Melanoma, primarily seen in fair-skinned, sun-exposed adults, is distinguished by the uncontrolled growth of atypical melanocytes, frequently manifesting the BRAF V600 mutation histologically and is typified by T1 hyperintensity.
Description
Melanoma is a highly aggressive malignancy that originates from melanocytes, cells responsible for the synthesis of the pigment melanin.1 It is often lethal due to its ability to spread rapidly and its resistance to treatment in the metastatic stage. Although typically arising in the skin, melanoma can also originate in the eyes, intestines, and other areas where melanocytes are found. Melanoma is distinct from nonmelanoma skin cancers because it spreads locally, regionally, and distantly.
Pathogenesis
Melanomas develop from the malignant transformation of melanocytes, usually due to an interplay of genetic and environmental factors. Prolonged exposure to ultraviolet (UV) radiation from the sun or tanning beds often causes DNA damage and genetic mutations, which can lead to uncontrolled melanocyte growth and melanoma development. In particular, mutations in the BRAF, NRAS, or KIT genes are known to promote melanocyte transformation. Melanoma has a relatively high risk of systemic spread.
Subtypes
There are several subtypes of melanoma, with the main clinical types being:
- Superficial spreading melanoma – most common and tends to grow slowly
- Nodular melanoma – tends to grow more rapidly in thickness rather than diameter
- Lentigo maligna melanoma – most often on chronically sun-damaged, elderly skin. Preinvasive confined to the epidermis (i.e. melanoma in-situ).
- Acral lentiginous melanoma – least common but most common in people with darker skin
Epidemiology, Risk Factors & Associations
- Most common in individuals with a history of intense, intermittent sun exposure, particularly those with fair skin, blue or green eyes, and red or blonde hair.
- Additional risk factors include a family history of melanoma, presence of multiple atypical nevi, and immunosuppression.
- Melanoma is the fifth most common cancer in men and the sixth in women in the UK.
Clinical Features
Melanoma usually presents as a pigmented skin lesion with irregular borders and varied colours (brown, black, red, blue, or white). Key features are often recalled using the ABCDE rule: Asymmetry, Border irregularity, Colour variation, Diameter greater than 6 mm, and Evolving changes.
Complications
Melanoma can metastasise early in its course due to its aggressive nature. Common sites of metastasis include the lymph nodes, lung, liver, brain, and bones. Metastatic spread to the lymph nodes represents the most common site of malignant melanoma metastases. Once metastasised, prognosis is poor.
Pathological Features
Histopathology
- Macroscopic: Melanomas vary in appearance but are often raised and irregular in shape with a varying colour palette ranging from skin-coloured to black.
- Microscopic: Characterised by the presence of atypical melanocytes with large, irregular, hyperchromatic nuclei, prominent nucleoli, and frequent mitotic figures.
Serology
- Elevated lactate dehydrogenase (LDH) levels are seen in advanced disease (increased tumour burden and metastatic activity) and are a poor prognostic factor.
Biochemistry
- The BRAF V600E mutation is commonly implicated in oncogenesis.
Radiological Features
General Features
- Melanomas, particularly when metastatic, demonstrate heterogeneous signal intensities on MRI due to variable melanin content, haemorrhage, and necrosis.
Metastatic Disease
Brain
- Usually presents as multiple lesions in the cortex and at the grey-white matter junction. Can also present in miliary form or as subependymal nodules.
- CT: Hyperdense lesions with moderate to intense contrast enhancement. Prominent perilesional oedema.
- MRI:
- Melanotic pattern: Typical hyperintense T1, hypointense T2 lesion
- Amelanotic pattern: Hypo- to iso-intense T1, hyper- to iso T2, relative to cortex.
Bone
- Usually osteolytic lesions, involving the axial skeleton
CT
- Non-contrast: Well-defined, solid, and enhancing nodules can be seen in metastatic disease. Lesions may demonstrate central necrosis or calcification.
- C+ Arterial/Venous: Post-contrast scans can reveal heterogeneous enhancement of lesions, reflecting their variable tissue components.
MRI
- T1: Lesions are typically hyperintense due to the paramagnetic effect of melanin.
- T2: Variable signal intensity due to different proportions of melanin, haemorrhage, and necrosis.
- T1 Gad+: Lesions often show pronounced enhancement due to their high vascularity.
US
- B-mode: In the context of lymph node assessment, malignant nodes often appear irregular or lobulated, hypoechoic with loss of the normal fatty hilum.
- Colour Doppler: May show increased intralesional vascularity.
NM
- PET FDG: Melanoma usually demonstrates high FDG uptake (98% sensitivity, 94% specificity)
Grading and Staging
Melanoma staging is based on the TNM classification system by the American Joint Committee on Cancer (AJCC). It takes into account the thickness of the tumour, presence of ulceration, involvement of lymph nodes, and presence of distant metastasis.
Staging for Melanoma as per AJCC
The American Joint Committee on Cancer (AJCC) staging system for melanoma uses the TNM classification, which is based on the tumor size and characteristics (T), regional lymph node involvement (N), and distant metastasis (M). Here is a summary of the staging criteria:
T
- Tis: Melanoma in situ (always includes Lentigo Maligna)
- T1: Tumor ≤1.0 mm thickness
- T1a: Without ulceration and mitosis <1/mm²
- T1b: With ulceration or mitoses ≥1/mm²
- T2: Tumor >1.0 mm and ≤2.0 mm thickness
- T2a: Without ulceration
- T2b: With ulceration
- T3: Tumor >2.0 mm and ≤4.0 mm thickness
- T3a: Without ulceration
- T3b: With ulceration
- T4: Tumor >4.0 mm thickness
- T4a: Without ulceration
- T4b: With ulceration
N
- N0: No regional lymph node metastasis
- N1: 1 regional lymph node metastasis
- N1a: Micrometastasis (clinically occult)
- N1b: Macrometastasis (clinically apparent)
- N2: 2-3 regional lymph node metastases
- N2a: Micrometastasis
- N2b: Macrometastasis
- N2c: In-transit metastases/satellites without nodal metastases
- N3: ≥4 metastatic lymph nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes
M
- M0: No distant metastasis
- M1: Distant metastases present
- M1a: Metastasis to skin, subcutaneous, or distant lymph nodes
- M1a(0): LDH not elevated
- M1a(1): LDH elevated
- M1b (0/1): Lung metastasis (LDH not elevated/LDH elevated)
- M1c (0/1): Metastasis to other visceral sites (LDH not elevated/LDH elevated)
- M1d (0/1): Any distant metastasis (LDH not elevated/LDH elevated)
- M1a: Metastasis to skin, subcutaneous, or distant lymph nodes
Stages Grouping
- Stage 0: Tis, N0, M0
- Stage I: T1-T2a, N0, M0
- Stage II: T2b-T4b, N0, M0
- Stage III: Any T, N1-N3, M0
- Stage IV: Any T, Any N, M1
Diagnosis
Diagnosis is typically made based on clinical findings and histological confirmation following punch or excisional skin biopsy (shave biopsy does not allow depth assessment). Dermoscopy may aid in the initial assessment.
Differential Diagnosis
- Benign naevus: smaller size, regular borders, and homogeneous colour
- Seborrhoeic keratosis: typically appears waxy and “stuck-on”
- Basal cell carcinoma: often translucent with telangiectasias
- Squamous cell carcinoma: may present as a firm, hyperkeratotic, or ulcerated nodule
Management
Wide surgical excision of the primary tumour is the first-line treatment for localised disease. For advanced or metastatic disease, treatments include immune checkpoint inhibitors, targeted therapy (for patients with BRAF-mutant melanomas), and, in some cases, chemotherapy or radiation therapy. Consultation with dermatology, surgical oncology, and medical oncology teams is typically required.
References