A 55-Year-Old with a Neck Lump and a Normal Fine-Needle Aspirate

Interpretation: A "reactive lymphoid tissue" FNA result in an adult with a persistent, firm neck lump and significant risk factors does not exclude malignancy. False-negative rates for FNA of cervical lymph nodes are significant (reported 5-20%), and a non-diagnostic or non-specific result must be treated with suspicion.

Key considerations:

• The patient is a high-risk individual (smoking, alcohol) - a neck lump in this group is a malignancy until proven otherwise.
• A normal flexible nasendoscopy does not exclude a primary - small primaries in the nasopharynx, tonsil, base of tongue, or pyriform fossa can be missed, and the primary may be occult.
• The most likely diagnosis is metastatic squamous cell carcinoma from an occult head and neck primary, but lymphoma, a branchial cyst (less likely at 55), and salivary gland pathology are also possible.

Next step: Repeat FNA with ultrasound guidance, and if still non-diagnostic, proceed to core needle biopsy or excision biopsy of the node. Ultrasound-guided FNA improves yield and allows assessment of node characteristics (size, shape, vascularity, calcification).

Do not simply reassure and discharge. Persistent unexplained cervical lymphadenopathy in an adult warrants a tissue diagnosis.

Investigation for an occult primary:

1. Full head and neck examination under anaesthesia (EUA) with:

   • Panendoscopy - direct examination of nasopharynx, oropharynx, hypopharynx, and larynx.
   • Targeted biopsies of the nasopharynx, both tonsils (tonsillectomy), and base of tongue - even if macroscopically normal, as these are common sites of occult primaries.
   • Bilateral random biopsies of the oropharynx/hypopharynx if no primary is seen.

2. Imaging:

   • Contrast-enhanced CT of the neck and chest.
   • MRI of the head and neck (superior soft tissue resolution, especially for oropharyngeal and nasopharyngeal primaries).
   • PET-CT - the key investigation for an occult primary.

3. HPV and p16 testing on the nodal tissue - critical, as HPV-positive disease is common in occult primaries (often oropharyngeal) and has a better prognosis and different staging.

Role of PET-CT:

• Detects occult primaries not seen on endoscopy or conventional imaging - reported detection rates of 20-40% in this setting.
• Identifies distant metastases - important for staging and treatment planning.
• Guides biopsy - can direct targeted biopsy of a suspicious site.
• Limitations: false positives (e.g., inflammatory/infective uptake), false negatives (small primaries), and availability/cost.

Practical sequence: EUA with panendoscopy and targeted biopsies + HPV/p16 testing + PET-CT. If a primary is found, treat accordingly. If no primary is found after thorough workup, manage as carcinoma of unknown primary - typically neck dissection followed by radiotherapy to the neck and potential mucosal sites, or definitive chemoradiotherapy.

Factors determining treatment approach:

1. Stage - tumour size, nodal burden, extranodal extension (ENE), and distant metastases. This patient has a single ipsilateral node; staging depends on size and ENE.
2. HPV/p16 status - p16-positive (HPV-associated) disease has a distinctly better prognosis and is staged separately (AJCC 8th edition).
3. Patient factors - age, comorbidity, smoking history (smoking worsens prognosis even in HPV-positive disease), fitness for surgery or chemoradiotherapy.
4. Tumour factors - resectability, functional considerations (speech, swallowing), base of tongue involvement.
5. Patient preference - surgery vs non-surgical organ preservation.

Treatment options:

• Surgery - transoral robotic surgery (TORS) or transoral laser microsurgery for the primary, with neck dissection; adjuvant radiotherapy ± chemotherapy based on pathology (positive margins, ENE, multiple nodes).
• Definitive radiotherapy or chemoradiotherapy - organ preservation approach; concurrent cisplatin for high-risk disease.

Influence of p16 status:

• Prognosis: p16-positive disease has significantly better overall and disease-free survival than p16-negative disease.
• Staging: AJCC 8th edition uses a separate staging system for p16-positive oropharyngeal cancer - nodal staging differs (e.g., a single ipsilateral node ≤6 cm may be N1).
• De-escalation: Clinical trials are investigating reduced-intensity treatment (lower radiotherapy dose, omission of chemotherapy, or surgery alone) for favourable p16-positive disease to reduce toxicity while maintaining outcomes. This is not yet standard of care outside trials.
• Smoking history modifies prognosis - the patient's 40 pack-year history is a negative prognostic factor even with p16 positivity.

Practical approach: Present both surgical and non-surgical options at MDT, with the patient's functional goals and smoking history factored into the discussion.