Human pathology
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Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer, with approximately 80% of cases related to Merkel cell polyomavirus (MCPyV). Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are the key rate-limiting enzymes of the tryptophan-to-kynurenine metabolic pathway. With aryl hydrocarbon receptor (AhR), an intracellular transcription factor, they play a role in escaping the immunosurveillance process in several cancers. ⋯ Kaplan-Meier and log-rank tests showed that MCC with lower IDO1 expression in tumor cells and with lower TDO2 and AhR expressions in TME had better overall survival than otherwise (P = .043, .008, and .035, respectively); lower TDO2 expression in TME was also associated with longer disease-specific survival (P = .016). This suggests that IDO1, TDO2, and AhR express differentially in tumor cells or TME and play different roles in tumorigenesis between MCPyV-positive and MCPyV-negative MCC that may affect the MCC biology. Evaluating IDO1/TDO2/AhR expression is important for selecting the most likely patients with MCC for immunotherapies targeting the IDO1/TDO2-AhR pathway.
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Enhancer of zeste homolog 2 (EZH2), an H3K27-specific histone methyltransferase, has been shown to be frequently overexpressed in various human cancers including lymphoma. Here we investigate the expression and functionality of EZH2 and H3K27me3 in extranodal NK/T-cell lymphoma, nasal type (ENKTL). Results of NanoString analysis revealed that EZH2 and related histone H3 families were up-regulated genes in ENKTL tissues. ⋯ Furthermore, inhibition of EZH2 by 3-deazaneplanocin A significantly suppressed tumor cell growth. Interestingly, pharmacologic suppression of the JAK3/STAT3 pathway effectively reduced EZH2 and enhanced H3K27me3 in NK/T tumor cell lines. Our data suggest that EZH2 and H3K27me3 are important prognostic markers and potential therapeutic targets in ENKTL.
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The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. ⋯ In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy.
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Some pathologists have observed that fewer trainees from US medical schools are entering pathology residency. This trend was measured and further explored using Main Residency Match (MRM) data from 2008 to 2017, obtained from the National Resident Matching Program (NRMP). Over the past decade, there was an increase of 93 (508 in 2008 versus 601 in 2017, an 18.3% increase) pathology positions offered in the MRM. ⋯ The primary reason for this decline was because fewer seniors from US allopathic medical schools participated in the MRM for pathology positions (326 in 2008 versus 232 in 2017, a 28.8% decrease); however, the underlying reasons for this decline are unknown. In conclusion, over the past decade, substantially fewer seniors from US allopathic medical schools sought/filled pathology residency positions in the MRM. These findings are relevant for pathology residency recruitment, especially in the context of a projected decline in US pathologist workforce.
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Hepatoblastoma (HBL) is a hepatic malignancy of infants and young children, which is often cured by combinations of surgery and chemotherapy. Management of refractory and metastatic HBL is challenging. Comprehensive genomic profiling was performed on 31 refractory and metastatic HBL using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. ⋯ No alterations in TP53 were identified, and alterations in the DNA repair pathways were rare. Refractory and metastatic HBL is characterized by a general paucity of GA and is dominated by frequent CTNNB1 mutation and overall low TMB. Although potentially targetable GA are seen on occasion in HBL and a small number of cases have high TMB with potential to respond to immune checkpoint inhibitors, advanced HBL will remain a treatment challenge.