# Melanoma: Surgical Principles

## Introduction

Melanoma is the deadliest form of skin cancer and the fifth most common cancer in the United States, with incidence rising steadily over the past several decades. While melanoma accounts for only 1% of skin cancers, it is responsible for the majority of skin cancer deaths. Surgery is the primary treatment for localized melanoma, and the surgeon's understanding of appropriate excision margins, sentinel lymph node biopsy, and the role of adjuvant therapies is critical to optimizing patient outcomes.

## Epidemiology and Risk Factors

Approximately 100,000 new cases of melanoma are diagnosed annually in the United States, with a lifetime risk of approximately 1 in 38. Ultraviolet radiation exposure is the most significant modifiable risk factor, and intermittent, intense sun exposure producing blistering sunburns carries higher risk than chronic exposure. Phenotypic risk factors include fair skin (Fitzpatrick type I-II), red or blonde hair, blue eyes, freckling tendency, and an inability to tan. A total nevus count exceeding 50, the presence of dysplastic (atypical) nevi, and giant congenital melanocytic nevi all increase risk. Family history is relevant in 8-12% of melanoma patients who have a first-degree relative with melanoma, and associated germline mutations include CDKN2A (p16), CDK4, BAP1, and MC1R variants. Immunosuppression, particularly in organ transplant recipients, confers a 2-8 fold increased risk. Patients with a history of melanoma have a 5-10% risk of developing a second primary melanoma.

## Clinical Features and Diagnosis

### ABCDE Criteria

The ABCDE criteria guide clinical evaluation of suspicious pigmented lesions: Asymmetry of the lesion, Border irregularity, Color variation with multiple shades of brown, black, red, white, or blue, Diameter greater than 6 mm (though melanomas can be smaller), and Evolving change in size, shape, or color over time.

### Subtypes

Superficial spreading melanoma is the most common type, accounting for 70% of cases. It demonstrates a radial growth phase before vertical invasion and occurs on intermittently sun-exposed areas. Nodular melanoma accounts for 15-30% of cases and is aggressive, exhibiting a vertical growth phase from the outset. It presents as a raised, darkly pigmented or amelanotic nodule and is identified by the "EFG" criteria: Elevated, Firm, and Growing. Lentigo maligna melanoma accounts for 5-10% of cases, arises in chronically sun-exposed areas such as the face and forearms in elderly patients, has a prolonged radial growth phase, and is associated with lentigo maligna (melanoma in situ). Acral lentiginous melanoma accounts for 5% of cases and occurs on the palms, soles, and subungual regions. It is the most common type in dark-skinned individuals, is not related to UV exposure, and the Hutchinson sign (pigment extending to the nail fold) is a characteristic finding. Desmoplastic melanoma is a spindle cell variant with neurotropic features that has a high local recurrence rate but a lower rate of lymph node metastasis.

### Biopsy Principles

Excisional biopsy with 1-3 mm margins is preferred for suspicious pigmented lesions, as it allows full assessment of Breslow thickness, ulceration, and mitotic rate. Incisional or punch biopsy is acceptable for large lesions, facial lesions, or subungual melanoma where excisional biopsy is impractical, and the thickest or most atypical area should be sampled. Shave biopsy should be avoided when melanoma is suspected, as it may transect the deep margin and compromise accurate Breslow depth measurement. A wide excision should never be performed without a tissue diagnosis.

<image>Clinical and dermoscopic illustration showing the four main melanoma subtypes - superficial spreading, nodular, lentigo maligna, and acral lentiginous - with characteristic appearance, typical anatomic location, and key histologic features including Breslow depth measurement from the granular layer to the deepest point of invasion</image>

## Staging (AJCC 8th Edition)

### Key Prognostic Factors

Breslow thickness is the single most important prognostic factor, measured in millimeters from the granular layer to the deepest invasive melanoma cell. The presence of ulceration upstages the T category and is an independent adverse prognostic factor. Mitotic rate was removed from formal staging in the AJCC 8th edition but remains an important prognostic variable. Sentinel lymph node status is the most important prognostic factor for recurrence and survival after Breslow thickness.

### T Classification

T1 melanoma is 1.0 mm or less in thickness, subdivided into T1a (less than 0.8 mm without ulceration) and T1b (less than 0.8 mm with ulceration or 0.8-1.0 mm). T2 is greater than 1.0 mm to 2.0 mm, T3 is greater than 2.0 mm to 4.0 mm, and T4 is greater than 4.0 mm, each subdivided into "a" (without ulceration) and "b" (with ulceration).

### N Classification

The N classification is based on the number of involved regional lymph nodes and the presence of in-transit, satellite, or microsatellite metastases.

### Stage Groupings

Stage I-II represents localized disease without nodal or distant metastases. Stage III indicates regional disease with lymph node involvement or in-transit metastases. Stage IV denotes distant metastatic disease, sub-classified by site as M1a (skin, soft tissue, or distant lymph nodes), M1b (lung), M1c (non-CNS visceral), and M1d (CNS), with further stratification by LDH level.

## Wide Local Excision

Wide local excision is the definitive surgical treatment, with margins determined by Breslow thickness to reduce local recurrence:

| Breslow Thickness | Recommended Excision Margin |
|-------------------|---------------------------|
| In situ | 0.5–1.0 cm |
| ≤1.0 mm | 1.0 cm |
| 1.01–2.0 mm | 1–2 cm |
| >2.0 mm | 2.0 cm |

The recommended margins per NCCN Guidelines are 0.5-1.0 cm for melanoma in situ, 1.0 cm for Breslow thickness of 1.0 mm or less, 1-2 cm for Breslow thickness of 1.01-2.0 mm, and 2.0 cm for Breslow thickness greater than 2.0 mm. The depth of excision extends down to but does not include the deep fascia, as fascia resection does not improve outcomes. Narrower margins may be necessary in cosmetically or functionally sensitive areas such as the face and digits with appropriate counseling, and Mohs micrographic surgery or staged excision may be used for lentigo maligna on the face. Primary closure is preferred, with local flaps or skin grafts used when primary closure is not feasible.

## Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy is recommended for melanoma with Breslow thickness of 0.8 mm or greater, or for thinner melanomas with adverse features such as ulceration, high mitotic rate, lymphovascular invasion, or young age. The technique involves preoperative lymphoscintigraphy with technetium-99m sulfur colloid to identify the draining basin or basins, followed by intraoperative identification with a gamma probe and/or blue dye (isosulfan blue or methylene blue) or indocyanine green. The false-negative rate is 5-10%, and the identification rate exceeds 95% at experienced centers. The MSLT-I trial demonstrated that sentinel lymph node biopsy provides important staging information and identifies patients who may benefit from completion lymphadenectomy or adjuvant therapy, with improved disease-free survival though no overall survival benefit for the entire group. Pathologic assessment uses serial sectioning with H&E staining and immunohistochemistry for S-100, HMB-45, and Melan-A.

<image>Illustration demonstrating the sentinel lymph node biopsy technique for melanoma, showing injection of radiotracer and blue dye around the primary tumor site, lymphoscintigraphy imaging identifying the sentinel node in the draining basin, and intraoperative identification using a handheld gamma probe</image>

## Completion Lymph Node Dissection

The DeCOG-SLT and MSLT-II trials demonstrated that completion lymph node dissection after positive sentinel lymph node biopsy does not improve melanoma-specific survival compared to observation with ultrasound surveillance of the nodal basin. Current practice therefore favors observation with nodal basin ultrasound every 4-6 months for most patients with a positive sentinel node, though completion lymph node dissection may still be considered for high-volume nodal disease or extranodal extension. Therapeutic lymph node dissection remains indicated for clinically palpable, biopsy-proven nodal disease.

## Adjuvant and Systemic Therapy

### Adjuvant Therapy for Stage III

Immune checkpoint inhibitors including pembrolizumab (anti-PD-1) and nivolumab (anti-PD-1) significantly improve recurrence-free survival in resected stage III melanoma, as demonstrated by the KEYNOTE-054 and CheckMate-238 trials. BRAF/MEK targeted therapy with dabrafenib plus trametinib is effective for BRAF V600E/K-mutant stage III melanoma and improves relapse-free survival as shown in the COMBI-AD trial. Adjuvant radiation is considered for desmoplastic melanoma, close margins, or extensive nodal disease with extracapsular extension.

### Stage IV / Unresectable Disease

Immune checkpoint inhibitor combination therapy with ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) achieves durable responses in 50-60% of patients, while single-agent anti-PD-1 achieves response rates of 35-45%. BRAF/MEK inhibitor combinations for BRAF-mutant melanoma (vemurafenib/cobimetinib, dabrafenib/trametinib, encorafenib/binimetinib) produce rapid response rates but eventual resistance develops. Neoadjuvant immunotherapy is an emerging paradigm for resectable stage III-IV disease, with pathologic complete response rates of 40-60% using combination nivolumab/ipilimumab as demonstrated in the NADINA and SWOG S1801 trials.

## Special Situations

Subungual melanoma is treated with amputation at the level of the DIP joint for fingers or the IP joint for the thumb and great toe; more proximal amputation is not beneficial. Mucosal melanoma is rare and aggressive, treated with wide excision when feasible, though recurrence rates are high and adjuvant therapy should be considered. Ocular melanoma is managed by ophthalmologic oncology; hepatic metastases are common, and its biology is distinct from cutaneous melanoma. Unknown primary melanoma, presenting with nodal or distant metastases without an identifiable primary, is treated similarly to known primary melanoma of equivalent stage.

## Key Clinical Pearls

Excisional biopsy is the gold standard for suspicious pigmented lesions, and shave biopsy should be avoided when melanoma is suspected to preserve accurate Breslow depth assessment. Wide excision margins are determined by Breslow thickness, not clinical appearance, and NCCN guidelines should be followed. Sentinel lymph node biopsy is the most important staging procedure for melanomas 0.8 mm or thicker and guides adjuvant therapy decisions. Completion lymph node dissection is no longer mandatory for positive sentinel nodes, and ultrasound surveillance is the standard approach per MSLT-II. Adjuvant immunotherapy with anti-PD-1 agents has transformed the management of resected stage III melanoma and should be offered to all eligible patients.

## References

1. Swetter SM, Thompson JA, Albertini MR, et al. NCCN Guidelines: Melanoma: Cutaneous, Version 2.2024. *J Natl Compr Canc Netw*. 2024.
2. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma (MSLT-II). *N Engl J Med*. 2017;376(23):2211-2222.
3. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (KEYNOTE-054). *Lancet Oncol*. 2018;19(10):1325-1338.
4. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. *CA Cancer J Clin*. 2017;67(6):472-492.