Larynx and hypopharynx

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

Normal histology

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

False vocal cords and other supraglottic larynx: ciliated, columnar epithelium extending into ventricle of Morgagni, with submucosal modified salivary gland epithelium

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

Subglottic larynx: epithelium resembles trachea/major bronchi – ciliated columnar epithelium with submucosal glands

Inflammatory/infectious lesions

Acute laryngoepiglottitis

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

Croup: laryngotracheobronchitis in children; inflammatory narrowing produces inspiratory stridor

Amyloidosis

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

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

Contact ulcer

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

Crohn’s disease

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)

DD: Wegener’s granulomatosis

Fungi

May need special stains to diagnose when inflammation or hyperkeratosis is also present (Archives 1986;110:141)

Local excision may be curative

Adenocarcinoma, NOS

Non-salivary gland types are rare in larynx

Usually not in glottis

May arise from surface epithelium

Lymphoepithelioma-like carcinoma

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

Metastases

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)

Mucoepidermoid carcinoma

Very rare

Usually supraglottic

Neuroendocrine carcinoma

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

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

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

Small cell carcinoma

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

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

Chondrosarcoma

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

Liposarcoma

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

Lymphoma

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

Melanoma

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

Paraganglioma

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

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

Primary tumor (T)

TX: primary tumor cannot be assessed

T0: no evidence of primary tumor

Tis: carcinoma in situ

T1-T3: vary by site (below)

T4a: tumor invades through 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: tumor invades prevertebral space, encases carotid artery or invades mediastinal structures

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 (i.e. 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 tissues, paraglottic space or minor thyroid cartilage erosion (e.g. inner cortex)

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 minor thyroid cartilage erosion (e.g. inner cortex)

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

Regional lymph nodes (N)

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

Notes: 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

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

Distant metastasis (M)

MX: distant metastasis cannot be assessed

M0: no distant metastasis

M1: distant metastasis

Stage grouping

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

Grossing

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

Features to report

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