Melanoma has been steadily increasing in incidence worldwide, with risk related to sun exposure. Most melanomas begin in and present with cutaneous disease, but they can also begin in mucosal sites. About half arise in preexisting nevi, but many begin in apparently normal skin. Melanoma can also present in nodal or visceral sites without a known cutaneous or mucosal primary. About 10% of patients with melanoma have a familial history, and mutations in certain genes, such as CDKN2A, have been identified in some families. Ocular melanoma is the most common cancer of the eye, and uveal melanomas have a distinct biology and behavior. Epidemiology, diagnosis, and staging of melanoma are discussed in MKSAP 18 Dermatology.
Advances in systemic therapy during the past decade have resulted in significant improvements in survival for metastatic melanoma patients. These advances include the use of molecular therapy targeted at specific gene mutations and immunotherapy, including the use of immune checkpoint inhibitors.
Melanoma has the potential to behave quite aggressively, but it is a highly curable disease when detected and treated early with simple excision. For localized melanomas, prognosis is related to the depth of invasion, either by Clark level (I to V) or by Breslow's depth. A high mitotic rate, lymphovascular invasion, and the presence of bleeding or ulceration are poor prognostic signs. Surgical resection margins for melanomas do not have to be excessive: 1-cm margins are acceptable for lesions that are less than 1 mm in thickness. Patients with melanomas between 1 mm and 2 mm in thickness should be resected with a 2-cm margin provided that a skin graft is not required for closure. Patients with lesions that are greater than 2 mm in thickness should be resected with 2-cm margins. Early-stage patients can be assessed clinically and do not need radiographic staging (for example, CT and PET) and surveillance.
As the depth of invasion increases, the risk of nodal and ultimately distant metastasis increases. Nodal metastases are uncommon and need not be assessed if the patient has thin lesions with a Breslow depth of less than 1 mm. Assessing for lymph node metastasis with lymphatic mapping and sentinel lymph node biopsy is often recommended for intermediate and thicker melanomas. If the sentinel node is positive, a lymph node dissection commonly yields other positive nodes. Although prophylactic lymphadenectomies or completion node dissections for those with positive sentinel nodes have not definitively shown an overall survival benefit, node dissections can be curative in 20% to 50% of patients who present with or who develop regional nodal disease. The use of interferon as adjuvant therapy for resected high-risk disease has been extensively studied and is FDA approved. Although there is some demonstrated improvement in disease-free survival, the overall survival benefit is uncertain, and this therapy is associated with considerable side effects. Adjuvant ipilimumab (see below) also has shown modest benefit in disease-free survival, but as of yet, no overall survival benefit has been shown. Adjuvant nivolumab has been recently shown to be more effective than ipilimumab in node-positive disease.
For distant metastatic disease, surgery may still play a significant role. Melanoma can present with solitary or oligometastatic disease amenable to resection that is curable in some patients. Standard cytotoxic chemotherapy is associated with low response rates and no longer plays a large role in the treatment of metastatic melanoma. The biologic agents interferon-alfa and interleukin-2 can induce responses in some patients, but they cause considerable toxicity and are generally used only in specialized referral centers. The current focus is on targeted therapy for patients with specific gene mutations and on the use of checkpoint inhibitors of programmed cell death transmembrane proteins.
Approximately one half of melanomas harbor a BRAF gene mutation (most commonly V600E), and another 20% have a MEK or NRAS mutation; all of these mutations activate the mitogen-activated protein kinase pathway. Melanomas with these mutations may respond to oral therapy with the BRAF inhibitors vemurafenib and dabrafenib. Combining BRAF inhibitors with MEK inhibitors trametinib and cobimetinib improves the rate and duration of response. These are available as combined oral agents.
In addition to the efficacy of BRAF inhibitors, the use of immune checkpoint inhibitors has revolutionized the therapy and prognosis of patients with metastatic melanoma. Cellular immunity is based on T cells recognizing peptide fragments expressed on the surface of antigen-presenting cells when bound to histocompatibility complex molecules. Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a potent down-regulator of this process. CTLA4 is stimulated by T-cell activation and various cytokines, serving as an inhibitory factor or braking “checkpoint” on immune activation. The antibody against CTLA4, ipilimumab, can result in dramatic tumor response, albeit in a small percentage of patients. Tumor response is independent of BRAF status.
The programmed cell death-1 (PD-1) receptor is another transmembrane protein that acts as an inhibitory molecule when bound to the PD-ligand 1 and stops tumor cell apoptosis while down-regulating other aspects of T-cell immune response. Nivolumab and pembrolizumab are both anti–PD-1 antibodies that can result in significant melanoma response rates with sometimes durable response and dramatic survival improvement. Ipilimumab alone has a relatively low response rate and is associated with considerable toxicity, with various immune-related adverse events that can include colitis, hepatitis, pneumonitis, and endocrine insufficiency syndromes. Similar side effects can occur with nivolumab and pembrolizumab but are less frequent, and these antibodies are associated with a higher response rate (30% to 40%). Combining ipilimumab with nivolumab improves results compared with ipilimumab or nivolumab alone. The best dosage, schedule, and sequence for these newer agents continue to be explored.
All patients should be encouraged to perform skin self-examinations as well as receive annual skin evaluations by a dermatologist for life. Patients with early-stage melanoma need not undergo routine blood testing or imaging studies in the absence of signs or symptoms.