3.3.7 Malignant 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. There may be a familial (genetic) predisposition in 5-10% of cases, such as a germline mutation in the CDKN2A gene. Melanoma is slightly more frequent in female patients, the average age at diagnosis is 40-50 years. Melanoma occurs mainly in adults and is exceptional in children.

The following types are observed 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 frequency in Caucasians, higher in people of colour.

Most melanomas arise on normal skin. Risk factors of melanoma include fair skin, red-blond hair, freckles, blue eyes, history of sunburn as a child, UV exposure, large number (>100) of melanocytic naevi, and personal or familial (1st degree relative) history of melanoma. Melanoma is one of the tumors with the highest mutational charge. Assays determining the genetic expression profile measure of various sets of genes define a gene signature. This signature may be useful to evaluate the prognostic, the metastatic potential and the possible treatments.

The most frequent somatic mutations involve BRAF, NRAS, NF1, PTEN, and KIT. These genes are involved in the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositol-3-kinase) signalling pathways. These pathways control proliferation, activation, differentiation and survival of cells. The most frequent mutation, found in 50% of melanoma involves the codon 600 of BRAF. BRAF V600E (substitution of a valine to glutamic acid) is found in 80-90% of cases, and BRAF V600K (substitution of a valine to lysine) is found in 5-12% of cases. These mutations induce an activation of the MAPK pathway. Other mutations involve NRAS (15-30%), NF1 (10-15%) and KIT (<10%).

Melanoma occurring on intermittently UV exposed regions often present BRAF V600E mutations. In contrast, melanomas occurring on chronically sun exposed regions more frequently present NRAS, NF1 or BRAF V600K mutations.

Superficial spreading melanoma (SSM), the most frequent form, typically presents as a heterogeneous, irregular, pigmented skin lesion with a rapid evolution. Nodular melanoma presents as a pigmented (or not) nodule of the skin. Acrolentiginous melanoma is found on the extremities. The lesions may be ulcerated. Lentigo maligna melanoma (Dubreuilh melanoma) is an irregular pigmented lesion of sun- exposed areas typically found in elderly people.

Suspicious features are known as the ABCDE criteria and include: A for Asymmetry, B for irregular Border, C for inhomogeneous Color, D for Diameter over 6 mm, E for rapid Evolution. Additional danger signs include bleeding, crusting, ulceration, inflammation.

Melanoma can arise anywhere on the skin, and occasionally also on mucosa (vagina, mouth, sinuses, choroid, retina, anus/rectum,). Lentigo maligna melanoma occurs on chronic sun damaged skin (face, scalp, trunk, extremities) and acrolentiginous melanoma on the extremities. Rarely, the diagnosis may be performed at the metastatic stage and the primary tumour is not found any longer.

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 site, 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’s disease or Lentigo maligna of Hutchinson). High cumulative sun damage melanoma.

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

AJCC (American Joint Committee on Cancer) Staging.

The evidence-based updated AJCC melanoma staging system guides patient treatment with cutaneous melanoma, provides better prognostic estimates and precises the stratification of patients entering clinical trials.

Table 1. AJCC Melanoma Staging system, 8th Edition.

Adapted from Gershenwald et al, 2017

Dermatoscopy is essential for the differentiation between melanoma and other skin tumours (atypical naevi, pigmented epithelial tumours, etc). Other useful methods for early non-invasive diagnosis are confocal reflectance microscopy or electric impedance spectroscopy and / or gen expression profiles.

Genetic profiling may be proposed to selected patients with familial or multiple primary melanoma.

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

Metastatic melanoma can be associated with abnormalities in the blood test and elevated serum LDH (lactate dehydrogenases) is used in the staging of advanced melanoma (elevated LDH is associated with worse prognosis).

There are varying types of histopathologic patterns in all MM`s. Highlight is an asymmetrical 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 is possible. Mitosis rate, immunohistochemistry and molecular diagnostic of mutation type status is for further examination necessary. Lesions must be classified according to TNM classification. Sentinel node biopsy is part of the staging of patients with invasive melanomas with risk factors to rule out the presence of micrometastasis in the lymph nodes.

The clinical course is strongly associated with the tumor thickness (Breslow depth), which is the thickness between the stratum granulosum of the epidermis and the deepest melanoma cell in mm, and the presence of ulceration on histological examination. The 10 year survival is around 95% for thin melanomas (<1 mm) compared to 40-50% for thick melanomas (>4 mm). The main prognostic factors apart from the tumor thickness and ulceration are the presence of nodal and visceral involvement and are summarized in the AJCC TNM (tumor, node, metastasis) prognostic 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. In patients with distant metastasis the prognosis is significantly reduced may vary depending of the number, size and localization of metastasis.

The diagnosis is suspected clinically and confirmed by the histopathological examination of the whole skin lesion. The clinical diagnosis by the dermatologist is based on a combination of the following analyses of any skin tumour in the differential diagnosis of melanoma and prior to the excision:

1. Visual analysis (ABCDE or EFG rule)

2. Intra-individual comparative analysis with other pigmented lesions on patients skin

3. Chronologic analysis of changes (evolution)

4. A dermatoscopic evaluation of a skin tumour within the differential diagnosis of melanoma is mandatory prior to the excision. Clinical and dermatoscopic photos are highly recommended before the excision of the tumour for clinical pathological correlation and final diagnosis. Reflectance confocal microscopy, when available, increases the accuracy of early non-invasive diagnosis.

In patients with risk factors and atypical mole syndrome the digital follow-up (Total body photography and digital dermatoscopy) are recommended to identify new and changing lesions that are indicative of early melanoma. After confirmation of the diagnosis, the staging may include blood test, ultrasonography of the regional lymph nodes, thoracic-abdominal-pelvic CT scan, brain CT scan or MRI and PET-TDM.

Prognostic is evaluated by AJCC pathological (pTNM) prognostic staging.

Differential diagnoses include melanocytic naevi of different types, pigmented skin carcinoma, seborrhoeic keratosis, dermatofibroma or vascular lesions among others.

The treatment of a suspected lesion is done by immediate excision under local anaesthesia. Usually in atypical nevi (intraepidermal dysplasia), a 0.5 cm safety margin is sufficient.

After histological confirmation and after having determined the Breslow thickness, an excision of the scar is performed with margins of 1 to 2 cm depending on the Breslow thickness.

A sentinel lymph node biopsy may be performed (if the Breslow is >0.8 mm). Adjuvant therapy is discussed in patients with a high risk of metastasis (stage IIB, IIC, III or IV after surgery) and may include targeted therapy (in cases with a V600 mutation of the oncogene BRAF) or immunotherapy. Therapy of systemic metastases includes: immunotherapy with checkpoint inhibitors (anti-PD1 and anti-CTLA-4), targeted therapy (BRAF and MEK inhibitors) if BRAF V600 mutation is present (around half of the cases), or a clinical trial. Radiotherapy is used only in selected cases, and chemotherapy is very poorly efficient and not generally indicated.

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 patient: sun protection, 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.