A12. Malignant melanoma

Epidemiology
- Only 2% of skin cancer
- Responsible for most skin cancer-related deaths
- Higher incidence in sun-rich countries like Australia compared to Europe
- Paradoxically common in Northern Europe
- Average age at onset ~50
Risk factors
- Excessive UV exposure
  - Especially high doses over short period, in contrast to non-melanoma skin cancer
- Fitzpatrick skin type I and II
  - Easily burns
  - Almost never suntans
  - Often have freckles
- Precancerous lesions
  - Dysplastic nevi
  - Dysplastic nevus syndrome – 100% risk of developing melanoma
  - Lentigo maligna
  - Congenital nevi
- Indoor tanning
- Sunburns in childhood (> 3)
- Positive family history
- Immunosuppression
- Familial genetic mutations
  - BRAF (most common)
  - NRAS
  - p16 family
Pathology
- BRAF mutation is found in 50%
- Breslow depth, mitotic rate and presence of ulceration on histology are important prognostic factors
- 2 growth phases:
- Radial/horizontal growth phase
  - Tumor grows horizontally along epidermis
  - No capacity to metastasize
- Vertical growth phase
  - Tumor grows vertically into the dermis
  - Can metastasize
Subtypes
- Superficial spreading melanoma
  - 60% of all cases
  - Slow radial growth phase, mostly superficial spreading
- Nodular melanoma
  - 20% of all cases
  - Reddish-brownish-blackish nodule
  - Can be ulcerated
  - Has no radial growth phase, only vertical
  - Poorer prognosis
- Lentigo maligna melanoma
  - 10% of cases
  - Originates from lentigo maligna in elderly
  - Slow radial growth phase
  - Lesion is often a large and irregularly shaped patch
- Acral lentiginous melanoma
  - 5% of cases
  - Slow radial growth phase
  - Occurs on nailbeds, palms and soles of dark-skinned and Asian persons
  - Unrelated to UV exposure
- Amelanotic melanoma
  - Non-pigmented nodule
Clinical features
- Pruritic, bleeding skin lesion
- On the back or chest in men
- On extremities in women
Diagnosis
- Presumptive clinical diagnoses made with ABCDE criteria – these help distinguish between naevi and melanoma
  - Asymmetry
  - Border irregular
  - Colour irregular
  - Diameter enlarged (> 5 mm)
  - Evolution (changes over time)
- Ugly duckling sign
  - The lesion looks different from other nevi on the same patient
- Dermoscope
- Histopathological
  - Gives definitive diagnosis
  - Full-thickness biopsy with 1 – 2 mm safety margin
  - Shows atypical melanocytes and atypical architecture
  - Important to look for BRAF mutation in the biopsy
Prognosis
- Breslow depth – from the top of the stratum granulosum to the deepest invasive cell
- Presence of ulceration
- Number of mitoses
- Clark level
- The subtype
- Presence of metastasis
  - Usually metastasizes to liver, lung, brain, bone
  - Can metastasize into unusual locations like the heart and gallbladder
  - Metastases are black
- Localized disease – cancer confined to primary site
  - 84% of cases
  - 98% 5-year survival
- Regional disease – cancer spread to regional lymph nodes
  - 9% of cases
  - 63% 5-year survival
- Metastatic disease – cancer has metastasized
  - 4% of cases
  - 22% 5-year survival
Staging
- TNM
- T = Based on Breslow depth
  - “a” – if there is no ulceration
  - “b” – if there is ulceration
- N – lymph node
  - Any melanoma with lymph node involvement is stage III
- M – metastasis
  - Any melanoma with metastasis is stage IV
Treatment
- Immediate complete excision upon clinical suspicion is the gold standard
- A sufficiently large safety margin (1 – 2 cm, depending on Breslow stage) must be used
- Non-surgical treatment
  - For stage III and stage IV melanoma
  - Immune checkpoint inhibitors
    - Commonly used for advanced disease
    - Anti-CTLA-4 antibodies (Ipilimumab)
    - Anti-PD-1 antibodies (Nivolumab, Pembrolizumab)
  - Inhibitors of mutated proteins
    - BRAF inhibitor – dabrafenib, trametinib
    - MEK inhibitor – trametinib
  - Chemotherapy is not used