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Cirurgia de Cabeça e Pescoço
Lesões Pré Malignas de LaringeDr. Leonardo Guimarães Rangel
Erythroleukoplakia. This clinical term describes mixed formsof white and red mucosal changes and the lesion has similarimplications as an erythroplakia.
Pachydermia. This is another descriptive clinical term,now largely historical, indicating extensive thickening ofthe mucosa. It is not a histologic diagnosis.
Histopathologic terminologySquamous metaplasia. A term describing the replacementof normal respiratory epithelium by stratified squamousepithelium, a change common even in the subglotticregion of the nonsmoking, nonbronchitic urban adult15
and in the human fetal larynx.16 The process usuallyinvolves only the superficial epithelium, but may extendinto the seromucinous laryngeal glands. Squamous meta-plasia can follow persistent trauma or chronic irritation.There is no evidence that this lesion predisposes to malig-nancy and no treatment is recommended.
Squamous cell hyperplasia. This is a benign change inwhich the epithelium becomes thicker without cellular
atypia. The thickening is due to an increase in the pricklecell (acanthosis) and/or basal cell layers. Epithelial hyper-plasia may be covered with a conspicuous keratin layer(Figure 3). Squamous cellular differentiation is well pre-served, and this type of epithelial change is reversible.Squamous cell hyperplasia usually represents a responseto injury and is not regarded as a precancerous lesion. Bi-opsy may be performed to establish a definitive diagnosis.
Pseudoepitheliomatous hyperplasia (pseudocarcinomatous hyper-plasia). This term describes an exuberant reactive or repar-ative overgrowth of squamous epithelium with extensionof bulbous rete processes into the lamina propria. Thehyperplastic epithelium may simulate well-differentiatedsquamous cell carcinoma, especially when it appearsdetached from the surface as a result of cross-cutting. Theabsence of epithelial cellular atypia and the presence ofan inflammatory infiltrate are useful diagnostic pointers.Pseudoepitheliomatous hyperplasia may be associatedwith a granular cell tumor, several specific chronicinflammatory conditions (tuberculosis in particular),mycotic diseases and, occasionally, primary eosinophilicgranuloma of the larynx17 (Figure 4). Also, it may mimicrecurrent tumor in biopsies taken from patients previouslyirradiated for treatment of laryngeal squamous cell carci-noma. There is no evidence that pseudoepitheliomatoushyperplasia is a potentially malignant lesion, and
FIGURE 1. Nonkeratinized epithelium of the vocal cord. [Colorfigure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 2. Pseudostratified ciliated columnar ("respiratory’’)epithelium with interspersed goblet cells. [Color figure can beviewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 3. Epithelial hyperplasia with keratosis. Epithelialmaturation is without any abnormalities and surface is coveredwith a conspicuous keratin layer. [Color figure can be viewed inthe online issue, which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1811
Epitélio Normal
Erythroleukoplakia. This clinical term describes mixed formsof white and red mucosal changes and the lesion has similarimplications as an erythroplakia.
Pachydermia. This is another descriptive clinical term,now largely historical, indicating extensive thickening ofthe mucosa. It is not a histologic diagnosis.
Histopathologic terminologySquamous metaplasia. A term describing the replacementof normal respiratory epithelium by stratified squamousepithelium, a change common even in the subglotticregion of the nonsmoking, nonbronchitic urban adult15
and in the human fetal larynx.16 The process usuallyinvolves only the superficial epithelium, but may extendinto the seromucinous laryngeal glands. Squamous meta-plasia can follow persistent trauma or chronic irritation.There is no evidence that this lesion predisposes to malig-nancy and no treatment is recommended.
Squamous cell hyperplasia. This is a benign change inwhich the epithelium becomes thicker without cellular
atypia. The thickening is due to an increase in the pricklecell (acanthosis) and/or basal cell layers. Epithelial hyper-plasia may be covered with a conspicuous keratin layer(Figure 3). Squamous cellular differentiation is well pre-served, and this type of epithelial change is reversible.Squamous cell hyperplasia usually represents a responseto injury and is not regarded as a precancerous lesion. Bi-opsy may be performed to establish a definitive diagnosis.
Pseudoepitheliomatous hyperplasia (pseudocarcinomatous hyper-plasia). This term describes an exuberant reactive or repar-ative overgrowth of squamous epithelium with extensionof bulbous rete processes into the lamina propria. Thehyperplastic epithelium may simulate well-differentiatedsquamous cell carcinoma, especially when it appearsdetached from the surface as a result of cross-cutting. Theabsence of epithelial cellular atypia and the presence ofan inflammatory infiltrate are useful diagnostic pointers.Pseudoepitheliomatous hyperplasia may be associatedwith a granular cell tumor, several specific chronicinflammatory conditions (tuberculosis in particular),mycotic diseases and, occasionally, primary eosinophilicgranuloma of the larynx17 (Figure 4). Also, it may mimicrecurrent tumor in biopsies taken from patients previouslyirradiated for treatment of laryngeal squamous cell carci-noma. There is no evidence that pseudoepitheliomatoushyperplasia is a potentially malignant lesion, and
FIGURE 1. Nonkeratinized epithelium of the vocal cord. [Colorfigure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 2. Pseudostratified ciliated columnar ("respiratory’’)epithelium with interspersed goblet cells. [Color figure can beviewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 3. Epithelial hyperplasia with keratosis. Epithelialmaturation is without any abnormalities and surface is coveredwith a conspicuous keratin layer. [Color figure can be viewed inthe online issue, which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1811
Erythroleukoplakia. This clinical term describes mixed formsof white and red mucosal changes and the lesion has similarimplications as an erythroplakia.
Pachydermia. This is another descriptive clinical term,now largely historical, indicating extensive thickening ofthe mucosa. It is not a histologic diagnosis.
Histopathologic terminologySquamous metaplasia. A term describing the replacementof normal respiratory epithelium by stratified squamousepithelium, a change common even in the subglotticregion of the nonsmoking, nonbronchitic urban adult15
and in the human fetal larynx.16 The process usuallyinvolves only the superficial epithelium, but may extendinto the seromucinous laryngeal glands. Squamous meta-plasia can follow persistent trauma or chronic irritation.There is no evidence that this lesion predisposes to malig-nancy and no treatment is recommended.
Squamous cell hyperplasia. This is a benign change inwhich the epithelium becomes thicker without cellular
atypia. The thickening is due to an increase in the pricklecell (acanthosis) and/or basal cell layers. Epithelial hyper-plasia may be covered with a conspicuous keratin layer(Figure 3). Squamous cellular differentiation is well pre-served, and this type of epithelial change is reversible.Squamous cell hyperplasia usually represents a responseto injury and is not regarded as a precancerous lesion. Bi-opsy may be performed to establish a definitive diagnosis.
Pseudoepitheliomatous hyperplasia (pseudocarcinomatous hyper-plasia). This term describes an exuberant reactive or repar-ative overgrowth of squamous epithelium with extensionof bulbous rete processes into the lamina propria. Thehyperplastic epithelium may simulate well-differentiatedsquamous cell carcinoma, especially when it appearsdetached from the surface as a result of cross-cutting. Theabsence of epithelial cellular atypia and the presence ofan inflammatory infiltrate are useful diagnostic pointers.Pseudoepitheliomatous hyperplasia may be associatedwith a granular cell tumor, several specific chronicinflammatory conditions (tuberculosis in particular),mycotic diseases and, occasionally, primary eosinophilicgranuloma of the larynx17 (Figure 4). Also, it may mimicrecurrent tumor in biopsies taken from patients previouslyirradiated for treatment of laryngeal squamous cell carci-noma. There is no evidence that pseudoepitheliomatoushyperplasia is a potentially malignant lesion, and
FIGURE 1. Nonkeratinized epithelium of the vocal cord. [Colorfigure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 2. Pseudostratified ciliated columnar ("respiratory’’)epithelium with interspersed goblet cells. [Color figure can beviewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 3. Epithelial hyperplasia with keratosis. Epithelialmaturation is without any abnormalities and surface is coveredwith a conspicuous keratin layer. [Color figure can be viewed inthe online issue, which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1811
ep estratificado não
queratinizado
ep pseudoestratificado
colunar ciliado
Alterações Intra-epiteliais
ClínicaLeucoplasia
Eritroplasia
Leucoeritroplasia
Paquidermia
Alterações Intra-epiteliais
ClínicaLeucoplasia
Lesão branca que não pode ser removida com manobras e que
não pode ser atribuída a condição específica (cândida)
Sem Correlação Histológica
Alterações Intra-epiteliais
ClínicaEritroplasia
placa avermelhada na mucosa
Não é diagnóstico Histológico
Associado com Atipias e Carcinoma
Alterações Intra-epiteliais
ClínicaLeucoeritroplasia
placa avermelhada e branca na mucosa
Não diagnóstico Histológico
Associado com Atipias e Carcinoma
Alterações Intra-epiteliais
ClínicaPaquidermia
Espessamento
Não diagnóstico Histológico
característica histórica
Próximo passo ?
Alterações Intra-epiteliais
HistológicaMetaplasia Escamosa
Hiperplasia C. Escamosas
Hiperplasia Pseudocarcinomatosa
Queratose
Ortoqueratose
Paraqueratose
Alterações Intra-epiteliais
HistológicaMetaplasia Escamosa
Subst de epitélio respiratório por escamoso
é comum : subglote (fetos, adultos urbanos)
trauma persistente
inflamação crônica
sem aumento de risco para malignização Robbins- pathology
Alterações Intra-epiteliais
HistológicaHiperplasia C. Escamosas
aumento da espessura do epitélio
camadas basais aumentadas
sem atipías
reversível
sem associação a malignidade
Erythroleukoplakia. This clinical term describes mixed formsof white and red mucosal changes and the lesion has similarimplications as an erythroplakia.
Pachydermia. This is another descriptive clinical term,now largely historical, indicating extensive thickening ofthe mucosa. It is not a histologic diagnosis.
Histopathologic terminologySquamous metaplasia. A term describing the replacementof normal respiratory epithelium by stratified squamousepithelium, a change common even in the subglotticregion of the nonsmoking, nonbronchitic urban adult15
and in the human fetal larynx.16 The process usuallyinvolves only the superficial epithelium, but may extendinto the seromucinous laryngeal glands. Squamous meta-plasia can follow persistent trauma or chronic irritation.There is no evidence that this lesion predisposes to malig-nancy and no treatment is recommended.
Squamous cell hyperplasia. This is a benign change inwhich the epithelium becomes thicker without cellular
atypia. The thickening is due to an increase in the pricklecell (acanthosis) and/or basal cell layers. Epithelial hyper-plasia may be covered with a conspicuous keratin layer(Figure 3). Squamous cellular differentiation is well pre-served, and this type of epithelial change is reversible.Squamous cell hyperplasia usually represents a responseto injury and is not regarded as a precancerous lesion. Bi-opsy may be performed to establish a definitive diagnosis.
Pseudoepitheliomatous hyperplasia (pseudocarcinomatous hyper-plasia). This term describes an exuberant reactive or repar-ative overgrowth of squamous epithelium with extensionof bulbous rete processes into the lamina propria. Thehyperplastic epithelium may simulate well-differentiatedsquamous cell carcinoma, especially when it appearsdetached from the surface as a result of cross-cutting. Theabsence of epithelial cellular atypia and the presence ofan inflammatory infiltrate are useful diagnostic pointers.Pseudoepitheliomatous hyperplasia may be associatedwith a granular cell tumor, several specific chronicinflammatory conditions (tuberculosis in particular),mycotic diseases and, occasionally, primary eosinophilicgranuloma of the larynx17 (Figure 4). Also, it may mimicrecurrent tumor in biopsies taken from patients previouslyirradiated for treatment of laryngeal squamous cell carci-noma. There is no evidence that pseudoepitheliomatoushyperplasia is a potentially malignant lesion, and
FIGURE 1. Nonkeratinized epithelium of the vocal cord. [Colorfigure can be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 2. Pseudostratified ciliated columnar ("respiratory’’)epithelium with interspersed goblet cells. [Color figure can beviewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 3. Epithelial hyperplasia with keratosis. Epithelialmaturation is without any abnormalities and surface is coveredwith a conspicuous keratin layer. [Color figure can be viewed inthe online issue, which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1811
Alterações Intra-epiteliais
HistológicaHiperplasia Pseudocarcinomatosa
aumento da espessura do epitélio
invadem lâmina própria
sem atipías
processo inflamatório
simula malignidade
pensar em tuberculose, fungo, granuloma eosinofílico
http://anatpat.unicamp.br
Alterações Intra-epiteliais
HistológicaQueratose
deposição anormal de queratina na superfície do epitélio
como o epitélio não é queratinizado é errado termo hiperqueratose
resposta a um mecanismo traumático ao epitelio
Alterações Intra-epiteliais
HistológicaQueratose
Associada a Acantose
etapas da maturação preservada
sem atipias
não é pré cancerígena
queratose
acantoseproc inflam crônico
http://anatpat.unicamp.br
Alterações Intra-epiteliais
HistológicaOrtoqueratose
deposição anormal de queratina
na superfície do epitélio
Não há núcleo
(aumento da camada Granular)
http://anatpat.unicamp.br
Alterações Intra-epiteliais
HistológicaParaqueratose
Deposição de Queratina
Com núcleos
maturação errada
turnover aumentado do epitelio
http://anatpat.unicamp.br
Lesões Prémalignas
Lesões pré-malignas
Neoplasia Intraepitelia ≈ Displasia
se refere a alteração arquitetural do epitélio
é a primeira lesão com alteração neoplásica
Atipia
se refere a alteração celular
Sistemas de Classificação
✤ OMS
✤ Sistema de Displasia Epitelial (NIC)
✤ Sistema Ljubljana
São Diferentes e não intercambiáveis
✤ Laryngeal Intraepithelial neoplasia
✤ (LIN) : I-III
✤ LIN I - displasia mínima
Friedmann I, Ferlito A. Granulomas and neoplasms of the larynx. 1988
CLINICAL REVIEW David W. Eisele, MD, Section Editor
Squamous Epithelial Changes of the Larynx: Diagnosis and Therapy
Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,1
Kenneth O. Devaney, MD, JD, FCAP,2 Julia A. Woolgar, FRCPath, PhD,3 Pieter J. Slootweg, MD, DMD, PhD,4 Vinidh Paleri, MS, FRCS (ORL-HNS),5
Robert P. Takes, MD, PhD,6 Primoz Strojan, MD, PhD,7 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS(Hon),8 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg1
1ENT Clinic, University of Udine, Udine, Italy, 2Department of Pathology, Allegiance Health, Jackson, Michigan, 3Cellular Pathology, University Hospital Aintree, Longmoor Lane,Liverpool, United Kingdom, 4Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 5Department of Otolaryngology–Head and NeckSurgery, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom, 6Department of Otolaryngology–Head and Neck Surgery, RadboudUniversity Nijmegen Medical Center, Nijmegen, The Netherlands, 7Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia, 8Department ofOtolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre, Nottingham, United Kingdom.
Accepted 20 May 2011
Published online 3 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21862
ABSTRACT: It can be confusing for clinicians to work their way throughthe tangle of pathologic terms used in surgical pathology reports todescribe squamous abnormalities in laryngeal biopsies. After a briefreview of the normal microscopic anatomy of the larynx and time-honored clinical designations for surface-based abnormalities, thisreport sorts pathologic changes into 2 groups: those changes that donot carry a premalignant potential (including squamous metaplasia,squamous hyperplasia, pseudoepitheliomatous hyperplasia, keratosis,and parakeratosis) and those that do (including dyskeratosis, laryngeal
intraepithelial neoplasia [LIN], atypia, dysplasia, and carcinoma in situ).Generally, lesions in the first group do not require additional therapy orclose follow-up; lesions in the second group, however, demand eithersome form of local therapy or close follow-up to monitor for thedevelopment of a more aggressive pathology.VC 2011 Wiley Periodicals,Inc. Head Neck 34: 1810–1816, 2012
KEY WORDS: squamous epithelial changes, histopathologicclassification, larynx, pathology, therapy, prognosis
Several identical squamous epithelial changes that can beidentified in the larynx and are presumed to have thepotential to develop into invasive cancer are, dependingon the particular author writing the report, variouslydescribed in the current literature as field cancerization,potentially cancerous/malignant lesion, precancerous/pre-malignant lesion, or latent cancer. If nothing else, thisplethora of different terms serves to point out our imper-fect ability to relate morphologic changes to biologicpotential.1 The profusion of competing proposals for thecategorization of laryngeal squamous intraepithelialchanges2–12 is evidence of the continuing debate and con-troversy throughout the multidisciplinary team withrespect to recognition, classification, histologic diagnosisand standardization, management, and prognosis of thesechallenging lesions.
Normal histologyIn health, the anterior epiglottic surface, the upper half
of the posterior epiglottic surface, the superior margin ofthe aryepiglottic folds, and the vocal cords are coveredby nonkeratinized stratified squamous epithelium (Figure1). The ventricular folds, ventricle, saccule, and subglottic
region are lined with pseudostratified ciliated columnarepithelium, with interspersed goblet cells (Figure 2).Seromucinous glands are present in the lamina propriaand are particularly numerous on the posterior epiglotticsurface, false cords, ventricle, saccule, and subglottis.These glands, however, are sparse or absent in the vocalcord.
Intraepithelial changesBoth types of normal laryngeal epithelium, stratified
squamous and respiratory epithelium, are subject to a spec-trum of abnormal epithelial proliferation. The followingterminology has evolved:
Clinical terminologyLeukoplakia. The term means "white plaque’’ and is aclinical term describing any white lesion on a mucousmembrane that cannot be wiped off or ascribed to anyspecific condition (eg, Candidal infection). The term hasno histologic implications13 and is not synonymous with"cancer’’ or "malignancy.’’14
Erythroplakia. This is a clinical term describing any red-dish plaque on the mucosal surface. It is not a histologicdiagnosis, but, epithelial atypia is common and invasivecarcinoma is present in a substantial proportion ofbiopsies.14
*Corresponding author: A. Ferlito, ENT Clinic, University of Udine, Udine, Italy.E-mail: a.ferlito@uniud.it
1810 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
The lesion is always contained at its deep aspect by thebasal lamina,24 although the underlying ducts may beinvolved. In carcinoma in situ, all layers of the epitheliumare replaced by malignant cells, whereas in severe dyspla-sia, some rudimentary maturation in the most superficialepithelial layers is preserved. Stratification is lacking.4
The lesion may be multicentric in origin and may befound in all laryngeal regions, although it is most frequentin the vocal cords and, particularly, in the anterior half ofthe true vocal cords. The role of human papillomavirus,in the genesis of these lesions, if any, is unknown.29
The first descriptions of this lesion were published earlyin the 20th century30 and the term "carcinoma in situ’’(Figure 8) (also called intraepithelial, or superficial, or pre-invasive carcinoma, or stage 0) was introduced by Brodersin 1932.31 There are considerable discrepancies in thereported incidence, generally cited as 0.4 cases per 100,000in the general population,32 rising in "high risk’’ cohorts.Carcinoma in situ may be accompanied by undiagnosedinvasive areas resulting in understaging of the lesion fol-lowing pathologic examination23,33,34 and the inclusion ofcases with microinvasive cancers distorts findings on theoutcome and prognosis of this lesion. Therefore, the diag-nosis of carcinoma in situ on the basis of a small biopsyspecimen can be accepted only with reservations.35 For reli-able assessment a full excisional biopsy is mandatory andmultiple sections from the whole surgical specimen shouldbe examined to rule out invasion. Carcinoma in situ adja-cent to invasive cancer is a mundane finding. Areas sug-gesting carcinoma in situ have been found in spindle cellcarcinoma,36 in basaloid squamous cell carcinoma,36 and incombined small cell neuroendocrine carcinoma.37 On the
other hand, not all invasive carcinomas are preceded bysevere dysplasia/carcinoma in situ. Although it has beensuggested that many invasive cancers of the larynx areinvasive from the start, unlike cervical intraepithelial neo-plasia,14 it is more likely that invasive cancer developsfrom normal cells through intermediate stages that may beof short duration.Furthermore, it should be remembered that nondysplas-
tic surface mucosa may overlie invasive carcinoma, dueto either lateral spread of carcinoma within the connectivetissue or carcinoma arising within salivary ducts.Sometimes a lesion is found to be a "false’’ carcinoma
in situ, given that adjacent biopsy specimens may showboth intraepithelial carcinoma and areas of frank infiltra-tive carcinoma.38 In some cases described as carcinomain situ, interruptions of the basement membrane are foundby immunocytochemical investigations (staining for lami-nin and/or type IV collagen).39 However, interruptedbasement membrane also can mean partly reconstitutedbasement membrane since it reflects the interplaybetween atypical cells and stroma and is without diagnos-tic or biologic significance in terms of invasion.Severe dysplasia and squamous cell carcinoma in situ
are defined by Crissman et al23 as SIN grade 3. Ferlito etal33 agreed with the notion that carcinoma in situ is aform of intraepithelial neoplasm and that the term "laryn-geal intraepithelial neoplasia’’ would encompass both car-cinoma in situ and all grades of dysplasia. Like cervicalintraepithelial neoplasia, its laryngeal counterpart may bedefined as "a spectrum of intraepithelial change whichbegins as a generally well-differentiated neoplasm, tradi-tionally classified as mild dysplasia, and ends with inva-sive carcinoma.’’40 Blackwell et al7 found that the histol-ogy of biopsies demonstrating severe dysplasia did notdiffer significantly from biopsies demonstrating carci-noma in situ, implying that severe dysplasia and carci-noma in situ both represent the same intraepithelial neo-plastic change.
FIGURE 6. Moderate dysplasia shown at the right side incomparison with normal epithelial maturation at the left side.Atypical cells with prominent nucleoli occupy the entire lowerhalve of the epithelium. Keratosis is confined to the dysplasticarea. [Color figure can be viewed in the online issue, which isavailable at wileyonlinelibrary.com.]
FIGURE 5. In mild dysplasia, cytologic atypia remains confined tothe lower third part of the epithelial thickness. Surface showsslight keratosis. [Color figure can be viewed in the online issue,which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1813
✤ Laryngeal Intraepithelial neoplasia
✤ (LIN) : I-III
✤ LIN II - displasia moderada
Friedmann I, Ferlito A. Granulomas and neoplasms of the larynx. 1988
CLINICAL REVIEW David W. Eisele, MD, Section Editor
Squamous Epithelial Changes of the Larynx: Diagnosis and Therapy
Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,1
Kenneth O. Devaney, MD, JD, FCAP,2 Julia A. Woolgar, FRCPath, PhD,3 Pieter J. Slootweg, MD, DMD, PhD,4 Vinidh Paleri, MS, FRCS (ORL-HNS),5
Robert P. Takes, MD, PhD,6 Primoz Strojan, MD, PhD,7 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS(Hon),8 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg1
1ENT Clinic, University of Udine, Udine, Italy, 2Department of Pathology, Allegiance Health, Jackson, Michigan, 3Cellular Pathology, University Hospital Aintree, Longmoor Lane,Liverpool, United Kingdom, 4Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 5Department of Otolaryngology–Head and NeckSurgery, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom, 6Department of Otolaryngology–Head and Neck Surgery, RadboudUniversity Nijmegen Medical Center, Nijmegen, The Netherlands, 7Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia, 8Department ofOtolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre, Nottingham, United Kingdom.
Accepted 20 May 2011
Published online 3 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21862
ABSTRACT: It can be confusing for clinicians to work their way throughthe tangle of pathologic terms used in surgical pathology reports todescribe squamous abnormalities in laryngeal biopsies. After a briefreview of the normal microscopic anatomy of the larynx and time-honored clinical designations for surface-based abnormalities, thisreport sorts pathologic changes into 2 groups: those changes that donot carry a premalignant potential (including squamous metaplasia,squamous hyperplasia, pseudoepitheliomatous hyperplasia, keratosis,and parakeratosis) and those that do (including dyskeratosis, laryngeal
intraepithelial neoplasia [LIN], atypia, dysplasia, and carcinoma in situ).Generally, lesions in the first group do not require additional therapy orclose follow-up; lesions in the second group, however, demand eithersome form of local therapy or close follow-up to monitor for thedevelopment of a more aggressive pathology.VC 2011 Wiley Periodicals,Inc. Head Neck 34: 1810–1816, 2012
KEY WORDS: squamous epithelial changes, histopathologicclassification, larynx, pathology, therapy, prognosis
Several identical squamous epithelial changes that can beidentified in the larynx and are presumed to have thepotential to develop into invasive cancer are, dependingon the particular author writing the report, variouslydescribed in the current literature as field cancerization,potentially cancerous/malignant lesion, precancerous/pre-malignant lesion, or latent cancer. If nothing else, thisplethora of different terms serves to point out our imper-fect ability to relate morphologic changes to biologicpotential.1 The profusion of competing proposals for thecategorization of laryngeal squamous intraepithelialchanges2–12 is evidence of the continuing debate and con-troversy throughout the multidisciplinary team withrespect to recognition, classification, histologic diagnosisand standardization, management, and prognosis of thesechallenging lesions.
Normal histologyIn health, the anterior epiglottic surface, the upper half
of the posterior epiglottic surface, the superior margin ofthe aryepiglottic folds, and the vocal cords are coveredby nonkeratinized stratified squamous epithelium (Figure1). The ventricular folds, ventricle, saccule, and subglottic
region are lined with pseudostratified ciliated columnarepithelium, with interspersed goblet cells (Figure 2).Seromucinous glands are present in the lamina propriaand are particularly numerous on the posterior epiglotticsurface, false cords, ventricle, saccule, and subglottis.These glands, however, are sparse or absent in the vocalcord.
Intraepithelial changesBoth types of normal laryngeal epithelium, stratified
squamous and respiratory epithelium, are subject to a spec-trum of abnormal epithelial proliferation. The followingterminology has evolved:
Clinical terminologyLeukoplakia. The term means "white plaque’’ and is aclinical term describing any white lesion on a mucousmembrane that cannot be wiped off or ascribed to anyspecific condition (eg, Candidal infection). The term hasno histologic implications13 and is not synonymous with"cancer’’ or "malignancy.’’14
Erythroplakia. This is a clinical term describing any red-dish plaque on the mucosal surface. It is not a histologicdiagnosis, but, epithelial atypia is common and invasivecarcinoma is present in a substantial proportion ofbiopsies.14
*Corresponding author: A. Ferlito, ENT Clinic, University of Udine, Udine, Italy.E-mail: a.ferlito@uniud.it
1810 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
The lesion is always contained at its deep aspect by thebasal lamina,24 although the underlying ducts may beinvolved. In carcinoma in situ, all layers of the epitheliumare replaced by malignant cells, whereas in severe dyspla-sia, some rudimentary maturation in the most superficialepithelial layers is preserved. Stratification is lacking.4
The lesion may be multicentric in origin and may befound in all laryngeal regions, although it is most frequentin the vocal cords and, particularly, in the anterior half ofthe true vocal cords. The role of human papillomavirus,in the genesis of these lesions, if any, is unknown.29
The first descriptions of this lesion were published earlyin the 20th century30 and the term "carcinoma in situ’’(Figure 8) (also called intraepithelial, or superficial, or pre-invasive carcinoma, or stage 0) was introduced by Brodersin 1932.31 There are considerable discrepancies in thereported incidence, generally cited as 0.4 cases per 100,000in the general population,32 rising in "high risk’’ cohorts.Carcinoma in situ may be accompanied by undiagnosedinvasive areas resulting in understaging of the lesion fol-lowing pathologic examination23,33,34 and the inclusion ofcases with microinvasive cancers distorts findings on theoutcome and prognosis of this lesion. Therefore, the diag-nosis of carcinoma in situ on the basis of a small biopsyspecimen can be accepted only with reservations.35 For reli-able assessment a full excisional biopsy is mandatory andmultiple sections from the whole surgical specimen shouldbe examined to rule out invasion. Carcinoma in situ adja-cent to invasive cancer is a mundane finding. Areas sug-gesting carcinoma in situ have been found in spindle cellcarcinoma,36 in basaloid squamous cell carcinoma,36 and incombined small cell neuroendocrine carcinoma.37 On the
other hand, not all invasive carcinomas are preceded bysevere dysplasia/carcinoma in situ. Although it has beensuggested that many invasive cancers of the larynx areinvasive from the start, unlike cervical intraepithelial neo-plasia,14 it is more likely that invasive cancer developsfrom normal cells through intermediate stages that may beof short duration.Furthermore, it should be remembered that nondysplas-
tic surface mucosa may overlie invasive carcinoma, dueto either lateral spread of carcinoma within the connectivetissue or carcinoma arising within salivary ducts.Sometimes a lesion is found to be a "false’’ carcinoma
in situ, given that adjacent biopsy specimens may showboth intraepithelial carcinoma and areas of frank infiltra-tive carcinoma.38 In some cases described as carcinomain situ, interruptions of the basement membrane are foundby immunocytochemical investigations (staining for lami-nin and/or type IV collagen).39 However, interruptedbasement membrane also can mean partly reconstitutedbasement membrane since it reflects the interplaybetween atypical cells and stroma and is without diagnos-tic or biologic significance in terms of invasion.Severe dysplasia and squamous cell carcinoma in situ
are defined by Crissman et al23 as SIN grade 3. Ferlito etal33 agreed with the notion that carcinoma in situ is aform of intraepithelial neoplasm and that the term "laryn-geal intraepithelial neoplasia’’ would encompass both car-cinoma in situ and all grades of dysplasia. Like cervicalintraepithelial neoplasia, its laryngeal counterpart may bedefined as "a spectrum of intraepithelial change whichbegins as a generally well-differentiated neoplasm, tradi-tionally classified as mild dysplasia, and ends with inva-sive carcinoma.’’40 Blackwell et al7 found that the histol-ogy of biopsies demonstrating severe dysplasia did notdiffer significantly from biopsies demonstrating carci-noma in situ, implying that severe dysplasia and carci-noma in situ both represent the same intraepithelial neo-plastic change.
FIGURE 6. Moderate dysplasia shown at the right side incomparison with normal epithelial maturation at the left side.Atypical cells with prominent nucleoli occupy the entire lowerhalve of the epithelium. Keratosis is confined to the dysplasticarea. [Color figure can be viewed in the online issue, which isavailable at wileyonlinelibrary.com.]
FIGURE 5. In mild dysplasia, cytologic atypia remains confined tothe lower third part of the epithelial thickness. Surface showsslight keratosis. [Color figure can be viewed in the online issue,which is available at wileyonlinelibrary.com.]
SQUAMOUS EPITHELIAL CHANGES OF THE LARYNX
HEAD & NECK—DOI 10.1002/HED DECEMBER 2012 1813
✤ Laryngeal Intraepithelial neoplasia
✤ (LIN) : I-III
✤ LIN III -
✤ displasia grave
✤ Ca in situ
Friedmann I, Ferlito A. Granulomas and neoplasms of the larynx. 1988
CLINICAL REVIEW David W. Eisele, MD, Section Editor
Squamous Epithelial Changes of the Larynx: Diagnosis and Therapy
Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,1
Kenneth O. Devaney, MD, JD, FCAP,2 Julia A. Woolgar, FRCPath, PhD,3 Pieter J. Slootweg, MD, DMD, PhD,4 Vinidh Paleri, MS, FRCS (ORL-HNS),5
Robert P. Takes, MD, PhD,6 Primoz Strojan, MD, PhD,7 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS(Hon),8 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg1
1ENT Clinic, University of Udine, Udine, Italy, 2Department of Pathology, Allegiance Health, Jackson, Michigan, 3Cellular Pathology, University Hospital Aintree, Longmoor Lane,Liverpool, United Kingdom, 4Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 5Department of Otolaryngology–Head and NeckSurgery, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom, 6Department of Otolaryngology–Head and Neck Surgery, RadboudUniversity Nijmegen Medical Center, Nijmegen, The Netherlands, 7Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia, 8Department ofOtolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre, Nottingham, United Kingdom.
Accepted 20 May 2011
Published online 3 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21862
ABSTRACT: It can be confusing for clinicians to work their way throughthe tangle of pathologic terms used in surgical pathology reports todescribe squamous abnormalities in laryngeal biopsies. After a briefreview of the normal microscopic anatomy of the larynx and time-honored clinical designations for surface-based abnormalities, thisreport sorts pathologic changes into 2 groups: those changes that donot carry a premalignant potential (including squamous metaplasia,squamous hyperplasia, pseudoepitheliomatous hyperplasia, keratosis,and parakeratosis) and those that do (including dyskeratosis, laryngeal
intraepithelial neoplasia [LIN], atypia, dysplasia, and carcinoma in situ).Generally, lesions in the first group do not require additional therapy orclose follow-up; lesions in the second group, however, demand eithersome form of local therapy or close follow-up to monitor for thedevelopment of a more aggressive pathology.VC 2011 Wiley Periodicals,Inc. Head Neck 34: 1810–1816, 2012
KEY WORDS: squamous epithelial changes, histopathologicclassification, larynx, pathology, therapy, prognosis
Several identical squamous epithelial changes that can beidentified in the larynx and are presumed to have thepotential to develop into invasive cancer are, dependingon the particular author writing the report, variouslydescribed in the current literature as field cancerization,potentially cancerous/malignant lesion, precancerous/pre-malignant lesion, or latent cancer. If nothing else, thisplethora of different terms serves to point out our imper-fect ability to relate morphologic changes to biologicpotential.1 The profusion of competing proposals for thecategorization of laryngeal squamous intraepithelialchanges2–12 is evidence of the continuing debate and con-troversy throughout the multidisciplinary team withrespect to recognition, classification, histologic diagnosisand standardization, management, and prognosis of thesechallenging lesions.
Normal histologyIn health, the anterior epiglottic surface, the upper half
of the posterior epiglottic surface, the superior margin ofthe aryepiglottic folds, and the vocal cords are coveredby nonkeratinized stratified squamous epithelium (Figure1). The ventricular folds, ventricle, saccule, and subglottic
region are lined with pseudostratified ciliated columnarepithelium, with interspersed goblet cells (Figure 2).Seromucinous glands are present in the lamina propriaand are particularly numerous on the posterior epiglotticsurface, false cords, ventricle, saccule, and subglottis.These glands, however, are sparse or absent in the vocalcord.
Intraepithelial changesBoth types of normal laryngeal epithelium, stratified
squamous and respiratory epithelium, are subject to a spec-trum of abnormal epithelial proliferation. The followingterminology has evolved:
Clinical terminologyLeukoplakia. The term means "white plaque’’ and is aclinical term describing any white lesion on a mucousmembrane that cannot be wiped off or ascribed to anyspecific condition (eg, Candidal infection). The term hasno histologic implications13 and is not synonymous with"cancer’’ or "malignancy.’’14
Erythroplakia. This is a clinical term describing any red-dish plaque on the mucosal surface. It is not a histologicdiagnosis, but, epithelial atypia is common and invasivecarcinoma is present in a substantial proportion ofbiopsies.14
*Corresponding author: A. Ferlito, ENT Clinic, University of Udine, Udine, Italy.E-mail: a.ferlito@uniud.it
1810 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012Such an approach has significant implications: the
changes occurring in LIN are considered as morphologicmanifestation of a neoplastic process, not as a precancer-ous lesion.21,22,41 In contrast, the current literature sug-gests that many observers believe laryngeal dysplasia tobe a precancerous or premalignant condition, and not adiscrete neoplastic process in its own right.42–44 This con-fusion in terminology occurs because the term "cancer’’is typically associated with an invasive process, which isnot the case in LIN. Since some lesions are reversibleand others do not progress, "potentially cancerous’’ isoffered as a more meaningful term than "precancerous.’’For classification purposes, 3 stages of carcinoma in
situ, similar to those described for the more commonsquamous cell carcinoma, have been distinguished: (1)well-differentiated (grade I); (2) moderately differentiated(grade II); and (3) poorly differentiated (grade III). Thishistopathologic entity45 is represented under both theUnion Internationale Contre le Cancer (UICC)46 and theAmerican Joint Committee on Cancer (AJCC)47 classifi-cation as "Tis.’’
Development of Invasive CancerIt is difficult to accurately predict the development of
invasive laryngeal malignancy in these lesions. Widelyvarying differences with respect to the probability of ma-lignant progression in mild, moderate, and severe dyspla-
sia are found in the literature. This probability is reportedto vary from 0% to 30%, 0% to 44%, and 20% to 57%of the cases, respectively.4,8,48–53 In a meta-analysis of940 cases, Weller et al54 demonstrated an overall malig-nant transformation rate of 14%, with a mean time to ma-lignant transformation of 5.8 years for laryngeal dysplas-tic lesions. The malignant transformation rate was higherwith increased severity of dysplasia grade (30.4% forsevere vs 10.6% for mild/moderate grades).The role of p53 expression has been widely studied
with somewhat contradictory results. Nylander et al55
found no indication of a clinical or prognostic signifi-cance of p53 expression in squamous cell carcinoma ofthe head and neck in contrast to the conclusion of Fieldet al,56 who stated that, in patients with "end-stage dis-ease,’’ overexpression of this gene correlated "with avery poor prognosis.’’ Kushner et al57 expressed the viewthat there is a significant correlation between p53 labelingindex and Ki-67 score, concluding that altered p53 pro-tein expression is probably an early event in oral carcino-genesis in the floor of the mouth and is associated withdysregulation of cell proliferation at this site. However, arecent meta-analysis of biomarkers in laryngeal dysplasiaconcluded that currently there is no good evidence for theuse of biomarkers in predicting the future behavior of la-ryngeal dysplastic lesions.58
Interobserver VariabilityIt should be acknowledged that there is an element of
subjectivity in the diagnosis of dysplastic (LIN) lesionsof the larynx. This, in part, is why there are
FIGURE 7. Severe dysplasia is characterized by full-thicknessepithelial atypia with some preserved maturation indicated byflattening of the cells in the upper epithelial layers. [Color figurecan be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 8. In carcinoma in situ, cellular maturation has entirelydisappeared. Superficial cells show the same abnormalities as theones lying in the more basal part. At the left side, remaining normalepithelium shows surface maturation. [Color figure can be viewedin the online issue, which is available at wileyonlinelibrary. com.]
FERLITO ET AL.
1814 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
✤ Laryngeal Intraepithelial neoplasia
✤ (LIN) : I-III
✤ LIN III -
✤ displasia grave
✤ Ca in situ
Friedmann I, Ferlito A. Granulomas and neoplasms of the larynx. 1988
CLINICAL REVIEW David W. Eisele, MD, Section Editor
Squamous Epithelial Changes of the Larynx: Diagnosis and Therapy
Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,1
Kenneth O. Devaney, MD, JD, FCAP,2 Julia A. Woolgar, FRCPath, PhD,3 Pieter J. Slootweg, MD, DMD, PhD,4 Vinidh Paleri, MS, FRCS (ORL-HNS),5
Robert P. Takes, MD, PhD,6 Primoz Strojan, MD, PhD,7 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS(Hon),8 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg1
1ENT Clinic, University of Udine, Udine, Italy, 2Department of Pathology, Allegiance Health, Jackson, Michigan, 3Cellular Pathology, University Hospital Aintree, Longmoor Lane,Liverpool, United Kingdom, 4Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 5Department of Otolaryngology–Head and NeckSurgery, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom, 6Department of Otolaryngology–Head and Neck Surgery, RadboudUniversity Nijmegen Medical Center, Nijmegen, The Netherlands, 7Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia, 8Department ofOtolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre, Nottingham, United Kingdom.
Accepted 20 May 2011
Published online 3 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21862
ABSTRACT: It can be confusing for clinicians to work their way throughthe tangle of pathologic terms used in surgical pathology reports todescribe squamous abnormalities in laryngeal biopsies. After a briefreview of the normal microscopic anatomy of the larynx and time-honored clinical designations for surface-based abnormalities, thisreport sorts pathologic changes into 2 groups: those changes that donot carry a premalignant potential (including squamous metaplasia,squamous hyperplasia, pseudoepitheliomatous hyperplasia, keratosis,and parakeratosis) and those that do (including dyskeratosis, laryngeal
intraepithelial neoplasia [LIN], atypia, dysplasia, and carcinoma in situ).Generally, lesions in the first group do not require additional therapy orclose follow-up; lesions in the second group, however, demand eithersome form of local therapy or close follow-up to monitor for thedevelopment of a more aggressive pathology.VC 2011 Wiley Periodicals,Inc. Head Neck 34: 1810–1816, 2012
KEY WORDS: squamous epithelial changes, histopathologicclassification, larynx, pathology, therapy, prognosis
Several identical squamous epithelial changes that can beidentified in the larynx and are presumed to have thepotential to develop into invasive cancer are, dependingon the particular author writing the report, variouslydescribed in the current literature as field cancerization,potentially cancerous/malignant lesion, precancerous/pre-malignant lesion, or latent cancer. If nothing else, thisplethora of different terms serves to point out our imper-fect ability to relate morphologic changes to biologicpotential.1 The profusion of competing proposals for thecategorization of laryngeal squamous intraepithelialchanges2–12 is evidence of the continuing debate and con-troversy throughout the multidisciplinary team withrespect to recognition, classification, histologic diagnosisand standardization, management, and prognosis of thesechallenging lesions.
Normal histologyIn health, the anterior epiglottic surface, the upper half
of the posterior epiglottic surface, the superior margin ofthe aryepiglottic folds, and the vocal cords are coveredby nonkeratinized stratified squamous epithelium (Figure1). The ventricular folds, ventricle, saccule, and subglottic
region are lined with pseudostratified ciliated columnarepithelium, with interspersed goblet cells (Figure 2).Seromucinous glands are present in the lamina propriaand are particularly numerous on the posterior epiglotticsurface, false cords, ventricle, saccule, and subglottis.These glands, however, are sparse or absent in the vocalcord.
Intraepithelial changesBoth types of normal laryngeal epithelium, stratified
squamous and respiratory epithelium, are subject to a spec-trum of abnormal epithelial proliferation. The followingterminology has evolved:
Clinical terminologyLeukoplakia. The term means "white plaque’’ and is aclinical term describing any white lesion on a mucousmembrane that cannot be wiped off or ascribed to anyspecific condition (eg, Candidal infection). The term hasno histologic implications13 and is not synonymous with"cancer’’ or "malignancy.’’14
Erythroplakia. This is a clinical term describing any red-dish plaque on the mucosal surface. It is not a histologicdiagnosis, but, epithelial atypia is common and invasivecarcinoma is present in a substantial proportion ofbiopsies.14
*Corresponding author: A. Ferlito, ENT Clinic, University of Udine, Udine, Italy.E-mail: a.ferlito@uniud.it
1810 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
Such an approach has significant implications: thechanges occurring in LIN are considered as morphologicmanifestation of a neoplastic process, not as a precancer-ous lesion.21,22,41 In contrast, the current literature sug-gests that many observers believe laryngeal dysplasia tobe a precancerous or premalignant condition, and not adiscrete neoplastic process in its own right.42–44 This con-fusion in terminology occurs because the term "cancer’’is typically associated with an invasive process, which isnot the case in LIN. Since some lesions are reversibleand others do not progress, "potentially cancerous’’ isoffered as a more meaningful term than "precancerous.’’For classification purposes, 3 stages of carcinoma in
situ, similar to those described for the more commonsquamous cell carcinoma, have been distinguished: (1)well-differentiated (grade I); (2) moderately differentiated(grade II); and (3) poorly differentiated (grade III). Thishistopathologic entity45 is represented under both theUnion Internationale Contre le Cancer (UICC)46 and theAmerican Joint Committee on Cancer (AJCC)47 classifi-cation as "Tis.’’
Development of Invasive CancerIt is difficult to accurately predict the development of
invasive laryngeal malignancy in these lesions. Widelyvarying differences with respect to the probability of ma-lignant progression in mild, moderate, and severe dyspla-
sia are found in the literature. This probability is reportedto vary from 0% to 30%, 0% to 44%, and 20% to 57%of the cases, respectively.4,8,48–53 In a meta-analysis of940 cases, Weller et al54 demonstrated an overall malig-nant transformation rate of 14%, with a mean time to ma-lignant transformation of 5.8 years for laryngeal dysplas-tic lesions. The malignant transformation rate was higherwith increased severity of dysplasia grade (30.4% forsevere vs 10.6% for mild/moderate grades).The role of p53 expression has been widely studied
with somewhat contradictory results. Nylander et al55
found no indication of a clinical or prognostic signifi-cance of p53 expression in squamous cell carcinoma ofthe head and neck in contrast to the conclusion of Fieldet al,56 who stated that, in patients with "end-stage dis-ease,’’ overexpression of this gene correlated "with avery poor prognosis.’’ Kushner et al57 expressed the viewthat there is a significant correlation between p53 labelingindex and Ki-67 score, concluding that altered p53 pro-tein expression is probably an early event in oral carcino-genesis in the floor of the mouth and is associated withdysregulation of cell proliferation at this site. However, arecent meta-analysis of biomarkers in laryngeal dysplasiaconcluded that currently there is no good evidence for theuse of biomarkers in predicting the future behavior of la-ryngeal dysplastic lesions.58
Interobserver VariabilityIt should be acknowledged that there is an element of
subjectivity in the diagnosis of dysplastic (LIN) lesionsof the larynx. This, in part, is why there are
FIGURE 7. Severe dysplasia is characterized by full-thicknessepithelial atypia with some preserved maturation indicated byflattening of the cells in the upper epithelial layers. [Color figurecan be viewed in the online issue, which is available atwileyonlinelibrary.com.]
FIGURE 8. In carcinoma in situ, cellular maturation has entirelydisappeared. Superficial cells show the same abnormalities as theones lying in the more basal part. At the left side, remaining normalepithelium shows surface maturation. [Color figure can be viewedin the online issue, which is available at wileyonlinelibrary. com.]
FERLITO ET AL.
1814 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
✤ LIN I
✤ LIN II
✤ LIN III
Weller MD, Nankivell PC, McConkey C, Paleri V, Mehanna HM. The risk and interval to malignancy of patients with laryngeal dysplasia; a sys- tematic review of case series and meta-analysis. Clin Otolaryngol 2010;
CLINICAL REVIEW David W. Eisele, MD, Section Editor
Squamous Epithelial Changes of the Larynx: Diagnosis and Therapy
Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS (Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP,1
Kenneth O. Devaney, MD, JD, FCAP,2 Julia A. Woolgar, FRCPath, PhD,3 Pieter J. Slootweg, MD, DMD, PhD,4 Vinidh Paleri, MS, FRCS (ORL-HNS),5
Robert P. Takes, MD, PhD,6 Primoz Strojan, MD, PhD,7 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS (Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS(Hon),8 Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg1
1ENT Clinic, University of Udine, Udine, Italy, 2Department of Pathology, Allegiance Health, Jackson, Michigan, 3Cellular Pathology, University Hospital Aintree, Longmoor Lane,Liverpool, United Kingdom, 4Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands, 5Department of Otolaryngology–Head and NeckSurgery, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom, 6Department of Otolaryngology–Head and Neck Surgery, RadboudUniversity Nijmegen Medical Center, Nijmegen, The Netherlands, 7Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia, 8Department ofOtolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre, Nottingham, United Kingdom.
Accepted 20 May 2011
Published online 3 October 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21862
ABSTRACT: It can be confusing for clinicians to work their way throughthe tangle of pathologic terms used in surgical pathology reports todescribe squamous abnormalities in laryngeal biopsies. After a briefreview of the normal microscopic anatomy of the larynx and time-honored clinical designations for surface-based abnormalities, thisreport sorts pathologic changes into 2 groups: those changes that donot carry a premalignant potential (including squamous metaplasia,squamous hyperplasia, pseudoepitheliomatous hyperplasia, keratosis,and parakeratosis) and those that do (including dyskeratosis, laryngeal
intraepithelial neoplasia [LIN], atypia, dysplasia, and carcinoma in situ).Generally, lesions in the first group do not require additional therapy orclose follow-up; lesions in the second group, however, demand eithersome form of local therapy or close follow-up to monitor for thedevelopment of a more aggressive pathology.VC 2011 Wiley Periodicals,Inc. Head Neck 34: 1810–1816, 2012
KEY WORDS: squamous epithelial changes, histopathologicclassification, larynx, pathology, therapy, prognosis
Several identical squamous epithelial changes that can beidentified in the larynx and are presumed to have thepotential to develop into invasive cancer are, dependingon the particular author writing the report, variouslydescribed in the current literature as field cancerization,potentially cancerous/malignant lesion, precancerous/pre-malignant lesion, or latent cancer. If nothing else, thisplethora of different terms serves to point out our imper-fect ability to relate morphologic changes to biologicpotential.1 The profusion of competing proposals for thecategorization of laryngeal squamous intraepithelialchanges2–12 is evidence of the continuing debate and con-troversy throughout the multidisciplinary team withrespect to recognition, classification, histologic diagnosisand standardization, management, and prognosis of thesechallenging lesions.
Normal histologyIn health, the anterior epiglottic surface, the upper half
of the posterior epiglottic surface, the superior margin ofthe aryepiglottic folds, and the vocal cords are coveredby nonkeratinized stratified squamous epithelium (Figure1). The ventricular folds, ventricle, saccule, and subglottic
region are lined with pseudostratified ciliated columnarepithelium, with interspersed goblet cells (Figure 2).Seromucinous glands are present in the lamina propriaand are particularly numerous on the posterior epiglotticsurface, false cords, ventricle, saccule, and subglottis.These glands, however, are sparse or absent in the vocalcord.
Intraepithelial changesBoth types of normal laryngeal epithelium, stratified
squamous and respiratory epithelium, are subject to a spec-trum of abnormal epithelial proliferation. The followingterminology has evolved:
Clinical terminologyLeukoplakia. The term means "white plaque’’ and is aclinical term describing any white lesion on a mucousmembrane that cannot be wiped off or ascribed to anyspecific condition (eg, Candidal infection). The term hasno histologic implications13 and is not synonymous with"cancer’’ or "malignancy.’’14
Erythroplakia. This is a clinical term describing any red-dish plaque on the mucosal surface. It is not a histologicdiagnosis, but, epithelial atypia is common and invasivecarcinoma is present in a substantial proportion ofbiopsies.14
*Corresponding author: A. Ferlito, ENT Clinic, University of Udine, Udine, Italy.E-mail: a.ferlito@uniud.it
1810 HEAD & NECK—DOI 10.1002/HED DECEMBER 2012
Malignização 14% em 5.8 anos
0- 30 %
0-40 %
20-57 %
conduta
✤ Lesões sem potencial maligno
✤ seguimento 4/4 meses
✤ avaliação das causas com possível modificação
✤ Tabagismo, DRGE, lesão estrutural…..
conduta
✤ Lesões com potencial maligno
✤ seguimento mensal por 3 meses / bimestral 2x/ trimestral 2x/ semestral ……
✤ resseção completa se possível
✤ avaliação das causas com possível modificação
✤ Tabagismo, DRGE, lesão estrutural…..
obrigado
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