Last revised 18 January 2012
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Table of contents
Primary references, normal anatomy, normal histology
Inflammatory/infectious lesions: acute laryngoepiglottitis, amyloidosis, chronic laryngitis, contact ulcer, Crohn’s disease, eosinophilic angiocentric fibrosis, fungi, histoplasmosis, nonspecific granulomas, rhinosclerosis, tuberculosis
Benign tumors: aneurysmal bone cyst, chondroma, chondrometaplasia, cysts, giant cell tumor, granular cell tumor, hemangioma, mucinosis, mucous membrane plasmacytosis, papilloma, plasmacytoma, pleomorphic adenoma, rhabdomyoma, teflonoma, verruca vulgaris, verruciform xanthoma, vocal cord polyp
Premalignant lesions: hyperplasia, verrucous hyperplasia, dysplasia
Squamous cell carcinoma: general, basaloid, glottic, hypopharynx, papillary, pyriform sinus, spindle cell, subglottic, supraglottic, transglottic, verrucous
Other carcinoma: adenoid cystic, adenocarcinoma, lymphoepithelioma-like, metastases, mucoepidermoid, neuroendocrine, small cell
Other malignancies: angiosarcoma, chondrosarcoma, liposarcoma, lymphoma, melanoma, paraganglioma, rhabdomyosarcoma
Miscellaneous: staging-larynx, staging-hypopharynx, grossing, features to report
AJCC Cancer Staging Manual (7th ed)
American Journal of Surgical Pathology (AJSP), March 1977 to Oct 2004
Archives of Pathology and Laboratory Medicine (Archives), Jan 1976 to Oct 2004
Human Pathology (Hum Path), Mar 1970 to Sept 2004
Modern Pathology (Mod Path), Jan 1988 to Oct 2004
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby-Year Book, Inc., 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Journal search terms: larynx, vocal cord, glottic, hypopharynx, epiglottis
Please refer to these primary references for more detailed discussions and photographs
Tubular structure between pharynx/root of tongue and trachea at level of cervical vertebrae C4-C6 in males, somewhat higher in females and during childhood
Composed of cartilaginous tissue that undergoes ossification and may completely replace cartilage by age 20
At puberty, increases in size in males due to enlargement of cartilages
Cartilages are connected by ligaments and moved by numerous muscles
Staging anatomy:
Anterior limit is anterior or lingual surface of suprahyoid epiglottis, thyrohyoid membrane, anterior commissure and anterior wall of subglottic region (composed of thyroid cartilage, cricothyroid membrane and anterior arch of cricoid cartilage)
Posterior and lateral limits include laryngeal aspect of aryepiglottic folds, arytenoids region, interarytenoid space and posterior surface of subglottic space (mucous membrane covering surface of cricoid cartilage)
Superolateral limits are tip and lateral borders of epiglottis
Inferior limit is plane passing through inferior edge of cricoid cartilage
Supraglottic portion: epiglottis (lingual and laryngeal aspects), false vocal cords (ventricular bands), aryepiglottic folds (laryngeal aspect), arytenoid cartilages, ventricles; derived from third and fourth branchial pouches; inferior boundary is horizontal plane passing through lateral margin of ventricle at its junction with superior surface of vocal cord
Glottic portion: true vocal cords (superior and inferior surfaces) and anterior and posterior commissures; derived from sixth branchial pouch
Subglottic portion: between lower border of true vocal cords and first tracheal cartilage (or lower margin of cricoid cartilage); derived from sixth branchial pouch
Anterior commissure: convergence of thyroepiglottic, vestibular and vocal ligaments and conus elasticus; tendon provides anterior attachment for true vocal cords; tendon also separates glottic and supraglottic parts of larynx
Arytenoid cartilage: two hyaline cartilages at upper border of cricoid cartilage at back of larynx that support the vocal cords; each is pyramidal; apex is surmounted by small, conical, corniculate cartilage
Conus elasticus: extends from superior border of cricoid cartilage to free edge of vocal cord, then thickens to form vocal ligament, which runs length of true vocal cord close to mucosal surface, then continues along floor of ventricle as thyroglottic ligament
Cricoid cartilage: hyaline cartilage that is smaller but thicker and stronger than thyroid cartilage; upper edge is 1 cm below true vocal cords at mid larynx; forms the only complete trachiobronchial ring with posterior quadrate lamina (deep and broad, 2-3 cm high) and anterior arch that is narrow and convex; articulates with inferior horns of thyroid cartilage
Cuneiform cartilages: two small, elongated pieces of cartilage on either side of aryepiglottic fold
Epiglottis: thin, bicycle saddle-like, elastic fibrocartilage
Apex is attached to inner thyroid cartilage just above anterior commissure by thyroepiglottic ligament
Projects up behind tongue and body of hyoid bone, partly covers laryngeal entrance
Sides are attached to arytenoid cartilages by aryepiglottic folds
Upper and anterior surface is free, covered by mucous membrane reflected onto pharyngeal tongue and lateral wall of pharynx to form median and lateral glossoepiglottic folds
Median glossoepiglottic fold divides area between base of tongue and epiglottis into two valleculae
Not essential for respiration, phonation or deglutition
Hyoid bone: supports thyrohyoid and hyoepiglottic ligaments; not strictly part of larynx
Hypopharynx: comprises posterolateral pharyngeal wall (from level of floor of valleculae to level of inferior border of cricoid cartilage), postcricoid esophagus (has anterior wall and extends from level of arytenoids cartilages superiorly to inferior border of cricoid cartilage) and pyriform sinuses (lie lateral to and below opening of larynx, each bounded laterally by medial aspect of thyroid lamina and medially by aryepiglottic fold)
Pre-epiglottic space: bounded posteriorly by epiglottic cartilage and thyroepiglottic ligament, anteriorly by thyroid cartilage and thyrohyoid membrane, superiorly by hypoepiglottic ligament; space communicates laterally with paraglottic space above ventricle
Pyriform sinus: not strictly part of larynx; inverted 3 sided pyramid with apex inferiorly at level of cricopharyngeus muscle, bounded superiorly by glossoepiglottic folds, medially by aryepiglottic folds, laterally by pharyngeal wall
Thyroid cartilage: largest cartilage of larynx; shield shaped forming anterior surface of larynx and acute angle in midline of neck (laryngeal prominence, Adam’s apple); originally only hyaline cartilage, but ossifies at age 25 at sites of muscle origin or insertion; lower edge is 1 cm below anterior commissure
Lymphatics: separate systems exist above and below ventricle; are also subdivided as superficial (mucosal) and deep; few lymphatics are present in true vocal cord
Pyriform sinus drains laterally into deep cervical nodes, occasionally to paratracheal nodes
Supraglottic lymphatics drain through thyrohyoid membrane into upper cervical and anterosuperior nodes
Subglottic lymphatics drain into prelaryngeal (Delphian) node on cricothyroid membrane, then into pretracheal, paratracheal and supraclavicular nodes
Diagrams: sagittal section, coronal section #1, #2, entrance viewed from above, laryngoscopic view, laryngeal cartilages, vocal cords and muscles, muscles, ligaments #1, #2
Gross images: true and false vocal cords
Endoscopic images: (1) larynx, (2) larynx-labeled
Junction between epithelial types may be abrupt or separated by transitional area; patches of squamous epithelium in respiratory epithelium are common, particularly in smokers
Dendritic melanocytes may be present in basal layer, particularly in blacks
Epiglottis: stratified squamous epithelium similar to oral cavity, with modified salivary glands that secrete thick mucous; laryngeal surface also has pits containing mucous glands
Cartilage has full thickness fenestrae that communicate with preepiglottic “space”, which contains fat and areolar tissue
Micro images: epiglottis #1, #2, #3
False vocal cords and other supraglottic larynx: ciliated, columnar epithelium extending into ventricle of Morgagni, with submucosal modified salivary gland epithelium
Micro images: false vocal cord
Glottis: space between two vocal cords
Hypopharynx: covered by non-keratinizing stratified squamous epithelium; contains mucosal glands, scattered lymphoid aggregates, rich lymphatic plexus
Reinke’s space: lamina propria of true vocal cord, between base of squamous epithelium and vocal ligament
True vocal cords: stratified squamous epithelium with no/rare submucosal glands
Gross images: normal vocal cords
Micro images: true vocal cord, true and false vocal cords
Virtual slides: normal vocal cords
Subglottic larynx: epithelium resembles trachea/major bronchi – ciliated columnar epithelium with submucosal glands
Inflammatory/infectious lesions
Also called acute supraglottitis
Rare; due to Haemophilus influenza type B or Streptococcus pyogenes; reduced incidence due to childhood vaccine for H. influenza
May produce sudden lethal swelling of epiglottis and vocal cords
Gross: red and edematous epiglottis
Micro: acute inflammatory infiltrate with edema, extending to adjacent soft tissues
Micro images: H. influenza (gram stain)
Virtual slides: H. influenza laryngitis
Croup: laryngotracheobronchitis in children; inflammatory narrowing produces inspiratory stridor
1% of laryngeal tumors; usually asymptomatic
Mean age 38 years, more common in men
Usually localized but may be associated with multifocal disease
Does not develop into myeloma but may recur locally and occasionally cause death after a prolonged period
May be due to immunocyte dyscrasias or MALT tumor (since lymphocytes are monoclonal)
Laboratory: usually negative for monoclonal proteins by serum or urine electrophoresis
Treatment: surgical excision
Gross: polypoid or granular lesions, mean 1.6 cm
Micro: acellular amorphous eosinophilic infiltrate in stroma, often accentuated around vessels and seromucous glands; sparse lymphoplasmacytic infiltrate
Micro images: apolipoprotein AI and transthyretin amyloidosis of larynx
Additional images: (1) amyloid deposition in lamina propria; (2) perivascular (A) and periglandular (B) amyloid deposition; (3) lymphoplasmacytic infiltrates near amyloid deposition; (4) apple-green birefringence with Congo red stain and polarized light; (5) kappa light chain restriction (left-kappa, right-lambda)
Positive stains: Congo red; light chain restriction
References: Mod Path 2000;13:528, Am J Path 2000;156:1911 (apolipoprotein AI amyloidosis)
Chronic (nonspecific) laryngitis
Commonly due to upper respiratory tract infection, overuse of voice, heavy exposure to tobacco smoke or alcohol
Case reports: CMV laryngitis and probable lymphoma in AIDS patient (Archives 1992;116:539)
Micro: lymphocytic infiltrate with variable plasma cells and histiocytes; variable epithelial hyperplasia
Also called granulomatous ulcer, posterior commissure ulcer
At level of posterior commissure, near vocal process of arytenoid cartilage
May recur after local excision, but eventually subsides
Treatment: conservative (don’t excise), because surgical trauma may cause recurrence
Micro: ulcerated or hyperplastic epithelium (occasionally pseudoepitheliomatous hyperplasia), overlying exuberant granulation tissue
References: Archives 1990;114:825
May have ulcerative and granulomatous lesions in epiglottis or elsewhere in larynx
Eosinophilic angiocentric fibrosis
Rare upper respiratory tract inflammatory lesion
May be variant of granuloma faciale that occurs more commonly in nasal cavity
Case report with Wegener’s granulomatosis (J Clin Path 2001;54:640)
Micro images: perivascular fibrosis with obliteration of vascular lumina, adjacent eosinophils, lymphocytes and plasma cells
DD: Wegener’s granulomatosis
May need special stains to diagnose when inflammation or hyperkeratosis is also present (Archives 1986;110:141)
Local excision may be curative
See also Histoplasmosis, below
Case reports: Aspergillus infection with pseudoepitheliomatous hyperplasia, resembling carcinoma (Hum Path 1983;14:184)
Micro images: A: Candida infection with marked pseudoepitheliomatous hyperplasia; B: PAS+ fungi
Common cause of fungal laryngitis in US (also blastomycosis)
Early lesions are in vocal cords and epiglottis
Granulomatous lesion involving anterior larynx is likely to be histoplasmosis
Case reports: epiglottic mass in 78 year old retired soil science professor in nonendemic region (Archives 2004;128:574)
DD: laryngeal carcinoma (clinically)
Usually men, unilateral, symptomatic
Often at vocal process of arytenoid cartilage
50% post-traumatic, often post-intubation or after laryngeal biopsy
Foreign body granulomas may occur after injection of Teflon into paralyzed vocal cords
Micro: ulceration and highly cellular granulation tissue with granulomas
DD: sarcoidosis, tuberculosis, histoplasmosis
Rare; chronic granulomatous disease of nasal cavity (95-100%), nasopharynx (18-43%), larynx (15-40%), trachea (12%) or bronchi (2-7%) caused by Klebsiella rhinoscleromatis
Usually low socioeconomic environments of central/South America, Africa, Middle East, Philippines, India; rare in US (usually immigrants)
Most common in young adults
Slowly progressive with remission and relapse; not fatal unless it obstructs the airway
Treatment: antibiotics for months to years; possibly steroids, surgery to treat airway compromise and tissue deformity
Microbiology: MacConkey agar cultures are 50-60% sensitive; bacteria is gram negative, encapsulated, nonmotile, diplobacillus, member of Enterobacteriaceae, not normal flora, infective via drops or contamination of material that is inhaled
Case reports: supraglottic granulomas in 27 year old man from Central America (Archives 2001;125:159)
Micro: catarrhal/atrophic, granulomatous and sclerotic stages; initially squamous metaplasia and inflamed granulation tissue; later pseudoepitheliomatous squamous hyperplasia with foamy macrophages (Mikulicz cells containing bacteria), plasma cells with Russell bodies, granulomatous inflammation; late-fibrosis, lymphocytes and plasma cells but no Mikulicz cells
Positive stains: PAS, Giemsa, Steiner or Hotchkiss-McManus stains for gram negative bacteria
EM: large phagosomes containing bacilli and finely granular material (antibodies on bacterial surface and aggregates of bacterial mucopolysaccharides)
DD: Rosai-Dorfman disease, leprosy, other granulomatous processes
May simulate carcinoma clinically
Begins with edema of posterior interarytenoid space, then spreads to epiglottis, aryepiglottic fold and vocal cords
Micro: granulomas with variable caseation necrosis
Positive stains: acid-fast
Benign tumors
Rare; <10 cases reported
Comparable to bony disease
Case reports: 22 year old man with subglottic mass (Archives 2001;125:673)
Treatment: conservative surgery; don’t recur
Micro: mononuclear and multinucleated giant cells surround cavernous spaces filled with blood; also spindle cells and mature osteoid; non-atypical mitotic figures present
DD: telangiectatic osteosarcoma (clearly malignant cells in vascular background), giant cell tumor (less cystic, more nuclei in giant cells)
Present in <1% of laryngectomies
Usually arise posteriorly from cricoid cartilage and project anteriorly, causing partial obstruction; rarely present in thyroid cartilage
Children and adults, usually 2 cm or less
Highly associated with chondrosarcoma
Some advocate treatment as chondrosarcoma due to high association
Micro: resemble normal cartilage but with lobular architecture and slightly larger nuclei, only rarely multiple nuclei; no atypia, no mitotic figures, no necrosis
DD: low grade chondrosarcoma
2% of laryngeal specimens
Gross: nodules < 1 cm, usually on vocal cords; may be multifocal
Micro: elastic rich cartilage nodules, composed of small, uniform, eosinophilic chondrocytes without nuclear abnormalities; usually no lobular pattern of hyaline cartilage; margins are indistinct with peripheral zone of transition between cartilage and surrounding tissue
Ductal (75%) or saccular (24%); lined by squamous or respiratory mucosa or both
Ductal cyst: due to dilation of mucous glands; small, superficial, usually in true vocal cord or epiglottis
Laryngocele: air containing dilation of tip of ventricle that communicates with ventricle via a narrow stalk; either internal or external or both; may become infected and accumulate pus (laryngopyocele)
Micro images: three types of laryngocele
Oncocytic cyst: type of ductal cyst lined partially or completely by oncocytes; often has papillary infoldings; may recur; rarely is diffuse within the larynx
Saccular cyst: due to distention of laryngeal saccule; large, deep, often within ventricle; may cause neonatal airway obstruction; contains mucus
Tonsillar cyst: squamous lined crypt-like structure with abundant lymphoid follicles in cyst wall
Rare; < 50 cases reported
Benign but can invade into vital structures or cause airway obstruction
Usually involves thyroid cartilage in areas of enchondral ossification, with extension into adjacent structures
Case reports: 23 year old man with 4 cm mass arising in thyroid cartilage (Archives 1994;118:834)
Treatment: excision; no recurrences reported
Micro: numerous multinucleated osteoclast-like giant cells within cellular and vascular stroma containing plump, oval mononuclear cells with nuclei similar to giant cells; expansile and infiltrative growth; frequent mitotic figures; often secondary cystic degeneration, reactive bone formation; no cytologic atypia
Micro images: (1) submucosal polypoid tumor without surface involvement; (2) reactive bone formation (left) and cystic degeneration (lower right); (3) giant cells and mononuclear cells (inset: mitotic figure); (4) osteoclast-like giant cells have nuclei similar to mononuclear cells
DD: giant cell reparative granuloma (aggregated cells, often near areas of hemorrhage, no giant cells with 20+ nuclei; more fibrotic stroma), brown tumor of hyperparathyroidism, osteoblastoma (fewer giant cells, broad sheets of mineralized osteoid), aneurysmal bone cyst, nonossifying fibroma, foreign body reaction, fibrous histiocytoma
References: Mod Path 2001;14:1209
Also called myoblastoma
May occur in children
Gross: small, yellow, covered by epithelium
Micro: nests of cells with granular and eosinophilic cytoplasm, bland small round/oval nuclei; may have overlying pseudoepitheliomatous hyperplasia
Micro images: A/B: marked pseudoepitheliomatous hyperplasia simulating invasive squamous cell carcinoma; C: S100+
Positive stains: S100, PAS
DD: invasive squamous cell carcinoma
Usually cavernous with thick walled vessels
Infants: sessile, poorly circumscribed subglottic mass, often with obstructive symptoms, and with massive hemorrhage after biopsy; 50% have skin hemangiomas
Adults: much less common, usually supraglottic
Treatment: laser therapy, systemic steroids, interferon, intralesional steroid injection
Very rare in larynx
Case reports: 3 year old boy intubated at age 2 months with recurrent respiratory infections (Hum Path 1990;21:856)
For upper aerodigestive tract cases, 2/3 were men, mean age 54 years, range 40-67 years
Affects larynx, pharynx, palate, lips, mouth, tongue and trachea
Treatment: none successful although apparently a benign process
Gross: cobblestone or warty appearance of mucosa
Micro: psoriasiform epithelial hyperplasia with dyskeratosis and dense subepithelial plasmacytosis; plasma cells are mature but diffuse and expansive
Stains: polyclonal light chains
References: AJSP 1994;18:1048
Warty outgrowths of laryngeal surface epithelium
Micro: proliferative well-differentiated squamous epithelium overlying fibrovascular cores with koilocytotic change (enlarged, often multiple, wrinkled nuclei); may have mild to moderate dysplasia (increased cellularity, loss of regularity of basal layer, hyperchromatic nuclei extending from basal to intermediate layers), mitotic activity is common; tumors in respiratory mucosa have less apparent maturation
Micro images: papilloma #1,
#2,
#3,
inverted papilloma
Children
Usually multiple
Occur on true vocal cords, false cords, epiglottis, subglottic area, rarely tracheobronchial tree
Recurs commonly, possibly years after excision or destruction; recurrences often cease at puberty; recurrences may be massive and rapid, leading to airway compromise and tracheostomy or laryngectomy
Associated with HPV 6 and 11 in most cases
Rarely extends into tracheostomy stoma or laryngeal soft tissue (invasive papillomatosis), rarely develops squamous cell carcinoma after radiation therapy or spreads/progresses to lower respiratory tract as papillomas or squamous cell carcinoma
Treatment: excision, electrodesiccation, laser surgery, cryosurgery; treatment may destroy vocal cords; laryngectomy if extensive involvement
Adults
Usually men, solitary
Recurrences frequently exhibit dysplasia
DD: verrucous carcinoma
Head and neck plasmacytomas uncommon in children; in adults are associated with long survival
Case reports: 12 year old girl with plasmacytoma and localized amyloidosis of larynx (Hum Path 2001;32:132)
Case reports: 40 year old woman with tumor of false vocal cord with squamous metaplasia (Archives 1986;110:245)
Has predilection for head and neck, including larynx
Treatment: local excision; usually no recurrence
Micro: cells often have cross striations, also intracytoplasmic crystal-like particles
Subtypes include adult, fetal cellular and fetal myxoid types
Teflon used to correct unilateral laryngeal paralysis; rarely infiltrates into soft tissues of neck and larynx
Micro: foreign body granulomatous reaction with birefringent material
References: Hum Path 1990;21:617
Uncommon
Case reports: 37 year old woman with HPV 6/11 in true vocal cord lesion (Archives 1991;115:895)
Micro: superficial, keratotic vocal cord lesion; has prominent keratohyaline granular layer, parakeratosis, sharp acanthotic pegs
Positive stains: HPV
DD: verrucous carcinoma
References: AJSP 1982;6:357
Case reports: child with systemic lipid storage disorder (AJSP 1989;13:309)
Also called laryngeal nodule or singer’s nodule
Noninflammatory response to injury causing hoarseness
More common in heavy smokers or singers due to inflammation, allergic or immunologic causes, possibly secondary to hemorrhage
Almost never transforms to malignancy
Treatment: excision or vocal rest
Gross: smooth, round, 1-3 mm growths on true vocal cords, often on anterior third
Gross images: laryngeal polyp
Endoscopic images: vocal cord polyp #1, #2
Micro: (a) telangiectatic polyps with stratified squamous epithelium overlying numerous thin-walled dilated vessels and fibrinous exudates in edematous mucosa, variable chronic inflammatory infiltrate, or (b) gelatinous polyps with stratified squamous epithelium, edematous submucosa containing fibrin and proliferating fibroblasts, thin walled vessels present but less than telangiectatic subtype; vessels may resemble thrombosed varices
DD: angioma (usually supraglottic, vessel walls are thicker, doesn’t respond to vocal rest)
Premalignant lesions
Also called keratosis
Usually involves true vocal cords and interarytenoid area
Associated with smokers, singers and others who use voices excessively
Gross: white thickening of involved areas; verrucous keratosis if undulating warty configuration; pachyderma larynges if extensive keratinization
Micro: when in respiratory (ciliated columnar) epithelium (false cord, ventricle, subglottic region), initially hyperplasia of reserve cells under epithelium, then replacement of epithelium by full thickness reserve cells, then complete squamous metaplasia; may have hyperkeratotic epithelium
No nuclear abnormalities are present, but underlying submucosal glands persist
Pseudoepitheliomatous hyperplasia: exuberant reactive overgrowth of squamous epithelium without atypia; may resemble invasive squamous cell carcinoma
DD: dysplasia (nuclear atypia)
Irreversible mucosal lesion of upper aerodigestive tract that tends to progress to verrucous carcinoma or conventional squamous cell carcinoma
For columnar epithelium, resembles cervical dysplasia
Associated with HPV 16 and p53 expression
Leukoplakia: clinical term describing any white lesion on a mucous membrane; usually associated with mucosal thickening and not dysplasia
Erythroplakia: clinical term describing red lesion on a mucous membrane; usually associated with dysplasia or malignancy
In smokers, for squamous epithelium, features of nuclear pleomorphism, mitotic activity, abnormal mitotic figures and stromal inflammation are associated with progression to invasive carcinoma
Keratosis: increase in surface keratin, often with prominent granular cell layer and orthokeratin (cells without nuclei) mixed with parakeratin (flat keratotic cells with pyknotic nuclei); not related to dysplasia
Dyskeratosis: abnormal keratinization of epithelial cells
Dysplasia: spectrum of abnormal epithelial maturation and cellular atypia that may or may not precede invasive carcinoma
Carcinoma in situ: full thickness dysplasia of mucosa without violation of basement membrane; same as severe dysplasia
Overall, low risk of development of invasive squamous cell carcinoma after dysplasia; for mild dysplasia, 7% develop in situ or invasive carcinoma vs. 24% with moderate dysplasia vs 25% with severe dysplasia
High risk of progression to invasive carcinoma for severe keratinizing dysplasia vs. non-keratinizing dysplasia
Treatment: mild/moderate dysplasia may be reversible; severe dysplasia requires intervention (vocal cord stripping, surgery, radiation therapy, endoscopic laser resection), as well as surveillance of entire upper aerodigestive tract
Gross: erythema of involved areas
Mild dysplasia: normal or mildly disordered basal layer with retained maturation and stratification of upper layers; mild nuclear atypia and possibly mitotic figures in basal third of epithelium; no abnormal mitotic figures; variable keratosis and chronic inflammatory infiltrate
Moderate dysplasia: moderate nuclear atypia, usually with prominent nucleoli and mitotic figures, most pronounced in lower two thirds of epithelium; cell maturation and stratification are present in upper layer; no abnormal mitotic figures; variable keratosis
Severe/high grade: marked nuclear abnormalities and loss of maturation greater than two thirds of epithelium; large atypical nuclei, some bizarre; nuclear pleomorphism is common; may have prominent nucleoli; mitotic figures high in epithelium, often abnormal
Keratinizing dysplasia: defined as lesions in which epithelial alterations are so severe that there is a high probability of progression to invasive carcinoma; includes dyskeratotic cells and mitotic figures, with variable atypical forms above basal zone, variable surface keratinization
Carcinoma in situ: full thickness nuclear abnormalities without stromal invasion; cells are usually keratinized, but may be basal-like; often lumped together with severe dysplasia; may represent peripheral portion of invasive carcinoma
Papillary carcinoma in situ: papillary fronds with a fibrovascular core covered by squamous epithelium with marked atypia
Note: invasion may occur by dysplastic cells without full thickness epithelial involvement
Micro images: (1) nonkeratinizing dysplasia: A-mild; B-moderate; C-severe/carcinoma in situ; (2) severe dysplasia-keratinizing; (3) carcinoma in situ extending into seromucous glands
References: Mod Path 2002;15:229
Squamous cell carcinoma
9,000 new cases annually in US; 40% mortality
Represents 90% of all laryngeal cancers
96% male; usually ages 40+ (but can occur in younger patients)
Major risk factors are smoking, enhanced by heavy alcohol consumption
HPV is not an early factor, but positive in 20%, usually HPV 16
EBV a factor in 40% of hypopharyngeal carcinomas (Hum Path 1999;30:1071)
Site influences histology and clinical behavior – either glottic, supraglottic or transglottic
Spread is limited by tough membranes / ligaments
Recurrence rate of 3% per year, second primary rate is 5% per year, usually in lung
Metastases to regional lymph nodes and lungs; direct extension to thyroid gland and jugular vein
Prognostic features: TNM; also tumor grade, tumor size, mitotic count, vascular invasion, margins
5 year survival by site: glottic – I: 90%; II: 85%; III: 60%; IV: <5%; supraglottic – I: 85%; II: 75%; III: 45%; IV: <5%; transglottic: 50%; subglottic: 40%
Case reports: nodal metastasis occurring post-radiation therapy with mixture of squamous cell carcinoma and rhabdomyosarcoma (AJSP 1993;17:415)
Gross: pink to gray ulcerated mass; vocal cord lesions often keratotic
Gross images, contributed by Dr. Steven Catinchi-Jaime - malignant fibrous histiocytoma and squamous cell carcinoma arising in a vocal chord: #1; #2
Micro: invasion indicated by desmoplasia around malignant squamous cells, often with keratinization at periphery; progression of columnar epithelium areas is similar to squamous cell carcinoma of cervical or lung; progression of vocal cord tumors is similar to squamous cell carcinoma of skin or esophagus
Well, moderate or poorly differentiated, based on degree of keratinization, pearl formation, intercellular bridges, mitotic activity
Smaller tumors are usually better differentiated
Micro images: squamous cell carcinoma #1, #2, #3; microinvasive carcinoma - A: arising from carcinoma in situ; B-arising from non-dysplastic epithelium; C-invasive although no apparent violation of basement membrane; invasive carcinoma with desmoplastic response; A-nested growth pattern; B-discohesive growth; keratin granuloma associated with invasive carcinoma (B: cytokeratin stain)
Micro images, contributed by Dr. Steven Catinchi-Jaime - malignant fibrous histiocytoma and squamous cell carcinoma arising in a vocal chord: #3; #4; #5; #6; #7; #8; #9; #10; #11; alpha-1-antichymotrypsin; vimentin; CD68; cytokeratin AE1/AE3
Positive stains: AE1, AE3, p53 (50%, usually wild type)
References: Hum Path 1999;30:274 (HPV), Mod Path 2002;15:229
Basaloid squamous cell carcinoma
Highly malignant, median survival 18 months (for all sites in head and neck)
Heavy smokers or drinkers, often with advanced disease at diagnosis and other primary tumors in the area
Usually men, ages 50+ years
Usually base of tongue, hypopharynx or supraglottic larynx
Case reports: tumor with prominent spindle component (Archives 1995;119:181)
Treatment: radical surgical excision, radical neck dissection, supplemental radiochemotherapy
Gross: firm to hard, tan-white masses, may have central necrosis, up to 6 cm
Micro: typical areas of squamous cell carcinoma (invasive and in situ) with nests or cords of small crowded cells with minimal cytoplasm, hyperchromatic nuclei, comedonecrosis, prominent hyalinization and peripheral palisading, small cystic spaces and mitotic activity
Positive stains: 34betaE12 (100%), AE1-AE3, CAM5.2, EMA, CEA (53%), S100 (39%), NSE (weak, 75%), PAS and Alcian blue (material within cystic spaces)
Negative stains: synaptophysin, chromogranin, muscle specific actin, GFAP
EM: rare tonofilaments, variable desmosomes
DD: adenoid cystic carcinoma (no significant pleomorphism, no mitotic activity, no squamous differentiation), small cell carcinoma (positive neuroendocrine markers)
References: AJSP 1992;16:939, Hum Path 1998;29:609 (34betaE12), Hum Path 1986;17:1158
Glottic squamous cell carcinoma
Arises from true vocal cord, anterior and posterior commissure or vocal processes of arytenoid cartilage; 60% of all laryngeal cases
Causes hoarseness when tumor is small, leading to early detection and high cure rate
High cure rate also due to lack of lymphatics in true vocal cord; may spread to opposite cord
T1: confined to free edge of vocal cord; 90% cure rate, usually no nodal metastases
T2: extends beyond vocal cord with maintained or limited mobility of vocal cord; may spread to nearby cricoid cartilage posteriorly; 7% have ipsilateral nodal metastases
T3: vocal cord completely immobile; deep invasion of thyroarytenoid muscle is present, often subglottic extension, which may occur under an intact mucous membrane; treated with total laryngectomy; usually not necessary to sample epiglottis if not grossly involved
Treatment: radiation therapy, surgical excision (laser, endoscopic removal [cordectomy], hemilaryngectomy for T2 lesions)
Micro: invasion usually limited to tissue superficial to conus elasticus, vocal ligament and thyroglottic ligament
Hypopharynx squamous cell carcinoma
Uncommon
Poor prognosis, tends to present with advanced disease
Prognostic factors are size, local spread, nodal involvement
Gross: flat plaques with raised edges and superficial ulceration; often involves multiple sites within hypopharynx and extends into adjacent mucosal areas, but usually not into laryngeal cartilage; often involves thyroid gland
Micro: coexists with in situ carcinoma; usually typical squamous cell carcinoma, spindle cell and basaloid subtypes
References: J Clin Path 2003;56:81
Papillary squamous cell carcinoma
Uncommon; exophytic growth pattern, features of carcinoma in situ plus foci of invasion
Mean age in 60’s
Usually in larynx, oral cavity, oropharynx, hypopharynx and sinonasal tract
Associated with HPV
Relatively good prognosis; usually T2
Difficult to determine invasion in biopsy specimens, although should consider invasive if clinically appreciable exophytic mass plus marked atypia, even without definitive stromal invasion
Treatment: surgery
Gross: often solitary with exophytic or papillary growth; 2 mm to 4 cm
Micro: finger-like projections with fibrovascular cores or broad based bulbous growth with rounded projections and limited fibrovascular cores; overlying squamous epithelium is malignant; usually no/limited surface keratinization
DD: verrucous carcinoma (minimal atypia), laryngeal papillomatosis (bland epithelial proliferation with no/minimal atypia)
Pyriform sinus squamous cell carcinoma
Close to, although not part of larynx; these tumors frequent invade the supraglottic larynx under an intact mucous membrane
Usually destroys posterior edge of thyroid cartilage
Usually associated with alcoholism
2/3 die of disease or associated medical disorders
Treatment: total laryngectomy with preoperative chemotherapy or postoperative radiation therapy
Also called sarcomatoid carcinoma, carcinosarcoma
Uncommon in larynx; more common elsewhere in upper aerodigestive tract
90% male; mean age 66 years, range 35-92 years
Associated with smoking (87%), alcohol (48%), history of radiation therapy
71% are glottic; 59% are T1
May recur locally (18%) or have distant metastases (14%); 18% die of disease
Nodal metastases may have epithelial or stromal patterns or both
Prognostic factors: depth of invasion more important than differentiation of spindle component
Treatment: surgery with or without radiation; 45% recur
Gross: polypoid (99%) tumors, mean size 2 cm
Micro: squamous cell carcinoma with spindle cell component (reactive, sarcomatous or variant of squamous cell carcinoma) that is often storiform or pleomorphic, may contain foci of benign or malignant cartilage or bone; frequent mitotic activity; often squamous cell carcinoma in situ
Micro images: (1) A-differentiated squamous cell carcinoma (top) with undifferentiated spindle cell proliferation (bottom); B-malignant spindle cells (left) and epithelioid cells (right); (2) hypocellular and collagen rich tumor has nuclear pleomorphism and atypical mitotic figures
Positive stains: vimentin, 34betaE12, AE1-AE3; variable smooth muscle actin
Negative stains: CAM 5.2
DD: reactive conditions, pure sarcoma
References: AJSP 2002;26:153, Hum Path 1997;28:664
Subglottic squamous cell carcinoma
Also called infraglottic; by definition arise from region inferior to vocal cords to lower border of cricoid cartilage
Less than 5% of all cases; very rare to arise at this site; usually an extension of glottic tumor
May be defined to include glottic tumors with subglottic extension of 1 cm or more
Often spreads laterally to cricoid cartilage; often destroys interthyrocricoid membrane with invasion of prelaryngeal wall and thyroid gland
Cervical nodal metastases in 15%, paratracheal nodal metastases in 50%
Treatment: excision with radical lymph node dissection
Supraglottic squamous cell carcinoma
30% of all cases
Usually detected late; early symptom is often referred pain to ear
By definition, arise above true vocal cords from epiglottis, ventricle, angle between epiglottis and ventricle, aryepiglottic fold, arytenoid body, false vocal cord
Does not invade thyroid cartilage as long as lower edge is above ventricle and anterior commissure
Only 1% invade glottis
40% have nodal metastases, often clinically undetected
Epiglottic cancer: either above or below level of hyoid bone (hyoepiglottic ligament); if above hyoid bone, can invade base of tongue
Ventricular band/aryepiglottic fold cancer: rich lymphatic supply, often cervical node metastases
Treatment: horizontal supraglottic partial laryngectomy (to preserve the voice); radiation therapy not useful due to presence of necrosis
Transglottic squamous cell carcinoma
By definition, crosses ventricle vertically and is associated with fixed vocal cord
Less than 5% of all cases
Highest incidence of nodal metastases (52%), often clinically undetected
Surgery should include neck dissection since metastases to cervical nodes are common, particularly for tumors > 4 cm
1-4% of laryngeal cancers
Has cytologic and architectural features normally associated with a reactive process, but with ability to invade normal tissue
Locally destructive, but almost never metastasizes; associated cervical adenopathy may be reactive and not metastatic disease
Usually men in 50’s to 60’s; associated with tobacco smoking or chewing
Occurs anywhere in upper aerodigestive tract
5 year survival 78% (better after surgery than radiation therapy)
May coexist with conventional squamous cell carcinoma (if both present, must treat more aggressive component)
HPV negative
Difficult diagnosis to make, particularly from biopsies
Treatment: surgery; radiation not recommended in general since ineffective and may cause anaplastic transformation
Gross: large, white-tan exophytic tumor fixed to normal structures; up to 10 cm; attached by broad base
Micro: invasive cancer with well differentiated squamous epithelium that lacks features of squamous cell carcinoma; by definition has no dysplastic features above basal zone; uniform cells without atypia or mitotic figures; marked surface keratinization (church-spire keratosis), broad rete pegs with pushing but not an infiltrative margin; may have prominent lymphoplasmacytic and histiocytic infiltrate
DD: papilloma, well differentiated squamous cell carcinoma, verrucous keratosis (no invasion), pseudoepitheliomatous hyperplasia, verrucae vulgaris, papillomatosis
Other carcinoma
Most common laryngeal minor salivary gland neoplasm
Same histology as salivary gland tumors
Arise in supraglottic and subglottic regions (distribution of salivary glands); extensive perineurial invasion, metastasize distantly
Long clinical course, but ultimately poor survival
May be associated with squamous cell carcinoma, particularly if supraglottic and either high grade or solid variants; these cases are extremely aggressive with 40% mortality within a year
Adenocarcinoma, NOS
Non-salivary gland types are rare in larynx
Usually not in glottis
May arise from surface epithelium
Lymphoepithelioma-like carcinoma
top
Often men, mean age 64 years
Usually p53+ but EBV negative
Usually cervical nodal metastases at diagnosis; 1/3 die of disease
Often mixed with classic squamous cell carcinoma
References: Hum Path 1996;27:1172
Rare; renal cell carcinoma and melanoma are among most common; laryngeal lesion may be initial presenting lesion
Also breast and lung metastases
Thyroid carcinomas involve larynx by direct extension
Case reports: 54 year old man with supraglottic metastatic renal cell carcinoma 7 years after nephrectomy (Archives 2000;124:1833)
Micro images: 1-primary renal cell carcinoma; 2-metastatic renal cell carcinoma of larynx with intact overlying squamous mucosa
Very rare
Usually supraglottic
Difficult to distinguish paraganglioma, carcinoid and small cell carcinoma in small biopsies without stains
Neuroendocrine carcinomas are most common non-squamous carcinoma of larynx
Preferred terminology: well differentiated, moderately differentiated and poorly differentiated (small or large cell type) neuroendocrine carcinoma for carcinoid, atypical carcinoid, small cell undifferentiated and large cell undifferentiated carcinoma (Mod Path 2002;15:264)
Usually men ages 50-70 years, 2/3 are heavy smokers
Usually supraglottic
43% have lymph nodal metastases
Poor prognostic factors: cervical nodal metastases, positive margins, vascular invasion
Gross: polypoid lesions 2 mm to 4 cm, arising in submucosa
Micro: large polyhedral cells with hyperchromatic nuclei; also anaplastic cells, areas of necrosis and mitotic figures
Positive stains: usually chromogranin, keratin, CEA, calcitonin, p53 (50%)
EM: dense core neurosecretory granules
Well differentiated neuroendocrine carcinoma (carcinoid tumor)
Rare; <20 cases described
Usually supraglottic larynx, often near arytenoid or aryepiglottic fold
In one study, 1 of 13 died of disease, although may have metastases to liver, bone, lymph node and skin with prolonged survival
Micro: nests and cords of relatively uniform cells with salt and pepper chromatin; may have oncocytic cells, clear cells, spindle cells
Micro images: sharply demarcated nests of uniform cells
DD: paraganglioma, medullary carcinoma
Moderately differentiated neuroendocrine carcinoma (atypical carcinoid)
May be most common nonsquamous malignancy of larynx
Usually elderly male cigarette smokers
Clearly malignant and more aggressive than atypical carcinoids at other sites, so term “atypical carcinoid” may mislead clinicians
5 year survival 48%; 10 year survival 30%; after follow up, 43% have nodal metastases, 22% have metastases to skin or subcutaneous tissue, 44% have distant spread
Usually supraglottic, often on arytenoid cartilage
Case reports: tumors in 2 patients causing death 13 and 33 months after diagnosis (Archives 1992;116:253)
Treatment: surgical resection; not radiation sensitive
Micro: usually nests or sheets of epithelioid cells with round/oval nuclei (often with peripheral palisading), stippled chromatin, occasional nucleoli, variable hyperchromasia; more pleomorphism, mitotic figures, and infiltration than well differentiated neuroendocrine tumors; often mixed with other forms of carcinoma
Micro images: (1) irregular cell nests of moderately pleomorphic cells with mitotic figures and often small foci of necrosis; (2) moderately differentiated neuroendocrine carcinoma (a: H&E; c: TTF1 neg; E: p53+; vs. medullary carcinoma of thyroid (b: H&E; d: TTF1+; f: p53+
Positive stains: chromogranin, synaptophysin, cytokeratin, calcitonin, CEA
Negative stains: TTF1 (positive in only 13%)
References: Mod Path 2004;17:631 (TTF1)
Poorly differentiated neuroendocrine carcinoma (small cell carcinoma)
See below
Aggressive tumor with common cervical, nodal and distant metastases
Less than 0.5% of all cases
May be associated with squamous cell carcinoma
Usually age 50+, men, heavy smokers
Micro: sheets of small to medium sized cells with minimal cytoplasm, hyperchromatic nuclei with no prominent nucleoli; resembles lung tumor; may have foci of squamous or glandular differentiation
Micro images: cords of pleomorphic cells with minimal cytoplasm
Positive stains: variable neuroendocrine markers
Negative stains: CK20
DD: basaloid squamous cell carcinoma, solid variant of adenoid cystic carcinoma
Other malignancies
Angiosarcoma
Often associated with local radiation therapy
Gross: polypoid mass of epiglottis
0.5% of primary laryngeal tumors
Mean age 64 years, range 25-91 years; 80% male
69% arise in cricoid, 9% in thyroid cartilage, 14% in both
18-30% recur (more common with higher grade); death usually due to recurrence and not distant metastases
46% are grade I, 49% grade II, 5% grade III
37% have associated chondroma
Myxoid and dedifferentiated variants may have worse prognosis; surprisingly, grade may not be associated with clinical outcome
Treatment: complete excision with sparing of vocal cords
Gross: usually 3 cm or more, invasion into bone of ossified laryngeal cartilage
Micro: diagnostic fields often small; have atypical, neoplastic chondrocytes with loss of normal architecture and distribution, and invasion of bone; laryngeal cartilage usually has undergone endochondral ossification
Low grade chondrosarcoma: slight increase in cellularity, mild atypia with binucleated chondrocytes within 1 lacuna; difficult to distinguish from chondroma; can report as “cartilaginous tumor without obvious evidence of malignancy, further classification pending removal of entire lesion”
High grade chondrosarcoma: hypercellular with enlarged, binucleated and multinucleated atypical cells with increased nuclear to cytoplasmic ratio, irregular nuclear chromatin, prominent nucleoli, mitotic figures (may be atypical), variable tumor necrosis
Dedifferentiated chondrosarcoma: also called chondrosarcoma with additional malignant mesenchymal component
DD: vocal process of arytenoid cartilage (normal finding), chondroid metaplasia, chondroma
References: AJSP 2002;26:836, AJSP 1988;12:314 (dedifferentiated chondrosarcoma)
Clear cell chondrosarcoma
Very rare
Case reports: 57 year old man (AJSP 2002;26:386)
Positive stains: S100, collagen type II
Negative stains: keratin
Molecular: loss of 9p22 and 18q21
90% men, ages 37-77 years
Usually supraglottic larynx or pyriform sinus
Cases described had recurrence, usually at higher grade, but no metastases, AJSP 1990;14:134
Case reports: pedunculated mass of aryepiglottic fold that obstructed airway, with frequent local recurrence (Archives 1985;109:294),
Treatment: local excision may be curative
Gross: yellow polypoid masses, 2-6 cm
Micro: often well differentiated liposarcomas with atypical cells, scattered lipoblasts and infiltration
Usually supraglottic
Diffuse large B cell lymphoma is most common subtype
Case reports: NK/T cell lymphoma-nasal type developing in hypopharynx after renal transplant (Hum Path 2001;32:1264)
Treatment: radiation therapy
Rare; <100 cases reported
5 year survival: poor; usually death from metastatic disease in 3-4 years
Case reports: 53 year old male smoker with no primary melanocytic lesions (Archives 2001;125:271)
Treatment: excision without neck dissection; radiation therapy may be helpful for mucosal lesions
Micro: pleomorphic polygonal epithelioid cells or spindle cells; often with cytoplasmic and nuclear melanin; abnormal mitotic figures; may have in situ melanoma
Positive stains: S100, HMB45, vimentin
Negative stains: cytokeratin, iron
Malignant behavior in 3-25% (some may have actually been moderately differentiated neuroendocrine carcinomas); 15% recur locally
70% male, mean age 47 years
Commonly involves aryepiglottic fold
Micro: cell nests (Zellballen) surrounded by sustentacular cells
Positive stains: chromogranin, synaptophysin, neuron-specific enolase, GFAP and S100 (sustentacular cells)
Negative stains: keratin, calcitonin
DD: moderately differentiated neuroendocrine carcinomas (keratin+, S100-, GFAP-)
References: Hum Path 1979;10:191 (head and neck tumors), AJSP 1979;3:85
Rhabdomyosarcoma
Infants and children
Usually embryonal type, botyroid subtype
Miscellaneous
TNM staging - larynx
Excludes carcinomas of lateral or posterior pharyngeal wall, pyriform fossa, postcricoid area or base of tongue
Excludes nonepithelial tumors
Anatomical boundaries are described above under Normal Anatomy / Staging Anatomy
Larynx
Primary tumor (T) - larynx
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
Subsites (important for T categories):
Supraglottis: suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds (laryngeal aspect), arytenoids, false vocal cords
Glottis: true vocal cords, including anterior and posterior commissures
Subglottis: subglottis
Supraglottis
T1: Tumor limited to one subsite of supraglottis with normal vocal cord mobility
T2: Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g. mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx
T3: Tumor limited to larynx with vocal cord fixation, or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space or inner cortex of thyroid cartilage erosion
T4a: Moderately advanced local disease
Tumor invades thorough the thyroid cartilage or invades tissues beyond the larynx (e.g. trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus)
T4b: Very advanced local disease
Tumor invades prevertebral space, encases carotid artery or invades mediastinal structures
Glottis
T1: Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility
T1a: Tumor limited to one vocal cord
T1b: Tumor involves both vocal cords
T2: Tumor extends to supraglottis or subglottis, or with impaired vocal cord mobility
T3: Tumor limited to the larynx with vocal cord fixation or invades paraglottic space, or inner cortex of the thyroid cartilage
T4a: Moderately advanced local disease
Tumor invades thorough the outer cortex of the thyroid cartilage or invades tissues beyond the larynx (e.g. trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus)
T4b: Very advanced local disease
Tumor invades prevertebral space, encases carotid artery or invades mediastinal structures
Subglottis
T1: Tumor limited to the subglottis
T2: Tumor extends to vocal cord(s) with normal or impaired mobility
T3: Tumor limited to larynx with vocal cord fixation
T4a: Moderately advanced local disease
Tumor invades cricoid or thyroid cartilage or invades tissues beyond the larynx (e.g. trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid or esophagus)
T4b: Very advanced local disease
Tumor invades prevertebral space, encases carotid artery or invades mediastinal structures
Regional lymph nodes (N) - larynx
Level I: submental, submandibular; contains the submental and submandibular triangles bounded by the anterior and posterior bellies of the digastric muscle, and by the hyoid bone inferiorly, and the body of the mandible superiorly
Level II: upper jugular; contains the upper jugular lymph nodes and extends from the level of the skull base superiorly to the hyoid bone inferiorly
Level III: mid-jugular; contains the middle jugular lymph nodes from the hyoid bone superiorly to the level of the lower border of the cricoid cartilage inferiorly
Level IV: lower jugular; contains the lower jugular lymph nodes from the level of the cricoid cartilage superiorly to the clavicle inferiorly
Level V: posterior triangle; contains the lymph nodes in the posterior triangle bounded by the anterior border of the trapezius muscle posteriorly, the posterior border of the sternocleidomastoid muscle anteriorly, and the clavicle inferiorly; for description purposes, Level V may be further subdivided into upper, middle and lower levels corresponding to the superior and inferior planes that define Levels II, III and IV
Level VI: prelaryngeal, pretracheal, paratracheal; contains the lymph nodes of the anterior central compartment from the hyoid bone superiorly to the suprasternal notch inferiorly; on each side, the lateral boundary is formed by the medial border of the carotid sheath
Level VII: upper mediastinal; contains the lymph nodes inferior to the suprasternal notch in the superior mediastinum
Diagrams: levels
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3: Metastasis in a lymph node more than 6 cm in greatest dimension
Notes:
Metastases at level VII are considered regional lymph node metastases
True vocal cords are nearly devoid of lymphatics, so nodal metastases are rare; supraglottis has rich and bilaterally interconnected lymphatic network
Midline nodes are considered ipsilateral nodes
Distant metastasis (M) - larynx
M0: No distant metastasis
M1: Distant metastasis
Stage grouping - larynx
0 : Tis N0 M0
I : T1 N0 M0
II : T2 N0 M0
III : T3 N0 M0 or T1-T3 N1 M0
IVA : T4a N0-N1 M0 or T1-T4a N2 M0
IVB : Any T N3 M0 or T4b any N M0
IVC : Any T any N M1
Primary tumor (T) – hypopharynx
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor limited to one subsite of hypopharynx or 2 cm or less in greatest dimension
T2: Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest dimension without fixation of hemilarynx
T3: Tumor more than 4 cm in greatest dimension or with fixation of hemilarynx or extension to esophagus
T4a: Moderately advanced local disease – tumor invades thyroid / cricoid cartilage, hyoid bone, thyroid gland or central compartment soft tissue (prelarynageal strap muscles and subcutaneous fat)
T4b: Very advanced local disease - tumor invades prevertebral fascia, encases carotid artery or involves mediastinal structures
Notes: hypopharynx subsites are pyriform sinuses (left and right), lateral and posterior hypopharyngeal walls and postcricoid region
Regional lymph nodes (N) –hypopharynx
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3: Metastasis in a lymph node more than 6 cm in greatest dimension
Notes
● Mediastinal lymph nodes are considered distant metastases
● Midline nodes are considered ipsilateral
● Metastases at level VII are considered regional lymph node metastases
● A designation of U or L may be used to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)
● Selective neck dissection ordinarily includes 6+ lymph nodes; radical / modified radical neck dissection ordinarily includes 10+ lymph nodes
● Survival is significantly worse when metastases involve lymph nodes beyond the first echelon of lymphatic drainage, particularly lymph nodes in levels IV and V; thus, the region of nodal involvement should also be reported
Level I: submental, submandibular; contains the submental and submandibular triangles bounded by the anterior and posterior bellies of the digastric muscle, and by the hyoid bone inferiorly, and the body of the mandible superiorly
Level II: upper jugular; contains the upper jugular lymph nodes and extends from the level of the skull base superiorly to the hyoid bone inferiorly
Level III: mid-jugular; contains the middle jugular lymph nodes from the hyoid bone superiorly to the level of the lower border of the cricoid cartilage inferiorly
Level IV: lower jugular; contains the lower jugular lymph nodes from the level of the cricoid cartilage superiorly to the clavicle inferiorly
Level V: posterior triangle; contains the lymph nodes in the posterior triangle bounded by the anterior border of the trapezius muscle posteriorly, the posterior border of the sternocleidomastoid muscle anteriorly, and the clavicle inferiorly; for description purposes, Level V may be further subdivided into upper, middle and lower levels corresponding to the superior and inferior planes that define Levels II, III and IV
Level VI: prelaryngeal, pretracheal, paratracheal; contains the lymph nodes of the anterior central compartment from the hyoid bone superiorly to the suprasternal notch inferiorly; on each side, the lateral boundary is formed by the medial border of the carotid sheath
Level VII: upper mediastinal; contains the lymph nodes inferior to the suprasternal notch in the superior mediastinum
Distant metastasis (M) – hypopharynx
M0: No distant metastasis
M1: Distant metastasis
Anatomic stage / prognostic groups – hypopharynx
0 : Tis N0 M0
I : T1 N0 M0
II : T2 N0 M0
III : T3 N0 M0 or T1-3 N1 M0
IVA : T4a N0-1 M0 or T1-4a N2 M0
IVB : T4b Any N M0 or Any T N3 M0
IVC : Any T Any N M1
Open in midline posteriorly, ink margins, take tissue for special studies
Fix specimen
Remove hyoid bone and inspect pre-epiglottic tissue
Slice larynx (see below) and photograph
For supraglottic and hypopharyngeal carcinomas, blocks should include relationship between tumor and anterior resection margin at base of tongue
For partial laryngectomy specimens, inferior margin is usually most critical
At least one section per 1 cm of tumor for large tumors, including tumor center and periphery and maximum depth of invasion
Submit entire tumor if can do so in 5 sections or less
Submit resection margins
Nonneoplastic mucosa
Bone or cartilage that is grossly involved by tumor
Thyroid gland if present
Lymph nodes
Tracheostomy site
Glottic tumors: show tumor relationship to ventricle, thyroid cartilage and cricoid cartilage by coronal section (plane dividing body into front and back, coronal section of normal larynx)
Epiglottic tumors: determine extent of invasion of preepiglottic space by sagittal sections (plane dividing body into right and left, sagittal section of larynx)
Pyriform sinus tumors: show invasion of supraglottic larynx and thyroid lamina by horizontal sections
References: J Clin Path 2000;53:171
Tumor size and location
Tumor histologic type and pattern
Tumor histologic grade
Depth of invasion of primary tumor
Pattern of invasion
Tumor extension to adjacent structures (indicate involvement or not)
Status of resection margins (distance from invasive carcinoma to mucosal and deep margins)
Vascular invasion
Perineural invasion
Presence of severe dysplasia/carcinoma in situ
Lymph nodes: for each level, number obtained, number involved by tumor, size of nodal metastases, presence of extracapsular spread
TNM staging
End of Larynx chapter