Management

Current management of malignant melanoma involves an initial excision biopsy and histological examination.

Following biopsy, surgery has been traditionally performed, though excision margins are controversial and influenced by functional and cosmetic considerations.

To confirm the diagnosis of the disease, histological examination is performed. The tumor, nodes, metastases (TNM) system of American Join Committee of Cancer (AJCC) is used for melanoma staging:

• stage 0 - the melanoma is in situ, meaning that it is in the epidermis but has not spread to the dermis
• stage IA - the melanoma is less than 1.0 mm in thickness. It is not ulcerated and has a mitotic rate of less than 1/mm2. It has not been found in lymph nodes or distant organs
• stage IB - the melanoma is less than 1.0 mm in thickness and is ulcerated or has a mitotic rate of at least 1/mm2, or it is between 1.01 and 2.0 mm and is not ulcerated. It has not been found in lymph nodes or distant organs
• stage IIA - the melanoma is between 1.01 mm and 2.0 mm in thickness and is ulcerated, or it is between 2.01 and 4.0 mm and is not ulcerated. It has not been found in lymph nodes or distant organs
• stage IIB - the melanoma is between 2.01 mm and 4.0 mm in thickness and is ulcerated, or it is thicker than 4.0 mm and is not ulcerated. It has not been found in lymph nodes or distant organs
• stage IIC - the melanoma is thicker than 4.0 mm and is ulcerated. It has not been found in lymph nodes or distant organs
• stage IIIA - The melanoma can be any thickness, but it is not ulcerated. It has spread to 1 to 3 lymph nodes near the affected skin area, but the nodes are not enlarged and the melanoma is found only when they are viewed under the microscope. There is no distant spread
• stage IIIB - The melanoma can be any thickness and is ulcerated. It has spread to 1 to 3 lymph nodes near the affected skin area, but the nodes are not enlarged and the melanoma is found only when they are viewed under the microscope. There is no distant spread
• stage IIIC - The melanoma can be any thickness and is ulcerated. It has spread to 1 to 3 lymph nodes near the affected skin area. The nodes are enlarged because of the melanoma. There is no distant spread
• stage IV - the melanoma has spread beyond the original area of skin and nearby lymph nodes to other organs such as the lung, liver, or brain, or to distant areas of the skin, subcutaneous tissue, or distant lymph nodes. Neither spread to nearby lymph nodes nor thickness is considered in this stage, but typically the melanoma is thick and has also spread to the lymph nodes

Treatment principles based on stage have been detailed (3):

Managing stages 0-II melanoma

• excision (1)
  • a clinical margin of at least 0.5 cm should be considered when excising stage 0 melanoma.
  • if excision for stage 0 melanoma does not achieve an adequate histological margin, discuss further management with the multidisciplinary team
  • excision with a clinical margin of at least 1 cm should be offered to people with stage I melanoma
  • offer excision with a clinical margin of at least 2 cm to people with stage II melanoma
• topical imiquimod should be considered to treat stage 0 melanoma in adults if surgery to remove the entire lesion with a 0.5 cm clinical margin would lead to unacceptable disfigurement or morbidity

Managing stage III melanoma

• completion lymph node dissection for stage III melanoma (1)
  • do not routinely offer completion lymph node dissection to people with stage III melanoma and micrometastatic nodal disease detected by SLNB unless:
    • there are factors that might make recurrent nodal disease difficult to manage, and
    • after discussion with the person and the specialist skin cancer multidisciplinary team
  • examples of factors that might make recurrent nodal disease difficult to manage include melanoma of the head and neck, people for whom stage III adjuvant therapies are contraindicated, or when regular follow-up is not possible
• therapeutic lymph node dissection for stage III melanoma
  • therapeutic lymph node dissection should be offered to people with palpable stage IIIB to IIID melanoma, or cytologically or histologically confirmed nodal disease detected by imaging

Adjuvant treatment of advanced or metastatic melanoma

Adjuvant therapy includes:

• immunotherapy: melanoma vaccines, interferons (IFN alfa-2), IL-2
• radiation therapy
• chemotherapy
• biochemotherapy: combination of chemotherapy with cytokine therapy

Use of drugs in this context is extremely specialised - and is a rapidly evolving field. However some examples of drugs used in adjuvant therapy include:

• recombinant interferon alfa-2b
  • mainly used in patients, who are at high risk of systemic recurrence after surgery, e.g., patients with primary or recurrent lymph node involvement
  • mediates antiproliferative effects including suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells
• peginterferon Alfa-2b
  • an option for the adjuvant treatment of stage III melanoma with lymph node involvement in adults who have had complete resection (1)
  • a pleiotropic cytokine. IFN-PEG-2b is characterized by the incorporation of a polyethylene glycol molecule (pegylation) to IFNalpha-2ß, which makes it larger and decreases its metabolism, with the benefit of prolonging plasma concentration
• dabrafenib, vemurafenib
  • inhibitors of RAF kinases are indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation
• trametinib
  • indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations
  • a reversible inhibitor of MEK1 and MEK2 activation and of MEK1 and MEK2 kinase activity
• ipilimumab
  • indicated for the treatment of advanced melanoma in adults.
  • a T-cell potentiator that specifically blocks the inhibitory signal of CTLA-4, resulting in T-cell activation, proliferation, and lymphocyte infiltration into tumors, leading to tumour cell death
  • enhancing T-cell mediated immune response

Notes:

• cytotoxic agents have been disappointing although imidazole carboxamide - DTIC - and vindesine may be used
  • NICE suggest considering the use of dacarbazine for people with stage IV metastatic melanoma if immunotherapy or targeted therapy are not suitable
• involved regional nodes are removed by block dissection and though prophylactic lymph node dissection is commonly practiced in the USA for thick tumours, it does not appear to improve survival and is rarely practised in the UK
• recurrent tumours and deeply invasive ones on a limb may respond to limb perfusion. The affected limb is arterially perfused with a cytotoxic agent for example, Melphalan. Recurrence is reduced but anaemia may be a serious side effect due to penetration of the bone marrow by the cytotoxic agent
• melanoma is not a homogenous disease
  • composed of biologically distinct subtypes
  • mutation in the BRAF gene plays a significant role in development of melanoma. RAF proteins are a family of protein-serine/threonine kinases
    • oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway, a signal transduction cascade that participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, differentiation, proliferation, and transformation to the cancerous state
    • MEK proteins are upstream regulators of the ERK pathway, which promotes cellular proliferation
    • BRAF V600E mutations cause constitutive activation of the BRAF pathway, which includes MEK1 and MEK2
      • over 90 % of all BRAF mutations in melanoma are caused by a glutamic-acid-for-valine substitution at position 600 (V600E)
      • identification of BRAF V600 somatic mutations in melanoma led to the development of molecularly targeted therapies, which improved the prognosis of metastatic melanoma patients compared to chemotherapy
• most patients are followed up for 10 years. Patients are seen at regular intervals: 3 monthly for the first 2 years and then 6 monthly.

Reference:

• NICE (July 2022).Melanoma: assessment and management
• Balch CM et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27: 6199-206.
• Drummer R et al. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2015; 26: v126-v32