What is the most appropriate treatment for a 69-year-old patient with a 5 cm left-sided neck mass, well-differentiated squamous cell carcinoma with p16 positivity, and no identified primary site on PET/CT scan and directed biopsies?

Treatment for P16-Positive Squamous Cell Carcinoma with Unknown Primary in the Neck

Concurrent chemotherapy and radiation therapy is the most appropriate treatment recommendation for this 69-year-old patient with a large (5 cm) p16-positive squamous cell carcinoma in the neck with no identified primary site.

Patient Characteristics and Diagnosis

• 69-year-old patient
• 5 cm left-sided neck mass
• Well-differentiated squamous cell carcinoma with p16 positivity
• No primary tumor identified despite comprehensive workup (PET/CT, panendoscopy, directed biopsies)

Treatment Algorithm

Step 1: Understand the Disease Classification

This case represents a squamous cell carcinoma of unknown primary (CUP) with p16 positivity, which strongly suggests HPV-related disease likely originating from the oropharynx, even though the primary site was not identified.

Step 2: Determine Appropriate Treatment

1. First-line treatment: Concurrent chemoradiotherapy

   • This approach is supported by ESMO guidelines as the standard treatment for non-resectable patients 1
   • Chemoradiation has demonstrated higher response rates, longer disease-free progression, and longer overall survival compared to radiotherapy alone 1

2. Why not surgical options?

   • The large size (5 cm) of the mass makes this a high-risk lesion
   • For squamous cell carcinoma with cervical metastases and unknown primary, surgery alone is insufficient 1
   • Neck dissection followed by radiation would be suboptimal for a mass this size 2
   • Bilateral neck dissection would be unnecessarily aggressive given the p16 positivity suggesting an oropharyngeal origin

Step 3: Implementation of Chemoradiotherapy

• Platinum-based regimens remain the standard chemotherapy for concurrent chemoradiotherapy 1
• Radiation should target both sides of the neck and potential mucosal sites where the primary might be located
• For p16-positive disease, consideration of de-escalated radiation doses may be appropriate based on recent evidence

Important Considerations

P16 Status and Its Implications

• P16 positivity strongly suggests HPV-related disease, typically with better prognosis
• However, caution is needed as p16 can occasionally be expressed in cutaneous squamous cell carcinomas (approximately 32%) 3
• HPV testing should be performed to confirm the association when possible

Common Pitfalls to Avoid

1. Don't assume all p16-positive tumors are oropharyngeal in origin

   • While p16 is a surrogate marker for HPV in oropharyngeal cancer, it can be expressed in cutaneous SCCs as well 4, 3

2. Don't undertreat with surgery alone

   • Regional control rates are significantly improved with combined modality treatment 2, 5

3. Don't overtreat with extensive surgery plus radiation

   • For p16-positive disease, concurrent chemoradiation provides excellent outcomes without the morbidity of extensive surgery

4. Don't neglect post-treatment surveillance

   • Close follow-up is essential for early detection of recurrence or emergence of a primary tumor
   • Evaluation of thyroid function at 1,2, and 5 years is recommended for patients receiving neck radiation 1

Follow-up Recommendations

• Treatment response should be evaluated by clinical examination and imaging (CT or MRI)
• FDG-PET may be useful to evaluate response and determine if subsequent neck dissection is needed
• Regular surveillance for emergence of a primary tumor or recurrence
• Monitor for treatment sequelae, particularly swallowing and respiratory function

The evidence strongly supports concurrent chemoradiotherapy as the optimal approach for this patient, balancing disease control with quality of life considerations.