Melanoma: The Facts

Melanoma is the fastest growing cancer in the US.

Melanoma Research Foundation Fact Sheet
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This Fact Sheet is provided courtesy of the Melanoma Research Foundation.

A Call to Arms in the Battle against Mucosal Melanoma

I. Mucosal Melanoma: A Rare and Complex Adversary

Melanoma is a disease that commonly surprises both patients and physicians with its tenacity and its divergent behavior. As my clinical oncology practice consists primarily of patients battling metastatic melanoma, I often witness the unfortunate ability of this cancer to spread from its site of origin to other parts of the body, with virtually no organ escaping the potential for invasion. During these discussions, patients and loved ones often reference the common misconception that melanoma can only be found on the skin. However, not only can melanoma originate in the skin and spread to other areas of the body, but melanoma can also begin in parts of the body other than the skin. Mucosal melanoma is one such important example.

Melanoma, regardless of where on the body it occurs, originates from normal pigment cells called melanocytes. These melanocytes produce melanin, the vital pigment which protects the skin from damage caused by the sun's ultraviolet rays. Like any other cell in the body, melanocytes can transform into cancerous cells, and when this transformation occurs, the end result is the development of melanoma. Although normal melanocytes are present in the skin, they are also present elsewhere, such as the mucosal surfaces of the body. These mucosal surfaces line the sinuses, nasal passages, oral cavity, vagina, anus, and other areas. In fact, while there are approximately 800 melanocytes per square millimeter in the skin of the abdomen, there are 1,500 melanocytes per square millimeter present within the mucous membranes of the nose and mouth. Like the melanocytes found in the skin, these mucosal melanocytes can also become cancerous. This transformation results in the development of a type of melanoma called mucosal melanoma.

Although first described in 1856, mucosal melanoma is not a well-known entity due to its relative rarity. Indeed, of the 69,000 cases of melanoma diagnosed in the United States in 2010, less than 5% were mucosal melanoma. Slightly over half of all mucosal melanomas begin in the head and neck region, approximately one quarter of mucosal melanomas arise from the anorectal region, and another 20% arise from the female urogenital tract. Melanomas originating in mucosal surfaces lining the esophagus, gallbladder, bowel, conjunctiva, urethra, and other sites are far less common.

While melanoma arising from the skin and mucosal surfaces all originate from melanocytes, cutaneous melanoma and mucosal melanoma differ dramatically in their behavior and underlying biology. The initiation and development of cutaneous melanoma is usually associated with a history of sun exposure, particularly during childhood; however, this association is certainly not the case for mucosal melanoma. Indeed, at this time, no clear predisposing exposures, family history, or other risk factors have been established for this disease.

II. The Inadequacy of our Current Therapeutic Armamentarium

As with most cases of melanoma, complete surgical removal of the primary mucosal melanoma provides patients with the greatest likelihood of a cure. Unfortunately, mucosal melanoma is difficult to diagnose due to its rarity, the associated low clinical suspicion by patients and physicians, and the nonspecific symptoms caused by these tumors (see Table). Many cases are quite advanced once identified, as a significant amount of time can pass before the detection and diagnosis of mucosal melanoma.

Even if the primary mucosal melanoma is surgically resected, in all too many cases, melanoma cells have already spread from the primary lesion into the bloodstream and lymphatic vessels of the body. These metastatic cells can land in any organ of the body, but have a particular predilection for the lungs, liver, brain, lymph nodes, and intestines. Although they can remain dormant for many months or even years, ultimately these cells will begin to grow and may spread elsewhere throughout the body.

Body System	Sub-Site	Common Presenting Symtoms
Gastrointestinal	Anorectal Esophageal Gallbladder	Bleeding, rectal pain, mass lesion Difficulty swallowing, pain with swallowing Abdominal pain, jaundice
Respiratory	Sinonasal Oral Cavity	Difficulty breathing, nose bleeds Pigmented spot or mass
Urogenital	Vulvovaginal Urethral	Vaginal bleeding or discharge, pigmented spot or mass, itching Blood in the urine
Ocular	Conjunctival	Pigmented spot

Once mucosal melanoma metastasizes, it becomes an extremely difficult disease to treat. While surgery or radiation can sometimes help to relieve symptoms, rarely can the cancer be fully eradicated. Furthermore, the drugs currently available to treat metastatic melanoma, whether originating in the skin or a mucosal surface, can help some people, these agents do not work in all cases. Even when they do, the benefit is all too often short-lived. Although there certainly are exceptions, metastatic mucosal melanoma is considered fatal and it is thus quite clear that we are in desperate need of new and effective treatments for this disease.

III. Know Thy Enemy

Over the past several years, significant advances have been made in our understanding of melanoma. Elegant work delineating how melanoma can evade the natural protection of the immune system has led to the development of a number of new agents that enhance cancer immunity. Ipilimumab is one such drug that recently demonstrated improved survival rates for patients with metastatic melanoma when compared to results obtained with a melanoma vaccine. The significance of these findings cannot be overstated, as ipilimumab is the first treatment shown to improve survival in patients with advanced melanoma. Another significant finding has been the discovery that approximately 50% of melanomas harbor a mutation in a protein called BRAF. This mutation is important in driving growth and progression in the melanomas characterized by such an abnormality. Recent studies have demonstrated that PLX4032 (now RG7204), a drug that inactivates mutant BRAF, causes major tumor shrinkage in 80% of treated patients; however, this dramatic effect was only observed in patients whose tumors harbored the mutated BRAF protein. No benefit was observed in patients whose tumors were characterized by a normal BRAF.

This association of treatment efficacy with a specific molecular subgroup of melanoma has important implications for how we think about this disease. Small studies suggest that melanomas harboring a BRAF mutation behave differently than those without a mutation, as is consistent with the hypothesis that the BRAF mutation is not only a marker of sensitivity to a drug such as PLX4032, but also an indicator of a unique clinical subgroup of melanoma. Indeed, based on work by investigators such as Dr. Boris Bastian, the recipient of the Melanoma Research Foundation 2008 Established Investigator Award which was funded by the Susan Fazio Foundation, it is becoming increasingly evident that melanoma is not one disease, but rather a family of unique diseases, each characterized by various underlying molecular abnormalities. Mucosal melanoma is one such unique subgroup in this emerging molecular subclassification system of melanoma. This subclassification system has tremendous implications for the development of new and effective therapies for patients with this disease. We are now able to test such novel therapies in patients with the specific genetic subsets of melanoma most likely to benefit from a particular therapeutic strategy. We believe that this new era of targeted drug development in specific molecular subsets of melanoma will lead to the much needed and long-awaited identification of agents that can meaningfully improve the lives of patients with metastatic melanoma.

One significant molecular difference between mucosal and cutaneous melanoma is the relatively low frequency of BRAF mutations in mucosal melanoma. Rather, mucosal melanoma is often characterized by mutations or other alterations affecting the activity of a protein called KIT. Like mutant BRAF in cutaneous melanoma, these changes in KIT play an important role in tumor growth in mucosal melanoma characterized by such an abnormality, thus raising the possibility that using a drug that inactivates KIT in these cases may be an effective therapeutic strategy. Interestingly, in another rare type of cancer called gastrointestinal stromal tumor (GIST), changes in KIT similar to that seen in mucosal melanoma have been shown to be important in tumor growth and progression. A drug called imatinib mesylate which blocks the activity of KIT has proven to be a remarkably effective treatment for this disease. Given this similarity between GIST, mucosal melanoma, and other melanoma subtypes characterized by KIT alterations such as melanoma arising from acral surfaces (palms of the hands, soles of the feet, or the nail beds) and melanomas arising from chronically sun-damaged skin, we designed a clinical trial to test whether imatinib would work in patients with melanoma characterized by an abnormal KIT protein as it does in patients with GIST.

IV. A New Strategy to Combat Mucosal Melanoma

The interim results of our clinical trial of imatinib for patients with melanoma harboring an abnormal KIT protein were presented at the 2009 American Society of Clinical Oncology Annual Meeting. At the time of this presentation, we had tested 146 melanoma samples for the presence of an abnormal KIT protein. We found that 24% of mucosal melanomas harbored such an abnormality. Thirty percent of acral melanomas and 9% of melanomas arising from chronically sun-damaged surfaces also harbored an abnormal KIT. We treated 15 patients whose tumors harbored an abnormal KIT protein with imatinib: 7 had mucosal melanoma, 8 had acral melanoma, and 1 had melanoma arising from chronically sun-damaged skin. Of the 12 patients who had had follow-up scans by that time, 4 had achieved significant or complete disappearance of their tumor, with most of the others achieving control of their tumor growth.

One patient who had the complete disappearance of her mucosal melanoma with imatinib is an 82 year old female with disease arising from the vaginal mucosa and involving the bladder and lymph nodes. Her tumor had grown despite the use of chemotherapy. Before she started treatment with imatinib, she was suffering from a significant amount of pelvic pain and vaginal bleeding; however, after only 2 weeks of therapy, she experienced complete resolution of these symptoms. After 6 weeks of therapy, her dominant pelvic tumor mass had decreased in size from 7 cm to 2 cm. After 18 weeks of treatment, no tumor could be seen on her CT and MRI studies.

Because of the promising results of our study, as well as those of two other studies of imatinib in molecularly selected patients with melanoma led by Drs. F. Stephen Hodi at the Dana-Farber Cancer Institute and Jun Guo at the Beijing Cancer Hospital in China, a large international phase III trial of nilotinib, another inhibitor of KIT, has been initiated. This study is designed to definitively evaluate the efficacy of KIT inhibition in melanomas harboring KIT mutations. It is of significant importance to patients battling advanced mucosal melanoma, especially given the frequency of cases driven by such KIT alterations.

V. Forging Alliances to Cure Mucosal Melanoma

Although the strategy of KIT inhibition holds great promise for improving the lives of patients with mucosal melanoma, it will unlikely be curative for most patients with advanced disease. To develop more successful therapies, we must forge close alliances between the key individuals who have an interest in this disease: the patients battling mucosal melanoma, the doctors caring for them, the laboratory researchers delving into the unique biology of this melanoma subtype, and the clinical researchers developing new treatments for this disease. Funding must be identified to promote such collaborative efforts, as well as support on-going and new avenues for research. By working together, we can gain a more complete understanding of the biology of mucosal melanoma. This understanding can then be translated into the development of novel, more effective, and potentially curative therapies.

–Dr. Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York City