Head & Neck Cancer (Part 1): Biology, Workup and Staging

Overview

• Epidemiology (US 2025): ~71,000 new cases, ~16,000 deaths. Worldwide ~900,000 cases and ~450,000 to 480,000 deaths per year (GLOBOCAN 2022); ~4% of all cancers; median age 60 yrs.
• Sex: M > F ~2.5:1 overall, ~4:1 for oropharynx, ~7:1 for larynx. Oropharyngeal incidence rising, especially in younger patients and developed countries; incidence and mortality ↑ in black men.
• Sites (anatomic subdivisions):
  • Oral cavity and lip: floor of mouth (FOM), oral (anterior 2/3) tongue, buccal mucosa, alveolar ridge/gingiva, hard palate, retromolar trigone.
  • Oropharynx: base of tongue (BOT), tonsils, inferior surface of soft palate, uvula, posterior pharyngeal wall.
  • Nasopharynx: behind nasal cavity, includes superior surface of soft palate. EBV-associated (esp. WHO type II/III).
  • Hypopharynx: pyriform sinus, postcricoid, posterior wall.
  • Larynx: supraglottis (false cords, arytenoids, epiglottis), glottis (includes commissures), subglottis. Glottis presents earliest (hoarseness).
  • Nasal cavity and paranasal sinuses (maxillary > ethmoid > frontal): late presentation, poor prognosis.
  • Salivary glands: separate section.
• Histology: >90% squamous cell carcinoma (HNSCC).
• 5-yr OS: overall ~67%; varies by site (e.g., HPV+ oropharynx ~80 to 90% vs HPV− ~50%).

Risk factors

• Tobacco (most important, ~75% of all HNSCC). Black tobacco (cigars, pipe) confers ↑ risk vs blonde tobacco. Synergistic with alcohol.
• Alcohol: independent and synergistic with tobacco.
• HPV (high-risk types 16, 18): ~70% of oropharyngeal SCC in the US. Better prognosis. p16+ by IHC = surrogate.
• EBV: nasopharyngeal carcinoma (NPC), endemic forms (WHO type II/III).
• Immunosuppression: leukemia, post-transplant, HIV.
• Occupational: nickel, radium, mustard gas, wood dust (→ sinonasal adenocarcinoma). Sun (lip). Betel nut chewing (oral). Poor diet (↓ vitamin A/B).
• Plummer-Vinson syndrome: postmenopausal women >50 y/o, iron-deficiency anemia, hypopharyngeal webs, dysphagia; ↑↑ risk of SCC of the postcricoid hypopharynx, oral cavity, and esophagus.
• Fanconi anemia (short stature, skeletal defects, marrow failure or AML history) and dyskeratosis congenita: ↑↑ risk of HNSCC (young age).

HPV biology (high-yield)

• HPV+ oropharyngeal SCC rose from ~17% in the 1980s to 1990s to up to ~70% today. Mainly HPV 16 or 18, especially men <60 y/o without significant alcohol/smoking history.
• Viral E6 and E7 → ↓↓ p53 and RB (tumor suppressors) → loss of cell-cycle regulation → ↑↑ chromosomal instability. Loss of RB → ↑↑ p16.
• p16 by IHC (≥70% of tumor cells, moderate to strong nuclear AND cytoplasmic staining) = excellent surrogate for biologically relevant HPV, is not genotype specific, and is better than HPV DNA detection (DNA does not necessarily reflect E7 activity). In HPV− HNSCC, p16/CDKN2A is commonly inactivated by deletion or inactivating mutation (promoter methylation also occurs).
• HPV+ tumors have wild-type TP53 and RB1 and ↑↑ p16; >50% of tobacco/alcohol-associated (HPV−) tumors carry TP53 mutation with ↓ p16.
• Do NOT routinely check p16 for KNOWN non-oropharyngeal primaries (oral cavity, larynx, hypopharynx): no OS difference by HPV status there. EXCEPTION: test p16/HPV in a metastatic cervical node with unknown primary (implicates oropharynx). HPV− with LN+ → ↓ cure by ~50% vs HPV+ with multiple ipsilateral LN <6 cm (good prognosis).
• Risk stratification (RTOG 0129): HPV+ and ≤10 pack-yr = best prognosis; HPV+ >10 pack-yr with N2b to N3, OR HPV− ≤10 pack-yr with T2 to T3 = intermediate (note: HPV+ >10 pack-yr with N0 to N2a is LOW risk; HPV− ≤10 pack-yr with T4 is HIGH risk); HPV− and >10 pack-yr = poor. RTOG 0129: 3-yr OS HPV+ vs HPV− 82.4% vs 57.1%.
• Plasma circulating tumor HPV DNA (cfHPV): two consecutive positive tests PPV ~94% for recurrence; consecutive negatives NPV ~100%.

EBV and nasopharynx

• EBV drives NPC WHO type II (differentiated) and type III (undifferentiated); ↑↑ in China and northern Africa. WHO type I (keratinizing) is relatively more common in Western/nonendemic countries with a stronger tobacco association; nonkeratinizing remains the predominant type overall, and keratinizing NPC is still EBV-associated in most cases (HPV association not established).
• EBER ISH (EBV-encoded small RNA in situ hybridization) is the preferred test; EBER+ has better OS than EBER−. Post-treatment plasma EBV DNA is an excellent prognostic marker (not yet SOC).

Premalignant mucosal lesions

• Leukoplakia: benign ~80% of the time.
• Erythroplakia: ~90% show severe dysplasia, carcinoma in situ, or invasive disease. Red velvety patch with a distinct interface, occasionally pebbled/granular (tongue, lower lip, FOM, buccal mucosa, oral commissure).

Cervical lymph node levels

Diagnostics / workup

• H&P: fiberoptic endoscopy, bimanual palpation. Look for synchronous primary (~5%).
• Diffuse mucosal abnormalities plus a malignant neck node without a clear primary (esp. lower neck) → triple endoscopy (laryngoscopy/pharyngoscopy + bronchoscopy + esophagoscopy) to exclude synchronous tumors.
• CT with contrast: sufficient in most HNSCC.
• MRI: for skull-base, sinuses, and nasopharynx.
• PET: for locally advanced disease (T3 to T4, ≥ N1); good for baseline and response after definitive chemoRT (do ~12 weeks after completion). For NPC with LN+, body CT + bone scan or PET (bone is the most common met site).
• Biopsy: FNA > excisional biopsy (excisional risks tumor seeding). If a node is excised, complete the staging workup and select definitive surgery, RT, or chemoRT per primary site and multidisciplinary plan (excision does not automatically mandate neck dissection). p16 IHC (oropharynx); EBV testing (nasopharynx).
• Pre-treatment: dental clearance (extractions before RT), nutritional and swallowing eval (?PEG), audiology if cisplatin planned, smoking/alcohol cessation counseling.

Staging (AJCC 8th ed for most sites; use AJCC v9 for nasopharynx dx from 1/1/2025 and HPV-associated oropharynx dx from 1/1/2026)

• HPV+ (p16+) oropharynx and nasopharynx have separate staging systems; for all other primary sites the TNM stage grouping is the same. Nasopharynx AJCC v9 (dx from 2025; table column shows AJCC 8th): advanced radiologic ENE added to N3; I = T1 to T2, N0 to N1 (IA N0, IB N1); II = T1 to T2 N2 or T3 N0 to N2; III = T4 or N3; IVA = M1a (≤3 metastatic lesions); IVB = M1b (>3 lesions).
• Oral cavity T: uses depth of invasion (DOI), not tumor thickness. Extrinsic tongue muscle infiltration no longer defines T4. Superficial bone/tooth-socket erosion alone by a gingival primary does not qualify for T4.
• For a known p16− oropharyngeal primary, T0 does not apply; but T0 is used for p16−/EBV− cervical nodal SCC of unknown primary. Larynx/hypopharynx: vocal cord paralysis → no less than T3.
• Extranodal extension (ENE) is included in N staging for p16− disease (clinically overt ENE → cN3b; pathologic ENE → pN3b, except a single ipsilateral node ≤3 cm with ENE = pN2a; poorer prognosis). ENE = skin invasion, dense tethering, nerve invasion with dysfunction, extension outside the node into connective tissue. Microscopic (ENEmi, ≤2 mm) or macroscopic (ENEma, >2 mm); both count as ENE+ (no separate N step-up by extent). Identified by pathology (pENE, most sensitive), imaging (rENE, marks a worse form), or clinical exam (cENE). Radiographic ENE supports but alone is insufficient.
• p16+ oropharynx: combines T4a/T4b into a single T4. N1 = ≥1 ipsilateral node, none >6 cm; N2 = contralateral or bilateral; N3 = >6 cm. Only 3 nonmetastatic stages: I (T0 to T2, N0 to N1), II (T0 to T2 N2 or T3 N0 to N2), III (T4 or N3); metastatic = IV.
• CUP with HPV+ is regarded as oropharyngeal; CUP with EBV+ as nasopharyngeal.
• For p16− disease: early-stage = I, II, and low-volume III (T1 or T2, N0 or N1); locally/locoregionally advanced = III and IV (large T3 or T4 primary, or bulky N2/N3 nodes).

Continued in: Head & Neck Cancer (Part 2): Treatment, NPC, CUP and Recurrent Disease