In order to diagnose a melanoma, a physician will remove the primary cancer and a pathologist will examine the sample under a microscope. Once melanoma is diagnosed, there are three critical factors that need to be determined:
- the thickness of the melanoma
- the genomic profile of the melanoma
- whether or not the melanoma has spread (metastasized) to other parts of the body.
These factors help determine prognosis, treatment and are part of the overall staging evaluation for melanoma. The stage of melanoma is key in order to determine treatment options and outcomes.1,2,3,4
Thickness: An important feature of the tumor is the thickness, which is measured in millimeters. Melanoma is divided into 3 groups based on thickness:
- thin melanomas (< 1 mm thickness)
- intermediate melanomas (1 to 4 mm in thickness)
- thick melanomas (> 4 mm).
The thickness of the melanoma is important because it will have an impact on whether the tumor has spread, which is the other critical factor used to determine the stage of disease. The thicker a melanoma is, the more likely it is to have spread to lymph nodes at the time of diagnosis.4
Sentinel Lymph Node Biopsy In general, when melanoma spreads, it spreads to lymph nodes near the cancer first. Lymph nodes are small, bean-shaped structures that are part of the immune system. They are found throughout the body and are interconnected by lymph channels. Melanoma tends to spread through lymph channels that drain into lymph nodes in the local area of the primary skin melanoma. Once a pathologist has determined the thickness of the tumor, the next step in pathological staging may involve surgical removal and examination of the local lymph nodes to determine if apparently normal lymph nodes contain melanoma cells.
The sentinel lymph node (SLN) biopsy technique has improved the ability to detect small amounts of melanoma in lymph nodes. A SLN biopsy is a technique that relies on intra-operative lymphatic mapping. During a SLN biopsy, a physician injects a tracer (radioactive isotope and/or blue dye) into the area of the primary melanoma. The tracer, which is taken up by the lymph system, identifies the so-called “sentinel lymph node” which is the first lymph node that could be potentially involved with melanoma. Lymphatic mapping can be performed prior to surgery to aid the physician in determining which lymph node group is the primary drainage basin for any particular area of skin and it can also be used on the day of surgery to identify which lymph node is the first node (sentinel lymph node).2,3
During a SLN biopsy, the physician removes the SLN through a small incision and then a pathologist examines the SLN under the microscope to detect whether or not there is any evidence of melanoma cells. Patients who have a positive sentinel node (melanoma identified) are counseled to undergo removal of all the lymph nodes in the region, while patients who have a negative sentinel node do not undergo further surgery.
There is evidence that surgical removal of involved lymph nodes may improve survival. This may especially be true when only one lymph node is involved with melanoma. Ideally, if there is no melanoma involvement in the lymph nodes, the removal of lymph nodes should be avoided. It is important to know about the presence of local lymph nodes involved with spread of melanoma, as this is one of the criteria frequently used to identify patients at high risk for development of recurrent disease and is also an entrycriteria for clinical trials evaluating the role of additional therapy.
Melanoma can spread by local extension (through the lymph system, as described above) and/or by the blood to distant sites. Satellite lesions can also occur in the skin adjacent but separate from the primary melanoma. These are sometimes called in-transit metastases, implying that secondary melanomas have grown in the skin on their way to spreading to local lymph nodes. Any organ can be involved by metastases from malignant melanoma, but the lungs and liver are the most common sites.
In 3-5% of patients, melanoma is present in lymph nodes or other organs without an identifiable primary site and these patients are said to have “melanoma of unknown origin.” In such cases, it is believed that the primary melanoma underwent spontaneous regression, while the metastasis remained. Patients with unknown primary in the lymph nodes or in distant sites have stage III or IV disease and are treated as outlined for malignant melanomas of these stages.
Genomic or Biomarker Testing: The purpose of looking for biomarkers and genomic alterations in the cancer’s DNA is to identify targets that can be treated with precision cancer medicines. Precision cancer medicine utilizes molecular diagnostic & genomic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.5,6
Genetic Mutations in Melanoma
Not all melanoma cells are alike. They may differ from one another based on what genes have mutations. Testing for biomarkers or genomic alterations is performed to identify genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific colon cancer cells with specific genetic mutations.5,6
BRAF: The BRAF V600 kinase is a pathway in cells that is active in cellular replication and spread. BRAF V600 mutations (either V600K or V600E) result in unchecked cellular replication and spread, resulting in the growth of cancer cells.5
PD-1: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.6
Staging of Melanoma
Doctors need to determine the stage or the extent of the spread of the cancer. A cancer’s stage is a key factor in determining the best treatment. This requires a number of additional tests beyond the initial biopsy and lymph node evaluation.
Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body. This method is more sensitive and precise than an X-ray.
Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays and can often distinguish more accurately between healthy and diseased tissue. MRI gives better pictures of tumors located near bone than CT, does not use radiation as CT does, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the tumor.
Positron emission tomography (PET): Positron emission tomography (PET) scanning has been used to improve the detection of cancer in lymph nodes. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that spontaneously emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons). The positrons react with electrons in the cancer cells, which creates the production of gamma rays. The gamma rays are then detected by the PET machine, which transforms the information into a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.
Bone Scan: A bone scan is used to determine whether cancer has spread to the bones. Prior to a bone scan, a surgeon injects a small amount of radioactive substance into a vein. This substance travels through the bloodstream and collects in areas of abnormal bone growth. An instrument called a scanner measures the radioactivity levels in these areas and records them on x-ray film.
Patients with melanoma in situ (stage 0) have melanoma cells only in the outer layer of skin (epidermis). There is no invasion of the deeper layer (dermis) and therefore essentially no potential for spread.
Stage I Patients with stage I malignant melanoma have cancer that is found in the outer layer of the skin (epidermis) and/or the upper part of the inner layer of skin (dermis) but has not spread to lymph nodes. The primary melanoma is less than 2 millimeters (1/16 of an inch) thick.
Patients with stage II melanoma have cancer that is 1 to 2 millimeters with ulceration or greater than 2 mm with or without ulceration. Stage II melanoma has spread to the lower part of the inner layer of skin (dermis), but not into the tissue below the dermis or into nearby lymph nodes.
Stage III melanoma includes cancers of any thickness that have spread to the regional lymph nodes. The extent or amount of tumor in the lymph nodes is the most important prognostic factor for patients with stage III melanoma.
Patients with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes or other distant sites in the body, such as the liver, lungs, or brain.
1 Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012.
2 Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998.
3 Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012.
4 Cancer Facts & Figures 2017. American Cancer Society website. Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf.
5 Ascierto P, McArthur G, Dreno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF V600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology. 2016;17 (9): 1248-1260.
6 Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for Advanced Melanoma Met Co-Primary Endpoints and Will Be Stopped Early [press release]. Merck website. Available at: https://www.mrknewsroom.com/news-release/oncology-newsroom/mercks-pivotal-keynote-006-study-first-line-treatment-advanced-melano. Accessed April 8, 2015.