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Melanoma

What is it ?
And how serious is it?

Melanoma is a cancer that attacks skin cells called melanocytes. These cells are present in the skin but also in the mucous membranes and other tissues.
Melanomas are thus cutaneous(skin-specific)
but can also attack mucous, conjunctival, or nervous system tissues.

For purposes of this topic, the information will mostly be focused on melanoma (skin cancers).

In France, the incidence of skin cancer has increased since the 1980s,
with an estimated annual increase of 4.7% in men
and 3.2% in women from 1980 to 2004.

The number of new cases of melanoma is estimated at 15,513 in 2018 (51% in men), with 1,975 deaths.

The United States saw 83,362 cases of melanoma in 2015; it is the 5th most common cancer with over 9,000 deaths per year.

The median age at diagnosis is 66 years for men and 60 years for women, while the incidence rate by age group has increased from the age of 20 in both sexes (2018 data). 
The incidence of skin cancers is highest in Australia-New Zealand and North America.

Prevalence is directly related to geography(latitude) and therefore exposure to ultraviolet radiation, the main risk factor for cutaneous melanoma, particularly for lighter skin types. Other risk factors are mainly genetic.

Clinical presentation

Cutaneous melanoma usually presents as a pigmented lesion,
newly appearing or developing on a pre-existing birthmark or mole(nevus) that gradually changes.
The warning signs for Melanoma follow the ABCDE rule :
Asymmetry : Most skin cancers are asymmetrical. Border : Melanoma borders are usually uneven with ragged edges. Normal moles are typically smooth and even. Color : Look for multiple colors, which are a warning sign. Diameter/Dark : Larger lesions (greater that the eraser on a pencil) should be noted and examined. Evolving : Change in size, shape or color is a warning sign, as is itching or bleeding.
Note that these criteria remain reductive and it should be remembered that
any modified, newly appearing, persistent, or hemorrhagic skin lesion requires medical attention.

Melanoma can also present as a nonspecific pink papule,
especially with so-called achromic melanomas. The dermatologist will perform
a clinical examination of the skin and the lesion itself.
A dermatoscopic examination (a tool with magnifying lens and polarized light)
is an integral part of the clinical examination.
Based on a certain number of validated criteria, the exam may result in surgical excision of the entire lesion.

A pathological examination of the removed tissue then enables a more certain diagnosis. A tissue biopsy is not recommended because of the limited histological analysis of the lesion, although it is an option in certain cases
(e.g., large lesions.)

Screen for any suspicious lesions

Self-monitoring is a key element of effective management. Should a skin lesion appear, persist, or change, see a doctor, whatever its color or location.

Analysis of genotyping

Analysis of genotyping and therefore of BRAF mutation status is an essential step
in any therapeutic strategy.

Targeted therapies and immunotherapy

Targeted therapies (BRAF inhibitor + MEK inhibitor) and immunotherapies (mainly immune checkpoint inhibitors) have revolutionized the management of melanoma. Classic chemotherapy is no longer part of the first-line care landscape.

Treatments evolution

Metastatic melanoma no longer must be a short-term fatal disease, but now can be a potentially chronic disease kept in remission with or without the need to maintain specific treatment.

There remains progress to be made,
particularly in management strategies at early and more advanced stages of the disease.
For this reason, inclusion in clinical research trials must always be considered.

Different subtypes
and tumor growth

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 Dubreuilh melanoma
(found on skin chronically exposed to the sun).

These different histological subtypes do not present the same evolutionary characteristics nor do they have the same mutational molecular profile.
For example, while SSM melanomas exhibit a BRAF activating mutation on the MAPK kinase pathway in nearly 50%, this is only found in about 0 to 15% of Dubreuilh or Acral lentiginous melanoma melanomas.

The primary diagnostic factors to consider are :

Tumor thickness 
(the Breslow index), which is measured in mm on histological sections
Whether or not
the primary tumor is ulcerated
The status of the sentinel node
aimed at detecting
the presence or absence of micrometastasis (small groups of spreading cancer cells)
in the lymph node drainage area.
 
The sentinel node procedure will be offered on a case-by-case basis, depending on the Breslow index
and/or the ulcerative nature
of the primary tumor.

After pathological diagnosis, and with a Breslow index greater than or equal to 1 mm
or if sentinel node procedure is recommended,
a complete imaging workup including
a cerebral and Thoraco-Abdominal scan should be performed.
Depending on the case, a brain MRI and PET scan will be considered. While mutational analysis (exploration for BRAF mutations in particular) is not carried out systematically for all melanomas,
its indication will be considered on a case-by-case basis.

Treatments

The different therapeutic strategies are determined based on stage of the disease.
(The specific criteria are according to 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 <1 mm,
2 cm for melanoma thickness > 1 mm.
An associated sentinel lymph node technique is strictly a therapeutic procedure. Rather, it is another prognostic tool to further assess possible risk of recurrence
and to rule out other medical treatment.

For stage III or removable stage IV melanomas(after surgical management),
additional treatment will be offered
according to BRAF mutation status.
Targeted therapies (a combination of BRAF inhibitor + MEK inhibitor)
and anti-PD1 antibody immunotherapies are recommended
for melanoma tumors with a high risk of recurrence.
Typical treatment duration in these instances is one year.

For stage IV melanoma,treatment is decided based on BRAF mutation status. The different possibilities of first-line metastatic treatment including targeted therapies, immunotherapy as a monotherapy or in combination (antiCTLA4 + anti PD1 antibodies), or radiation therapy. Inclusion in a clinical research trial is decided by a multidisciplinary team depending on :

  • BRAF mutation status
  • the patient's comorbidities
  • the presence or absence of brain tumors
  • speed of tumor progression, size of the tumor mass, the presence or absence of other potentially threatening symptoms