Metastatic Melanoma

Excerpt

The incidence of primary cutaneous melanoma has increased steadily for several decades and remains the most lethal form of cutaneous neoplasm. If diagnosed in the early stages, melanoma has high survival rates, approximating 94%. According to the National Cancer Institute (NCI), from 2014 to 2018, the incidence of metastatic melanoma was estimated to be 0.9 per 100,000. Mucosal and ocular melanomas typically have worse prognoses. Melanoma was once considered a very aggressive cancer that was resistant to traditional therapies such as chemotherapy, radiation, and even single-agent targeted therapies in their early stages of development. A dramatic improvement in the quality of life and overall survival of patients with metastatic melanoma has resulted after the advent of various new combinations of targeted therapies and different modalities of immunotherapies.

Melanoma is distinct from nonmelanoma skin cancers because it spreads locally, regionally, and distantly. An individual's risk of metastasis is directly related to the depth of invasion and ulceration of the primary lesion. The early stages of cancer metastasis involve invasion, angiogenesis, extravasation, dissemination, and colonization of the target organ. Patients with clinically node-negative disease and those with negative sentinel lymph node biopsy can still present with distant metastatic disease. Moreover, complete lymph node dissection has not been proven to offer a survival benefit to patients with node-positive disease.

There are reports of the transfer of melanoma from a donor to a recipient after an organ transplant, even when the transplant was performed years after the donor was diagnosed with melanoma. Such distant seeding suggests the possibility of early subclinical micrometastasis in melanoma. According to the American Society of Clinical Oncology (ASCO), only about 4% of melanomas are present with metastasis. Therefore, distant metastasis may involve several factors, including tumor microenvironment and immune surveillance. A search for metastasis-specific genetic alterations in melanoma has not been particularly successful. However, copy number alterations, MITF amplification, TERT promoter mutations, and CDKN2A loss occur at higher frequencies in metastatic melanomas than in primary melanomas. Melanoma has a propensity for spreading to the central nervous system (CNS), leading to high morbidity, mortality as well as resistance to therapy due to the blood-brain barrier.