Skin Cancer (Melanoma)
by D. Bafaloukos, M.D., Medical Oncologist

Introduction

Melanoma is a malignant tumor of melanocytes and the most malignant form of skin cancer.

It is found in the skin and mucous membranes and the most common sites are the face and legs. Malignant melanoma affects both genders, and affects people aged between 20-70 years, with a median age of 48 years.

Melanoma has attracted a lot of interest lately, due to increased frequency and possible correlation with sunlight, as well as the discovery of new effective drugs. It is estimated that the risk of melanoma is 1:50, with increasing rate, and 130,000 new cases are diagnosed per year worldwide.

 

Risk factors

The main risk factors for melanoma are:

  • Ultraviolet (UV) radiation: Scientists believe that the global increase in the incidence of melanoma is largely associated with increasing time of sun exposure, and with the expansion of the ozone hole. Artificial sources of UV radiation, such as artificial tanning equipment, can also damage the skin and increase the risk of melanoma.
  • Light-colored skin: Melanoma is more frequent in people with fair skin who burn easily in the sun and tan lightly, have lentigines (freckles), or light-colored hair (red, blond) and eyes (blue, gray). Melanoma frequency among whites is far higher than among blacks, probably because of the harmful effects of the sun.
  • Large number (> 50) of ordinary moles: Having many common nevi (with normal shape, color and limits) increases the risk of developing melanoma.
  • Dysplastic nevi: They are quite frequent, and they differ from common moles in that they are larger in size, have irregular shape and may appear in a variety of colors. The risk of melanoma is greater for people who have dysplastic nevi and in those with a family history of dysplastic nevi and melanoma.
  • Personal history of melanoma or skin cancer: People who have a history of melanoma are at high risk for developing a second melanoma. Some patients develop more than two primary melanomas on their skin. Also, people with a history of one or more of the common skin cancers (basal cell carcinoma or squamous cell carcinoma) are at increased risk of dying from melanoma.
  • Family history of melanoma: Some families have an increased incidence of melanoma. Having two or more close relatives with this disease is a risk factor.
  • Severe sunburn: People who report history of at least one severe sunburn (appearing with prolonged redness or blisters) especially in childhood are at increased risk for developing melanoma in adulthood.
  • The environment and living habits: Individuals at high risk for melanoma must consult their physician often, and should stay informed about the disease, its symptoms and ways of prevention and protection.

 

Symptoms and signs

Early warning signs are:

  • Change in color of a preexisting nevus
  • Increase in the size of a nevus
  • Appearance of an uneven coloring (dark brown to black) and mix colors
  • Appearance of irregular boundaries and insolence (elevation) of the preexisting nevus
  • Itching
  • Bleeding (recognized as one of the signs of advanced disease)

There can also be further changes in the color of nevus, as some portion of discoloration, or appearance of a reddish, dark blue or grayish tint. Bleeding usually occurs after minor trauma and sometimes appears after the above changes.

 

The "ABCDE" system is a mnemonic for detecting suspicious lesions:

A. Asymmetry: One half of nevus is not like the other half.

B. Border irregularity: The boundaries of the lesion forming indentations to the surrounding healthy skin.

C. Color variegation: The lesion shows a mixture of colors and shades.

D. Diameter: Increases in the largest diameter of the lesion.

E. Evolution: The size of normal nevi usually does not change within a period of weeks or months, while the size of melanomas changes.

 

Clinical types

Based on histological criteria and the way they grow, the following types of malignant skin melanomas are identified:

  1. Endoepidermal malignant melanoma
  2. Lentigo malignant melanoma
  3. Superficially spreading malignant melanoma
  4. Nodular malignant melanoma
  5. Acral malignant melanoma
  6. Desmoplastic melanoma
  7. Amelanotic malignant melanoma
  8. Childhood melanoma
  9. Malignant mucosal melanoma
  10. Ocular melanoma

 

Diagnosis

Biopsy: For diagnosis, it is necessary to perform a biopsy (surgical removal of the lesion and examination of morphological characteristics under the microscope).

The most important information from the histological assessment of the biopsy for further comprehensive treatment of melanoma are:

  • The “Breslow thickness” of the infiltration of melanoma (in mm)
  • The “Clark level of invasion”
  • The number of mitoses
  • The presence or absence of ulceration
  • The presence or not of automatic lesion regression.
  • Invasion or not of the lymphatic vessels or capillary blood vessels

 

Poor prognostic factors

  • Large Breslow thickness (> 4 mm)
  • High Clark’s level of invasion (≥ IV)
  • Older age
  • Male
  • Localization in the head and neck region
  • Nodular type
  • Ulceration of the surface
  • Increased number of mitoses
  • Lack of invasion with lymphocytes at the tumor borders
  • Satellite lesions
  • Existence of melanoma cells in the blood vessels

 

Treatments of melanoma

 

Surgical treatment

Surgery aims to cure the disease and remains the treatment of choice in treating primary melanomas. It is important to radically remove the melanoma, along with sufficient healthy skin surrounding it. In parallel, a biopsy of the "sentinel node" is important to exclude lymph nodes infiltration.

 

Sentinel lymph node (SLN)

The sentinel lymph node is the first lymph node that receives the lymph from the melanoma site.

For melanomas thicker than 1mm, based on histological, ultrasonographic or dermoscopic examination, there is increased likelihood of microscopic metastases in regional lymph nodes. Infiltration of regional lymph nodes is the strongest predictor of disease progression, and determines the appropriate treatment, since the presence of lymph node metastasis reduces survival by 40%. SLN biopsy is performed by injecting dye (usually isosulfan blue or patent blue), or radiolabelled colloid (technetium sulfur colloid or colloidal ilbumin), or a combination of all the above, to the tumor or in the biopsy cavity.

Most researchers agree that the combination of blue dye and radiolabelled colloid achieved higher rates of sentinel node localization. If the sentinel lymph node (SLN) is positive, then all lymph nodes of the region are removed surgically.

 

Adjuvant prophylactic immunotherapy

If the melanoma has depth invasion > 4 mm, and / or positive SLN, then the suggested treatment is prophylactic immunotherapy. In particular, following surgery interferon (IFNa-2b) is administered intravenously daily for one month, at high dosage (20 million units/m2) and then subcutaneously 3 times per week, for 11 months in smaller doses (10 million units).

The administration of interferon has increased metastasis-free interval and survival in patients with resected high-risk melanoma, and especially the subset that shows skin ulceration in primary melanoma.

Vaccines are also being tested. Among the most promising ones is the vaccine MAGE-3; a large multicenter study comparing prophylactic MAGE-3 vs placebo is underway, without any results having been published yet.

 

Metastatic disease - new drugs

When melanoma generalizes, ie gives metastases, the prognosis, until recently, was very poor and the survival of these patients was 6-9 months. For the past 30 years, no drug has been approved for melanoma, and the most effective chemotherapy drug has been decarbazine (DTIC). Response to DTIC is around 10-15%. Combinations of chemotherapeutic drugs offer better response, but do not increase survival.

 

Recent discoveries

Recently, scientists discovered a promising finding: in order to have an activated pathway in metastatic melanoma, mutations in a particular position within a specific gene are required (V600 in the B-RAF gene). They found that 50% of melanoma patients bearing this mutation can be treated effectively by targeted therapy drugs that target this exact position. These drugs are vemurafenib and dabrafenib, approved in Europe and the U.S.A. 

At the American Society of Clinical Oncology (ASCO) conference in 2012, researchers announced updated results of a study comparing vemurafenib with DTIC. This clinical study, called BRIM-3, involved 1350 patients with metastatic melanoma, and showed that vamurafenib significantly improved overall survival, and survival without disease progression. Specifically, the risk of death decreased by 63% and the risk of disease progression by 74%, while 50% of patients responded to the new drug, compared to only 5% that responded to DTIC. The overall survival reached 16 months.

In another study, another inhibitor of B-RAF, dabrafenib, appeared to have similar response with vemurafenib (50%). It is a highly effective drug for brain metastases, with or without radiotherapy, with very good tolerance levels by patients.

In a study comparing dabrafenib and DTIC (BREAK-3 study, ASCO 2012), dabrafenib seemed to reduce the risk of recurrence and death by 70%, while metastatic melanoma was reduced in 53% of patients.

 

Immunotherapy

Another drug that increased the survival of patients with melanoma is ipilimumab. It is based on immunotherapy, because it is a monoclonal antibody against the CTL-4 protein receptor, activating the T-lymphocytes, which become "killer cells" for malignant melanoma cells. This drug may be given to patients who do not have a B-RAF mutation. The increase in survival was shown in two large studies.  When all studies were analyzed retrospectively, among all patients who have received ipilimumab to date, 24% of them lived three years. The interesting observation is that if metastatic melanoma patients who received immunotherapy survive for three years, the chances of living to 10 years is very high! The drug has been approved in Europe and the U.S.A.

Another promising discovery of an "immunotherapy" monoclonal antibody against the PD-1 protein receptor, which aims to activate T–lymphocytes, is nivolumab. This drug acts faster than ipilimumab and offers lasting remissions in approximately 40% of patients with metastatic melanoma, with less toxicity. A recent study has shown that a combination of nivolumab and ipilimumab can have very promising results and good tolerance of drugs to the patient.

 

Impact on survival

There is no doubt that the newer therapies (immunotherapy and targeted therapies) have improved the survival of patients with metastatic melanoma. In a significant proportion of them (about 25 %), survival exceeds 3 years with either vemurafenib or ipilimumab.

Unfortunately, resistance to these drugs is developed after a period ranging from a few months to a few years, and research now focuses on overcoming this resistance by combining different drugs. Researchers have already reported very encouraging results from the combination of targeted therapies (dabrafenib + trametinib, vemurafenib + cobimetinib).

The trametinib and cobimetinib are MEK gene inhibitors, and are used in cases of patients carrying a B-RAF mutation. The research community eagerly awaits the results of such studies combining targeted drugs and immunotherapy.

 

Conclusion

In conclusion, more treatment options for metastatic melanoma are available, with much greater success than in the past, even in the case of very advanced disease.

 

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