Malignant melanoma is the leading cause of skin-related death in Caucasians, but rare in populations with darker pigmented skin color. More than 300,000 melanoma skin cancers occurred globally in 2020. Over the last decade, the annual cases of melanoma have increased by nearly 50% worldwide. In the Nordic countries, there has been a more than a four-fold increase during the period 1980-2016. Increases in incidence rates vary considerably across the world among different ethnicities and geographical locations. Melanoma is disproportionally reported among fair-skinned Caucasians which reflects decreased photoprotection from reduced melanin and their sensitivity to sun exposure. Australia, New Zealand, and Nordic countries (Norway, Denmark, and Sweden) have the highest rate of melanoma. Habits related to sun exposure, especially short intermittent exposure with sunburns appear to be the main risk factor. Hereditary risk factors including skin type are also important. Other important risk factors include the number of melanocytic nevi and the number of dysplastic melanocytic nevi. Inherited forms of melanoma are less frequent and are associated with a germline mutation in several cancer-related genes (e.g. CDKN2A, CDK4, MITF, or BAP1).
Primary cutaneous malignant melanoma is thought to develop in a multi-step process. Precursor lesions, such as dysplastic melanocytic nevi develop into a melanoma in situ and further into invasive melanoma and eventually metastatic melanoma. Classification of melanoma is based on histological features, the role of UV damage in its development, and genetic features. The most frequent histological subtypes are superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral melanoma. Rare subtypes are melanomas arising in blue nevus, congenital melanocytic nevus, or in other rare forms of melanocytic nevi.
The histopathological features of malignant melanomas may vary. A typical feature, often facilitating the diagnosis of melanoma, is the presence of a pagetoid growth pattern. The pagetoid growth pattern is characterized by the growth of melanoma cells in the upper layers of the epidermis (as opposed to the localization of normal melanocytes in basal layers of the epidermis). The melanoma cells can be large and rich in the cytoplasm, small or even spindly. In a subset of melanomas, there are areas with abundant melanin and in other melanomas, melanin pigment is scarce or absent. Tumor cell nuclei are enlarged, often with a prominent nucleolus and mitoses are present at a variable degree.
Immunohistochemistry is often used to distinguish malignant melanoma from other tumor types. Traditionally, antibodies towards different S100 proteins have been used as immunohistochemical markers of melanocytes, however, antibodies also stain positive in e.g. Langerhans cells and nerve fibers. Other markers such as Melan-A (MART1, MLANA), tyrosinase (TYR), melanogenesis associated transcription factor (MITF), and SOX10 stain melanocytes more specifically and are useful to determine if a tumor is of melanocytic origin. Proliferation markers are also widely used in the differential diagnostics of melanocytic lesions with uncertain malignant potential. The most accepted markers for cells active in the cell cycle are antibodies binding to Ki-67 (MKI67) and the presence of Ki-67 positive melanocytic cells is often used in routine pathology to distinguish malignant melanoma from benign melanocytic tumors. Molecular investigations of melanoma and detection of mutations in BRAF gene (mainly V600 codon) play a role in the selection of patients for targeted therapy with anti-BRAF inhibitors. The finding of mutations in the promoter region in TERT gene, homozygous deletion of CDKN2A gene, or several other deletions and amplifications (CCND1, C-MYC, BAP1, PTEN, or genome-wide aberrations) may be helpful in the diagnosis of melanocytic lesions with uncertain malignant potential.
Patients that present with an advanced tumor stage at a time for diagnosis and patients with relapse of melanoma after surgical removal generally have a poor prognosis. In patients diagnosed with localized disease, the most important prognostic indicator is the thickness of the tumor at the time of diagnosis. The tumor thickness is measured in mm (according to a system initially described by Breslow) and is the dominating parameter for determining the tumor stage (T-stage) of melanoma. Other prognostic factors include mitotic rate and ulceration as well as clinical factors such as patient age, gender, the anatomic site of the primary tumor, and presence of regional lymph node- or distant metastasis. The 5-year survival rate is 99% for patients with localized disease and 27% for patients with advanced disease (presence of distant metastasis). The survival of patients with advanced disease has improved in the past decade with the development of targeted- and immunotherapy options.