What is the best treatment approach for a patient with melanoma, axillary and mediastinal lymphadenopathy?

Treatment of Melanoma with Axillary and Mediastinal Lymphadenopathy

For melanoma with axillary and mediastinal lymphadenopathy, first-line systemic immunotherapy with anti-PD-1 monotherapy (pembrolizumab or nivolumab) or combination ipilimumab/nivolumab represents the standard of care, with surgical resection reserved only for isolated, completely resectable disease after comprehensive staging excludes additional metastases. 1

Initial Diagnostic Workup

Before initiating treatment, several critical steps must be completed:

• Obtain tissue confirmation of metastatic disease through fine-needle aspiration (preferred) or open biopsy of the lymphadenopathy 2
• Perform BRAF mutation testing on the biopsy specimen, as this is mandatory for all patients with stage III/IV disease and determines eligibility for targeted therapy 1
• Complete staging with CT chest/abdomen/pelvis and consider PET-CT to define the full extent of disease and exclude additional visceral metastases 1, 2
• Obtain brain MRI even with minimal symptoms, given the high incidence of CNS involvement in metastatic melanoma 2
• Measure baseline serum LDH for prognostic stratification 2

Critical Pitfall: Sarcoid-Like Lymphadenopathy

Be aware that immunotherapy itself can cause benign "sarcoid-like lymphadenopathy" that mimics progressive disease on imaging 3, 4. This immune-related phenomenon occurs in approximately 10% of patients receiving checkpoint inhibitors and paradoxically correlates with treatment response 4. Always obtain tissue diagnosis of new or enlarging lymphadenopathy during immunotherapy before concluding disease progression 3.

Treatment Algorithm Based on Disease Extent

If Disease is Limited and Completely Resectable (Oligometastatic)

Surgical approach:

• Complete surgical resection with R0 margins (tumor-free margins) should be pursued if axillary and mediastinal disease represents isolated, completely resectable metastases 1, 5
• Mandatory pre-operative staging with CT or PET-CT is required to exclude additional metastases before undertaking aggressive surgical intervention 1
• For axillary disease: complete lymph node dissection of the entire nodal basin is required; removal of individual tumor-bearing nodes alone is insufficient 1
• For mediastinal disease: surgical resection is only appropriate if complete R0 resection is technically achievable 5

Post-surgical adjuvant therapy: After complete resection of stage III disease, adjuvant systemic therapy is mandatory 1:

• Preferred options: Anti-PD-1 therapy with nivolumab or pembrolizumab, OR dabrafenib/trametinib combination for BRAF-mutated disease 1
• These adjuvant therapies significantly improve disease-free survival and overall survival 1

If Disease is Unresectable or Disseminated (Standard Scenario)

This represents stage III unresectable or stage IV disease requiring systemic therapy as primary treatment 1:

First-line systemic therapy options (in order of preference):

1. Anti-PD-1 monotherapy (pembrolizumab or nivolumab) - standard of care for all patients regardless of BRAF status 1

2. Combination ipilimumab/nivolumab - offers higher response rates but significantly increased toxicity; consider for patients requiring rapid disease control 1, 6

   • Dosing per FDA label: ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab monotherapy 6

3. BRAF/MEK inhibitor combination (dabrafenib/trametinib) - for BRAF V600-mutated melanoma; can be used first-line or after immunotherapy failure 1

The choice between anti-PD-1 monotherapy versus combination therapy depends on:

• Disease burden and tempo of progression (aggressive disease may warrant combination therapy) 1
• Patient performance status and ability to tolerate toxicity 1
• Presence of symptomatic disease requiring rapid response 1

Special Consideration: Unresectable Stage IIIB/C Disease

For patients with unresectable stage IIIB/C disease (bulky regional lymphadenopathy without distant metastases), talimogene laherparepvec (T-VEC) intralesional therapy is an additional option if lesions are accessible for injection 1.

Second-Line Treatment Options

If first-line anti-PD-1 monotherapy fails:

• Add ipilimumab to create combination therapy 1
• Switch to BRAF/MEK inhibitors if BRAF-mutated and not previously used 1

If first-line combination ipilimumab/nivolumab fails:

• BRAF/MEK inhibitors for BRAF-mutated disease 1
• Clinical trial enrollment strongly recommended 1

If all approved therapies exhausted:

• Cytotoxic chemotherapy (dacarbazine or temozolomide) has modest activity and can provide palliative benefit 1

Role of Radiation Therapy

Palliative radiation should be considered for:

• Symptomatic mediastinal lymphadenopathy causing compression symptoms 1
• Painful or bulky axillary disease not responding to systemic therapy 1
• Radiation is NOT recommended as adjuvant therapy after complete resection in the modern era 1

Clinical Trial Enrollment

Patients with metastatic melanoma should preferentially be enrolled in clinical trials whenever available, as this represents the highest standard of care for advancing treatment options 1. The landscape of melanoma therapy continues to evolve rapidly with novel immunotherapy combinations and targeted agents.

Key Pitfalls to Avoid

• Do not operate on apparent oligometastatic disease without comprehensive staging - occult additional metastases are common and negate surgical benefit 1
• Do not pursue incomplete (R1/R2) resections - residual disease eliminates survival benefit and delays effective systemic therapy 5
• Do not misinterpret vaccine-related or immunotherapy-related lymphadenopathy as disease progression - obtain tissue confirmation 3, 4, 7
• Do not use routine imaging for early-stage melanoma - CT and PET-CT are not indicated for stage I-II disease 2