Pathogenesis of Internal Melanoma
Internal melanoma develops from melanocytes that are present in non-cutaneous sites of the body, including mucous membranes, the eyes, and the central nervous system. While cutaneous melanoma is more common and well-studied, internal melanomas arise from the same cell type but in different anatomical locations.
Origin and Development
Internal melanomas develop from melanocytes that originate from the neural crest during embryonic development. These melanocytes migrate to various locations throughout the body, including:
- Mucous membranes (oral, nasal, genital, anorectal)
- Ocular tissues
- Leptomeninges and central nervous system
- Gastrointestinal tract
- Genitourinary tract
- Lymphatic tissues
Unlike cutaneous melanoma, which is strongly associated with UV light exposure 1, internal melanomas typically develop through different pathogenic mechanisms since these tissues are not exposed to UV radiation.
Molecular Pathogenesis
The molecular landscape of internal melanomas differs from that of cutaneous melanomas:
Mutation Profiles: While cutaneous melanomas frequently harbor BRAF and NRAS mutations, internal melanomas show different genetic alterations 1:
Genetic Factors: Family history of melanoma, prior melanoma, and certain genetic mutations can increase risk for both cutaneous and internal melanomas 1
Histopathological Features
Internal melanomas share some histological features with cutaneous melanomas but may present with unique characteristics:
- Architectural features include asymmetry, confluence of growth, marked cellularity, and poor circumscription 2
- Cytological features include irregular and thick nuclear membranes and prominent nucleoli 2
- Histology reports should include information on maximum thickness, mitotic rate, presence of ulceration, and regression 1
Anatomical Site-Specific Pathogenesis
Central Nervous System Melanoma
- Primary CNS melanomas most commonly develop in the leptomeninges 3
- Intramedullary melanomas of the spinal cord are rare but can occur 3
- These tumors develop from melanocytes normally present in the leptomeninges
Mucosal Melanoma
- Arises from melanocytes present in mucous membranes
- Different molecular profile compared to cutaneous melanomas
- Often diagnosed at later stages due to hidden locations
Ocular Melanoma
- Develops from melanocytes in the uveal tract
- Has distinct genetic alterations compared to cutaneous melanoma
- Metastatic patterns differ from cutaneous melanoma (preferential liver metastasis)
Cellular Plasticity and Progression
Recent research highlights the role of cellular plasticity in melanoma progression:
- Melanomas exhibit phenotypic plasticity and trans-differentiation along vascular and neural lineages 4
- Stem cell-like properties and EMT-like transitions contribute to drug resistance 4
- Depending on the tissue site and oncogenic mutations, melanoma can arise from either melanocyte stem cells or differentiated melanocytes 4
Epigenetic Factors
Epigenetic changes play a crucial role in internal melanoma development:
- Alterations in microRNA expression can affect cell growth, differentiation, and death 5
- Epigenetic modifications can influence melanoma progression and treatment resistance 5
- These changes have become novel targets for treating melanoma patients 5
Clinical Implications
Understanding the pathogenesis of internal melanoma is critical for:
- Early detection through appropriate imaging and diagnostic techniques
- Selection of appropriate treatment strategies based on molecular profiles
- Development of targeted therapies specific to the molecular drivers of internal melanomas
Internal melanomas generally have poorer prognosis than cutaneous melanomas due to delayed diagnosis, anatomical location challenges for surgical resection, and different molecular profiles that may respond differently to current therapies 3.