Cancer of Unknown Primary with Cervical Nodal Metastases

Cancer of unknown primary with cervical nodal metastases is a metastatic cancer in neck lymph nodes (most often squamous cell carcinoma) in which the primary site is not found after full clinical, radiological and endoscopic assessment. Most primaries are in the oropharynx (tonsil and base of tongue), nasopharynx, hypopharynx or larynx, and a thorough search is potentially curative.

It forms about 3% to 5% of head and neck cancers and about 1% to 2% of all cancers of unknown primary, with an incidence of about 0.5 to 1 case in 100,000 people each year. Median age is 55 to 65, with a male predominance.

Risk factors match those of head and neck squamous cell carcinoma: smoking, alcohol, HPV infection (oropharyngeal), EBV (nasopharyngeal), and betel quid use.

Pathophysiology. Squamous cell carcinoma in the upper and mid neck (levels II and III) usually comes from the oropharynx, nasopharynx, oral cavity, hypopharynx or larynx. Lower neck (level IV and supraclavicular) nodes suggest a primary in the chest or abdomen (lung, oesophagus, breast, gastrointestinal tract). Adenocarcinoma suggests thyroid, salivary gland, lung or breast origin, and melanoma and neuroendocrine tumours are less common causes.

Prognosis. HPV-positive tumours have 5-year survival of about 80% to 90%. HPV and EBV-negative disease has 5-year survival of about 50% to 70%, falling with extranodal extension, nodal stage and smoking.

• A painless, firm neck mass, often fixed or enlarging, usually solitary and cystic in HPV-related disease.
• Sore throat, otalgia, dysphagia, hoarseness, trismus or oral ulcer (suggesting a primary).
• Weight loss and cranial nerve palsies in advanced disease.
• Fever, night sweats or other systemic symptoms if lymphoma is possible.

Red flags.

• Airway compromise, stridor or bleeding.
• Rapidly enlarging fixed nodes or cranial nerve deficits.
• Supraclavicular nodes (search the chest and abdomen).

• Full head and neck examination with flexible nasopharyngolaryngoscopy, dental assessment, and palpation of the neck, thyroid, oral cavity and tonsils.
• Ultrasound directed fine needle aspiration cytology or core biopsy of the node (open biopsy is avoided to prevent tumour spread). Immunohistochemistry and molecular testing: p16 with HPV in situ hybridisation or PCR, EBER in situ hybridisation for EBV, cytokeratins, TTF-1, thyroglobulin, GATA3 and PSA when adenocarcinoma is found, and S100 and SOX10 for melanoma.
• Imaging before endoscopy: contrast MRI or CT of the head and neck, CT of the chest, and FDG-PET-CT (improves primary detection by about 25% to 30%).
• Examination under anaesthesia with panendoscopy (nasopharynx, oropharynx, hypopharynx, larynx, oesophagus) and directed biopsies, bilateral palatine tonsillectomy and tongue base mucosectomy (transoral laser or robotic), which identify a primary in 30% to 70%.
• Audiometry, nutritional and swallowing assessment, and dental review before radiotherapy.

Differential diagnosis.

• Lymphoma, tuberculous lymphadenitis and reactive lymphadenopathy
• Branchial cyst (including cystic nodal metastasis in HPV-related disease)
• Metastasis from thyroid, salivary gland, lung, oesophageal, breast or gastrointestinal primaries
• Melanoma and Merkel cell carcinoma metastasis

Management is decided by a head and neck multidisciplinary team, with curative intent.

Early nodal disease (N1, no extranodal extension). Neck dissection alone or definitive radiotherapy alone, with the other modality kept in reserve.

More advanced nodal disease or extranodal extension. Neck dissection followed by radiotherapy with concurrent cisplatin, or definitive chemoradiotherapy.

• Radiotherapy: involved nodal levels 66 to 70 Gy in 33 to 35 fractions, and 54 to 60 Gy elective dose to the bilateral neck and potential mucosal primary sites (nasopharynx, oropharynx, hypopharynx, larynx), delivered by intensity modulated radiotherapy.
• Concurrent chemotherapy: cisplatin 40 mg/m2 IV once weekly during radiotherapy, for 6 to 7 doses, with 1 to 2 L of IV hydration, magnesium and potassium supplementation and antiemetic prophylaxis; maximum 40 mg/m2 each week and a cumulative dose of about 240 mg/m2; monitoring: creatinine and creatinine clearance before each dose, potassium, magnesium, FBC weekly, audiometry at baseline and after treatment, neuropathy, nausea, dental and swallowing assessment; adjustment: give only when creatinine clearance is 50 mL/min or more (weekly carboplatin AUC 1.5 to 2 is the alternative), hold for neutrophils under 1.0 x 10^9/L or platelets under 100 x 10^9/L, reduce by 25% for grade 2 ototoxicity or neuropathy and stop for grade 3, avoid aminoglycosides and other nephrotoxins

Primary found. Treatment follows the site specific plan and is tailored from there.

Supportive care. Dental extraction and fluoride care before radiotherapy, prophylactic gastrostomy for patients at risk of swallowing failure, speech and swallowing rehabilitation, mouth care, nutritional support, and smoking and alcohol cessation.

Non-squamous histology. Treatment is directed by the likely tumour type: thyroid or salivary cancer by surgery and radiotherapy, melanoma by surgery and immunotherapy, and lymphoma by haematology referral.

Recurrent or metastatic disease.

• Immunotherapy (PD-L1 positive tumours, with or without platinum based chemotherapy): pembrolizumab 200 mg IV over 30 minutes every 3 weeks (or 400 mg every 6 weeks) for up to 24 months or until progression or unacceptable toxicity; maximum 200 mg each 3-week dose; monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis, infusion reactions; adjustment: no renal or mild hepatic dose adjustment, withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily, stop permanently for grade 3 to 4 toxicity (except endocrinopathies controlled on replacement) and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks

Monitoring. Clinical examination and endoscopy every 1 to 3 months in year 1, every 2 to 4 months in year 2, then every 6 months to year 5. PET-CT 12 weeks after chemoradiotherapy. Thyroid function every 6 to 12 months after neck radiotherapy.

Referral and escalation.

• Urgent referral (within 2 weeks) to a head and neck cancer service for any unexplained persistent neck lump.
• Emergency assessment for airway compromise or bleeding.

Special groups.

• HPV-related disease: de-intensified treatment is considered in a specialist setting, and prognosis is better.
• Older adults and frail patients: radiotherapy alone or weekly carboplatin, with geriatric assessment.
• Renal impairment or hearing loss: avoid cisplatin and use an alternative.
• Pregnancy: individualised planning with delay of radiotherapy where possible.