Pathology of the Larynx

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Pathology of the Larynx

Nikolay Popnikolov M.D., Ph.D.Fellow, UTMB Dept. of Pathology

January 2002

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Normal Anatomy and Histology

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Laryngeal Epithelium

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Goblet Cells and Columnar Mucinous Cells

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Squamous Epithelium

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Seromucinous Glands

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Duct from Seromucinous Glands

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Seromucinous Glands

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Oncocytic Transformation of Seromucinous Epithelium

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Vocal Process of the Arythenoid Cartilage

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Chondroid Metaplasia

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Non-neoplastic Lesions of the Larynx

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Tuberculosis

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Granulomatous Inflammation

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Fungal Infections

HistolplasmosisCoccidiomycosisCryptococcosisBlastomycosisAspergilosisCandidiasis

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Other Granulomatous Diseases

LeprosyTertiary SyphilisSarcoidosisCrohn’s diseaseWegener’s granulomatosis

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Acute Epiglottitis

Haemophylus influenzae type BReddened, markedly edematous supraglottic structures Edema with marked infiltrate of neutrophyls with or without microabscess formation

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Diphtheria

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Diphtheria

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Vocal Cord Nodules

Usually bilateralAnterior or middle third of true vocal cord Any age group Related to chronic voice abuseHoarseness or voice changes

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Vocal Cord Polyps

Usually single Middle third of true vocal cord, but may originate from the ventricular area Any age group Sessile, raspberry-like, pedunculated Related to chronic voice abuse, infection, ETOH, smoking, hypothyroidismHoarseness or voice changes

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Vocal Cord Polyp

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Edematous-Myxoid Type

Submucosal accumulation of pale blue to pink material admixed with sparsely cellular and variably vascularized stroma

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Vascular-Hyaline Type

Dilated submucosal vascular spaces and deposition of dense eosinophilic fibrin-like material

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Vocal Cord Polyp: Fibrous Type

Moderately cellular submucosal proliferation of uniform oval to spindle-shaped cells with varying amount of fibrous tissue deposition

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Laryngocele

Abnormal dilatation of the saccule (appendix of the ventricle) containing air and maintaining an open communication with laryngeal lumenMen >womenBilateral - 25%Hoarseness, lateral neck mass, dyspnea, dysphagia, laryngopyocele (pain)

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Laryngocele: Types

Internal:laryngocele confined to the intrinsic larynx External:dilated sac projects upward and laterally Combined

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Laryngocele: Etiology

Acquired:increased intralaryngeal pressure (glassblowers, musicians, weight lifters) CongenitalSCC in 15% of cases

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Laryngocele

Smooth -surfaced, sac-like structure usually filled with air

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Laryngocele

Respiratory epithelial-lined (ciliated, columnar) cyst with a fibrous wallSquamous metaplasiaOncocytic metaplasia

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Laryngocele: Differential Diagnosis

Branchial cleft cystOncocytic papillary cystadenomaLaryngeal cysts

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Contact Ulcers of the Larynx (Pyogenic Granuloma of the Larynx)

Benign, tumor-like condition, occurring most commonly along the posterior aspect of one or both vocal cordsMen>Women, usually adultsHoarseness, dysphagia, sore throat, dysphonia, difficulty breathing, choking, painEtiology: vocal abuse, acid regurgitation, postintubation trauma

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Ulcerated, polypoid, nodular, or fungating mass with a beefy red to tan-white appearance, up to 3 cm in diameter

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Ulcerated lesion with associated fibrinoid necrosis, granulation tissue, acute and chronic inflammation

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Giant cells, vascular proliferation, and spindle cells

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Contact Ulcers of the Larynx: Differential Diagnosis

Infectious diseasesSCCSpindle cell carcinomaVascular neoplasms: lobular capillary hemangioma, angiosarcoma, Kaposi’s sarcoma

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Laryngeal Amyloidosis

Extracellular accumulation of fibrillar proteinsSystemic or localizedPrimary or secondaryMen > women, in the 5th and 6th decades Polypoid mass (glottis and supraglottis) or diffuse mucosal swelling (subglottis)Hoarseness

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Extracellular, eosinophilic, amorphous material deposited randomly throughout submucosa; depositions around or within the walls Disappearance of the seromucous glands, Mixed chronic inflammatory infiltrate

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Congo red: apple-green birefringence under polarized light

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Subglottic Stenosis

Congenital or acquiredRare; acquired > congenitalProgressive respiratory difficulty, stridor, dyspnea, air hunger, hoarseness, abnormal cry, aphonia, dysphagiaEtiology: trauma, neoplasms, infectious or autoimmune diseases, idiopathic

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Subglottic Stenosis

Narrowing of the endolaryngeal diameter with mucosal or submucosal mass or bulgingHistologic picture depends on the causeIdiopathic stenosis: submucosal fibrous proliferation with associated non-specific chronic inflammationDifferential diagnosis: infectious diseases, Wegener’s granulomatosis, collagen vascular diseases, neoplasms

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Idiopathic Subglottic Stenosis

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Terminology of Epithelial Changes

Leukoplakia:white lesion on a mucosal membrane (clinical)Erythroplakia:red lesion on a mucosal membrane (clinical)Hyperplasia:thickening of epithelial surface as a result of an absolute increase in the number of cells.Pseudoepitheliomatous hyperplasia:exuberant reactive or reparative overgrowth of squamous epithelium with no cytologic evidence of malignancy.

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Keratosis:presence of keratin on an epithelial surfaceParakeratosis:presence of nuclei in the keratin layerDyskeratosis:abnormal keratinization of epithelial cellsUlceration:erosion or loss of surface epitheliumMetaplasia:change from one histologic tissue type to another

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Koilocytosis:cytoplasmic vacuolization suggestive of viral (HPV) effectDysplasia or atypia:abnormal maturation and cellular aberrationsCarcinoma in situ:full thickness epithelial dysplastic change with an intact basement membrane.Superficially (microscopically) invasive SCC:SCC in which there is violation of the basement membrane with invasion into the underlying stroma.

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Hyperplastic Epithelial Changes

Reactive or reparative benign process, reflecting the epithelial response to a stimulus or an injuryMen > womenOccurs anywhere, but mainly along the true vocal cordsHoarsenessEtiology: smoking, ETOH, voice abuse, chronic inflammation

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Flat, papillary, or verrucoid lesion with a white (leukoplakic) or red (erythroplakic) appearanceSmall or diffuseThickening of epithelial surface as a result of an absolute increase in the number of cellsPresence of superficial keratin layer (keratosis) or nuclei in the superficial keratin layer (parakeratosis)

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Presence of keratohyaline granules in the granulosa cell layerPresence of koilocytosisPresence of cytologic atypiaPresence of dyskeratosisDifferential diagnosis: contact ulcer, verruca vulgaris, verrucous carcinoma, well-differentiated ”conventional” SCC

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Keratosis with Epithelial Hyperplasia w/o Dysplasia

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Laryngeal Leukoplakia with a Papillary or Verrucoid Appearance

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Laryngeal Leukoplakia with a Papillary or Verrucoid Appearance

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Dysplastic Epithelial Changes

Men > womenOccurs anywhere, but mainly along the anterior portion of the true vocal cords, 25% bilateralHoarsenessEtiology: smoking, ETOH, chronic inflammation, voice abuse, Vit A deficiency, environmental exposure

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Localized, circumscribed flat or papillary area with white, red or gray appearanceCytologic alterations: hyperchromasia, increase of nuclear/cytoplasmic ratio, mitoses, crowding of cells with loss of cellular polarityBegins in basal or parabasal areas

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Dysplastic Epithelial Changes: Grading

Mild:lower 1/3 of the thickness of epithelium Moderate:lower 2/3 of the thickness of epithelium Severe:from 2/3 to almost complete thickness

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Normal maturation of the superficial layers of the epitheliumIntact basement membraneMay be associated with keratosis or dyskeratosis, or other hyperplastic changesFull-thickness dysplasia (carcinoma in situ) is not a prerequisite prior to the development of an invasive CADifferential diagnosis: reactive epithelial changes, infectious disease, SCC

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Flat Keratosis with Epithelial Hyperplasia and Mild Dysplasia

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Keratosis with Moderate Dysplasia

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Severe Dysplasia without Keratosis

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Benign Neoplasms of the Larynx

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Laryngeal Papilloma

Benign, exophytic neoplastic growth composed of branching fronds of squamous epithelium with fibrovascular coresThe most common benign laryngeal neoplasmNo sex predilectionChanges in phonation, dyspnea, cough, dysphagia, stridorHPV types 6 and 11

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Laryngeal Papilloma

Juvenile type:multiple lesions with extensive growth and rapid recurrence, may remit spontaneously or persist into old ageAdult type:more often single, recurs less often, less likely to spread

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Exophytic, warty, friable, tan-white to red growths

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Papillary fronds of multilayered benign squamous epithelium containing fibrovascular coresLittle or no keratin production

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Laryngeal Papilloma

Absence of stromal invasionCertain degree of cellular atypiaKoilocytic changes

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Laryngeal Granular Cell Tumor

Men > womenHoarsenessAlong the posterior aspect of true vocal cord ( but also in supraglotic and infraglotic areas)

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Granular Cell Tumor

Solitary, polypoid, sessile, papillary, or cystic lesion, measuring up to 3.0 cm in diameter

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Granular Cell Tumor

Poorly circumscribed subepithelial lesion with syncytial, trabecular, or nested growth patternRound to polygonal cells with round to vesicular nuclei and coarsely granular cytoplasm. Poorly defined cell borders.Variable degree of cellular pleomorphismAbsence of mitoses or necroses

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S-100 Protein Immunostain

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Pseudoepitheliomatous hyperplasia

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Granular Cell Tumor

Cytoplasmic granules:PAS/d +, Alcian blue pH 2.5 +, trichrome + (red)Angulate bodies: needle shaped, PAS + bodies in the interstitial cells Tumor cells:S-100+, NSE + Interstitial cells with angulate bodies:S-100 - and myelin protein +EM:membrane bound autophagic vacuoles containing mitochondria, RER, myelin, axon-like structures

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Malignant Granular Cell Tumor

Rare ( 1% of all GCT)Do not occur in newbornsSize > 4 cmIncreased cellularity, pleomorphism, necrosis, prominent nucleoli, spindle shaped cells and > 2 mitoses/10 HPFMetastasize via lymphatics and blood vessels

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Chordoma

UncommonMales > femalesDyspnea, strydor, and hoarsenessMay originates from epiglottis, cricoid, arytenoid, or thyroid cartilages May arise in Reinke’s spaceLobulated, firm to hard, blue-gray, submucosal mass, usually < 1 cm

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Chordoma

Lobulated, normally looking chondrocytesAbsence of pleomorphism, binucleated chondrocytes, or mitotic activity

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Rhabdomyoma

Benign tumor of striated muscleAdult type:less commonMales > females; > 40 y/oHoarseness, dyspneaWell-defined, lobulated, red-brown mass, up to 5 cm in diameter

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Rhabdomyoma: Adult Type

Large polygonal to round cells with abundant deeply eosinophylic cyroplasm and one or two periphery placed vesicular nucleiNucleoli, cytoplasmic vacuolizationCross-striationAbsent mitosesAbundant cytoplasmic glycogen (diastase sensitive PAS positive)Desmin +, Myoglobin +

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Rhabdomyoma: Fetal Type

Very rareMale children < 3 y/oPosterior auricular subcutaneous tissue > nasopharynx, parotis, neckSolitary, well to moderately circumscribed nodule, 1-8 cm in size, gray to pink mucoid appearance

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Rhabdomyoma: Fetal Type

Spindle cells and immature muscle fibers with in a myxoid stromaCross-striation rarely discernible. Mature muscle fibers can be seen in the peripheryAbsence of mitoses, necrosis, and significant pleomorphism

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Malignant Laryngeal Neoplasms

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In Situ Squamous Cell Carcinoma

Males > females6th – 7th decadesMost often involves anterior portion of true vocal cordHoarsenessMay coexist with invasive SCCMay be isolated or multifocalCircumscribed or diffuse lesion with a white, red, or gray color and smooth or granular appearance

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In Situ Squamous Cell Carcinoma

Dysplastic process involves the entire thickness of the epitheliumLoss of cellular maturation and polarityIncrease of nuclear/cytoplaslic ratioNormal and abnormal mitosesKeratosis and dyskeratosisExtension into adjacent seromucinous glands

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Microinvasive or Superficially Invasive Squamous Cell Carcinoma

Nests of malignant cells that have penetrated the basement membrane and invaded superficially into the submucosaCapable of metastasizingDevelopment from carcinoma in situ or from epithelium with no evidence of CIS

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Invasive Squamous Cell Carcinoma

2.5% of all cancers in men0.5% of all cancers in women95% of all laryngeal carcinomasEtiology: ETOH (supraglottic), tobacco (glottic), asbestos, nickel, wood, isopropyl alcohol, radiationDD: reactive epithelial changes, pseudoepitheliomatous hyperplasia

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Invasive Squamous Cell Carcinoma

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Supraglottic Squamous Cell Carcinoma

25–40% of laryngeal SCCEpiglottis (base), false vocal cordsChanges in the quality of voice, dysphagia, odonophagia, hoarseness, hemoptisis, dyspneaMarginal carcinomas (suprahyoid epiglottis, aryepiglottic folds); remain quiescent for longer period and present at more advanced stage

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Ulcerated, flat, exophytic, or papillaryTend to be nonkeratinizingIn situ componentMitoses and necrosis

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Large, tan-white neoplasm in the right supraglottis, extending upward toward epiglottis

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Glottic SCC

Early: irregular area of mucosal thickeningAdvanced: exophytic, fungatic, endophytic, ulcerated massMore commonly keratinizing, well to moderately differentiatedIn situ componentInvasive component predominantly infiltrative

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Glottic SCC

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Glottic SCC

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Glottic SCC

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Subglottic Squamous Cell Carcinoma

5% of all laryngeal tumorsTend to remain clinically quiescent, presenting with advanced stageAirway obstruction (dyspnea, stridor) and vocal cord fixation (voice changes)Large exophytic, fungating, ulcerating, or endophyticTend to be keratinizing moderately to poorly differentiatedIn situ component is less commonInvasive pattern is predominantly infiltrative

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Subglottic SCC

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Subglottic Squamous Cell Carcinoma

Overall 5-year survival rate < 40%Spread: Into thyroarytenoid muscle (vocal cord fixation) Anteriorly: through cricothyroid membrane into thyroid gland superiorly: glottis and supraglottis inferiorly: trachea posteriorly: below the cricoid cartilage and into the esophagusLymphatic drainage: upper and lower jugular chains, perlaryngeal and paratracheal nodesStomal recurrent tumor

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Transglottic SCC

Involves both glottic and supraglottic structuresRepresents advanced tumorNodal metastases and extranodal spreadOverall 5-year survival rate < 40%

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Transglottic SCC

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Spindle Cell (Squamous) Carcinoma (SCSC)

Foci of conventional SCC associated with malignant spindle cell stromal componentSynonyms: carcinosarcoma, pleomorphic carcinoma, metaplastic carcinoma, collision tumor, pseudosarcoma, Lane tumorMen (85%), 6th –8th decadesTrue vocal cords > false vocal cords and supraglottis > oral cavity > skin > tonsil and pharynxSymptoms vary according to siteNo specific etiology

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Spindle cell component with variable degree of pleomorphism, mitosesFascicular, storiform, or palisading patterns; may be associated with myxomatous stroma

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Spindle cells are cytokeratin-positive, but negativity does not exclude the diagnosis

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Heterologous Elements

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Differential diagnosis: Reactive (fibroblastic) proliferationMalignant fibrous histiocytomaFibrosarcomaMalignant melanoma

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Controversial histogenesis. Epithelial derivation is support by:Association with conventional SCC ICH: cytokeratin + Cartilage or bone component have not been reported in metastasesMetastases may include conventional or/and spindle cell componentPoor prognosis (metastases in lymph nodes and lungs)

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Verrucous Carcinoma

Highly differentiated variant of SCC with focally destructive, but not metastatic capabilities1-3% of all laryngeal carcinomasMen > women, 6th – 7th decadesOral cavity > nasal fossa > sinonasal tract, nasopharynxLarynx: hoarsenessIn the larynx most common in the glottic areaPotential etiologic factors: tobacco, viruses

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Verrucous Carcinoma

Tan or white, warty, fungating, or exophytic, firm to hard mass, attached by a broad baseSquamous cell proliferation: uniform cells without dysplastic features and mitoses marked surface keratinization broad or bulbous rete pegs with pushing, NOT infiltrative marginDysplastic features limited and confined to basal soneMixed chronic immflammarory cell infiltrate

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Verrucous Carcinoma

Tan or white, warty, fungating, or exophytic, firm to hard mass, attached by a broad base

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Verrucous Carcinoma

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Verrucous Carcinoma

Squamous cell proliferation: uniform cells without dysplastic features and mitoses marked surface keratinization broad or bulbous rete pegs with pushing, NOT infiltrative marginDysplastic features limited and confined to basal zoneMixed chronic inflammatory cell infiltrate

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Verrucous Carcinoma

Differential diagnosis:Keratotic squamous papillomaReactive keratosis and epithelial hyperplasiaPseudoepitheliomatous hyperplasiaVerruca vulgarisKeratoacantoma“Conventional” SCC

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Verrucous Carcinoma

Metastasis in regional lymph nodes are rare, and distant metastases do not occurExcellent prognosis after complete surgical removalAnaplastic transformation may result in distant metastasesAdequate biopsy material with a good epithelial-stromal interface is critical for the interpretationCervical adenopathy- reactive changes

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Basaloid Squamous Cell Carcinoma

An invasive neoplasm, composed of basaloid cells UncommonMen > women, 6th – 7th decadesHypopharynx (pyriform sinus), larynx (supraglottis), and tongueHoarseness, dysphagia, pain, neck massEtiology: ETOH, tabaccoCell of origin: unclear

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Firm to hard, tan-white mass, often with associated central necrosisPatterns: solid, lobular, cell nests, cribriform, cords, trabeculae, gland-like, or cysticComedonecrosisIntercellular deposition of a hyaline or mucohyalin materialFocal squamous differentiation or association with SCC, SCCIS, squamous dysplasia, or spindle cell component

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Infiltrating tumor originating from the surface epithelium with solid growth pattern and comedonecrosis

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Small, closely apposed cells with hyperchromatic nuclei, scanty cytoplasm, marked mitotic activity, large cells or pleomorphism can be seen

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Basaloid SCC with Focal Keratinization

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Histochemistry:PAS+ and Alcian blue + material in the cystic spacesIHC:

cytokeratin (+), EMA (+), CEA (+), S-100 (+); chromogranin (-), synaptophysin (-), muscle-specific actin (-)EM:basaloid component: desmosomes, rare tonofilaments cystic spaces: stellate granules or replicated basal lamina

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Basaloid SCC: Differential Diagnosis

Adenoid cystic carcinomaNeuroendocrine carcinomaAdenosquamous carcinomaSpindle cell carcinoma

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Multifocal, deeply invasive, metastatic Metastases: lymph nodes, lung, bone, skin, brainMetastases include both basaloid and squamous componentsRapidly fatal

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Adenosquamous Carcinoma

Malignant high grade epithelial neoplasm with histologic features of adenocarcinoma and SCCUncommonMen > women, 6th – 7th decadesLarynx, hypopharynx, oral cavity, sinonasal cavityHoarseness, dysphagia, pain, neck mass, nasal obstructionEtiology: not clear (ETOH, tobacco)Cell of origin: unclear; possible a single totipotential cell from surface epithelium or seromucous glands

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Exophytic or submucosal, friable, edematous or granular mass with or without surface ulcerationsSCC component:Well to poorly differentiated, associated in situ carcinoma or invasive SCCIndividual cell keratinization, intercellular bridges, keratin pearl formation, dyskeratosisAdenocarcinoma component:In the submucosa, glandular differentiation, Both components can be admixedCellular pleomorphism, mitoses, necrosis, perineural invasion

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Histochemistry: PAS/d (+) and mucicarnine (+) intraluminal materialIHC: cytokeratin (+)Behaves very aggressively, irrespective of the size of neoplasm Early lymph node metastases, lung, liverPoor prognosis: 5-year survival rate of

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Neuroendocrine Carcinoma: Classification

Carcinoid(well differentiated)Atypical carcinoid(moderately differentiated)Small (“oat”) cell carcinoma(poorly differentiated)

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Neuroendocrine Carcinoma

Submucosal nodular or polypoid mass with tan-white appearance and up to 4 cm in diameterSurface ulceration may present in moderately or well-differentiated neuroendocrine carcinoma

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Carcinoid

Organoid or trabecular growth pattern with fibtovascular stromaGlands or squamous differentiation can be seenAbsence of surface ulceration

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Carcinoid

Uniform cells with centrally located round nuclei, vesicular chromatin, and eosinophilic cytoplasmAbsence of pleomorphism, mitoses, necrosesLow nuclear:cytoplasmic ratio

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Carcinoid

Histochemistry:PAS/d + mucin, argyrophiliaIHC:Cytokeratin +, Chromogranin +, NSE +, synaptophysin +EM:neurosecretory granules, cellular junctional complexes

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Atypical Carcinoid

Organoid, trabecular, cribriform, or solid gowth patternMild to marked cellular pleomorphismNucleoli may be prominentMitoses and focal necrosis Variable nuclear:cytoplasmic ratio

Surface ulceration andlymphovascular and perineural invasion

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Small Cell Carcinoma

Solid nests, sheets, or ribbons, with absence of fibrovascular stromaSurface ulcerationLymphovascular and perineural invasionGlandular or squamous differentiation is rarely seen

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Small Cell Carcinoma

Marked cellular pleomorphism, ‘crush’ artifacts, necrosis, hyperchromatic oval to spindle nuclei, abundant mitosesHigh nuclear:cytoplasmic ratioIHC: cytokeratin, chromogranin, synaptophysin, NSE positiveEM: rare neurosecretory granules

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Chondrosarcoma

RareMales >Females, 4th - 7th decadesCricoid > thyroid cartilage > arytenoidSmooth, lobulated, hard submucosal mass larger than 2 cm

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Chondrosarcoma (high grade)

Lobulated hypercellular tumor with hyperchromatic, pleomorphic nuclei and prominent nucleoliBinucleate or multinucleated cellsMitoses: usually

uncommon

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Synovial Sarcoma

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Synovial Sarcoma

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Synovial Sarcoma

Pathology of the Larynx

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