Melanoma

What is this ?

Melanoma is a cancer that develops at the expense of cells called melanocytes. These are present in the skin, but also in the mucous membranes, conjunctiva, and meninges. Melanomas are most frequently primarily cutaneous but can also be mucosal, ocular, or primarily meningeal (exceptionally).

Is it common ?

The information provided here will primarily focus on primary cutaneous melanomas. In France, the incidence of cutaneous melanoma has been increasing since the 1980s with an annual increase estimated at 2% in both men and women from 2010 to 2023.

Indeed, in metropolitan France, it is estimated that there will be 17,922 new cases of melanoma in 2023, of which 51% will be in men, with 1,980 deaths reported in the same year. The median ages at diagnosis are 68 years for men and 62 years for women.

In terms of incidence (number of new cases per year), melanoma ranks seventh among cancers in men and fourth among cancers in women. Between 1990 and 2023, melanoma has been constantly increasing in both women and men. It is the leading cancer in terms of frequency increase.

The highest incidence rates, for both sexes combined, are observed in Australia-New Zealand and North America.

These differences between countries reflect the diversity in terms of encountered phototype, latitude, and therefore exposure to ultraviolet radiation. They are the main risk factors for the occurrence of cutaneous melanoma, especially for light phototypes.

Other risk factors are mainly genetic (predisposing diseases or familial forms).

Interview with Professor Caroline Robert

Causes and risk factors

The risk factors for melanomas are multiple. They can be constitutional (related to the individual) or environmental (related to the environment).

Prolonged exposure to ultraviolet (UV) rays is the main environmental risk factor. Among the constitutional factors, one finds a disease, xeroderma pigmentosum, but also the presence of a congenital melanocytic nevus or the person's phototype.

Screening

Self-monitoring a mole or spot on the skin is a simple and very effective way to screen for melanoma.

Symptoms

Cutaneous melanoma usually presents as a pigmented lesion, newly appeared or developed on a preexisting nevus that gradually changes.

Well-known criteria should alert one to this melanoma, particularly the ABCDE rule for :

• Asymmetrical
• Irregular Borders
• Non-homogeneous Colors
• Diameter greater than 6 mm
• Lesional Evolution

A melanoma can also present as a nonspecific pink papule, particularly in the case of so-called amelanotic melanomas. The dermatologist will perform a clinical examination of the entire skin and the lesion itself.

A dermatoscope is a tool composed of a magnifying lens and polarized or non-polarized light. It is used during a clinical examination in case of a suspicious lesion based on a number of validated criteria. The result of the examination may (or may not) lead to the surgical excision of the entire lesion.

It is this histopathological examination of the entire specimen that will allow for a definitive diagnosis and an assessment of a number of prognostic factors detailed below.

A biopsy is not recommended, as it only allows for a partial histological analysis of the lesion; however, it may be considered in certain cases (particularly for large lesions).

Diagnosis

There are different histological subtypes of melanoma : superficial spreading melanoma (SSM), the most common form (found on skin exposed to the sun intermittently), nodular melanoma, acral lentiginous melanoma, and Dubreuil melanoma (found on skin exposed to the sun chronically).

These different histological subtypes do not have the same evolutionary characteristics and do not share the same mutational molecular profile (BRAF gene mutation).

The main validated histoprognostic factors are :

• Tumor thickness (Breslow index) measured in millimeters on histological sections.
• Whether the primary tumor is ulcerated or not.
• The status of the sentinel lymph node, aimed at detecting the presence or absence of micrometastasis in the lymphatic drainage area. The doctor will recommend the sentinel lymph node procedure on a case-by-case basis. Indeed, it is prescribed particularly based on the Breslow index and/or the ulcerated nature of the primary tumor.

A complete imaging workup includes : a brain and thoraco-abdomino-pelvic CT scan as well as an ultrasound of the lymphatic drainage area.

A histopathological workup is then performed to carry out this assessment.

The Breslow index must also be greater than or equal to 1 mm. Finally, the sentinel lymph node procedure can also be considered.

Depending on the case, a brain MRI and PET scan can also be discussed from the initial workup. Molecular biology mutational analysis (particularly for BRAF mutation) is not systematically performed for all melanomas; its indication will be determined on a case-by-case basis.

Treatments

Different Therapeutic Strategies are Defined According to the Stage of the Disease Established Based on the AJCC 8th Edition Classification.

For stage I-II melanomas

The treatment is surgical with surgical revision for safety margins: 1 cm if melanoma thickness according to Breslow is < 1 mm, and 2 cm for melanomas with thickness > 1 mm.

The sentinel lymph node technique, if associated, is not a therapeutic procedure per se. It is an additional prognostic tool to better assess the potential risk of future recurrence. This technique also helps determine the necessity of additional adjuvant medical treatment.

For stage III or stage IV melanomas

After surgical management, additional adjuvant treatment will be proposed based on BRAF mutation status. Targeted therapies (combination of BRAF inhibitor + MEK inhibitor) and immunotherapies with anti-PD-1 antibodies have marketing authorization for this indication for melanomas at high risk of recurrence.

The theoretical duration of adjuvant treatment is one year.

For stage IV melanomas

Treatment decisions will be based on BRAF mutation status. First-line metastatic treatment options, including targeted therapies, monotherapy or combination immunotherapy (anti-CTLA4 + anti-PD1 antibodies), radiotherapy, and inclusion in a clinical research trial, will be decided by a multidisciplinary team based on factors such as :

• BRAF mutation status
• Patient comorbidites
• Presence orabsence of brain metastases
• Evolution speed, tumor burden and the presence or absence of potentially threatening symptoms related to the disease.