3.3.7 Malignant Melanoma

2C30.Z

Often referred to just as melanoma.

In Europe, the incidence rate is <10-25 new melanoma cases per 100,000 inhabitants and is increasing by 5% yearly; in the USA 20- 30 per 100,000; and in Australia, where very high incidence is observed 50-60 per 100,000.

Melanoma occurs mainly in adults and is exceptional in children.

In order of decreasing frequency: Superficial spreading melanoma (SSM) 41%, Nodular melanoma (NMM) 14%, Lentigo maligna melanoma (LMM) 2.7-14%, Acral lentiginous melanoma (ALM) 1-5 % with lower in white colour population, higher in black colour.

Malignant tumour arising from neuroectodermal cells (melanocytes, naevus cells) with a high risk of metastasis.

Risk factors: fair skin, red-blond hair, freckles, blue eyes, history of sunburns as a child, UV exposure, large number (>100) of melanocytic naevi, and personal or family history of melanoma.

Lesions should be classified as suspicious according to ABCDE rule: A for Asymmetry, B for irregular Border, C for inhomogeneous Color, D for Diameter over 6 mm, E for rapid evolution.

Superficial spreading melanoma (SSM): heterogeneous, irregular, pigmented skin lesion with first a radial, later vertical growth, moderate time of evolution.

Lentigo maligna melanoma arising from a longstanding lentigo maligna (Dubreuilh) is an irregular pigmented lesion of sun-exposed areas.

Nodular melanoma: predominant aggressive rapid vertical growth phase. pigmented (or not) nodule of the skin.

Acrolentiginous melanoma is found on the extremities, sometimes appearing like a long-standing wart on the sole or a pigmented stripe in the nail plate.

Melanoma can arise anywhere on the skin, and occasionally also on mucosa (anus/rectum, vagina, mouth, sinuses, choroids, retina). Rarely, the diagnosis may be performed at the metastatic stage and the primary tumour is not found.

Traditional and new clinical classification:

Superficial spreading melanoma (SSM): heterogeneous, irregular,  pigmented skin lesion with a variable evolution. (Low Cumulative Sun damage melanoma).

Nodular melanoma: pigmented (or not) often eroded or bleeding nodule of the skin. No UV exposure preference.

Acrolentiginous melanoma is found on the extremities (plantar, nails). Low to no UVR exposure (or variable/incidental).

Lentigo maligna melanoma is an irregular pigmented lesion of sun-exposed areas arising from an intraepidermal Lentigo maligna (Dubreuilh) High Cumulative Sun damage melanoma.

Other subtypes are: melanoma arising in a congenital naevus, desmoplastic melanoma, mucosal melanoma, uveal melanoma.

Dermatoscopy essential for differentiation of precursor lesions (atypical naevi). Other methods confocal laser scan, electric impedance measures.

Genetic profiling.

According to type and histopathological grading imaging procedures are essential: ultrasound, MRI, CT or PET-CT.

Metastatic melanoma can be associated with elevated serum LDH (lactate dehydrogenases). 

Varying types of histopathologic patterns in all MM`s . Highlight is a aymmetrical tumour growth  with atypical melanocytes (clear cytoplasm, pleomorphic nuclei) growing in nests or singly, extending from the epidermal-dermal junction  involving the upper layers of the epidermis, then invading the dermis or subcutaneous fat (thickness (Breslow depth) in mm). Early invasion of lymph vessels or capillaries possible. Mitosis rate, immunohistochemistry and molecular diagnostic of mutation type status is for further examination necessary. TNM classification.

The clinical course is strongly associated with the tumor type  and the presence of ulceration on histological examination. The 10 year survival is around 95% for thin melanomas (<1 mm) compared to 40% for thick melanomas (>4 mm). The main other prognostic factors are the presence of nodal and visceral involvement and are summarized in the AJCC TNM (tumor, node, metastasis) stage (I-IV).

About 90% of melanomas are diagnosed as primary tumors without any evidence of metastasis. The tumor specific 10-year-survival for such tumors is 75 to 95%.The 10-year-survival is 30 to 50% for patients with satellite and in-transit metastases, 69-75% for patients with lymph node micrometastases, and 40 to 60% for those with clinically apparent regional lymph node metastases.

The diagnosis is suspected clinically, supported by dermatoscopy and confirmed by the histopathological examination.

The clinical diagnosis by the dermatologist is based on a combination of 3 analyses of any pigmented lesion: (1) visual analysis incl. ABCDE rule; (2) Intra-individual comparative analysis with other pigmented lesions on patients skin ; (3)  Chronologic analysis of changes (evolution).
Prognostic is evaluated by AJCC pathological (pTNM) prognostic stage grouping.

Differential diagnoses include melanocytic naevi of different types, pigmented basal cell carcinoma, seborrhoeic keratoses, dermatofibroma.

The treatment of a suspected lesion is by immediate excision under local anaesthesia. Usually in atypical neavi (intraepidermal dysplasia) 0.5 cm safety margin is sufficient.  If lesions are clinically highly suspicious for a melanoma the primary  safety margin is 1 - 2 cm. A sentinel lymph node biopsy may be performed (if the Breslow is >1 mm). Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team.

Adjuvant therapy is discussed in patients with a high risk of metastasis (micrometastases in sentinel lymph node) and may include targeted therapy (in cases with a V600 mutation of the oncogene BRAF) or immunotherapy.

Therapy of systemic metastases include: immunotherapy with checkpoint inhibitors (anti-PD1 +/- anti-CTLA-4), targeted therapy (BRAF and MEK inhibitors)  if BRAF V600 mutation is present (around half of the cases).

Follow-up: 5 years in intervals of 3-6 months with clinical examination and imaging, depending on risk group; looking for signs of recurrence and second primary melanomas, then life-long surveillance is recommended.

Prevention is based on the education of the population starting already in childhood incl. the parents, kindergarten and school. Five factors: sun protection factor cream, shadow, sunglasses, umbrella and UV protecting clothes. Self skin screening (ABCDE criteria), and skin screening of at-risk patients via themselves and partner/parents, and digital photo assessment. Governmental skin cancer screening campaigns. Telemedicine is helpful.