Advances In Melanoma

One person dies of melanoma every hour in the United States.1 Although the general public’s knowledge about skin cancer has certainly increased compared to 2 decades ago; the popularity of tanning has also soared. In fact, being tan has been portrayed as a near necessity by such shows as The Jersey Shore where “gym, tan, laundry” are part of a weekly routine for a group of 20-somethings living together. As rates of melanoma and non-melanoma skin cancer reach increased proportions in the population under 40, advances in melanoma treatment and even detection are continuing. These new tools and medications are helping dermatologists offer more options for treatment to their patients with melanoma.

Detection

While a total body skin exam remains the gold standard in melanoma detection, several new technologies have emerged to aid in diagnosis. Dermatoscopes have been available for several years, but it has only been in the last decade that the art of dermoscopy has gained significant traction in training programs. 

In this short amount of time, dermoscopy has become an accepted standard for evaluating the patterns of pigmented lesions to aid in the decision to perform a biopsy; however, it is also recognized that the limitation of this tool lies in the experience of the person interpreting the visualized pattern.

Newer technologies attempt to eliminate this source of human error. MelaFind (MELA Sciences, Inc., Irvington, NY) employs multispectral imaging — specifically 10 wavelengths between 430 nm and 950 nm — to illuminate the skin and capture an image of the pigmented lesion in question. The device then analyzes thousands of different features within the lesion and compares it to its database to produce a score that tells the practitioner the probability of it being atypical. 

Limitations include size of the pigmented lesion, location on the palms and soles and lesions located near the eye or underneath the nail. The score produced by MelaFind is meant to aid the physician in a decision to perform a biopsy. A study by Monheit et al published in the Archives of Dermatology demonstrated MelaFind’s sensitivity to be greater than 95%.2 

Another such diagnostic tool is confocal scanning laser microscopy that essentially creates a 3-dimensional image of a pigmented lesion with such high resolution that it is comparable to a standard pathology slide. As a result, confocal microscopy is thought to act as a “virtual biopsy” though again, interpretation is highly dependent on the training of the users. While both of these technologies have demonstrated impressive sensitivity, biopsy continues to be the definitive answer. 

All of these technologies rely, of course, on the patient visiting a dermatologist. There are, however, programs and services to potentially detect changes in lesions without an office visit. Total body photography has long been employed by physicians to track lesional changes in patients with multiple nevi. Patients can visit a MoleSafe Inc., clinic (http://molesafe.com/) and a technician will photograph lesions of concern and transmit these images to a physician located remotely who interprets the lesion(s) and writes a report on its level of concern and need for a biopsy for further evaluation. 

Additionally, many smartphone applications are available to patients to store, track and interpret pigmented lesions. SkinVision (https://skinvision.com/) is one such app that allows users to photograph a lesion, which is then analyzed remotely using an algorithm to advise patients on whether they should see a physician. DermoScreen is another app that requires a dermatoscope attachment to the iPhone and, in preliminary studies, has shown an 85% accuracy rate in interpreting pigmented lesions.3 

Some have postulated that these apps will help rather than replace dermatologists — especially in remote areas where access to a dermatologist is limited. Skeptics of the technology fear that these apps will give patients a false sense of security for potentially malignant lesions.

Once It Is Found

Because biopsy remains the ultimate diagnostic tool for melanoma, concern arises when borderline lesions are sampled. Concordance among dermatopathologists with regards to ambiguous melanocytic lesions is low. In fact, variable interpretation can occur even in lesions that are not considered to be morphologically ambiguous. 

Misclassification can result in severe consequences to the patient. To fill this gap, molecular studies have emerged to supplement the findings of hematoxylin and eosin slides. These molecular assays provide diagnostic and in some instances, prognostic information for melanomas. 

One such assay is fluorescence in situ hybridization (FISH) — a test performed by select pathology labs that employ cytogeneticists. 

For a specimen to be considered positive, it has to demonstrate 1 of the following criteria: (A) gain in ras-responding element binding protein 1 (RREB1)  relative to chromosome 6 centromere (CEP6) greater than 55%; (B) gain in RREB1 greater than 29%; (C) loss of myelobastosis oncogene relative to CEP6 greater than 40% or (D) gain in CCDN1 (cyclin D1) greater than 38%. While a positive FISH assay is not conclusive evidence that the lesion is melanoma, clinicians can use this information along with patient history and appearance of the lesion under the microscope (for characteristics such as thickness) to help guide them in treatment choices.4 

Similar to the FISH assay, but more comprehensive, is comparative genomic hybridization (CGH) that analyzes copy number variations relative to ploidy level in the DNA of each cell in a sample. Like FISH, CGH is a tool to help focus diagnosis.

Once a diagnosis of melanoma is made, staging becomes an important next step. A variety of tests can be used during this phase of diagnosis. DecisionDx-Melanoma (Castle Biosciences Inc., Friendswood, TX) is an mRNA expression-profiling test that can be used on biopsied tissue. The test quantifies expression of 31 genes from the primary tumor and applies a validated algorithm, which then classifies patients as low versus high risk. Myriad myPath Melanoma test (Myriad Genetics Inc., Salt Lake City, UT) also employs mRNA-based expression patterns to interpret ambiguous pigmented lesions.

Treating The Disease

In the past, the diagnosis of stage IV melanoma left patients with few options. Since 2011, a series of antibodies targeting the tumor itself have come onto the market improving survival rates significantly. The BRAF inhibitor vemurafenib (Zelboraf, Genentech, Inc.), which works in melanomas with the V600E mutation, was initially approved as a single agent but is now used in combination with other drug therapies to improve outcomes. Several trials are ongoing.

Earlier this year, the FDA approved the MEK inhibitor trametinib (Mekinist tablets, GlaxoSmithKline, LLC) and BRAF inhibitor dabrafenib (Tafinlar capsules, GlaxoSmithKline, LLC) as a combination therapeutic option for melanoma treatment. The combination therapy prevented advanced melanoma from progressing while causing less severe side effects than current standard targeted therapy drug.5 

In addition, ipilimumab (Yervoy, Bristol-Myers Squibb) is being combined with the human growth factor sargramostim (Leukine, sanofi-aventis U.S. LLC,), which has improved 1-year survival in a reported cohort of 245 patients.6 

On the experimental front, medications targeting programmed cell death-1 (PD-1) on T cells are beginning to garner attention as are PDL-1 antibodies. The idea behind this regimen is that PD-1 is present on T cells and PDL-1 is usually on antigen-presenting cells but can also be on tumor cells. When tumor cells express high levels of PDL-1, they can actually cause local immunosuppression by essentially “faking out” T cells. If this interaction can be disrupted, tumor shrinkage can and does occur. 

The FDA recently granted accelerated approval to pembrolizumab (Keytruda, Merck) for treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs. Pembrolizumab is the first FDA-approved drug that blocks the PD-1 cellular pathway. Pembrolizumab is intended for use following treatment with ipilimumab immunotherapy. 7 (For more information, see page 10)

Investigating another route, researchers are also interested in the role of nitrous oxide and its ability to inhibit the mTOR pathway, which is important for melanoma growth. When nitrous oxide production is blocked the mTOR pathway is also blocked, which can be associated with decreased melanoma tumor growth.

Putting It All Together

While new technology has yet to best physician biopsy of a pigmented lesion, several steps in the process of diagnosing and ultimately treating a melanoma have been greatly advanced. From diagnosis to tracking change to decision-making about performing a biopsy itself, devices have entered the market to aid the clinician in decision-making. Once a pigmented lesion is sampled, objective measurements of certain genes can reduce dermatopathologist discordance. Ultimately, the focus is on the patient and even in that arena, new targeted chemotherapeutics are providing more options for melanoma. 

The last 3 years have ushered in more change and hope in the field of melanoma than in the last 2 decades — whether it is detection or treatment — all are pointing in a positive direction for the patient. However, what remains to be improved is prevention. n

 

Dr. Mariwalla is a dermatologist in practice in West Islip, NY.

 

Disclosure: The author reports no relevant financial relationships. 

References

1. American Cancer Society. Cancer Facts & Figures 2014. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed October 7, 2014.

2. Monheit G, Cognetta AB, Ferris L, et al. The performance of MelaFind: a prospective multicenter trial. Arch Dermatol. 2011;147(2):188-194.

3. Rodriguez S. Professor creates iPhone app capable of screening for skin cancer. Los Angeles Times. May 8, 2014. http://touch.latimes.com/#section/-1/article/p2p-80142968/. Accessed October 7, 2014.

4. Nijhawan R, Votava HJ, Mariwalla K. Clinical application and limitations of the fluorescence in situ hypbridization (FISH) assay in the diagnosis and management of melanocytic lesions; a report of 3 cases. Cutis. 2012;90(4):189-195.

5. FDA.gov. Trametinib and Dabrafenib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm381451.htm. Updated January 14, 2014. Accessed October 7, 2014.

6. Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. Presented at: The 49th Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract CRA9007. 

7. FDA approves Keytruda for advanced melanoma [news release]. Silver Spring, MD: US Food and Drug Administration; September 4, 2014. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm. Accessed October 7, 2014.