WHAT’S NEW IN PATHOLOGY?

Issue 5 || March 2017

demonstrate loss of MMR proteins by immunohistochemistry (Hum Pathol THE LATEST NEWS IN 2016;49:1); however, the number of those patients ultimately determined DERMATOPATHOLOGY to have a germline mutation (and By Sara Shalin, M.D., Ph.D. MTS) is considerably smaller. Unlike colorectal carcinoma, where MMR IHC has high sensitivity (92% - 94%) Thus, it is imperative that evaluation and specificity (88% - 100%) in Sentinel lymph node is comprehensive. While official detecting Lynch syndrome, MMR IHC evaluation in melanoma guidelines have not been issued, most in sebaceous neoplasia has a Standard clinical practice is to dermatopathologists recommend that reasonable sensitivity (85%) but low perform a sentinel lymph node biopsy the minimum evaluation of a sentinel specificity (48%) (Genet Med on melanomas with a Breslow depth lymph node biopsy (if negative for 2014;16:711), leading to a high > 1.0 mm and clinically negative melanoma on initial sections) should number of false positive screens. regional lymph nodes. These sentinel include multiple deeper levels and lymph node biopsies are obtained by multiple (generally at least two) injecting a dye or radioactive tracer immunohistochemical stains against into the primary tumor bed. melanocytic antigens. For a nice ###### Radioactivity is detected in the review, see Arch Pathol Lab Med regional lymph node basin, with the 2013;137:1603. greatest activity corresponding to the “sentinel” node. Lymph nodes with ###### > 10% of the greatest activity reading Sebaceous neoplasia and can also be considered a sentinel testing for Muir-Torre node, which is why several sentinel Syndrome: the debate Arrow: focal sebaceous lymph nodes may be received. continues differentiation Sebaceous neoplasia is associated with Muir-Torre Syndrome (MTS), a Lastly, a small subset of patients with variant of Lynch syndrome. As MTS phenotype demonstrate ###### sebaceous neoplasms (adenomas, microsatellite stable tumors and intact sebaceomas and carcinomas) are MMR protein staining due to different relatively rare, their diagnosis should genetic mutations; these patients will ###### prompt consideration of screening for have a false negative screen. Some the syndrome. One screening method authors advocate universal screening uses mismatch repair protein (MMR) by MMR IHC for all sebaceous immunohistochemistry (MLH1, neoplasia. Others suggest offering MSH2, MSH6 and PMS2). Loss of Micrometastases ancillary testing to dermatologists, staining indicates an absence of the who can evaluate patients for other The presence of metastatic melanoma MMR protein, which leads to clinical criteria of the syndrome in a sentinel lymph node generally microsatellite instability and tumor (selective screening). Concerns still prompts a completion lymphaden- formation. Although MLH1 absence is exist regarding cost effectiveness of ectomy, and by AJCC staging most commonly detected in colorectal widespread screening and patient guidelines, even a single atypical cancers of Lynch syndrome, MSH2 is privacy and informed consent for melanocyte, detected by H&E or by the most frequently deleted MMR what could be viewed as a surrogate convincing immunohistochemistry, protein in sebaceous tumors. Up to for genetic testing (J Am Acad qualifies as a positive lymph node. 2/3 of sebaceous neoplasia will Dermatol 2016;75:1078). dysplastic nevi and atypical Spitz requested at the time of diagnosis of Molecular testing in tumors), the gene expression profile metastasis and can be performed with melanoma increased definitive diagnoses by 50% a variety of PCR based assays on Molecular testing has become a hot and reduced indeterminate diagnoses paraffin embedded, formalin fixed topic in dermatopathology. Both FISH by 43%. This increase in diagnostic tissue. An immunohistochemical stain and array CGH are relatively confidence also seemed to influence (VE1) is available and seems to established molecular ancillary tests subsequent treatment recommen- demonstrate good correlation with the for melanoma; lesions harboring dations (Medicine (Baltimore) molecular result, however it only molecular aberrations are more likely 2016;95:e4887). detects the most common mutation to be malignant than those without. (V600E) and not other variants. Currently, additional molecular based DecisionDx®-Melanoma: techniques are promoted as ancillary PD-L1: tests to help classify as malignant This RT-PCR based assay, designed to versus benign, to predict long term provide prognostic information to PD-L1 expression has been described behavior of documented melanoma patients diagnosed with primary in melanoma tumor cells and (indolent versus aggressive), and to cutaneous melanoma, is currently melanoma immune related cells. predict response to targetable drug being marketed by Castle Biosciences, Although several different companion therapies. Inc. It is performed on formalin fixed, assays are on the market to assess for paraffin embedded tissue, and PD-L1 expression by immunohisto- MyPath® Melanoma: examines expression of 28 melanoma chemistry (each linked to a different related genes and 3 housekeeping / drug), there are currently no A gene expression signature has been control genes to stratify patients into requirements for PD-L1 IHC testing in developed to help differentiate benign two groups, class I (low risk) and class melanoma in order to treat with a from malignant melanocytic 2 (high risk). The gene expression PD-1 or PD-L1 inhibitor. neoplasms and is marketed by Myriad profile was found to be an Genetic Laboratories as MyPath® independent predictor of metastatic Melanoma. This RT-PCR based assay risk when developed and validated Conflict of interest statement: I have is performed on formalin fixed, (Clin Cancer Res 2015;21:175). no financial relationships or conflicts paraffin embedded tissue and Moreover, when combined with of interest related to any of the assays evaluates expression levels of three sentinel lymph node biopsy results, discussed in this newsletter. groups of melanocytic related genes one study found that the gene (PRAME involved in cell expression profile combined with differentiation, S100A9 related genes sentinel lymph node biopsy improved involved in multiple cell signaling prognostication. Sentinel lymph node pathways, and immune related genes) negative patients with class 2 and control / housekeeping genes for signatures had lower rates of disease MEET a total of 23 genes examined. Numeric free survival, distant metastasis free THE scores are generated, with benign survival, and overall survival lesions scoring < -2 and malignant compared to sentinel lymph node AUTHOR lesions classified as scores > 0. Scores negative patients with class 1 between -2 and 0 are classified as signatures (J Am Acad Dermatol indeterminate. Separate large cohorts 2015;72:780). Proponents of this Sara Shalin is an Assistant Professor of have independently validated the gene assay say that the genetic signature Pathology and Dermatology at expression signature using expert provides additional prognostic University of Arkansas for Medical dermatopathologist diagnosis as the information for patients and may help Sciences in Little Rock, AR. She earned gold standard with sensitivities guide patient management (Curr Med her M.D. and Ph.D. degrees at Baylor ranging from 90% - 91.5% and Res Opin 2016;32:1599). College of Medicine, followed by a specificities ranging from 91% - 92.5% residency in Anatomic and Clinical (J Cutan Pathol 2015;42:244; BRAF: Pathology at Baylor College of Medicine Cancer 2017;123:617). This assay may and a fellowship at Beth Israel Deaconess improve diagnostic confidence by BRAF mutations are relatively Medical School (Harvard combined better classifying lesions as benign or common in cutaneous melanoma, Dermatopathology fellowship program). malignant; one study indicated that in leading to constitutive activation of a group of 218 diagnostically the MAPK pathway. BRAF inhibitors Dr. Shalin has been a contributor and challenging lesions (80% were (vemurafenib) may be used to treat editorial board member of indeterminate by histiology; tumors metastatic or unresectable melanoma PathologyOutlines.com since 2014, were comprised mostly of atypical that demonstrates a BRAF mutation publishing on topics ranging from junctional melanocytic proliferations, (most commonly V600E). BRAF melanoma biology to inflammatory skin mutation analysis is generally disease.