Pathology of the Larynx

Pathology of the Larynx Nikolay Popnikolov M.D., Ph.D. Fellow, UTMB Dept. of Pathology January 2002 1 Normal Anatomy and Histology 2 Normal Anat...
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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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Normal Anatomy and Histology

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Normal Anatomy and Histology

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Normal Anatomy and Histology

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Normal Anatomy and Histology

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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 aHistolplasmosis aCoccidiomycosis aCryptococcosis aBlastomycosis aAspergilosis aCandidiasis 20

Other Granulomatous Diseases aLeprosy aTertiary Syphilis aSarcoidosis aCrohn’s disease aWegener’s granulomatosis

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Acute Epiglottitis aHaemophylus influenzae type B aReddened, markedly edematous supraglottic structures aEdema 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 aUsually bilateral aAnterior or middle third of true vocal cord aAny age group aRelated to chronic voice abuse aHoarseness or voice changes 25

Vocal Cord Polyps aUsually single aMiddle third of true vocal cord, but may originate from the ventricular area aAny age group aSessile, raspberry-like, pedunculated aRelated to chronic voice abuse, infection, ETOH, smoking, hypothyroidism aHoarseness or voice changes 26

Vocal Cord Polyp

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Edematous-Myxoid Type

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

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Vascular-Hyaline Type

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

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Vocal Cord Polyp: Fibrous Type a Moderately cellular submucosal proliferation of uniform oval to spindle-shaped cells with varying amount of fibrous tissue deposition

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Laryngocele aAbnormal dilatation of the saccule (appendix of the ventricle) containing air and maintaining an open communication with laryngeal lumen aMen >women aBilateral - 25% aHoarseness, lateral neck mass, dyspnea, dysphagia, laryngopyocele (pain) 31

Laryngocele: Types aInternal: laryngocele confined to the intrinsic larynx aExternal: dilated sac projects upward and laterally aCombined 32

Laryngocele: Etiology aAcquired: increased intralaryngeal pressure (glassblowers, musicians, weight lifters) aCongenital aSCC in 15% of cases 33

Laryngocele

aSmooth -surfaced, sac-like structure usually filled 34with air

Laryngocele aRespiratory epitheliallined (ciliated, columnar) cyst with a fibrous wall aSquamous metaplasia aOncocytic metaplasia

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Laryngocele: Differential Diagnosis aBranchial cleft cyst aOncocytic papillary cystadenoma aLaryngeal cysts

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Contact Ulcers of the Larynx (Pyogenic Granuloma of the Larynx) aBenign, tumor-like condition, occurring most commonly along the posterior aspect of one or both vocal cords aMen>Women, usually adults aHoarseness, dysphagia, sore throat, dysphonia, difficulty breathing, choking, pain aEtiology: vocal abuse, acid regurgitation, postintubation trauma 37

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

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

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

a Ulcerated lesion with associated fibrinoid necrosis, granulation tissue, acute and chronic inflammation 39

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

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aGiant cells, vascular proliferation, and spindle cells

Contact Ulcers of the Larynx: Differential Diagnosis

aInfectious diseases aSCC aSpindle cell carcinoma aVascular neoplasms: lobular capillary hemangioma, angiosarcoma, Kaposi’s sarcoma 41

Laryngeal Amyloidosis aExtracellular accumulation of fibrillar proteins aSystemic or localized aPrimary or secondary aMen > women, in the 5th and 6th decades aPolypoid mass (glottis and supraglottis) or diffuse mucosal swelling (subglottis) aHoarseness 42

Laryngeal Amyloidosis a Extracellular, eosinophilic, amorphous material deposited randomly throughout submucosa; depositions around or within the walls a Disappearance of the seromucous glands, a Mixed chronic inflammatory infiltrate 43

Laryngeal Amyloidosis

aCongo red: apple-green birefringence under 44 polarized light

Subglottic Stenosis aCongenital or acquired aRare; acquired > congenital aProgressive respiratory difficulty, stridor, dyspnea, air hunger, hoarseness, abnormal cry, aphonia, dysphagia aEtiology: trauma, neoplasms, infectious or autoimmune diseases, idiopathic 45

Subglottic Stenosis aNarrowing of the endolaryngeal diameter with mucosal or submucosal mass or bulging aHistologic picture depends on the cause aIdiopathic stenosis: submucosal fibrous proliferation with associated non-specific chronic inflammation aDifferential diagnosis: infectious diseases, Wegener’s granulomatosis, collagen vascular diseases, neoplasms 46

Idiopathic Subglottic Stenosis

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Terminology of Epithelial Changes aLeukoplakia: white lesion on a mucosal membrane (clinical) aErythroplakia: red lesion on a mucosal membrane (clinical) aHyperplasia: thickening of epithelial surface as a result of an absolute increase in the number of cells. aPseudoepitheliomatous hyperplasia: exuberant reactive or reparative overgrowth of squamous epithelium with no cytologic evidence of 48malignancy.

Terminology of Epithelial Changes aKeratosis: presence of keratin on an epithelial surface aParakeratosis: presence of nuclei in the keratin layer aDyskeratosis: abnormal keratinization of epithelial cells aUlceration: erosion or loss of surface epithelium aMetaplasia: change from one histologic tissue type to another 49

Terminology of Epithelial Changes a Koilocytosis: cytoplasmic vacuolization suggestive of viral (HPV) effect a Dysplasia or atypia: abnormal maturation and cellular aberrations a Carcinoma in situ: full thickness epithelial dysplastic change with an intact basement membrane. a Superficially (microscopically) invasive SCC: SCC in which there is violation of the basement membrane with invasion into the underlying stroma. 50

Hyperplastic Epithelial Changes aReactive or reparative benign process, reflecting the epithelial response to a stimulus or an injury aMen > women aOccurs anywhere, but mainly along the true vocal cords aHoarseness aEtiology: smoking, ETOH, voice abuse, chronic inflammation 51

Hyperplastic Epithelial Changes aFlat, papillary, or verrucoid lesion with a white (leukoplakic) or red (erythroplakic) appearance aSmall or diffuse aThickening of epithelial surface as a result of an absolute increase in the number of cells aPresence of superficial keratin layer (keratosis) or nuclei in the superficial keratin layer (parakeratosis) 52

Hyperplastic Epithelial Changes aPresence of keratohyaline granules in the granulosa cell layer aPresence of koilocytosis aPresence of cytologic atypia aPresence of dyskeratosis aDifferential diagnosis: contact ulcer, verruca vulgaris, verrucous carcinoma, well-differentiated ”conventional” SCC 53

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 aMen > women aOccurs anywhere, but mainly along the anterior portion of the true vocal cords, 25% bilateral aHoarseness aEtiology: smoking, ETOH, chronic inflammation, voice abuse, Vit A deficiency, environmental exposure 57

Dysplastic Epithelial Changes aLocalized, circumscribed flat or papillary area with white, red or gray appearance aCytologic alterations: hyperchromasia, increase of nuclear/cytoplasmic ratio, mitoses, crowding of cells with loss of cellular polarity aBegins in basal or parabasal areas 58

Dysplastic Epithelial Changes: Grading aMild: lower 1/3 of the thickness of epithelium aModerate: lower 2/3 of the thickness of epithelium aSevere: from 2/3 to almost complete thickness

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Dysplastic Epithelial Changes aNormal maturation of the superficial layers of the epithelium aIntact basement membrane aMay be associated with keratosis or dyskeratosis, or other hyperplastic changes aFull-thickness dysplasia (carcinoma in situ) is not a prerequisite prior to the development of an invasive CA aDifferential diagnosis: reactive epithelial changes, infectious disease, SCC 60

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 aBenign, exophytic neoplastic growth composed of branching fronds of squamous epithelium with fibrovascular cores aThe most common benign laryngeal neoplasm aNo sex predilection aChanges in phonation, dyspnea, cough, dysphagia, stridor aHPV types 6 and 11 65

Laryngeal Papilloma aJuvenile type: multiple lesions with extensive growth and rapid recurrence, may remit spontaneously or persist into old age aAdult type: more often single, recurs less often, less likely to spread 66

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

a Papillary fronds of multilayered benign squamous epithelium containing fibrovascular cores 68a Little or no keratin production

Laryngeal Papilloma aAbsence of stromal invasion aCertain degree of cellular atypia aKoilocytic changes

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Laryngeal Granular Cell Tumor aMen > women aHoarseness aAlong the posterior aspect of true vocal cord ( but also in supraglotic and infraglotic areas)

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Granular Cell Tumor

aSolitary, polypoid, sessile, papillary, or cystic lesion, measuring up to 3.0 cm in diameter 71

Granular Cell Tumor a Poorly circumscribed subepithelial lesion with syncytial, trabecular, or nested growth pattern a Round to polygonal cells with round to vesicular nuclei and coarsely granular cytoplasm. Poorly defined cell borders. a Variable degree of cellular pleomorphism a Absence 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 a Cytoplasmic granules: PAS/d +, Alcian blue pH 2.5 +, trichrome + (red) a Angulate bodies: needle shaped, PAS + bodies in the interstitial cells a Tumor cells: S-100+, NSE + a Interstitial cells with angulate bodies: S-100 - and myelin protein + a EM: membrane bound autophagic vacuoles containing mitochondria, RER, myelin, axon-like structures 75

Malignant Granular Cell Tumor

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aRare ( 1% of all GCT) aDo not occur in newborns aSize > 4 cm aIncreased cellularity, pleomorphism, necrosis, prominent nucleoli, spindle shaped cells and > 2 mitoses/10 HPF aMetastasize via lymphatics and blood vessels

Chordoma

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aUncommon aMales > females aDyspnea, strydor, and hoarseness aMay originates from epiglottis, cricoid, arytenoid, or thyroid cartilages aMay arise in Reinke’s space aLobulated, firm to hard, blue-gray, submucosal mass, usually < 1 cm

Chordoma aLobulated, normally looking chondrocytes aAbsence of pleomorphism, binucleated chondrocytes, or mitotic activity 78

Rhabdomyoma aBenign tumor of striated muscle aAdult type: aless common aMales > females; > 40 y/o aHoarseness, dyspnea aWell-defined, lobulated, red-brown mass, up to 5 cm in diameter 79

Rhabdomyoma: Adult Type a Large polygonal to round cells with abundant deeply eosinophylic cyroplasm and one or two periphery placed vesicular nuclei a Nucleoli, cytoplasmic vacuolization a Cross-striation a Absent mitoses a Abundant cytoplasmic glycogen (diastase sensitive PAS positive) a Desmin +, Myoglobin +

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Rhabdomyoma: Fetal Type aVery rare aMale children < 3 y/o aPosterior auricular subcutaneous tissue > nasopharynx, parotis, neck aSolitary, well to moderately circumscribed nodule, 1-8 cm in size, gray to pink mucoid appearance 81

Rhabdomyoma: Fetal Type a Spindle cells and immature muscle fibers with in a myxoid stroma a Cross-striation rarely discernible. Mature muscle fibers can be seen in the periphery a Absence of mitoses, necrosis, and significant pleomorphism 82

Malignant Laryngeal Neoplasms

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In Situ Squamous Cell Carcinoma

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a Males > females a 6th – 7th decades a Most often involves anterior portion of true vocal cord a Hoarseness a May coexist with invasive SCC a May be isolated or multifocal a Circumscribed or diffuse lesion with a white, red, or gray color and smooth or granular appearance

In Situ Squamous Cell Carcinoma a Dysplastic process involves the entire thickness of the epithelium a Loss of cellular maturation and polarity a Increase of nuclear/cytoplaslic ratio a Normal and abnormal mitoses a Keratosis and dyskeratosis a Extension into adjacent seromucinous glands 85

Microinvasive or Superficially Invasive Squamous Cell Carcinoma

a Nests of malignant cells that have penetrated the basement membrane and invaded superficially into the submucosa a Capable of metastasizing a Development from carcinoma in situ or from epithelium with no evidence of CIS

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Invasive Squamous Cell Carcinoma a2.5% of all cancers in men a0.5% of all cancers in women a95% of all laryngeal carcinomas aEtiology: ETOH (supraglottic), tobacco (glottic), asbestos, nickel, wood, isopropyl alcohol, radiation aDD: reactive epithelial changes, pseudoepitheliomatous hyperplasia 87

Invasive Squamous Cell Carcinoma

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Supraglottic Squamous Cell Carcinoma a25–40% of laryngeal SCC aEpiglottis (base), false vocal cords aChanges in the quality of voice, dysphagia, odonophagia, hoarseness, hemoptisis, dyspnea aMarginal carcinomas (suprahyoid epiglottis, aryepiglottic folds); remain quiescent for longer period and present at more advanced stage 89

Supraglottic Squamous Cell Carcinoma aUlcerated, flat, exophytic, or papillary aTend to be nonkeratinizing aIn situ component aMitoses and necrosis

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Supraglottic Squamous Cell Carcinoma aLarge, tan-white neoplasm in the right supraglottis, extending upward toward epiglottis

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Supraglottic Squamous Cell Carcinoma

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Glottic SCC aEarly: irregular area of mucosal thickening aAdvanced: exophytic, fungatic, endophytic, ulcerated mass aMore commonly keratinizing, well to moderately differentiated aIn situ component aInvasive component predominantly infiltrative 93

Glottic SCC

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Glottic SCC

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Glottic SCC

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Subglottic Squamous Cell Carcinoma a 5% of all laryngeal tumors a Tend to remain clinically quiescent, presenting with advanced stage a Airway obstruction (dyspnea, stridor) and vocal cord fixation (voice changes) a Large exophytic, fungating, ulcerating, or endophytic a Tend to be keratinizing moderately to poorly differentiated a In situ component is less common a Invasive pattern is predominantly infiltrative 97

Subglottic SCC

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Subglottic Squamous Cell Carcinoma aOverall 5-year survival rate < 40% aSpread:

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 esophagus

Lymphatic drainage: upper and lower jugular chains, perlaryngeal and paratracheal nodes

Stomal recurrent tumor 99

Transglottic SCC aInvolves both glottic and supraglottic structures aRepresents advanced tumor aNodal metastases and extranodal spread aOverall 5-year survival rate < 40% 100

Transglottic SCC

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Spindle Cell (Squamous) Carcinoma (SCSC) a Foci of conventional SCC associated with malignant spindle cell stromal component a Synonyms: carcinosarcoma, pleomorphic carcinoma, metaplastic carcinoma, collision tumor, pseudosarcoma, Lane tumor a Men (85%), 6th –8th decades a True vocal cords > false vocal cords and supraglottis > oral cavity > skin > tonsil and pharynx a Symptoms vary according to site a No specific etiology 102

Spindle Cell (Squamous) Carcinoma (SCSC)

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Spindle Cell (Squamous) Carcinoma (SCSC) aSpindle cell component with variable degree of pleomorphism, mitoses aFascicular, storiform, or palisading patterns; may be associated with myxomatous stroma 104

Spindle Cell (Squamous) Carcinoma (SCSC)

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

Heterologous Elements

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Spindle Cell (Squamous) Carcinoma (SCSC) aDifferential diagnosis: aReactive (fibroblastic) proliferation aMalignant fibrous histiocytoma aFibrosarcoma aMalignant melanoma 107

Spindle Cell (Squamous) Carcinoma (SCSC) aControversial histogenesis. Epithelial derivation is support by: 9 Association with conventional SCC 9 ICH: cytokeratin + 9 Cartilage or bone component have not been reported in metastases aMetastases may include conventional or/and spindle cell component aPoor prognosis (metastases in lymph nodes and lungs) 108

Verrucous Carcinoma aHighly differentiated variant of SCC with focally destructive, but not metastatic capabilities a1-3% of all laryngeal carcinomas aMen > women, 6th – 7th decades aOral cavity > nasal fossa > sinonasal tract, nasopharynx aLarynx: hoarseness aIn the larynx most common in the glottic area aPotential etiologic factors: tobacco, viruses 109

Verrucous Carcinoma a Tan or white, warty, fungating, or exophytic, firm to hard mass, attached by a broad base a Squamous cell proliferation: 9 uniform cells without dysplastic features and mitoses 9 marked surface keratinization 9 broad or bulbous rete pegs with pushing, NOT infiltrative margin 9 Dysplastic features limited and confined to basal sone a Mixed chronic immflammarory cell infiltrate 110

Verrucous Carcinoma

a 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 a Squamous cell proliferation: 9 uniform cells without dysplastic features and mitoses 9 marked surface keratinization 9 broad or bulbous rete pegs with pushing, NOT infiltrative margin 9 Dysplastic features limited and confined to basal zone a Mixed chronic inflammatory cell infiltrate

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Verrucous Carcinoma aDifferential diagnosis: 9 Keratotic squamous papilloma 9 Reactive keratosis and epithelial hyperplasia 9 Pseudoepitheliomatous hyperplasia 9 Verruca vulgaris 9 Keratoacantoma 9 “Conventional” SCC 114

Verrucous Carcinoma aMetastasis in regional lymph nodes are rare, and distant metastases do not occur aExcellent prognosis after complete surgical removal aAnaplastic transformation may result in distant metastases aAdequate biopsy material with a good epithelialstromal interface is critical for the interpretation aCervical adenopathy- reactive changes 115

Basaloid Squamous Cell Carcinoma aAn invasive neoplasm, composed of basaloid cells aUncommon aMen > women, 6th – 7th decades aHypopharynx (pyriform sinus), larynx (supraglottis), and tongue aHoarseness, dysphagia, pain, neck mass aEtiology: ETOH, tabacco aCell of origin: unclear 116

Basaloid Squamous Cell Carcinoma a Firm to hard, tan-white mass, often with associated central necrosis a Patterns: solid, lobular, cell nests, cribriform, cords, trabeculae, gland-like, or cystic a Comedonecrosis a Intercellular deposition of a hyaline or mucohyalin material a Focal squamous differentiation or association with SCC, SCCIS, squamous dysplasia, or spindle cell component

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Basaloid Squamous Cell Carcinoma

a Infiltrating tumor originating from the surface epithelium 118with solid growth pattern and comedonecrosis

Basaloid Squamous Cell Carcinoma a Small, closely apposed cells with hyperchromatic nuclei, scanty cytoplasm, marked mitotic activity, large cells or pleomorphism can be seen 119

Basaloid SCC with Focal Keratinization

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Basaloid Squamous Cell Carcinoma

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a Histochemistry: PAS+ and Alcian blue + material in the cystic spaces a IHC: cytokeratin (+), EMA (+), CEA (+), S-100 (+); chromogranin (-), synaptophysin (-), muscle-specific actin (-) a EM: basaloid component: desmosomes, rare tonofilaments cystic spaces: stellate granules or replicated basal lamina

Basaloid SCC: Differential Diagnosis aAdenoid cystic carcinoma aNeuroendocrine carcinoma aAdenosquamous carcinoma aSpindle cell carcinoma

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Basaloid Squamous Cell Carcinoma aMultifocal, deeply invasive, metastatic aMetastases: lymph nodes, lung, bone, skin, brain aMetastases include both basaloid and squamous components aRapidly fatal 123

Adenosquamous Carcinoma a Malignant high grade epithelial neoplasm with histologic features of adenocarcinoma and SCC a Uncommon a Men > women, 6th – 7th decades a Larynx, hypopharynx, oral cavity, sinonasal cavity a Hoarseness, dysphagia, pain, neck mass, nasal obstruction a Etiology: not clear (ETOH, tobacco) a Cell of origin: unclear; possible a single totipotential cell from surface epithelium or seromucous glands 124

Adenosquamous Carcinoma a Exophytic or submucosal, friable, edematous or granular mass with or without surface ulcerations a SCC component: 9 Well to poorly differentiated, associated in situ carcinoma or invasive SCC 9 Individual cell keratinization, intercellular bridges, keratin pearl formation, dyskeratosis a Adenocarcinoma component: 9 In the submucosa, glandular differentiation, a Both components can be admixed a Cellular pleomorphism, mitoses, necrosis, perineural 125 invasion

Adenosquamous Carcinoma

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Adenosquamous Carcinoma aHistochemistry: PAS/d (+) and mucicarnine (+) intraluminal material aIHC: cytokeratin (+) aBehaves very aggressively, irrespective of the size of neoplasm aEarly lymph node metastases, lung, liver aPoor prognosis: 5-year survival rate of 127

Neuroendocrine Carcinoma: Classification aCarcinoid (well differentiated) aAtypical carcinoid (moderately differentiated) aSmall (“oat”) cell carcinoma (poorly differentiated) 128

Neuroendocrine Carcinoma aSubmucosal nodular or polypoid mass with tan-white appearance and up to 4 cm in diameter aSurface ulceration may present in moderately or well-differentiated neuroendocrine carcinoma 129

Carcinoid

a Organoid or trabecular growth pattern with fibtovascular stroma a Glands or squamous differentiation can be seen a Absence of surface ulceration 130

Carcinoid a Uniform cells with centrally located round nuclei, vesicular chromatin, and eosinophilic cytoplasm a Absence of pleomorphism, mitoses, necroses a Low nuclear:cytoplasmic 131ratio

Carcinoid a Histochemistry: PAS/d + mucin, argyrophilia a IHC: Cytokeratin +, Chromogranin +, NSE +, synaptophysin + a EM: neurosecretory granules, cellular junctional complexes 132

Atypical Carcinoid a Organoid, trabecular, cribriform, or solid gowth pattern a Mild to marked cellular pleomorphism a Nucleoli may be prominent a Mitoses and focal necrosis a Variable nuclear:cytoplasmic ratio a Surface ulceration and lymphovascular and perineural invasion

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Small Cell Carcinoma a Solid nests, sheets, or ribbons, with absence of fibrovascular stroma a Surface ulceration a Lymphovascular and perineural invasion a Glandular or squamous differentiation is rarely seen 134

Small Cell Carcinoma a Marked cellular pleomorphism, ‘crush’ artifacts, necrosis, hyperchromatic oval to spindle nuclei, abundant mitoses a High nuclear:cytoplasmic ratio a IHC: cytokeratin, chromogranin, synaptophysin, NSE positive a EM: rare neurosecretory 135granules

Chondrosarcoma aRare aMales >Females, 4th - 7th decades aCricoid > thyroid cartilage > arytenoid aSmooth, lobulated, hard submucosal mass larger than 2 cm 136

Chondrosarcoma (high grade) a Lobulated hypercellular tumor with hyperchromatic, pleomorphic nuclei and prominent nucleoli a Binucleate or multinucleated cells a Mitoses: usually uncommon

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Synovial Sarcoma

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Synovial Sarcoma

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Synovial Sarcoma

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