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Head and Neck Cancer

Part 4: Oncology and Hematology | Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 82

Key Clinical Points

  1. Alcohol and tobacco act synergistically as the most significant environmental risk factors for head and neck cancer.
  2. HPV-16 is the dominant viral subtype in oropharyngeal cancer; HPV-related tumors have better prognosis, especially in nonsmokers.
  3. EBV infection is frequently associated with nasopharyngeal cancer, particularly in endemic areas (East Asia, Mediterranean).
  4. HPV-related oropharyngeal cancer occurs in younger patients (40s-50s) vs tobacco-related (older than 60).
  5. Cisplatin weekly during radiotherapy over 6-7 weeks is standard for concomitant chemoradiotherapy.
  6. Five-year survival exceeds 50% in many trials for advanced disease; HPV-positive tumors have better prognosis.
  7. Cetuximab monotherapy shows inferior survival compared to cisplatin-based regimens in HPV-related cancers.
  8. Induction chemotherapy (docetaxel, cisplatin, 5-FU) before surgery/radiation allows organ preservation in laryngeal cancer.
  9. Second primaries develop in head and neck, lung, or esophagus; CT screening for lung cancer recommended in heavy smokers.
  10. Radiation therapy preferred for laryngeal cancer to preserve voice; surgery preferred for oral cavity lesions to avoid xerostomia.

1. DEFINITION & OVERVIEW

Head and neck cancers encompass malignancies arising from the upper aerodigestive tract, including oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, and salivary glands. Salivary gland tumors differ in etiology, histopathology, clinical presentation, and therapy. Thyroid malignancies are described separately in Chapter 397. Epithelial carcinomas typically originate from mucosal surfaces as squamous cell carcinomas. Salivary gland tumors are rare and histologically heterogeneous.

1.1 Classification by Site

• Primary Sites: ◦ Oral cavity ◦ Oropharynx ◦ Nasopharynx ◦ Hypopharynx ◦ Larynx ◦ Salivary glands ◦ Paranasal sinus tumors

1.2 Salivary Gland Tumors

• Origin: ◦ Major glands: parotid, submandibular, sublingual ◦ Minor salivary glands in submucosa of upper aerodigestive tract • Malignancy Rates: ◦ Parotid: Most are benign ◦ Submandibular/Sublingual: 50% are malignant ◦ Minor glands: Most are malignant • Common Malignant Types: ◦ Mucoepidermoid carcinoma ◦ Adenoid cystic carcinoma ◦ Adenocarcinomas

2. EPIDEMIOLOGY

In the United States, 66,920 new cases of head and neck cancers (oral cavity, pharynx, larynx) were estimated in 2023, accounting for ~6% of adult malignancies with 15,400 deaths. Worldwide incidence exceeds half a million annually. In North America/Europe, tumors typically arise from oral cavity/oropharynx/larynx. Oropharyngeal cancer incidence has increased in Western countries. Nasopharyngeal cancer is endemic in East Asia and Mediterranean regions.

2.1 Age and Sex Distribution

• Tobacco-related: >60 years ◦ HPV-related: 40s-50s ◦ EBV-related (Nasopharyngeal): All ages, including teenagers ◦ Sex: Male predominance in head and neck cancers, including HPV-positive tumors

2.2 Geographic Variation

• Nasopharyngeal cancer: Endemic in East Asia/Mediterranean ◦ HPV-related oropharyngeal cancer: Higher incidence in Western countries ◦ Alcohol/tobacco-related cancers: Decreased incidence in Western countries

2.3 Risk Factors

• Modifiable: ◦ Alcohol use ◦ Tobacco (smoking, smokeless) ◦ Marijuana ◦ Poor diet (low fruits/vegetables) ◦ Retinoid supplements in smokers ◦ Synergistic effect: alcohol + tobacco • Non-modifiable: ◦ Age ◦ Sex (male predominance) ◦ HPV/EBV status ◦ Genetic predisposition

3. ETIOLOGY & PATHOPHYSIOLOGY

Alcohol and tobacco are the most significant environmental risk factors, acting synergistically. Smokeless tobacco causes oral cancers. Other carcinogens include marijuana and occupational exposures (nickel refining, textile fibers). EBV is associated with nasopharyngeal cancer in endemic areas. HPV-16 is the dominant subtype in oropharyngeal cancer (>50% of cases in US). Nasopharyngeal cancer linked to salted fish consumption and indoor pollution.

• Mechanism: HPV oncogenes inhibit p53/RB tumor suppressor genes ◦ Clinical Profile: Associated with increased sexual partners/oral practices; better prognosis in nonsmokers ◦ Prevention: Nine-valent HPV vaccine may prevent disease (long latency period)

• Mechanism: EBV infection linked to nasopharyngeal cancer in endemic areas ◦ Screening: EBV antibody titers used for screening/high-risk populations ◦ Environmental Links: Associated with salted fish consumption and indoor pollution

3.3 Molecular Biology

• Differentiation: Squamous cell tumors classified by differentiation: well, moderately, poorly (poorly = worse prognosis) ◦ Nasopharynx: Nonkeratinizing/undifferentiated carcinoma with lymphocytes ◦ EGFR: Overexpression correlates with poor prognosis but not response to inhibitors ◦ HPV-positive: Show PI3K pathway alterations and KRAS mutations

4. CLINICAL FEATURES

Manifestations vary by tumor stage/site. Persistent symptoms (>2-4 weeks) warrant evaluation. Advanced disease may cause pain, otalgia, airway obstruction, cranial neuropathies, trismus, odynophagia, decreased tongue mobility, fistulas, and massive cervical lymphadenopathy.

4.1 Nasopharyngeal Cancer

• Early symptoms: Unilateral serous otitis media, nasal obstruction, epistaxis ◦ Advanced: Cranial nerve neuropathies from skull base involvement

4.2 Oral Cavity Cancer

• Clinical signs: Nonhealing ulcers, denture fit changes, painful lesions ◦ Premalignant: Leukoplakia/erythroplakia require biopsy

4.3 Tongue Base and Oropharynx Cancer

• Symptoms: Decreased tongue mobility, speech alterations ◦ HPV-related: Neck lymphadenopathy as first sign

4.4 Oropharynx and Hypopharynx Cancer

• Early symptoms: Sore throat, otalgia

4.5 Laryngeal Cancer

• Early symptom: Persistent hoarseness requiring specialist referral ◦ Diagnostic delay: Antibiotic treatment failure may delay diagnosis

4.6 Carcinoma of Unknown Primary

• Presentation: Enlarged lymph nodes without detectable primary lesion ◦ Significance: Squamous cell histology in upper neck nodes suggests head/neck origin; supraclavicular nodes may originate from chest/abdomen

5. DIFFERENTIAL DIAGNOSIS

Includes premalignant lesions (leukoplakia, erythroplakia) and second primary malignancies. Radiation therapy-induced sarcoma is rare but possible after prior radiotherapy.

5.1 Second Primary Malignancies

• Etiology: Not therapy induced; reflects carcinogen exposure ◦ Sites: Head/neck, lung, esophagus ◦ Screening: CT screening for lung cancer recommended in heavy smokers

5.2 Premalignant Lesions

• Lesions: Leukoplakia (white patch), erythroplakia (red patch) ◦ Pathology: May represent hyperplasia, dysplasia, carcinoma in situ, or invasive carcinoma ◦ Action: Require biopsy

6. INVESTIGATIONS & DIAGNOSIS

Physical exam includes mucosal inspection, palpation of floor of mouth/tongue/neck. Panendoscopy with biopsies of tonsils, nasopharynx, base of tongue, and pyriform sinus is essential. Imaging: CT/MRI for local staging; chest/abdomen CT for metastases; PET for distant disease evaluation.

6.1 Physical Examination Findings

• Inspect mucosal surfaces ◦ Palpate floor of mouth, tongue, neck ◦ Identify tumors, leukoplakia, erythroplakia (biopsy required)

6.2 Imaging Studies

• CT/MRI: Local disease extent ◦ Chest/abdomen CT: Screen for metastases; lung cancer screening in smokers ◦ PET: Distant metastases evaluation, treatment response monitoring

6.3 Diagnostic Algorithm

  1. Physical Examination: Mucosal inspection and palpation of floor of mouth, tongue, and neck.
  2. Biopsy: Perform for tumors, leukoplakia, or erythroplakia.
  3. Imaging (Local): CT/MRI to determine local disease extent.
  4. Imaging (Systemic): Chest/abdomen CT for metastasis screening; PET scan for distant evaluation and monitoring.
  5. Carcinoma of Unknown Primary (CUP) Assessment: Consider if no primary lesion is found.
  6. Panendoscopy: Perform with targeted biopsies of tonsils, nasopharynx, base of tongue, and pyriform sinus.
  7. Confirmation: Confirm squamous cell carcinoma and perform comprehensive staging.
  8. HPV-Specific Check: Recognize early lymph node spread in HPV-positive tumors.
  9. Advanced Endoscopy: Endoscopic examination under anesthesia (laryngoscopy, esophagoscopy, bronchoscopy).
  10. Comprehensive Sampling: Obtain multiple biopsies for diagnosis, extent, and second primaries.

Evaluation of Cervical Adenopathy without Primary Mucosal Lesion: 1. Initial Step: Physical Examination → FNA or excision of lymph node. 2. Histopathology Branch: ◦ If lymphoma, sarcoma, or salivary gland tumor → Specific workup. ◦ If squamous cell carcinoma (SCC) → Panendoscopy and directed biopsies. 3. Primary Search Result: ◦ If primary found (+) → Stage-specific multimodality therapy → Postoperative radiotherapy or chemoradiotherapy. ◦ If no primary found (-) → Consider curative neck dissection → Postoperative radiotherapy or chemoradiotherapy.

7. MANAGEMENT & TREATMENT

Treatment depends on stage: localized (surgery/radiation), locally advanced (chemoradiotherapy), recurrent/metastatic (palliative). HPV testing is recommended for oropharyngeal tumors. De-escalation protocols are under investigation to reduce long-term toxicity.

7.1 Localized Disease (T1/T2, Stage I/II)

• Prevalence: 30% of patients have localized disease ◦ Treatment: Surgery or radiation ◦ Laryngeal Cancer: Radiation preferred to preserve voice ◦ Oral Cavity: Surgery preferred to avoid xerostomia ◦ Neck Management: Prophylactic neck dissection recommended ◦ 5-year survival: 60-90% (95% for localized disease)

7.2 Locally or Regionally Advanced Disease

• Treatment: Combined-modality therapy (surgery/radiation/chemotherapy) ◦ Concomitant Chemoradiotherapy: Cisplatin weekly over 6-7 weeks ◦ Induction Chemotherapy: (docetaxel, cisplatin, 5-FU) for organ preservation in laryngeal cancer ◦ Prognosis: 5-year survival >50% in trials; HPV-positive tumors have better prognosis

• De-escalation: Protocols aim to reduce radiation toxicity (fibrosis, swallowing dysfunction) ◦ Research: Lower radiation doses, omission of induction chemotherapy ◦ Surgery: Robotic surgery for base of tongue/tonsil access ◦ Current Standard: Same as carcinogen-induced tumors

7.4 Recurrent and/or Metastatic Disease

• Prevalence: 5-10% present with metastases; 30-50% of advanced cases recur ◦ Intent: Palliative ◦ Systemic Therapy (EXTREME): cisplatin, 5-FU, and cetuximab as standard first-line

7.5 Treatment Summary by Stage

  1. Localized disease: Surgery/radiation (voice preservation for larynx; avoid xerostomia for oral cavity).
  2. Locally advanced: Concomitant chemoradiotherapy (cisplatin weekly), induction chemotherapy, HPV testing recommended.
  3. Recurrent/metastatic: EXTREME regimen (cisplatin/5-FU/cetuximab) as first-line.

8. PROGNOSIS & COMPLICATIONS

Overall 5-year survival: 60-90%. HPV-related oropharyngeal cancers have better prognosis (especially in nonsmokers). Advanced age/extensive disease at diagnosis confer poorer outcomes. Complications include xerostomia, osteoradionecrosis, mucositis, fibrosis, and second primary malignancies.

8.1 Survival Rates

• Overall: 60-90% ◦ HPV-related oropharyngeal: Better prognosis (especially in nonsmokers) ◦ Advanced nasopharyngeal: >80% survival in Southeast Asian studies ◦ Localized disease: 95% 5-year survival

8.2 Complications

• Radiation therapy: xerostomia, osteoradionecrosis, mucositis (70-80% grade 3/4), fibrosis ◦ Chemoradiotherapy: Increased toxicity (mucositis) ◦ Second primaries: head/neck, lung, esophagus (not therapy induced) ◦ Radiation-induced sarcoma: Rare but possible

8.3 Second Primary Malignancies

• Etiology: Not therapy induced; reflects carcinogen exposure ◦ Sites: head/neck, lung, esophagus ◦ Screening: CT screening recommended for heavy smokers with existing head/neck cancer

9. SPECIAL CONSIDERATIONS

Comorbidities associated with tobacco/alcohol use affect treatment outcomes and long-term risks. HPV-related tumors may benefit from de-escalation protocols to reduce toxicity while maintaining efficacy.

KEY PEARLS & HIGH-YIELD POINTS

• Synergy: Alcohol + Tobacco = major risk for head/neck cancer. ◦ HPV vs. Tobacco: HPV-related tumors (40s-50s) have better prognosis than tobacco-related (60+). ◦ Nasopharynx: Associated with EBV; high incidence in East Asia/Mediterranean. ◦ Larynx: Persistent hoarseness is the hallmark of early disease. ◦ Cisplatin: Standard for chemoradiotherapy (weekly over 6-7 weeks). ◦ EXTREME regimen: Standard first-line for metastatic disease (cisplatin/5-FU/cetuximab). ◦ TNM Staging: N1 ≤ 3 cm, N2 ≤ 6 cm, N3 > 6 cm; T4a involves invasion of skin or bone.