is shed on the biologicbehavior of both established and newly describedentities from clinical, pathologic, molecular and ge-netic studies so be prepared for continued evolu-tion. Table 1 lists newly identified or named salivary

gland tumors since 1967. Some, like basal cell ade-noma, polymorphous low-grade adenocarcinoma,epithelial-myoepithelial carcinoma and salivaryduct carcinoma have become important diagnosesin current surgical pathology practice.

Pathology ReportDespite the plethora of malignant salivary gland

tumor types presented to pathologists for diagnosis,there is consensus on a limited number of patho-logic observations that determine treatment andoutcome and should therefore comprise the pathol-ogy report of salivary malignancies. The majorpoints that should constitute all reports are 1) his-tologic type; 2) anatomic site of origin; 3) documen-tation of extent of disease to include information toallow TNM staging; 4) documentation of complete-ness of surgical excision and margin status. Docu-mentation of anatomic site of origin is important asit often reflects differences in outcome of salivarygland malignancies but it is not clear whether this isbecause of biologic parameters innate to the loca-tion, advanced stage or secondary to ease of surgi-cal extirpation with a clear margin. There is a trendfor more favorable survival for cancers originatingin intraoral and oropharyngeal minor salivaryglands compared with major glands (parotid andsubmaxillary). The exception is the generally poorersurvival for nasopharyngeal and paranasal sinusmalignancies (25). Tumor stage and clinical/patho-logic signs of local tumor aggressiveness are majorpredictors of distant metastasis and therefore ulti-mate outcome in salivary gland cancers of the pa-rotid gland (26).

TABLE 1. Newly Identified or Named Salivary Gland

Tumors since 1967

Basal cell adenoma (57)Adenosquamous carcinoma (96)Salivary duct carcinoma (91)Sialadenoma papilliferum (97)Epithelial-myoepithelial carcinoma (83)Intraductal papilloma (98)Membranous basal cell adenoma (11)Malignant (metastasizing) myoepithelioma (90)Inverted ductal papilloma (99)Large cell undifferentiated carcinoma (100)Lobular/terminal duct carcinoma (69, 70)Polymorphous low grade adenocarcinoma (68)Low grade papillary adenocarcinoma-palatal (74)Sialoblastoma (101)Clear cell oncocytoma (102)Dedifferentiated acinic cell carcinoma (36)Basal cell adenocarcinoma (66)Large cell neuroendocrine carcinoma (103)Salivary gland anlage tumor (104)Hyalinizing clear cell (intraductal) carcinoma (82)Low grade salivary duct carcinoma (77)High grade intraductal carcinoma (78, 79)

Salivary Gland Neoplasia (R.J. Zarbo) 299

Tumor StageBecause of the diversity of head and neck ana-

tomic sites in which salivary gland malignanciesmay arise, there is no single applicable stage sys-tem. For salivary gland cancers of the major glands(parotid, submaxillary, sublingual) there is a sepa-rate TNM clinical/pathologic staging system uni-fied between the American Joint Committee onCancer and the International Union Against Cancer(27). For minor salivary gland malignancies use ofAJCC/UICC guidelines for squamous cell carcino-mas occurring in the same regions of oral cavity/oropharynx, nasopharynx and paranasal sinus siteshas been shown to be a major outcome predictor bySpiro and colleagues (28). This was recently con-firmed by Vander Poorten et al. who found no his-topathologic or treatment parameters predictive ofsurvival in minor salivary gland carcinomas but didaffirm the prognostic value of T and M componentsof TNM classification (25). For the numerous headand neck sites, the M and N categories (exceptionnasopharynx) are the same but the specific patho-logic assessments of the T categories vary (27).Therefore, in order to improve report completenessand quality, a synoptic/checklist design dedicatedto salivary gland carcinomas would need to be cus-tomized for origin in minor glands by specific site ofinvolvement (e.g., lip and oral cavity, pharynx, lar-ynx, paranasal sinuses).

In all salivary gland malignancies it is importantfor the pathologist to completely document in theresection specimen the following to enable clinicalstaging, as specified in 1997 AJCC/UICC guidelines,to be pathologically confirmed:

1) For T component, aspects of size and localextension:

a. greatest tumor dimension in centimetersb. extraparenchymal extension (major glands)c. invasion of skull base or seventh nerve (major

glands)d. local extension/structures as per primary site

TNM classification (minor glands)2) For N component, aspects of number and size

of positive nodes:a. regional lymph node involvement documenta-

tion of single vs. multiple nodesb. size of involved lymph node in centimeters

Tumor GradeIn general, histologic/cytologic grade is predic-

tive of biologic behavior for salivary gland malig-nancies but lack of significance in survival studiescompounded by issues of subjectivity and interob-server variation limit the influence of tumor grade.For the classic salivary gland malignancies, grading isnot usually performed nor is there is any standardgrading scheme applicable to all types. In most sali-

vary gland cancers, the diagnostic classification itselfindicates tumor grade. For instance, certain entitiesare acknowledged as low grade (polymorphous lowgrade adenocarcinoma, basal cell adenocarcinoma,acinic cell adenocarcinoma) and some as high grade(salivary duct carcinoma, adenocarcinoma NOS,squamous cell carcinoma, undifferentiated carci-noma, adenosquamous carcinoma).

Grading of Adenoid Cystic and MucoepidermoidCarcinomas

Of the classic salivary type adenocarcinomas, twocancers, adenoid cystic carcinoma, mucoepider-moid carcinoma, exhibit a histologic spectrum inwhich grading is significant. One or more ap-proaches have been proposed for these specific his-tologic types with some success. Grading schemesthat appear to provide significant predictive insightinto the biologic behavior of adenoid cystic carci-noma and mucoepidermoid carcinoma should beapplied according to the schemes of Szanto (29)and Brandwein (30) modified after Auclair (31) andGoode et al. (32), respectively. In adenoid cysticcarcinomas, the tubular and cribriform patterns areconsidered low grade with increasing admixed solidcomponents contributing to higher grades 2 (great-er than 30% solid) and grade 3 (predominantlysolid) (Fig. 1). In mucoepidermoid carcinomas, thequantitative point scoring scheme considers thefollowing parameters indicative of higher grade: in-tracystic component less than 20%, presence ofneural invasion or necrosis, mitotic rate of 4 ormore per 10 high power fields and cellular anapla-sia. The point scores result in three grades of low,intermediate, and high. Predictions of long-termbiologic outcome by these two grading schemes areillustrated in Figure 2.

Grading of Carcinoma ex Pleomorphic AdenomaTortoledo et al. (33) and Brandwein and col-

leagues (34) have refined our understanding of bi-ologic behavior of malignancies confined within(carcinoma in situ) and extending out from (carci-noma ex) pleomorphic adenomas. In the noninva-sive (in situ) form, the behavior is similar to benignmixed tumor given complete surgical excision. Forcarcinomas ex pleomorphic adenoma, it is prog-nostically useful for the pathologist to measure ex-tension of the carcinoma in millimeters beyond thecapsule of the residual benign pleomorphic ade-noma and to identify whether the malignancy is oflow grade (e.g., polymorphous low grade adenocar-cinoma ex pleomorphic adenoma). In the study ofTortoledo and colleagues, extension greater than 6mm was predictive of a 70.5% recurrence rate com-pared with 16.5% recurrence for tumors extending

300 Modern Pathology

less than 6 mm. Moreover, of those carcinomasextending less than 8 mm, there were no deathsfrom disease despite the presence of lymph nodemetastases (33). In the pathologic examination ofbenign mixed tumors, the finding of prominentzones of hyalinization, especially in larger tumorsof the submandibular gland in older patients hasbeen associated with a greater likelihood of malig-nant transformation (35). This morphologic marker

of risk should dictate a complete sampling of thetumor to exclude malignancy.

Grading of Adenocarcinoma NOSMany of the newly described entities listed in

Table 1 were derived from this category of formerlyunclassifiable tumors. Although current adenocar-cinomas, not otherwise specified (NOS), show greatdiversity and there is no standardized gradingscheme, I agree with the proposal that an attemptshould be made to grade the unclassifiable cancersbased on cytomorphologic features, usually in athree-tiered scheme (24). I have found it conve-nient to apply a simple nuclear grading schemerather than the more detailed approaches to grad-ing of breast ductal carcinomas that consider tu-bule formation and mitotic activity as well. It islikely that the diverse neoplastic types still compris-ing the category of adenocarcinoma NOS will likelybe a fruitful source of newly identified tumor typesor tumors bearing specific markers indicative ofbiologic behavior. A good rule of thumb is that if asalivary gland adenocarcinoma does not nicely fitpreviously described entities, and a metastasis canbe excluded, then adenocarcinoma NOS is the ap-propriate diagnosis.

FIGURE 1. Grading of adenoid cystic carcinoma: low grade tubular pattern (A); low grade cribriform pattern (B); intermediate grade, partially solid(C); high grade solid (D).

FIGURE 2. Influence of grade on long-term survival, applying thethree-part grading schemes of Szanto and Brandwein to adenoid cysticcarcinoma (left) and mucoepidermoid carcinoma (right), respectively.


Dedifferentiated CarcinomaThe concept of dedifferentiation in salivary tu-

mor pathology is essentially the identification of theclonal evolution of a poorly differentiated or highgrade element arising within a low-grade carci-noma. This was first described in 1988 by Stanleyand colleagues who reported six cases of acinic cellcarcinoma that contained areas of poorly differen-tiated adenocarcinoma or undifferentiated carci-noma without histologic transition or a spectrumfrom the acinic cell element. These cases were clin-ically aggressive exhibiting significant nerve symp-toms of pain, paresthesia, or facial paralysis andpathologically widely invasive with early metastasis(36). This concept is to be contrasted with malig-nancy arising from a benign tumor (prototype car-cinoma ex pleomorphic adenoma) and the rare hy-brid tumors in which divergent differentiationresults in two or more different tumor entities thatarise simultaneously within the same topographicalarea (e.g., acinic cell carcinoma and salivary ductcarcinoma) (37).

In a dedifferentiated tumor, the anaplastic com-ponent may be juxtaposed to or located within theoriginal tumor but morphologically the original lineof differentiation is “lost” or a new line of differen-

tiation is expressed. This phenomenon may be con-sidered either de novo transformation to anotherdistinct tumor type (e.g., undifferentiated carci-noma arising in epithelial-myoepithelial carcinomaor myoepithelial carcinoma arising in adenoid cys-tic carcinoma) or histologic transformation to ahigher grade element within the low-grade carci-noma (e.g., undifferentiated carcinoma arisingwithin polymorphous low grade adenocarcinoma).This is distinguished from histologic transforma-tion within a high-grade carcinoma to anotherhigh-grade pattern, as in sarcomatoid salivary ductcarcinoma (38). Dedifferentiation has been docu-mented in acinic cell carcinoma (Fig. 3), mucoepi-dermoid carcinoma (39) adenoid cystic carcinoma(40), polymorphous low-grade adenocarcinoma(41) and epithelial-myoepithelial carcinoma (42).The histologic patterns may be sharply demarcatedor blended within the low grade tumor in varyingproportions with various appearances that have in-cluded glandular, squamous, polygonal cell, spin-dle cell and undifferentiated forms. Dedifferentia-tion has been noted ab initio or at recurrence, oftenpost radiation therapy. These morphologic obser-vations are significant and portend clinical aggres-siveness but molecular mechanisms of dedifferen-

FIGURE 3. Dedifferentiated acinic cell carcinoma with clear demarcation (left) of well differentiated acinic cell component shown at high power(upper right) and poorly differentiated element (lower right). (Case provided courtesy of Dr. Douglas Gnepp.)


tiation in salivary gland neoplasia are yet to beclarified. The potential for dedifferentiation inmany types of low-grade salivary gland cancerswould dictate that complete sampling should bethe standard approach to all salivary gland tumorsencountered at the gross bench.

New TechniquesSalivary gland tumors have been the subject of

most of the new techniques. This would includeflow cytometry DNA/SPF analysis, immunoprolif-eration markers PCNA and Ki-67, nucleolar counts(AgNORs) and assessments of oncoproteins p53and Her/2. However, these characterizations can beconsidered preliminary and are presently of noclinical utility. The interpretations are con-founded by issues of short follow-up, prolongednatural history of the disease, small sample sizedue to rarity of salivary gland tumors and lack ofmethod standardization (17). The current surgicalpathology approach to salivary gland tumor diag-nosis and characterization is a morphologic onewith limited use of immunohistochemistry in se-lect differential diagnoses, complemented with

time tested pathologic staging and documenta-tion of margins.

ImmunohistochemistryThere are few absolutes in salivary gland tumor

diagnosis given the marked spectrum and overlap

FIGURE 4. Calponin immunohistochemical staining of normal salivary gland defines tapered and triangular shaped myoepithelial cellssurrounding acini and intercalated ducts (arrow). Also outlined are smooth muscle cells of an artery and vein. Striated duct is unstained.

TABLE 2. Antibodies that May Be Helpful in Resolving

Difficult Differential Diagnoses

Nonspecific markers of luminal/acinar epithelial differentiationEpithelial membrane antigen (EMA)Carcinoembryonic antigen (CEA)Low molecular weight keratins (CK 8, 18, 19)

Nonspecific markers of myoepithelium (also seen in some ductalepithelial phenotypes)

S-100GFAPHigh molecular weight keratins (CK14)Vimentin

Markers of muscle differentiation (myoepithelium)Alpha-smooth muscle actinSmooth muscle myosin heavy chainCalponinCaldesmonp63

Markers of cell organelles/secretionsMitochondria (oncocytic metaplasia and oncocytic tumors)Amylase, lactoferrin, lysozyme, secretory component (acinar

differentiation)Type IV collagen, laminin, maspin


of differentiated cell types that participate in thenumerous benign and malignant tumors. Havingsaid that, Table 2 enumerates antibodies that maybe helpful in resolving difficult differential diag-noses when applied with astute morphologic cor-relation (43–51). Many immunohistochemical in-vestigations have pursued differentiation markers,especially of myoepithelium, to assist in classifica-tion. The first antibodies applied, directed to S-100protein, vimentin and GFAP, have been found to benonspecific in their reactivity. However, there ispromise for some of the newer myoepithelialsmooth muscle markers like alpha smooth muscleactin, smooth muscle myosin heavy chain, calponin(Fig. 4), caldesmon and p63 in select diagnosticsituations (46 – 49, 52, 53). This would include theidentification of neoplastic myoepithelium in bilay-ered tubules, cribriform structures or in spindledand myxoid stroma in pleomorphic adenomas,variants of basal cell adenoma and adenocarci-noma, adenoid cystic carcinoma, epi-myoepithelialcarcinoma, and noninvasive low-grade salivaryduct carcinoma. These stains are also confirmatoryof broad morphologic range of myoepithelial differ-entiation in the epithelioid, spindled, clear cell andplasmacytoid morphologic variants of myoepithe-lial carcinomas. Markers like EMA and CEA havebeen used to indicate acinar or glandular differen-tiation and selective markers for organelles, such asmitochondria, may be useful in selective differen-tial diagnoses of oncocytic tumors (50). Other sali-vary secretions like amylase, lactoferrin, lysozyme,secretory component and cell matrix componentstype IV collagen, laminin and maspin can be de-tected by immunohistochemistry but have notfound a diagnostic role. In general, immunohisto-chemistry as an ancillary diagnostic tool should beused sparingly and wisely as a morphologic adjunctbecause of the lack of specificity of many markersfor specific histologic tumor types.

Role of MyoepitheliumIn the future there may be some role for the

pathologic assessment of myoepithelial differentia-tion in salivary gland tumor types, as there appearsto be a modifying effect of this cell type on biologicbehavior. For instance, during development myoepi-thelium induces salivary gland morphogenesis andepithelial differentiation. This cell also appears to re-sist neoplastic transformation. In the neoplastic state,myoepithelium has a lower proliferation than basaltype epithelial cells and secretes excess substancesthat inhibit tissue invasion and metastasis. These ac-cumulated myxoid ground substances and basementmembrane components as well as numerous protein-ase inhibitors like maspin, a-1-antitrypsin, TIMP-1and protease nexin II all contribute to an anti-invasive

matrix for myoepithelial-rich salivary gland tumors(54). For example, myoepithelial carcinomas exhibitlobulated and pushing rather than infiltrative tissuegrowth patterns and prolonged survivals despite dis-tant metastasis (49). There is also some indicationthat myoepithelium may inhibit angiogenesis, furthercontributing to local growth and inhibition of metas-tasis (55). These factors may relate to the lobulated,pushing, hypovascular invasive character and pro-longed survivals despite distant metastasis attributedto tumors like epithelial-myoepithelial carcinoma andmyoepithelial carcinoma. Much further study isneeded before observations of this nature could betranslated clinically.

Review of Tumor EntitiesI have elected to discuss and illustrate the mor-

phology of a number of benign and malignant sal-ivary gland tumor entities that the practicing pa-thologist will encounter. These have been selectedbecause they readily simulate each other but havevery different clinical therapies and thereforeshould be included routinely in differentialdiagnosis.

Salivary Gland AdenomasThe salivary gland adenomas can be considered

to represent a morphologic spectrum of differenti-ation (Fig. 5). At the midpoint lie the more com-monly encountered pleomorphic adenomas whoseproliferation of epithelial ducts and myoepithelialderived stromal appearances, have been shown tobe monoclonal in original based on PCR analysis ofthe human androgen receptor gene (56). Therefore,it is the matrix production and mesenchymal mor-phologic metaplasia resulting in the “mixed” ap-

FIGURE 5. Schematic diagram depicting the overlapping cellulardifferentiation comprising the morphologic spectrum of the salivarygland adenomas. Pure ductal luminal differentiation (canalicularadenoma) depicted on the left with increasing degrees of myoepithelialparticipation in basal cell adenomas and pleomorphic adenomasprogressing to pure myoepithelial differentiation (myoepithelioma) onthe right.


pearance that distinguishes this classification fromother so-called basal cell adenomas and the raremyoepitheliomas. Whereas the myoepithelial com-ponent in the basal cell adenomas is usually histo-logically inapparent without the use of immuno-markers and matrix is lacking, by definition themyoepitheliomas are composed only of myoepithe-lial cells that may assume various and mixed mor-phologies but may exhibit some hyalinized andmyxoid matrix production as well. At the far end ofthe adenoma spectrum lie benign tumors com-posed purely of tubular cells, the canalicularadenomas.

Basal Cell AdenomasThe basal cell adenomas were first named by

Kleinsasser and Klein (57) in 1967 and formallyrecognized in the WHO classification in 1991 (58).This category excludes canalicular adenoma, whichwas formerly called a basal cell adenoma and ismore common in the oral cavity. The basal celladenomas are rare, accounting for 1.5% of all epi-thelial and 2.4% of all benign salivary gland tumorsin the AFIP registry (24). Most occur in the majorglands (75% parotid, 5% submaxillary gland) ofadults (mean age 58 years) with a 2:1 female predi-

lection. With the exception of the membranoustype, they are solitary and circumscribed. Thesetumors are treated by conservative excision andhave demonstrated a low recurrence rate. Also, withthe exception of the membranous type there is a 4%rate of malignant transformation. Most malignan-cies arising from basal cell adenomas are of thebasal cell type with rare nonbasaloid carcinomasreported (59).

The morphologic subtypes encompassed by theterm basal cell adenoma may look quite differenthistologically. The most common is the solid type,followed by the trabecular and trabecular-tubulartypes, the membranous and the rare tubular types(Fig. 6). All have a fibrous stroma and lack a myxo-chondroid matrix as in pleomorphic adenoma. Thetrabecular-tubular variant, however, exhibits subtlestromal spindled cellularity that has been shown tobe of myoepithelial origin, underscoring the rela-tionship to pleomorphic adenoma (43, 44, 60). Allvariants may demonstrate cystic change, squamouswhorls, frank keratinization or rare cribriform pat-terns. The common proliferation is that of uniform,cytologically bland basaloid cells with occasionalpalisading at the periphery. Darker basaloid cellsare noted at the periphery of nests with larger, paler

FIGURE 6. The solid (A), trabecular (B), trabecular-tubular (C), and tubular (D) morphologies encompassed by the term basal cell adenoma.


cells in central areas. There is myoepithelial differ-ential in all of the morphologic patterns of basal celladenoma which is inapparent morphologically buthas been recently demonstrated with antibodies tosmooth muscle proteins (Fig. 7) (46).

Membranous AdenomaThe membranous type of adenoma, also know as

the dermal analogue tumor, was first described in1977 by Headington and colleagues (11, 12). It oc-curs mainly in the parotid gland or may arise in aparotid lymph node thereby simulating a metasta-sis. This tumor may be associated with the autoso-mal dominant salivary gland-skin adnexal tumorsyndrome (Brooke-Spiegler). Cutaneous tumorshave been reported in 25–38% of individuals withmembranous adenomas of salivary gland (61, 62).These individuals may develop hundreds of dermalcylindromas, trichoepitheliomas and spiradenomasthat are morphologically mimicked by the salivarygland cylindroma-like adenomas (dermal ana-logue). A rare case of an intranasal salivary typemembranous adenoma occurring in this syndromehas also been described (63).

Histologically, basaloid nests and islands of cellsforming jigsaw patterns that are surrounded by aprominent hyalinized reduplicated basementmembrane and may have coalescent membranedroplets within characterize the tumor (Fig. 8). Cys-tic change and squamous metaplasia may be seenin larger solid nests.

Roughly half of the membranous adenomas aremultifocal and most are unencapsulated. These twofeatures in conjunction with the cylindroma-likepatterns with hyalinized basement membrane andoccasional origin within parotid lymph nodes maysimulate malignancy, especially adenoid cystic car-cinoma. However, the latter demonstrates a higherdegree of cytologic atypia with hyperchromatic an-gular nuclei or vesicular nuclei with distinct nucle-oli and true cribriform patterns associated with abasophilic matrix.

Membranous adenomas have a fairly high rate ofrecurrence (25%) and malignant transformation(28%) (64). Malignant transformation is recognizedhistologically as a destructive infiltrative basaloidgrowth beyond the confines of the gland or peri-neural or vascular invasion. Malignancy need not

FIGURE 7. Myoepithelial differentiation identified by immunostaining for calponin in solid (A), tubular (B), trabecular-tubular (C), andmembranous (D) basal cell adenomas. Note the positively stained spindled stromal cells of the trabecular-tubular adenoma (C) indicatingmyoepithelial derived stroma similar to that found in pleomorphic adenoma.


be associated with pleomorphism, necrosis or mi-totic activity in these tumors. This will be discussedfurther under basal cell adenocarcinoma.

Canalicular AdenomaThe canalicular adenoma (Fig. 9) has been a rec-

ognized entity since the 1950s and was formerlydesignated basal cell adenoma. It is typically en-countered as an intraoral minor salivary gland tu-mor usually in the upper lip or buccal mucosa ofindividuals over age 50 with a female predomi-nance. Clinically the tumor is perceived as a super-ficial, painless, compressible, slow growth. Canalic-ular adenomas account for roughly 1% of allsalivary gland tumors and 4% of all minor salivarygland tumors (24).

Microscopically, this tumor is usually encapsu-lated but roughly 22% are multifocal (65). It is com-posed of lines of columnar ductal-luminal cellsrather than basal type cells that form branchingdouble rows (canaliculi) that come together inter-mittently (beading) and may undergo cysticchange. The intervening stroma is characteristicallyparvicellular, edematous and finely vascular. Mixedsolid trabecular and adenoid basal cell patterns that

overlap with basal cell adenomas may be seen butdo not change the biologic behavior or the immu-nophenotype of S-100 protein positive and focallyGFAP positive but muscle marker negative cells (43,44, 46). However, these patterns in conjunctionwith the multifocal appearance may invoke addi-tional differential diagnoses of trabecular adenoma,basal cell adenocarcinoma or adenoid cystic carci-noma. Adenoid cystic carcinoma is the most criticalto identify because of differences in treatment andoutcome. Although occasionally circumscribed, itwould demonstrate true destructive infiltration,cribriform patterns, bilayered ducts and strong im-munoreactivity for muscle markers.

It is not uncommon for the pathologist to receivethese tumors as fragmented specimens likely due tothe cystic nature of many canalicular adenomas.Despite the appearance of having been “shelledout” so that margin assessment is compromised,recurrence is uncommon.

Basal Cell AdenocarcinomaBasal cell adenocarcinomas are low grade malig-

nancies so named in 1990 by Ellis and Wiscovitch(66). These tumors were previously recognized over

FIGURE 8. Membranous adenomas present worrisome features due to unencapsulation and, often, multifocality (A). Tumors are distinguished bybasaloid nests forming jig-saw patterns (B), surrounded by prominent hyalinized reduplicated basement membrane (C), with coalescent membranedroplets within cell nests (D).


the years with various labels like basaloid carci-noma, hybrid basal cell adenoma, adenoid cysticcarcinoma, carcinoma arising out of monomorphicadenoma and even sialoblastoma. The basal celladenocarcinomas are rare, accounting for 1–2% ofepithelial salivary malignancies. They usually occurin adults, average age 60, with no gender predilec-tion. All but one case reported in the palate havebeen in the major glands, mostly the parotid.Roughly 77% arise de novo with 23% arising withinpreexisting basal call adenomas. About 10 –14% ofbasal cell adenocarcinomas are associated with theskin adnexal tumor syndrome (67).

Basal cell adenocarcinomas exhibit the same cy-tology and patterns as the basal cell adenomas butthese growths are malignant as judged by destruc-tive local infiltration, neural and vascular invasion,lymph node metastasis and rarely distant pulmo-nary metastasis.

Histologically these tumors are often multicentric(63%) with patterns that are single or mixed solid,trabecular, tubular and membranous and lack myx-oid or myxochondroid matrix (Fig. 10). The latterfeature is helpful in discrimination from basaloidtype pleomorphic adenomas. To date only the solid

pattern of basal cell adenocarcinoma has metasta-sized (67). These basaloid tumors may be cytologi-cally bland or may exhibit some degree of pleomor-phism, increased mitoses, proliferative Ki-67 andapoptotic indexes compared with the adenomas.However, these measures are not helpful in theindividual case because of the overlap with theadenomas of similar pattern. Therefore the diagno-sis is based on infiltration and invasion of neuraland lymphovascular spaces. These features distin-guish basal cell adenocarcinomas from similar ap-pearing unencapsulated, multifocal membranousadenomas that don’t show destructive infiltrativegrowth or perineural or vascular invasion.

Basal cell adenocarcinomas are treated conserva-tively with the intent of clear margins. These arelow-grade malignancies with only one patient of 45with follow-up in the review of Muller and Barneswho died of disease. From that review there is alocal recurrence rate of 37%, an 8% rate of metas-tasis to cervical lymph nodes (four cases), only twocases (4%) with metastasis to lungs (67).

The chief differential diagnosis is that of adenoidcystic carcinoma which may share the solid, tubularand cylindroma-like patterns (Fig. 11). Often help-

FIGURE 9. Canalicular adenomas present typically in the upper lip, here of an edentulous female (A). Multifocality (B) may be encountered inroughly a quarter of cases. Typical histology (C) of branching canaliculi of columnar cells forming double rows with intermittent “beading” set in aparvicellular, edematous and finely vascular stroma. Variations may include mixtures of trabecular (D) and adenoid (E) basal cell patterns raisingadditional differential diagnoses but no differences in behavior or immunostaining profile.


ful are the presence of true cribriform structuresand bilayered ducts with intense immunostainingfor muscle markers in conjunction with the charac-ter of the nuclei in adenoid cystic carcinoma thatare either angular and hyperchromatic or vesicularwith prominent nucleoli.

Also a consideration is the infiltrative, solid,basaloid components of polymorphous low-gradeadenocarcinomas (Fig. 11). The cytologically blandPLGA however have numerous histologically di-verse low-grade patterns, which are characteristicand discussed in greater detail next. In additionadenosquamous carcinomas may have fields thatare basaloid, but also may have true mucous cells, aneoplastic squamous component and associatedcarcinoma in situ of the overlying mucosa. Basaloidsquamous carcinomas may also have a neoplasticsquamous component and a pseudoglandular ap-pearance with accumulation of a hyaline matrix butthese cancers exhibit a significant degree of anapla-sia compared with basal cell adenocarcinomas (Fig.12). Small cell carcinoma, primary or metastatic,may also be considered in the complete differentialdiagnosis of a basaloid salivary neoplasm (Fig. 12).Powdery chromatin, indiscernible nucleoli, spin-dled cells, nuclear molding, high mitotic rate, crush

artifact, single cell necrosis, and cytokeratin dots orneuroendocrine differentiation by immunohisto-chemistry are often helpful. Lastly, basaloid vari-ants of ameloblastoma may resemble the cytologi-cally bland basal cell salivary gland adenomas andadenocarcinomas as well but demonstrate periph-eral palisading and polarization of columnar cellsand an edematous stellate reticulum-like epithe-lium within the tumor nests (Fig. 12).

Polymorphous Low Grade Adenocarcinoma(PLGA)

Polymorphous low-grade adenocarcinoma is thename coined in 1984 by Evans and Batsakis to de-scribe a morphologically diverse histologic spec-trum of intraoral adenocarcinomas of similar low-grade cytology and biologic behavior (68). In theprevious year a more restricted histologic entity,now incorporated into PLGA, was described as ter-minal duct carcinoma by Batsakis et al. and alsorecognized as lobular carcinoma by two oral pa-thologists, Freedman and Lumerman (69, 70). Al-though the oral cavity, especially the palate, is thetypical site of involvement, rare cases have beenreported in the nasal cavity and nasopharynx (71).

FIGURE 10. Basal cell adenocarcinomas are distinguished from basal cell adenomas by local infiltration (A) but share the same histologic patterns,here solid (B) and tubular (C) patterns illustrated. The cytology is typically bland (D) and may not show increased pleomorphism and mitotic activitycompared with the adenomas.


In the major glands, PLGA may be observed as a lowgrade carcinoma arising from a pleomorphic ade-noma (33). PLGA occurs over a wide age range witha peak in the 7th decade and a 2:1 female predilec-tion (72). In my experience PLGA have been morecommon than adenoid cystic carcinomas in theoral cavity.

Although they are often well circumscribed,PLGA are infiltrative neoplasms that may extendinto muscle, bone, cartilage and commonly nerves.All histologic patterns are cytologically uniform andbland, characterized by vesicular (“open”) nucleiwith stippled chromatin and inconspicuous tosmall nucleoli (Fig. 13). Mitotic figures are rare andnecrosis not seen. What distinguish PLGA are themixtures of polymorphous growth patterns. Theseinclude solid (jigsaw), cribriform (pseudoadenoid),tubular (usually a single cell layer) (73), trabecular,fascicular (streaming), linear single cell (indian file),and cystic patterns (Figs. 14, 15). The proliferationsare often centered on a nidus, commonly a focus ofperineural invasion, lending a targetoid appear-ance. PLGA are only focally papillary, so an exten-sive papillary component should raise the possibil-ity of the more aggressive low-grade palatalpapillary adenocarcinoma (74, 75) or papillary cys-

tadenocarcinoma with its well developed papillaeand fibrous cores. Also potentially complicating in-terpretation is that the stroma may be fibrous, mu-coid or hyaline in appearance, not unlike that ofadenoid cystic carcinoma. A characteristic slategray-blue stroma also may mimic the mucoid-myxoid matrix of pleomorphic adenoma (72). PLGAstain strongly for EMA and S-100 protein but onlyfocally for GFAP and muscle markers (Zarbo un-published observations) (43, 44, 72).

Because of morphologic diversity and histologicoverlap, cases of PLGA are most likely to be misdi-agnosed as pleomorphic adenoma. The likely sce-nario is a small incisional biopsy that does notreflect the heterogeneous patterns or infiltrative na-ture and perineural invasion of PLGA or containsfocal stromal change simulating a myxochondroidmatrix. A fact worth filing is that pleomorphic ade-nomas of minor salivary gland are not often encap-sulated and may have focal extensions into adja-cent minor salivary gland that are seeminglyinfiltrative when interpreted in a narrow field con-text. A low power appreciation of the circumscribednature of pleomorphic adenomas of minor salivarygland compared with the widely infiltrative natureof PLGA and common perineural invasion are use-

FIGURE 11. Chief differential diagnosis of basal cell salivary neoplasms: basal cell adenocarcinoma (A); membranous adenoma (B); polymorphouslow-grade adenocarcinoma (C); adenoid cystic carcinoma (D).


ful histologic discriminants as is the intense stain-ing of pleomorphic adenoma for muscle markers ofmyoepithelial differentiation.

The differential diagnosis also commonly in-cludes adenoid cystic carcinoma because of com-mon cribriform, tubular and solid growth patternsand perineural invasion. However, unlike PLGA, thetubules of ACC are always bilayered rather thancomposed of a single layer, there is significant de-gree of nuclear atypia and immunostaining formuscle markers demonstrates intense staining in-dicative of myoepithelial differentiation.

PLGA are indolent neoplasms that are unlikely tocause death. The recurrence rate from a literaturereview and a large AFIP series is 9 –17%, of those40% were multiple recurrences (72, 76). Roughly 9%of PLGA have metastasized to regional lymphnodes. In the study of 164 cases, by Castle andcolleagues, 97.6% of patients were either alive orhad died of unrelated causes without evidence ofdisease with an average follow-up of 115.4 months(72). To date, only one case of a biopsy provendistant metastasis to lung has been documented(72). Unlike adenoid cystic carcinoma, PLGA aretreated by conservative wide excision. Therefore itis especially critical to diagnose a PLGA rather than

adenoid cystic carcinoma in any location but mostnotably in the palate as the latter diagnosis wouldresult in a more radical excision of the hard palate.

Intraductal Carcinoma of Salivary GlandsTen cases of low-grade ductal carcinoma in situ

were described in 1996 by Delgado, Klimstra,Albores-Saavedra as low grade salivary duct carci-noma. These were tumors in the parotid gland ofadults, one of which had stromal microinvasion(77). Of six patients with follow up, none with lowgrade salivary duct carcinoma have had any furtherevidence of disease. Four cases of high grade intra-ductal carcinomas were previously reported byAnderson et al. (78) and Chen (79) in major andminor salivary glands. Total parotidectomy appearsto be the therapy of choice as subtotal resectionwas followed by multiple recurrences in one caseand progression to invasive ductal carcinoma inanother.

Low grade intraductal carcinomas are unencap-sulated but circumscribed yet multifocal. On grossexamination the mass is focally to diffusely cystic.Microscopically ducts that retain the native myoep-ithelial cell layer exhibit partial to circumferential

FIGURE 12. Additional neoplasms with basal cell features: adenosquamous carcinoma (A); basaloid squamous cell carcinoma (B); small cellcarcinoma (C), inset cytokeratin dots; basaloid ameloblastoma (D).


intraductal proliferations that mimic patterns ofatypical ductal hyperplasia to carcinoma in situ ofbreast with micropapillary, tufted, solid or fenes-trated patterns (Fig. 16). The cytology is bland com-posed of ductal, apocrine or vacuolated cells withrare mitoses and no necrosis. Focal high-grade cy-tologic atypia was noted in one case. By immuno-histochemistry the epithelial cells stain strongly forS-100 protein, high molecular weight cytokeratinand mark for gross cystic disease fluid protein 15 inareas of apocrine differentiation. As in breast DCIS,the lesion must be well sampled and it may beuseful to apply muscle markers of myoepitheliumto rule out microinvasion.

The main differential diagnosis is that of salivaryduct carcinoma. This is an aggressive, invasive duc-tal carcinoma that also mimics breast cancer andhas a mean survival of 3 years. The ductal patternsof this high-grade cancer may bear a range of cyto-logic atypia, commonly have comedo necrosis andare truly invasive with irregular profiles, lacking amyoepithelial cell layer. The intraductal cribriformpatterns may simulate adenoid cystic carcinomabut lack the small basaloid cells, hyaline mem-branes and pseudocystic spaces containing baso-philic matrix material. Also a consideration is thepapillary cystic variant of acinic cell carcinoma in

which zymogen granules can be demonstrated bythe periodic acid-Schiff-diastase stain. Because oflow-grade cytology, PLGA may be entertained indifferential diagnosis but origin in minor not majorglands and the multitude of infiltrative patterns aredistinctive. The intracystic proliferations in papil-lary cystadenoma/cystadenocarcinoma differ inthat the papillae are well developed with fibrouscores lined by atypical, mitotically active cells.

Clear Cell CarcinomasAlthough this heterogeneous collection of sali-

vary gland cancers with clear cytoplasm may beillustrated as a continuum, this is not a biologicallyproven concept (Fig. 17). At one end of the spec-trum are monomorphic epithelial proliferations ofclear cells, which may have associated hyalinizedstroma (hyalinizing clear cell carcinoma) or non-hyalinized stroma and exhibit glandular or squa-mous differentiation or remain undifferentiated.These clear cell carcinomas stain for the markers ofepithelium- CEA, EMA but are negative for themuscle markers indicative of myoepithelium. Pre-viously, they have also been termed glycogen-richsquamous carcinoma and glycogen-rich adenocar-cinoma (80, 81).

FIGURE 13. Polymorphous low grade adenocarcinomas of all histologic patterns share low grade cytology with uniform, bland vesicular “open”nuclei with inconspicuous nucleoli.


Clear cell carcinomas also include the bimorphiccancers named epithelial- myoepithelial carcino-mas, composed of recognizable tubules cuffed byneoplastic, clear myoepithelial cells that may alsopredominate. These bimorphic clear cell neo-plasms exhibit their dual morphology both at thelight microscopic and immunophenotypic level.They have also been called adenomyoepithelioma,glycogen rich adenoma and glycogen richadenocarcinoma.

At the other end of the spectrum are monomor-phic proliferations of clear cells that are purelymyoepithelial in nature and designated clear cellmyoepithelial carcinoma. They stain for myoepi-thelial markers, especially S-100 protein and themuscle markers.

In the differential diagnosis of these three iden-tified forms of salivary clear cell carcinomas, con-sideration should be given to clear cell variants ofother salivary tumor entities like mucoepidermoidcarcinoma, acinic cell carcinoma and sebaceouscarcinoma. Lastly, metastatic renal cell carcinomais often a consideration. Its S-100 protein and mus-cle marker negative phenotype is like that of themonomorphic epithelial clear cell carcinomas butcan be excluded on clinical grounds and the pres-

ence of hypervascularity, hemorrhage, necrosis anda combined vimentin-cytokeratin phenotype.

Hyalinizing Clear Cell CarcinomaHyalinizing clear cell carcinoma is the designa-

tion coined in 1994 by Milchgrub and colleagues for11 cases of glycogen rich clear cell carcinomas oflow-grade biologic behavior that had an associatedhyalinized stroma. These cases involved mostly in-traoral minor glands, the majority in the base oftongue and palate, with a female predilection, butalso the parotid gland, larynx and subglottis (82).

On histologic examination, solid masses, nests,infiltrating cords and single file cells may be com-posed of either glycogen rich clear cells of mildcytologic atypia or smaller cells with eosinophiliccytoplasm (Fig. 18). Mitoses are rare. The degree ofstromal hyalinization varies within fields of thesame tumor, may not be present at all and thereforeperhaps just the simple designation clear cell car-cinoma fits best. It is probable that this categorycontains several clear cell, glycogen rich salivarygland neoplasms representing squamous and glan-dular differentiation and possibly subtle myoepi-

FIGURE 14. Polymorphous low grade adenocarcinoma histologic patterns: linear single cells (indian file) (A); tubular (B); solid (C); fascicular(streaming) (D).


thelial differentiation unappreciated with currenttechniques.

Since the initial report of 11 cases, I have identi-fied an additional five cases reported with rare tu-mors described in the nasopharynx and centrallywithin jaws (83– 85). At this time, no patients havedied from disease but follow-up has been relativelyshort given the prolonged nature of many salivarygland cancers. Based on 13 cases with follow-up,there is a recurrence rate of 8% (one case originat-ing in the nasopharynx) and a 15% rate of metas-tasis to regional lymph nodes (two intraoral cases).Given the small numbers and follow-up, knowledgeof the long-term biologic behavior is somewhat lim-ited so expect this entity to evolve.

Epithelial-Myoepithelial CarcinomaEpithelial-myoepithelial carcinoma (EMC) was

first described in 1972 by Donath, Seifert andSchmitz in the German literature (86) and recog-nized by the World Health Organization in the 1991classification (58). It is a rare entity that usuallyinvolves the parotid gland but may arise in theother major glands (submaxillary and sublingual)as well as the minor glands of the oral, nasal andparanasal cavities. EMC typically affects adults in

the 7th decade of life with a slight femalepredominance.

Although well circumscribed grossly, most casesdemonstrate infiltrative margins and perineural in-vasion. In the classic form there is a double cellproliferation composed of an inner layer of neo-plastic ductal cells that are associated with an outerlayer of prominent clear neoplastic myoepithelialcells. Also described are a sclerotic (hyalinizing)variant and a clear cell dominant variant (ductalpoor), where the epithelial cells forming the ductsare inapparent (Fig. 19). The potential for dediffer-entiation is also recognized in this entity (42, 87).

EMC has been historically considered a low-grade malignancy as reflected in the 39% recur-rence rate and 8.5% death rate in the MD Andersonseries of nine cases reported by Luna and col-leagues (88). More recently, Fonseca and Soareswho followed up 20 cases of EMC and showed acumulative survival of 87.1% at 5 years and 67.5% at10 years have challenged this notion (89). More-over, in this series the 41% recurrence, 35% meta-static rate, and 40% rate of death from disease sug-gests that with long-term follow-up, the biologicbehavior of EMC may be better appreciated as anintermediate grade malignancy.

FIGURE 15. Additional polymorphous low grade adenocarcinoma histologic patterns: myxoid (A); cribriform (pseudoadenoid) (B); jigsaw (C);cystic (D).


Clear Cell Myoepithelial CarcinomaFew clear cell carcinomas of purely myoepithelial

differentiation have been reported involving themajor glands (49, 90). They may exhibit varioushistologic appearances with tight nests, hyalinizedcords, trabeculae, vacuolated-signet ring cell-like

and lipoblast-like morphologies (Fig. 20) but morecommonly are seen mixed with other histologicmanifestations of myoepithelial carcinoma, dis-cussed next. Four cases of clear cell myoepithelialcarcinoma comprised 16% of 25 myoepithelial car-cinomas of all histologic types in the largest seriesreported (49). My literature search finds an addi-tional six cases, generally with poor follow-up (90,88). Compared with the other two types of clear cellcarcinomas discussed above, the clear cell myoep-ithelial carcinomas tend to have a more aggressivebiologic behavior with a 50% recurrence rate and a40% metastatic rate to lung and scalp. One of threecases in the series of Savera and colleagues diedfrom disease with a mean time to death of 32months although some with prolonged survivalshave been documented (49).

Myoepithelial CarcinomasSheldon first used the term myoepithelioma in

1943 to describe noncancerous and cancerous (lowgrade invasive) salivary gland tumors composed ofpurely spindled smooth muscle-like or anastomos-ing proliferations of stellate cells (92). In 1977 Criss-man reported the first case of malignant myoepi-

FIGURE 16. Low grade (in situ) salivary duct carcinoma forming an unencapsulated but circumscribed mass lesion in the parotid gland (A).Intraductal proliferations (B, C) mimic patterns of atypical hyperplasia and low grade DCIS of breast. Despite the florid proliferation, a retainedmyoepithelial cell layer can be demonstrated with immunostains to smooth muscle specific proteins, here calponin (D), to rule out microinvasion.

FIGURE 17. Schematic diagram shows the morphologies anddifferentiated cell types comprising the salivary gland clear cellcarcinomas with monomorphic epithelial and monomorphicmyoepithelial carcinomas at either end and bimorphic epithelial-myoepithelial carcinomas in between. Although a useful taxonomicillustration, this is not a biologically proven continuum and no inter-relationships are intended.


thelioma (spindle cell type) that metastasized to aregional lymph node (93). Many of these tumorshave been unrecognized and called malignantmixed tumors or carcinomas arising out of mixedtumors. Less than 75 cases have been reported,most occurring in the major glands in adults.Roughly 40% have presented de novo and the resthave arisen out of pleomorphic adenomas or out ofpreexisting myoepitheliomas.

Grossly, myoepithelial carcinomas are mostlymultinodular or diffuse infiltrative tumors. Micro-scopically, the periphery tends to be hypercellularwith central necrosis or accumulation of myxoidmatrix material.

We now recognize that the myoepithelial carci-nomas comprise a broader histologic category thanthe originally reported spindle cell types. Histolog-ically, there are no true glands formed although theepithelioid cell type may mimic adenocarcinomaby forming pseudoglands around myxoid groundsubstances. Usually more than one cell type com-poses an individual myoepithelial carcinoma (Fig.21). It is most common to see the epithelioid celltype followed by clear cells, then the plasmacytoidvariant followed by the spindle cell type (49). Most

(60%) are of low cytologic grade. The clinical out-come of myoepithelial carcinoma is not predictedby the degree of cytologic atypia, number of mito-ses or presence of necrosis. Chondroid metaplasiain a myoepithelial carcinoma may invoke the dif-ferential diagnosis of malignant mixed tumor be-cause of the similarity to pleomorphic adenoma.Squamous and sebaceous metaplasia may also beencountered. The tumor-associated matrix is moreoften myxoid than hyalinized.

All of the malignant myoepithelial cell types arewell defined by the nonspecific markers (S-100 pro-tein, vimentin, high molecular weight cytokeratin).Of the more specific smooth muscle markers ofmyoepithelium, calponin is superior to muscle spe-cific actin (HHF-35) and alpha smooth muscle actinbut yet fails to stain half of the epithelioid cell typeand 25% of the clear cell type (49). Therefore, toassure sensitivity of detection, it is best to approachthis diagnosis with a panel of specific and nonspe-cific antibodies.

Because of the diverse histologic appearances,myoepithelial carcinomas may invoke a broad dif-ferential diagnosis. The fact that they often requirea panel of antibodies to confirm myoepithelial dif-

FIGURE 18. Hyalinizing clear cell carcinoma characterized by infiltrating cords of mildly atypical cells with clear (A) to eosinophilic (B) cytoplasmin a hyalinized stroma. Tumor cells stain for markers of epithelium like EMA (C) but lack myoepithelial differentiation with only the desmoplasticmyofibroblastic stroma staining for muscle markers (D).


FIGURE 19. Epithelial-myoepithelial carcinomas usually have well circumscribed peripheral margins (A). Classic form is a double cell proliferationcomposed of a darker inner layer of ductal cells associated with a prominent outer layer of clear myoepithelial cells accentuated by immunostain forcalponin (inset) (B). Variations include sclerotic (hyalinizing) (C) and clear cell dominant (ductal poor) (D) morphologies.

FIGURE 20. Clear cell myoepithelial carcinomas may exhibit various appearances with tight nests (A), vacuolated-signet ring-like cells (B),hyalinized nests (C), and trabecular (D) histologic patterns. (Cases provided courtesy of Dr. Adnan Savera.)


ferentiation likely explains their infrequent diagno-sis. The epithelioid cell type may mimic true sali-vary gland adenocarcinomas like PLGA, adenoidcystic carcinoma and adenocarcinoma (NOS). Low-grade epithelioid myoepithelial carcinomas withtheir pseudolumens are distinguished by the ab-sence of true tubules and the presence of myoepi-thelial immunomarkers (Fig. 22). Basaloid squa-mous cell carcinoma may be considered in the caseof a high-grade epithelioid myoepithelial carci-noma with squamous metaplasia. Althoughbasaloid squamous cell carcinoma may exhibitpseudoadenoid structures and replicated basementmembrane, there is coexistent frank squamous cellcarcinoma and often in situ carcinoma of the over-lying mucosa.

The spindle cell variants of myoepithelial carci-noma may simulate true sarcomas like leiomyosar-coma, hemangiopericytoma, fibrosarcoma, and ma-lignant peripheral nerve sheath tumor. However,these true sarcomas are negative or only focally cyto-keratin positive although the smooth muscle neo-plasms will share the myogenic immunoprofile of themyoepithelial carcinomas.

Although the plasmacytoid myoepithelial carci-nomas may mimic true plasma cell neoplasms, they

lack intracytoplasmic immunoglobulin light chainsand are strongly cytokeratin and calponin positive(Fig. 22).

The differential diagnosis of the clear cell myoepi-thelial carcinomas has been discussed previously.

Myoepithelial carcinomas display a range of bio-logic behavior with 50% metastasizing to regionaland distant sites and 35% of patients dying of dis-ease (mean 32 months, range 2 months to 6 years)(49, 90, 91). At this time the usual treatment mo-dality is complete excision as the role of radiationtherapy or chemotherapy is undefined.

Salivary Duct CarcinomaSalivary duct carcinoma was identified in 1968 by

Kleinsasser, Klein and Hubner as an uncommon,high-grade primary salivary gland malignancy re-sembling ductal carcinoma of breast (94). Thesecancers arise predominantly in the parotid gland(85%) with few in the submaxillary gland and rarelyintraorally. The usual demographic profile is that ofadult males over 50 years of age. The aggressivebiologic behavior of SDC is evident in rapid clinicalgrowth and associated symptoms of facial nerveinfiltration.

FIGURE 21. Myoepithelial carcinoma nodular tumor growth with central loose accumulation of myxoid matrix (A). Various histologic patternsinclude cells with epithelioid (B), clear (C), spindled (D), myxoid-stellate (E), and plasmacytoid (F) appearances. (Cases provided courtesy of Dr.Adnan Savera.)


Microscopically, these adenocarcinomas are sim-ilar to mammary ductal carcinomas. They demon-strate a hyalinized, fibrous stroma infiltrated byneoplastic ducts composed of solid, cribriform andpapillary proliferations. There is often comedo ne-crosis and dystrophic calcifications may be present(Fig. 23). Cells are large with a range of cytologicatypia and may exhibit apocrine-like eosinophiliccytoplasm. Rarely, a myoepithelial layer associatedwith larger ducts can be visualized by light micros-copy or enhanced with immunostains for musclemarkers. This may represent precursor ductal car-cinoma in situ or cancerization of native preexistingexcretory ducts. Prognostically favorable pathologicobservations include an intraductal componentcomprising greater than 90% of the tumor andsmaller tumor size of less than 2–3 centimeters (95,96). Discrimination from the rarely reported purelyintraductal high grade carcinoma may require im-munohistochemistry to clarify (78, 79).

The immunoprofile of SDC is quite interesting.Similar to breast cancers, it marks for GCDFP-15,oncogene her/2, progesterone receptor and occa-sionally estrogen receptor (97). Oddly, 58% of SDCalso stain for prostatic acid phosphatase and 17%for prostate specific antigen. In addition, roughly

90% of SDC bear androgen receptors by immuno-histochemistry, which may prove to be a fruitfultarget for therapeutic hormonal intervention (98).

The rate of regional and distant metastasis is high(50 – 60%) and 70% of patients in the MD Andersonseries died from disease (95). Brandwein and col-leagues’ review of 58 cases demonstrated 55% ofpatients dead of disease within a mean of 29months (96). Therefore, these cancers are treatedaggressively with complete excision, radical neckdissection and postoperative radiation therapy.

CONCLUSION

This review has touched on practical clinical anddiagnostic issues of the past 30 years in salivarygland tumor pathology. The next 30 years will seedefinition of the genetic and proteomic underpin-nings of many of the morphologic and biologicdistinctions we currently recognize. Hopefully, thiswill translate into more effective therapies for pre-vention, local control and cure for many of thesalivary gland malignancies currently associatedwith notoriously protracted but lethal courses.

FIGURE 22. Myoepithelial carcinoma: epithelioid variant (A), pseudoglands stained for calponin (B); plasmacytoid variant (C), also stained forcalponin (D). (Cases provided courtesy of Dr. Adnan Savera.)


REFERENCES

1. Prasannan L, Pu A, Hoff P, Weatherly R, Castle V. Parotidcarcinoma as a second malignancy after treatment of child-hood acute lymphoblastic leukemia. J Pediatr Hematol On-col 1999;21:535– 8.

2. Modan B, Chetrit A, Alfandary E, Tamir A, Lusky A, Wolf M,et al. Increased risk of salivary gland tumors after low-doseirradiation. Laryngoscope 1998;108:1095–7.

3. Iezzoni JC, Gaffey MJ, Weiss LM. The role of Epstein-Barrvirus in lymphoepithelioma-like carcinomas. Am J ClinPathol 1995;103:308 –15.

4. Raab-Traub N, Rajadurai P, Flynn K, Lanier AP. Epstein-Barr virus infection in carcinoma of salivary gland. J Virol1991;65:7032– 6.

5. Abbey LM, Schwab BH, Landau GC, Perkins ER. Incidenceof second primary breast cancer among patients with a firstprimary salivary gland tumor. Cancer 1984;54:1439 – 42.

6. Sun EC, Curtis R, Melbye M, Goedert JJ. Salivary glandcancer in the United States. Cancer Epidemiol BiomarkersPrev 1999;8:1095–100.

7. Kotwall CA. Smoking as an etiologic factor in the develop-ment of Warthin’s tumor of the parotid gland. Am J Surg1992;164:646 –7.

8. Chung YF, Khoo ML, Heng MK, Hong GS, Soo KC. Epide-miology of Warthin’s tumor of the parotid gland in an Asianpopulation. Br J Surg 1999;86:661– 4.

9. Pinkston JA, Cole P. Cigarette smoking and Warthin’s tu-mor. Am J Epidemiol 1996;144:183–7.

10. Swanson GM, Burns PB. Cancers of the salivary gland:workplace risks among women and men. Annu Epidemiol.1997;7:369 –74.

11. Headington JT, Batsakis JG, Beals TF, Campbell TE, Sim-mons JL, Stone WD. Membranous basal cell adenoma ofparotid gland, dermal cylindromas and trichoepitheliomas.Comparative histochemistry and ultrastructure. Cancer1977;39:2460 –9.

12. Reingold IM, Keasbey LE, Graham JH. Multicentric dermal-type cylindromas of the parotid glands in a patient withflorid turban tumor. Cancer 1977;40:1702–10.

13. Jungehulsing M, Wagner M, Damm M. Turban tumour withinvolvement of the parotid gland. J Laryngol Otol 1999;113:779 – 83.

14. Depowski PL, Setzen G, Chui A, Koltai PJ, Dollar J, Ross JS.Familial occurrence of acinic cell carcinoma of the parotidgland. Arch Pathol Lab Med 1999;123:1118 –20.

15. Merrick Y, Labeck H, Nielsen H, Hansen HS. Familial clus-tering of salivary gland carcinoma in Greenland. Cancer1986;57:2097–102.

16. Autio-Harmainen H, Paakko P, Alavaikko M, Karvonen J,Leisti J. Familial occurrence of malignant lymphoepithe-lial lesion of the parotid gland in a Finnish family withdominantly inherited trichoepithelioma. Cancer 1988;61:161– 6.

17. Pinto AE, Fonseca I, Martins C, Soares J. Objective biologicparameters and their clinical relevance in assessing salivarygland neoplasms. Adv Anat Pathol 2000;7:294 –306.

FIGURE 23. Salivary duct carcinoma is an invasive high grade adenocarcinoma with histologic features similar to ductal carcinomas of breast:solid and cribriform patterns composed of high grade nuclei with comedo necrosis (A) and dystrophic calcification (B); hyalinized and desmoplasticstromal invasion (C). Foci of intraductal growth with retained myoepithelium (D) are usually focal, representing either residual precursor ductalcarcinoma in situ or cancerization of preexisting native ducts. The in situ (arrow head) and invasive (arrows) components can be clarified withstains for smooth muscle markers (E).


18. Voz ML, Agten NS, Van de Ven WJM, Kas K. PLAG1, themain translocation target in pleomorphic adenoma of thesalivary glands, is a positive regulator of IGF-II. Cancer Res2000;60:106 –13.

19. Hibbard MK, Kozakewich HP, Cin PD, Sciot R, Tan X, XiaoS, et al. PLAG1 fusion oncogenes in lipoblastoma. CancerRes 2000;60:4869 –72.

20. Regezi JA, Batsakis JG. Histogenesis of salivary gland neo-plasms. Otolaryngol Clin North Am 1977;10:297–307.

21. Batsakis JG. Salivary gland neoplasia: An outcome of mod-ified morphogenesis and cytodifferentiation. Oral Surg1980;49:229 –32.

22. Dardick I, van Nostrand AWP, Phillips MJ. Histogenesis ofsalivary gland pleomorphic adenoma (mixed tumor) withan evaluation of the role of the myoepithelial cell. HumPathol 1982;13:62–75.

23. Foote FWJ, Frazell EL. Tumors of the major salivary glands.Atlas of Tumor Pathology, first series, Fascicle 11. Washing-ton, DC: Armed Forces Institute of Pathology, 1954.

24. Ellis GL, Auclair PL. Tumors of the salivary glands. Atlas ofTumor Pathology, third series, Fascicle 11. Washington, DC:Armed Forces Institute of Pathology, 1996.

25. Vander Poorten VLM, Balm AJM, Hilgers FJM, Tan IB, KeusRB, Hart AAM. Stage as major long term outcome predictor inminor salivary gland carcinoma. Cancer 2000;89:1195–204.

26. Gallo O, Frankchi A, Bottai GV, Fini-Storchi I, Tesi G, BoddiV. Risk factors for distant metastases from carcinoma of theparotid gland. Cancer 1997;80:844 –51.

27. Fleming ID, Cooper JS, Henson DE, et al. (editors). Ameri-can Joint Committee on Cancer: AJCC Cancer Staging Man-ual. Fifth ed. Philadelphia: Lippincott-Raven, 1997.

28. Spiro RH, Thaler HT, Hicks WF, Kher UA, Huvos AH, StrongEW. The importance of clinical staging of minor salivarygland carcinoma. Am J Surg 1991;162:330 – 6.

29. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologicgrading of adenoid cystic carcinoma of the salivary glands.Cancer 1984;54:1062–9.

30. Brandwein M, Ivanov K, Wallace D, Hille JJ, Wang B, FahmyA, et al. Salivary mucoepidermoid carcinoma: A clinico-pathologic study of 80 patients with special reference tohistological grading. Am J Surg Pathol 2001;25:835– 45.

31. Auclair P, Goode R, Ellis G. Mucoepidermoid carcinoma ofintraoral salivary glands: evaluation and application ofgrading criteria in 143 cases. Cancer 1992;69:2021–30.

32. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carci-noma of the major salivary glands: clinical and histopatho-logic analysis of 234 cases with evaluation of grading crite-ria. Cancer 1998;82:1217–24.

33. Tortoledo ME, Luna MA, Batsakis JG. Carcinomas ex pleo-morphic adenoma and malignant mixed tumors. Histo-morphologic indexes. Arch Otolaryngol 1984;110:172– 6.

34. Brandwein M, Huvos HG, Dardick I, Thomas MJ, Theise ND.Noninvasive and minimally invasive carcinoma ex mixed tu-mor: a clinicopathologic and ploidy study of 12 patients withmajor salivary tumors of low (or no?) malignant potential.Oral Surg Oral Med Oral Pathol 1996;81:655–64.

35. Auclair PL, Ellis GL. Atypical features in salivary glandmixed tumors: their relationship to malignant transforma-tion. Mod Pathol 1996;9:652–7.

36. Stanley RJ, Weiland LH, Olsen KD, Pearson BW. Dediffer-entiated acinic cell (acinous) carcinoma of the parotidgland. Otolaryngol Head Neck Surg. 1988;98:155– 61.

37. Seifert G, Donath K. Hybrid tumours of salivary glands.Definition and classification of five rare cases. Eur J CancerB Oral Oncol 1996;32B:251–9.

38. Henley JD, Seo IS, Dayan D, Gnepp DR. Sarcomatoid sali-vary duct carcinoma of the parotid gland. Hum Pathol2000;31:208 –13.

39. Love GL, Sarma DP. Spindle cell mucoepidermoid carci-noma of submandibular gland. J Surg Oncol 1986;31:66 – 8.

40. Cheuk W, Chan JKC, Ngan RKC. Dedifferentiation in ade-noid cystic carcinoma of salivary gland. An uncommoncomplication associated with an accelerated clinicalcourse. Am J Surg Pathol 1999;23:465–72.

41. Pelkey TJ, Mills SE. Histologic transformation of polymor-phous low-grade adenocarcinoma of salivary gland. Am JClin Pathol 1999;111:785–91.

42. Alos L, Carrillo R, Ramos J, Baez C, Mallofre C, Fernandez A,Cardes A. High-grade carcinoma component in epithelial-myoepithelial carcinoma of salivary glands. Clinicopatho-logical, immunohistochemical and flow-cytometric studyof three cases. Virch Archiv 1999;434:291–9.

43. Zarbo RJ, Regezi JA, Batsakis JG. S-100 protein in salivarygland tumors: an immunohistochemical study of 129 cases.Head Neck Surg 1986;8:268 –75.

44. Zarbo RJ, Hatfield JS, Trojanowski JQ, Crissman JD, RegeziJA, Maisel H, et al. Immunoreactive glial fibrillary acidicprotein in normal and neoplastic salivary glands: a com-bined immunohistochemical and immunoblot study. SurgPathol 1988;1:55– 63.

45. Zarbo RJ, Bacchi CE, Gown AM. Muscle-specific proteinexpression in normal salivary glands and pleomorphic ad-enomas: an immunocytochemical study with biochemicalconfirmation. Mod Pathol. 1991;4:621– 6.

46. Zarbo RJ, Prasad AR, Regezi JA, Gown AM, Savera AT. Sal-ivary gland basal cell and canalicular adenomas. Immuno-histochemical demonstration of myoepithelial cell partici-pation and morphogenetic considerations. Arch Pathol LabMed 2000;124:401–5.

47. Savera AT, Gown AM, Zarbo RJ. Immunolocalization of threenovel smooth muscle-specific proteins in salivary gland ple-omorphic adenoma: Assessment of the morphogenetic role ofmyoepithelium. Mod Pathol 1997;10:1093–100.

48. Prasad AR, Savera AT, Gown AM, Zarbo RJ. The myoepithe-lial immunophenotype in 135 benign and malignant sali-vary gland tumors other than pleomorphic adenoma. ArchPathol Lab Med 1999;123:801– 6.

49. Savera AT, Sloman A, Huvos AG, Klimstra DS. Myoepithelialcarcinoma of the salivary glands. A clinicopathologic studyof 25 patients. Am J Surg Pathol 2000;24:761–74.

50. Prasad AR, Savera AT, Regezi JA, Zarbo RJ. Antimitochon-drial antibody—a diagnostic discriminant of salivary glandoncocytic tumors and acinic cell carcinomas [Abstract].Mod Pathol 1999;12:130A.

51. De Araujo VC, de Sousa SOM, Carvalho YR, de Araujo NS.Application of immunohistochemistry to the diagnosis ofsalivary gland tumors. Appl Immunohisto Molec Morphol2000;8:195–202.

52. Barbareschi M, Pecciarini L, Cangi MG, Macri E, Rizzo A,Viale G, et al. p63, a p53 analogue, is a selective myoepi-thelial nuclear marker in human breast tissue and neo-plasms [Abstract]. Mod Pathol 2001;14:21A.

53. Foschini MP, Scarpellini F, Gown AM, Eusebi V. Differentialexpression of myoepithelial markers in salivary, sweat andmammary glands. Int J Surg Pathol 2000;8:29 –37.

54. Sternlicht MD, Safarians S, Rivera SP, Barsky SH. Charac-terizations of the extracellular matrix and proteinase inhib-itor content of human myoepithelial tumors. Lab Invest1996;74:781–96.

55. Sternlicht MD, Barsky SH. The myoepithelial defense: ahost defense against cancer. Med Hypoth 1997;48:37– 46.

56. Lee P-S, Sabbath-Solitare, Redondo TC, Ongcapin EH. Mo-lecular evidence that the stromal and epithelial cells inpleomorphic adenomas of salivary gland arise from thesame origin: clonal analysis using human androgen recep-tor gene (HUMARA) assay. Hum Pathol 2000;31:498 –503.


57. Kleinsasser O, Klein HJ. Basalzelladenome der speichel-drusen. Arch Klin Exper Ohren Nasen und Kehlkopfheilk1967;189:302–16.

58. Seifert G, Sobin LH. Histological typing of salivary glandtumors. World Health Organization international histolog-ical classification of tumours. 2nd ed. New York: Springer-Verlag, 1991.

59. Nagao T, Sugano I, Ishida Y, Matsuzaki M, Konno A, KondoY, et al. Carcinoma in basal cell adenoma of the parotidgland. Path Res Pract 1997;193:171– 8.

60. Dardick I, Daley T, van Nostrand AW. Basal cell adenomawith myoepithelial cell-derived “stroma”: a new major sal-ivary gland tumor entity. Head Neck Surg 1986;8:257– 67.

61. Batsakis JG, Brannon RB, Sciubba JJ. Monomorphic adeno-mas of major salivary glands: a study of 96 tumors. ClinOtolaryngol 1981;6:129 – 43.

62. Luna MA, Tortoledo MME, Allen M. Salivary dermal analoguetumors arising in lymph nodes. Cancer 1987;59:1165–9.

63. Zarbo RJ, Ricci Jr A, Kowalczyk PD, Cartun RW, Knibbs DR.Intranasal dermal analogue tumor (membranous basal cellcarcinoma). Ultrastructure and immunohistochemistry.Arch Otolaryngol 1985;111:333–7.

64. Batsakis JG, Luna MA, el-Naggar AK. Basaloid monomor-phic adenomas. Annu Otol Rhino Laryngol 1991;100:687–90.

65. Daley TD. The canalicular adenoma: considerations on dif-ferential diagnosis and treatment. J Oral Maxillofac Surg.1984;42:728 –30.

66. Ellis GL, Wiscovitch JG. Basal cell adenocarcinomas of themajor salivary glands. Oral Surg Oral Med Oral Pathol 1990;69:461–9.

67. Muller S, Barnes L. Basal cell adenocarcinoma of the sali-vary glands. Report of seven cases and review of the liter-ature. Cancer 1996;78:2471–7.

68. Evans HL, Batsakis JG. Polymorphous low-grade adenocar-cinoma of minor salivary glands. A study of 14 cases of adistinctive neoplasm. Cancer 1984;53:935– 42.

69. Freedman PD, Lumerman H. Lobular carcinoma of in-traoral minor salivary gland origin. Report of twelve cases.Oral Surg Oral Med Oral Pathol 1983;56:157– 65.

70. Batsakis JG, Pinkston GR, Luna MA, Byers RM, Sciubba JJ,Tillery GW. Adenocarcinoma of the oral cavity: A clinico-pathologic studyof terminal duct carcinomas. J LaryngolOtol 1983;97:825–35.

71. Wenig BM, Harpaz N, Del Bridge C. Polymorphous low-grade adenocarcinoma of seromucous glands of the naso-pharynx: a report of a case and a discussion of the mor-phologic and immunohistochemical features. Am J ClinPathol 1989;92:104 –9.

72. Castle JT, Thompson LDR, Frommelt RA, Wenig BM, KesslerHP. Polymorphous low grade adenocarcinoma. A clinicopath-ologic study of 164 cases. Cancer 1999;86:207–19.

73. Regezi JA, Zarbo RJ, Stewart JC, Courtney RM. Polymor-phous low-grade adenocarcinoma of minor salivary gland:a comparative histologic and immunohistochemical study.Oral Surg Oral Med Oral Pathol 1991;71:469 –75.

74. Mills SE, Garland TA, Allen MSJ. Low-grade papillary ade-nocarcinoma of palatal salivary gland origin. Am J SurgPathol 1984;8:367–74.

75. Slootweg PJ, Muller H. Low-grade adenocarcinoma of theoral cavity. A comparison between the terminal duct andthe papillary type. J Cranio-Max Fac Surg 1987;15:359 – 64.

76. Vincent SD, Hammond HL, Finkelstein MW. Clinical andtherapeutic features of polymorphous low-grade adenocar-cinoma. Oral Surg Oral Med Oral Pathol 1994;77:41–7.

77. Delgado R, Klimstra D, Albores-Saavedra J. Low grade sal-ivary duct carcinoma. A distinctive variant with a low gradehistology and a predominant intraductal growth pattern.Cancer 1996;78:958 – 67.

78. Anderson C, Muller R, Piorkowski R, Knibbs DR, Vignotti P.Intraductal carcinoma of major salivary gland. Cancer 1992;69:609 –14.

79. Chen KTK. Intraductal carcinoma of the minor salivarygland. J Laryngol Otol 1983;97:189 –91.

80. Dardick I. Miscellaneous carcinomas. Salivary Gland Tu-mor Pathology New York: Igaku-Shoin; 1996. p. 239 – 43.

81. Batsakis JG. Clear cell tumors of salivary glands. Annu Otol1980;89:196 –7.

82. Milchgrub S, Gnepp DR, Vuitch F, Delgado R, Albores-Saavedra J. Hyalinizing clear cell carcinoma of salivarygland. Am J Surg Pathol 1994;181:74 – 82.

83. Tang SK, Wan SK, Chan JKC: Hyalinizing clear cell carci-noma of the salivary gland: report of a case with multiplerecurrences over 12 years. Am J Surg Pathol 1995;19:240 –1.

84. Berho M, Huvos AG: Central hyalinizing clear cell carci-noma of the mandible and the maxilla: a clinicopathologicstudy of two cases with an analysis of the literature. HumPathol 1999;30:101–5.

85. Simpson RHW, Sarsfield PT, Clarke T, Babajews AV: Clearcell carcinoma of minor salivary glands. Histopathology1990;17:433– 8.

86. Donath K, Seifert G, Schmitz R. Diagnose und ultrastrukturdes tubularen speichelgangcarcinoms. Epithelial-myoepitheliales schaltstustuckcarcinoma. Virch Arch A.1972;356:16 –31.

87. Simpson RHW, Clarke TJ, Sarsfield PTL, Gluckman PGC.Epithelial-myoepithelial carcinoma of salivary glands.J Clin Pathol 1991;44:419 –23.

88. Luna MA, Ordonez NG, Mackay B, Batsakis JG, Guillam-ondegui O. Salivary epithelial-myoepithelial carcinomas ofintercalated ducts: a clinical, electron microscopy and im-munocytochemical study. Oral Surg Oral Med Oral Pathol1985;59:482–90.

89. Fonseca I, Soares J. Epithelial-myoepithelial carcinoma ofthe salivary glands. A study of 22 cases. Virch Arch A PatholAnat 1993;422:389 –96.

90. Michal A, Skalova A, Simpson RHW, Rychterova V, Leivo I.Clear cell malignant myoepithelioma of the salivary glands.Histopathol 1996;28:309 –15.

91. Ogawa I, Nikai H, Takata T, Ijuhin N, Miyauchi M, Ito H, etal. Clear cell tumors of minor salivary gland origin. OralSurg Oral Med Oral Pathol 1991;72:200 –7.

92. Sheldon WH. So-called mixed tumors of the salivary glands.Arch Pathol 1943;35:1–20.

93. Crissman JD, Wirman JA, Harris A. Malignant myoepitheli-oma of the parotid gland. Cancer 1977;40:3042–9.

94. Kleinsasser O, Klein HJ, Hubner G. Salivary duct carci-noma: a group of salivary gland tumors analogous tomammary duct carcinoma. Arch Klin Exper Ohren 1968;192:100 –15.

95. Hui KK, Batsakis JG, Luna MA, Mackay B, Byers RM. Sali-vary duct carcinoma: a high grade malignancy. J LaryngolOtol 1986;100:105–14.

96. Brandwein MS, Jagirdar J, Patil J, Biller H, Kaneko M. Sali-vary duct carcinoma (cribriform salivary carcinoma of ex-cretory ducts). Cancer 1990;65:2307–14.

97. Wick MR, Ockner DM, Mills SE, Ritter JH, Swanson PE.Homologous carcinomas of the breasts, skin and salivaryglands. A histologic and immunohistochemical comparisonof ductal mammary carcinoma, ductal sweat gland carci-noma, and salivary duct carcinoma. Am J Clin Pathol 1998;109:75– 84.

98. Fan C-Y, Wang J, Barnes EL. Expression of androgenreceptor and prostatic specific markers in salivary ductcarcinoma. An immunohistochemical analysis of 13cases and review of the literature. Am J Surg Pathol2000;24:579 – 86.


99. Gerughty RM, Hennigar GR, Brown RM. Adenosquamouscarcinoma of the nasal, oral and laryngeal cavities: A clin-icopathologic survey of ten cases. Cancer 1968;22:1140 –55.

100. Abrams AM, Finck FM. Sialadenoma papilliferum. A previouslyunreported salivary gland tumor. Cancer 1969;24:1057–63.

101. Abbey LM. Solitary intraductal papilloma of the minor sali-vary glands. Oral Surg Oral Med Oral Pathol 1975;40:135–40.

102. White DK, Miller AS, McDaniel RK, Rothman BN. Invertedductal papilloma: A distinctive lesion of minor salivarygland. Cancer 1982;49:519 –24.

103. Nagao K, Matsuzaki O, Saiga H. Histopathologic studies ofundifferentiated carcinoma of the parotid gland. Cancer1982;50:1572–9.

104. Taylor GP. Congenital epithelial tumor of the parotidgland-sialoblastoma. Pediatr Pathol 1988;8:447–52.

105. Ellis GL. “Clear cell” oncocytoma of salivary gland. HumPathol 1988;19:862–7.

106. Hui KK, Luna MA, Batsakis JG, Ordonez NG, Weber R.Undifferentiated carcinomas of the major salivary glands.Oral Surg Oral Med Oral Pathol 1990;69:76 – 83.

107. Dehner LP, Valbuena L, Perez-Atayde A, Reddick RL, AskinFB, Rosai J. Salivary gland anlage tumor (“congenital pleo-morphic adenoma”): A clinicopathologic, immunohisto-chemical and ultrastructural study of nine cases. Am J SurgPathol 1994;18:25–36.


Documents

Review- Surgical Pathology of Salivary Gland Tumors for Practicing Pathologists- Richard Zarbo- Modern Path 2002