Unlike many other types of tumors, melanoma can be detected early in its progression by visual, noninvasive methods.
Ashfaq A. Marghoob, MD
Unlike many other types of tumors, melanoma can be detected early in its progression by visual, noninvasive methods. Data from a screening study conducted in Germany indicated that simply implementing a whole-body examination on a population-wide basis reduced mortality from melanoma by up to 50%.1Dermoscopy, also known as epiluminescence microscopy or dermatoscopy, is a procedure that involves viewing the skin with a magnifying device, either a dermatoscope or a digital imaging system.2It has been shown to improve the accuracy of melanoma diagnoses,3and although it is not formally recommended by any United States guidelines, the use of dermoscopy by chief residents in the US increased from 51% to 84% between 2000 and 2009.4Furthermore, primary care physicians who received only 2 hours of training in dermoscopy were able to better triage suspicious skin lesions without increasing the number of unnecessary expert consultations.5
Several additional technologies have been developed that can further improve the efficacy of dermoscopy in detecting melanoma. The use of sequential digital dermoscopic imaging (SDDI) improves the sensitivity and accuracy of melanoma diagnosis over standard dermoscopy.6This method is particularly useful in monitoring suspected lesions that lack specific hallmarks of malignancy because small changes can be more easily identified during follow-up visits with the patient.
Total body photography (TBP) may be used to monitor patients with especially high numbers of pigmented lesions and nevi and can help to identify minor changes that should be biopsied to check for the presence of melanoma. Results from a recently published prospective, 5-year, follow-up study indicate that the addition of TBP and SDDI to a regimen of full-body examinations and dermoscopy increased early diagnosis of melanoma in a high-risk population.7The discovery that BRAF kinase is mutated in 66% of malignant melanomas8led to the development of inhibitors, such as vemurafenib and dabrafenib, which specifically target the mutated form of the protein. These drugs produce high rates of objective tumor responses and improvements in overall survival in patients with metastatic melanoma harboring aBRAFV600Emutation.
Although these drugs produce beneficial results in patients with melanoma, both vemurafenib and dabrafenib can induce new skin lesions and changes to pre-existing lesions that may become malignant and require careful monitoring.9,10A recent prospective, follow-up study found that more than 20% of patients who received vemurafenib developed a second primary melanoma compared with approximately 5% of patients who did not receive this treatment.11In a recent research letter toJournal of the American Medical Association, researchers proposed using TBP and dermoscopy to monitor the volatile changes in atypical-pigmented lesions seen in patients taking BRAF inhibitors.12
“Due to these dynamic changes it may be quite difficult to monitor these patients without the presence of baseline imaging,” stated the study’s senior author, Ashfaq A. Marghoob, MD, of the Memorial Sloan Kettering Skin Cancer Center in New York City.
“Thus, prior to starting a BRAF inhibitor it may be helpful to obtain baseline total body photography, especially for those patients with many nevi,” Marghoob said.
The issue of how best to implement lesion surveillance in patients taking BRAF inhibitors will only become more urgent as the clinical use of these drugs moves beyond cases of advanced disease, according to Giuseppe Argenziano, MD, of the Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy. He noted that “the issue of such a high percentage of patients under vemurafenib developing a second primary melanoma will become especially relevant if this medication is approved as adjuvant treatment of high-risk melanoma patients (stage 2 and 3). Stage 2 and 3 patients have a longer survival and therefore a second primary melanoma may eventually affect their survival if not diagnosed in an early phase.”
The underlying mutation driving new primary melanomas and other lesions in patients being treated with BRAF inhibitors has not been definitively determined. Additional, alternative mutations in the RAS/RAF/MEK/ERK pathway have been proposed as possible drivers, and, indeed, NRAS mutations have been found in some secondary lesions.13
Given the positive trial data generated by binimetinib (MEK162) in cases of NRAS-mutated melanoma,14MEK inhibitors warrant further investigation in this setting. Checkpoint inhibitors such as the anti-PD-1 antibody pembrolizumab (lambrolizumab; MK-3475)15are also being tested in combination with BRAF inhibitors, and their effects on the development of secondary melanomas bear watching.
“The open question concerns the biology of these new melanomas. They are morphologically identical to conventional melanomas, but the real malignant potential still remains to be demonstrated,” Argenziano said.
Until the underlying cause of these secondary lesions is determined and rational treatment developed, the key to better patient care will rest on the clinician’s knowledge and use of current surveillance tools such as TBP and SDDI.