Melanoma, familial

Other Names: Hereditary Cutaneous Melanoma; Familial Cutaneous Melanoma; Hereditary Cutaneous (Skin) Melanoma; Hereditary melanoma

Familial melanoma (FM) is a rare inherited form of melanoma characterized by development of histologically confirmed melanoma in two first degrees relatives or more relatives in an affected family. Familial melanoma tends to occur earlier than non-familial melanoma. The average age of onset is often between 30 and 40 years, while non-familial melanoma typically occurs in the general population between 50 and 60. Earlier and later onset is nonetheless reported in some families. A higher frequency of multiple primary melanomas is also found. Melanoma generally presents as a pigmented lesion on the skin. It is often asymmetrical with irregular borders and color variegation. The diameter is often greater than 6 mm. The most common sites are the trunk, lower legs and back.

All four main clinicopathologic subtypes of primary cutaneous melanoma described (spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma) are observed. A variety of growth patterns are found with progression to a potential for metastasis to other organs. Atypical moles are often found in families with FM.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Melanoma
• Nevus(Mole)

30%-79% of people have these symptoms

• Abnormal hair morphology(Abnormality of the hair)
• Abnormality of the lymphatic system
• Dry skin
• Freckling

5%-29% of people have these symptoms

• Abnormality of extrapyramidal motor function
• Neoplasm of the breast
• Breast tumor
• Neoplasm of the pancreas(Cancer of the pancreas)
• Neoplasm of the stomach(Stomach tumor)
• Retinopathy(Noninflammatory retina disease)

Risk factors

The risk of familial melanoma is closely related to a wide range of genetic alterations in susceptibility genes but also appears to be influenced by phenotypic risk factors, such as pigmentation, freckling and nevi and sun reactions but also exposure to UV radiation. Complex interactions between genetic and environmental factors are therefore thought to underlie FM.

Genetics

The most common high-penetrance susceptibility gene implicated in FM is CDKN2A, accounting for predisposition in approximately 20% of FM. CDK4, another high risk gene, is rarely involved. Mutations of BAP1,POT1, TERF2IP, ACD,and TERT have recently been reported and penetrance remains to be determined. Medium penetrance genes include MC1R.Some twenty common genetic variants modulate risk for melanoma in low clustering families.

Diagnostic methods

FM is suspected in individuals when two or more close relatives have developed melanoma. A new or changing skin mole should be assessed to identify melanoma. Changes include color, border, size, and symmetry.

Differential diagnosis

The main differential diagnoses are seborrheic keratosis, atypical mole, familial atypical multiple mole melanoma and skin carcinoma.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

In some affected families, susceptibility is consistent with autosomal dominant inheritance but in most cases, a polygenic mode of inheritance appears likely. Patients should be informed that a family history of melanoma in one close relative is associated with an average 2-fold increased risk. History in more than one relative and relevant personal phenotypic characteristics such as multiple pigmented atypical melanocytic lesions result in a significantly higher risk.

Management and treatment

Long-term screening of individuals at high risk and monitoring in FM families is recommended. This involves a total-body skin examination by a qualified dermatologist every six months. Self-examination of skin should be encouraged. Treatment is similar to sporadic melanoma and is largely based on surgery at initial stages. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Encorafenib + binimetinib (Brand name: Braftovi + Mektovi)approved in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.
• Pembrolizumab (Brand name: Keytruda)Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
• Trametinib (Brand name: Mekinist)Treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA approved test.
• Trametinib and dabrafenib combination (Brand name: Mekinist And Tafinlar)approved combination for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
• Nivolumab (Brand name: Opdivo)Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. And treatment of patients with melanoma with involvement of lymph nodes or metestatic disease who have undergone complete resection.
• Aldesleukin (Brand name: Proleukin) Treatment of adults with metastatic melanoma.

Peginterferon Alfa-2b (Brand name: Sylatron) Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy

• Dabrafenib (Brand name: Tafinlar)Treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA approved test.

Technetium Tc99m sulfur colloid injection, lyophilized (Brand name: Technetium Tc99m Sulfur Colloi) Localization of lymph nodes draining a primary tumor in patients with melanoma when used with a hand-held gamma counter

• Ipilimumab (Brand name: Yervoy)

Prognosis

Prognosis is variable and depends on time of diagnosis, thickness, presence of ulceration, mitotic index, and possible lymph node involvement, and distant metastatic disease. Early diagnosis (with thin Breslow thickness) is associated with a high percentage of cure. Monitoring of melanoma families aims to detect melanoma offering skin surveillance resulting in a favorable prognosis.

NIH genetic and rare disease info

• NIH info on Melanoma, familial

Melanoma, familial is a rare disease.

Melanoma, familial Resources
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