What is the role of the TNM (Tumor, Node, Metastasis) staging system in determining treatment for a patient with melanoma?

Melanoma TNM Staging System and Its Role in Treatment Determination

The TNM staging system is the cornerstone for determining melanoma treatment, with the AJCC 8th edition (2017) serving as the mandatory framework that integrates tumor thickness, ulceration, lymph node involvement, and distant metastases to guide surgical margins, adjuvant therapy decisions, and surveillance intensity. 1, 2

Core TNM Components That Drive Treatment Decisions

T (Primary Tumor) Classification

• Breslow thickness is the single most powerful prognostic factor for localized melanoma and directly determines surgical excision margins 1:
  • In situ melanoma: 0.5 cm margins 1
  • ≤2 mm thickness: 1 cm margins 1
  • >2 mm thickness: 2 cm margins 1
• Ulceration presence upgrades stage and influences adjuvant therapy recommendations 1, 3
• Mitotic rate ≥1/mm² in thin melanomas (≤1 mm) indicates higher risk and may warrant sentinel lymph node biopsy (SLNB) 1

N (Regional Lymph Nodes) Classification

• SLNB is recommended for all patients with T1b or higher (tumors ≥0.8 mm or <0.8 mm with ulceration) according to AJCC 8th edition 1
• The number of involved lymph nodes is the most critical prognostic factor in Stage III disease 1, 4:
  • Single positive node: better prognosis
  • ≥4 positive nodes or nodes >3 cm: consider adjuvant nodal basin radiotherapy 5
• Complete lymph node dissection (CLND) is NOT recommended for sentinel node-positive patients based on recent evidence 1
• For clinically detectable (macroscopic) lymph node metastases, therapeutic lymph node dissection remains indicated 1

M (Distant Metastases) Classification

• Any distant metastasis automatically designates Stage IV disease regardless of primary tumor characteristics 2
• M1 subcategories determine prognosis and treatment approach 2:
  • M1a: distant skin/soft tissue/nonregional nodes (best prognosis)
  • M1b: lung metastases (intermediate prognosis)
  • M1c: non-CNS visceral metastases (worse prognosis)
  • M1d: CNS metastases (worst prognosis)
• Serum LDH must be documented at Stage IV diagnosis as it independently predicts poor outcome 1, 2, 4

Treatment Algorithms Based on TNM Stage

Stage 0-IIA (Lower Risk)

• Wide local excision alone with observation is the standard approach 1
• No adjuvant therapy indicated 1
• Routine imaging not recommended due to very low yield (false positives exceed true positives) 1

Stage IIB-IIC (High Risk)

• Wide local excision with appropriate margins 1
• Adjuvant therapy options (controversial, with evolving recommendations) 1:
  • Clinical trial enrollment is now preferred (55% of expert panel recommendation) 1
  • Anti-PD-1 therapy (nivolumab or pembrolizumab) emerging as standard 1, 6
  • High-dose interferon alfa-2b for 1 year (declining use due to toxicity and unclear overall survival benefit) 1
  • Observation remains acceptable (20% of expert panel) 1

Stage III (Regional Disease)

• Complete surgical resection of involved lymph nodes 1
• Adjuvant immunotherapy is now the preferred standard 1:
  • Nivolumab 480 mg IV every 4 weeks for 1 year (CHECKMATE-76K showed 58% reduction in recurrence risk; HR 0.42) 6
  • Pembrolizumab (alternative anti-PD-1 option) 1
  • Dabrafenib/trametinib for BRAF V600-mutated melanoma 1
• Adjuvant radiotherapy indications 5:
  • ≥4 positive nodes or nodes >3 cm 5
  • Extracapsular extension 4
  • Recurrent disease 5
  • Standard protocol: 30 Gy in 5 fractions over 2.5 weeks (achieves 85-88% 5-year locoregional control) 5

Stage IV (Distant Metastatic Disease)

• BRAF mutation testing is mandatory before initiating systemic therapy 1, 2
• First-line systemic therapy options 1:
  • Anti-PD-1 monotherapy (pembrolizumab or nivolumab) for all patients regardless of BRAF status 1
  • Nivolumab plus ipilimumab combination (median OS not reached vs 19.9 months with ipilimumab alone; HR 0.55) 6
  • BRAF/MEK inhibitor combination (dabrafenib/trametinib) for BRAF V600-mutated disease 1
• Surgical resection or stereotactic radiation should be considered for oligometastatic disease (single or limited metastases) as it offers potential for long-term disease control 1
• Brain metastases management 5:
  • Stereotactic radiosurgery preferred over whole brain radiation therapy 5
  • Hold BRAF/MEK inhibitors 3 days before and after fractionated radiotherapy, 1 day before/after stereotactic radiosurgery 5

Critical Staging Workup Requirements

Initial Assessment by Stage

• Stage 0-IIA: History, physical examination, complete skin examination only 1
• Stage IIB-IIC: Add SLNB consideration 1
• Stage III:
  • Chest X-ray, complete blood count, LDH, alkaline phosphatase 1
  • Abdominal ultrasound and regional lymph node ultrasound 1
  • CT chest/abdomen/pelvis or PET-CT (yield 0.5-3.7% for positive SLNB, 4-16% for clinically positive nodes) 1
• Stage IV:
  • Document all metastatic sites and serum LDH 1, 2
  • Brain MRI for neurological symptoms 1
  • BRAF mutation testing mandatory; NRAS and c-KIT if BRAF wild-type 2

Common Pitfalls and Caveats

Sentinel Lymph Node Biopsy Controversies

• SLNB improves staging and disease-free survival but has not definitively shown overall survival benefit in MSLT-I trial 1
• The procedure has near-zero morbidity when performed by experienced teams 1
• For thin melanomas (<1 mm), SLNB positivity rate is only 2.7-6.2%, making routine use controversial 1
• For thick melanomas (≥4 mm), SLNB positivity is 30-40% and strongly predicts outcome 1

Imaging Overuse

• Routine cross-sectional imaging in Stage I-II disease has very low yield and high false-positive rates leading to unnecessary anxiety and invasive procedures 1
• Imaging should be reserved for symptomatic patients or those with Stage III-IV disease 1

Adjuvant Therapy Evolution

• High-dose interferon alfa-2b improves disease-free survival but NOT overall survival, with significant toxicity 1
• Anti-PD-1 therapy has largely replaced interferon as the adjuvant standard for Stage IIB-IV disease 1, 6
• Pegylated interferon alfa-2b is NOT recommended by expert consensus 1

Radiation Therapy Timing

• Adjuvant radiotherapy is NOT routinely recommended except for specific high-risk features 1, 5
• Consider for desmoplastic melanoma with neurotropism, inadequate margins when re-excision impossible, or bulky nodal disease 1, 5

Prognostic Stratification Beyond Basic TNM

While TNM remains the foundation, additional factors refine prognosis 1, 3:

• Age and sex have prognostic value but are secondary to Breslow thickness 1
• Anatomic site influences outcome (trunk/head worse than extremities) 1
• Time interval to metastases predicts survival in Stage IV disease 1
• Elevated LDH in Stage IV independently predicts worse outcome 1, 2

1, 2, 5, 4, 6, 3