Metastatic melanoma
Introduction
Metastatic melanoma is an advanced form of melanoma, a type of skin cancer that originates in the melanocytes, the cells responsible for producing melanin, the pigment that gives skin its color. When melanoma spreads beyond its original site to other parts of the body, it is termed metastatic. This condition is known for its aggressive nature and poses significant challenges in terms of treatment and prognosis.
Pathophysiology
Melanoma arises from genetic mutations in melanocytes, often triggered by ultraviolet radiation exposure. These mutations can lead to uncontrolled cell growth and the formation of malignant tumors. In metastatic melanoma, cancer cells break away from the primary tumor and travel through the lymphatic system or bloodstream to distant sites, such as the lungs, liver, brain, and bones.
The metastatic process involves several steps: local invasion, intravasation into blood vessels, survival in circulation, extravasation into new tissue, and proliferation at the secondary site. Key molecular pathways implicated in melanoma metastasis include the MAPK/ERK pathway, PI3K/AKT pathway, and Wnt signaling pathway. Mutations in genes such as BRAF, NRAS, and KIT are common in melanoma and contribute to its metastatic potential.
Clinical Presentation
The clinical presentation of metastatic melanoma varies depending on the organs involved. Common symptoms include:
- **Cutaneous manifestations**: New skin lesions or changes in existing moles, such as asymmetry, border irregularity, color variation, diameter enlargement, and evolving nature.
- **Lymphadenopathy**: Swelling of lymph nodes, often palpable in the neck, armpits, or groin.
- **Respiratory symptoms**: Persistent cough, shortness of breath, or chest pain if the lungs are affected.
- **Neurological symptoms**: Headaches, seizures, or cognitive changes if metastasis occurs in the brain.
- **Hepatic symptoms**: Jaundice, abdominal pain, or weight loss indicating liver involvement.
- **Skeletal symptoms**: Bone pain or fractures due to bone metastases.
Diagnosis
The diagnosis of metastatic melanoma involves a combination of clinical examination, imaging studies, and histopathological analysis.
- **Dermatological examination**: A thorough skin examination is crucial for identifying suspicious lesions.
- **Biopsy**: Histological examination of the primary tumor and metastatic sites confirms the diagnosis. Techniques include excisional biopsy, punch biopsy, and fine-needle aspiration.
- **Imaging**: Computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans are used to assess the extent of metastasis.
- **Molecular testing**: Genetic testing for mutations in BRAF, NRAS, and KIT guides targeted therapy decisions.
Treatment
The treatment of metastatic melanoma has evolved significantly with the advent of targeted therapies and immunotherapies. Traditional treatments such as chemotherapy and radiation therapy are now supplemented or replaced by more effective options.
Targeted Therapy
Targeted therapies focus on specific genetic mutations within melanoma cells.
- **BRAF inhibitors**: Drugs like vemurafenib and dabrafenib target the BRAF V600E mutation, inhibiting the MAPK/ERK pathway and reducing tumor growth.
- **MEK inhibitors**: Often used in combination with BRAF inhibitors, MEK inhibitors like trametinib block downstream signaling in the MAPK pathway.
- **KIT inhibitors**: For melanomas with KIT mutations, drugs such as imatinib may be effective.
Immunotherapy
Immunotherapy harnesses the body's immune system to fight cancer cells.
- **Checkpoint inhibitors**: Drugs like ipilimumab, nivolumab, and pembrolizumab block immune checkpoints (CTLA-4, PD-1) to enhance T-cell response against melanoma cells.
- **Cytokine therapy**: Interleukin-2 (IL-2) can stimulate immune activity, though its use is limited by significant side effects.
Other Treatments
- **Surgery**: Surgical resection may be considered for isolated metastases or to alleviate symptoms.
- **Radiation therapy**: Used for palliation or in combination with other treatments, particularly for brain metastases.
Prognosis
The prognosis for metastatic melanoma varies based on several factors, including the location and number of metastases, the patient's overall health, and response to treatment. Historically, metastatic melanoma had a poor prognosis, with a median survival of less than a year. However, advances in targeted therapy and immunotherapy have improved outcomes, with some patients achieving long-term remission.
Research and Future Directions
Ongoing research aims to improve the understanding and treatment of metastatic melanoma. Areas of focus include:
- **Biomarkers**: Identifying biomarkers for early detection and treatment response.
- **Combination therapies**: Exploring combinations of targeted therapies and immunotherapies to enhance efficacy.
- **Novel agents**: Developing new drugs that target different pathways or mechanisms of resistance.