Pathophysiology
Summary
Melanoma arises from melanin-producing melanocytes situated in the stratum basale of the epidermis. UV exposure, specifically from UVA & UVB rays, is the most significant environmental risk factor for melanoma, especially intense, intermittent sun exposures (peeling sunburns), particularly during childhood. Light skin, red hair, freckles, & light eyes, as well as, immunosuppression and the presence of numerous or atypical nevi amplify risk.
Genetic factors also significantly influence melanoma risk. Familial melanoma is often linked to CDKN2A mutations, which encode the p16 tumor suppressor, resulting cell cycle progression. Xeroderma pigmentosum and acquired mutations in the BRAF proto-oncogene (often V600E mutations) are also increase the risk of melanoma. Vemurafenib, which targets the mutated BRAF, is used in patients with the BRAF mutation.
Melanomas initially spread horizontally, displaying radial growth along the dermo-epidermal junction. Superficial spreading melanomas are the most prevalent, extending upwards into the superficial epidermis following radial growth phase (melanoma in situ). Superficial melanomas are most common on back and legs in sun-exposed areas, and appear as flat irregular lesions with grey, brown, or black color.
Following horizontal growth phase, melanomas advance to vertical growth phase by breaking through basement membrane into dermis. The depth in the vertically-growing melanomas can be estimated using Breslow’s thickness, which serves as a key metastasis risk predictor.
Melanoma's diverse subtypes showcase varied characteristics. Nodular melanoma, notorious for swift vertical growth, presents with darkly pigmented nodules and has poor prognosis. In contrast, lentigo maligna, often found in the elderly with sun-damaged skin, exhibits prolonged radial growth. Acral lentiginous melanoma, predominant in dark-skinned individuals, manifests as dark spots on sun-sheltered areas, such as the palms or soles. This subtype of melanoma can present with subungual melanomas—dark streaks under the fingernails or toenails—and has a very poor prognosis.
Melanoma cells arise from neural crest cells and exhibit hallmark histopathological features like numerous mitotic figures, large nuclei & eosinophilic nucleoli, and positive staining for S-100 protein. Identification of melanomas adheres to the ABCDE mnemonic: Asymmetry, irregular or notched Borders, Color variability, Diameter typically ≥ 6 mm, and swift Evolution in appearance.
Lesson Outline
Don't stop here!
Get access to 155 more Pathophysiology lessons & 13 more medical school learning courses with one subscription!
FAQs
Melanocytes are specialized cells situated in the stratum basale of the epidermis, responsible for producing melanin, a pigment that shields the skin from UV radiation. They create melanin and store it small organelles known as melanosomes. These melanosomes are then transported to the surrounding keratinocytes, dispersing melanin throughout the epidermis. Melanoma arises from the neoplastic proliferation of melanocytes, often instigated by UV-induced DNA damage in skin cells.
The BRAF proto-oncogene is a common acquired genetic mutation in melanoma. The most frequent mutation involves the substitution of valine for glutamic acid, known as the V600E mutation. This mutation activates the MAP-kinase and ERK signaling pathways, leading to unchecked cell cycle progression and melanocyte growth. Vemurafenib is a drug designed to target and inhibit this mutated BRAF, effectively treating melanomas with this specific mutation by halting the aberrant signaling pathway and tumor growth.
Melanomas initially exhibit a ‘radial growth’ phase, expanding laterally in the epidermis along the dermoepidermal junction. They then transition to the ‘vertical growth’ phase, penetrating the basement membrane to invade the dermis. Once melanoma cells breach the basement membrane and enter the dermis, they are deemed malignant. The depth of this invasion, known as Breslow's thickness, is a crucial predictor of metastasis risk: the deeper the melanoma, the higher the metastatic potential. Melanomas first spread to regional lymph nodes before metastasizing to distant organs, notably the brain and lungs.
Melanomas possess distinct characteristics. They are asymmetrical, have irregular or notched borders, and exhibit color variability within the same lesion. Typically, they are large, often exceeding a diameter of 6mm. Melanomas also undergo rapid changes or "evolution" over time. Different melanoma subtypes can vary in appearance, from superficial spreading melanomas that are flat and irregularly colored to nodular melanomas with dark pigmented nodules and acral lentiginous melanomas that manifest as dark spots on palms, soles, or beneath nails.
UV exposure, especially during childhood and from intense sunburns, is the primary environmental risk factor for melanoma. Genetic predispositions include having light skin, red hair, freckles, light eyes, as well as numerous or atypical nevi. A family history of melanoma, especially linked to mutations in the CDKN2A gene, significantly increases risk. Conditions like xeroderma pigmentosum, which impairs DNA repair, and immunosuppressive states also increase the risk of developing melanoma.
MCAT® is a registered trademark of the Association of American Medical Colleges. The United States Medical Licensing Examination (USMLE®) is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). NAPLEX® is a registered trademark of the National Association of Boards of Pharmacy. PANCE© is a registered trademark of the National Commission on Certification of Physician Assistants. NCLEX® is a registered trademark and service mark of the National Council of State Boards of Nursing, Inc. None of the trademark holders are endorsed by nor affiliated with Sketchy or this website.
