Cases highlight gray areas
Genetic expression profiling
Dr. High emphasizes that "Rather than using morphologic analysis to assess genetic potential, there is increased promise for using actual genetic testing to assess melanoma." In a recent study, the presence of telomerase reverse transcriptase (TERT) promoter mutations provided the most accurate prediction of aggressive behavior in 56 patients with spitzoid melanocytic neoplasms (p<0.0001).3 At a median follow-up of 32.5 months, four patients – all with TERT promoter mutations – had died of disseminated disease. None of the 52 surviving patients had such mutations.
Dr. High adds that genetic testing may be used for prognostic purposes, not just for diagnosis. "There is evidence that a new 31-gene expression profiling test (31-GEP) can distinguish high-risk melanoma from low-risk melanoma, at least in many instances." This 31-GEP test predicted metastatic risk in multple cohorts of primary cutaneous melanoma (ROC = 0.93, 0.91, respectively).4 Kaplan-Meier analysis showed that five-year disease-free survival (DFS) rates in the development cohort for predicted low-risk and high-risk cases were 100% and 38%, respectively (P < 0.0001). DFS rates for the validation set were 97% and 31% for predicted low-risk and high-risk cases, respectively (P < 0.0001).
Dr. High speculates that this type of prognostic testing could prove particularly useful in certain situations, such as melanoma of less than 1 mm in depth (or perhaps between 0.76 mm and 1 mm) but with mitotic activity, and those persons who undergo SLN biopsy with negative results. Among SLN-negative cases that were identified as high-risk by the 31-GEP test, a recent report showed that at five years' follow-up, 67% had recurred, and 83% of patients had died.5
"Since we really want to know how a melanocytic lesion will behave on a genetic basis," Dr. High says, "it is reasonable to assume that the future of dermatopathology testing modalities will be genetically-based, rather than morphologically based."
With more than 6,000 mutations described in melanoma, he said, attempting to distinguish malignant lesions from benign atypical nevi by histologic examination is more subjective than people realize.
Immunohistochemistry (IHC) can be helpful, but there is no "melanoma stain," he says. Each IHC stain has strengths and limitations. For example, human melanoma black (HMB)-45, demonstrates "zonal" staining, with lesser expression with descent of melanocytes in nevi, and it is generally a sign of benignity. However, in lesions with what Dr. High called "dusty" melanocytes, such as deep penetrating nevi (DPN) and so-called "clonal" nevi, this result can give unhelpful results.
The tumor suppressor protein p16 is normally expressed in a mosaic pattern, with nuclear and cytoplasmic staining, in most benign melanocytic nevi, including most Spitz nevi, he said. Conversely, loss of p16, particularly loss of nuclear expression of p16, is a concerning feature that is more often associated with melanoma. Loss of p16 expression in melanocytic lesions can be a surrogate of biallelic loss of portions of chromosome 9p21, which in turn can be an indicator of a lesser prognosis in spitzoid melanocytic lesions.
"Broader stains for general badness involve combining a MART-1/Melan A stain (a marker of melanocytes), with Ki67 (a marker of cellular proliferation)," Dr. High says. This combination allows the examiner to gauge the architecture of a melanocytic process, and to note, more specifically, which melanocytes/melanocytic nests have increased proliferation.
Disclosures: Dr. High reports no relevant financial interests.
3. Lee S, Barnhill RL, Dummer R, et al. TERT promoter mutations are predictive of aggressive clinical behavior in patients with spitzoid melanocytic neoplasms. Sci Rep. 2015;5:11200. doi: 10.1038/srep11200.
4. Gerami P, Cook RW, Wilkinson J, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res. 2015;21(1):175-83.
5. Zager JS, Messina J, Sondak VK et al. Performance of a 31-gene expression profile in a previously unreported cohort of 342 cutaneous melanoma patients. Poster 186. Presented at: American Society of Clinical Oncology Annual Meeting. June 3-7, 2016; Chicago.