TRPS1 is a sensitive immunohistochemical marker for breast carcinoma, but its expression in melanoma remains incompletely characterized, and mucosal melanoma has been underrepresented in prior studies. We evaluated TRPS1 expression in a mucosal-enriched cohort of 64 melanomas (54 primary and 10 metastatic) and 10 benign melanocytic nevi using whole-tissue sections. TRPS1 expression was scored semi-quantitatively, and a cutoff-sensitivity analysis was performed. In this mucosal-enriched cohort (51.6% mucosal, predominantly acral cutaneous), moderate-to-high TRPS1 expression (score ≥ 3) was observed in 10 of 64 melanomas (15.6%; 95% CI, 8.7–26.4), including 7 of 33 mucosal melanomas (21.2%; 95% CI, 10.7–37.8) and 3 of 21 cutaneous melanomas (14.3%; 95% CI, 5.0–34.6). None of the 10 metastatic melanomas showed moderate-to-high expression (0%; 95% CI, 0–27.8). Among the TRPS1-positive cases, SOX10 was positive in all 8 cases tested, and S100, Melan-A, and HMB45 were positive in 7 of 8, 7 of 8, and 9 of 10 cases tested, respectively. The positivity rate decreased progressively across cutoffs, without a sharp threshold effect. These findings indicate that TRPS1 positivity does not exclude melanoma, and that TRPS1 negativity should not exclude melanoma either. A melanocytic panel combining a sensitive nuclear marker (SOX10 or S100) with a lineage-specific cytoplasmic marker (Melan-A or HMB45) should be performed for any cutaneous or mucosal tumor in which melanoma is in the differential diagnosis, regardless of TRPS1 status.
High-grade dysplastic nodules (HGDN) are recognized precursors of hepatocellular carcinoma in cirrhosis, yet their distinction from macro-regenerative nodules (MRN) relies entirely on morphologic features that exist along a continuum rather than as discrete thresholds, with no ancillary marker available to adjudicate this boundary. Whether these lesions represent distinct molecular states remains unknown. We performed whole-transcriptome spatial profiling (GeoMx Digital Spatial Profiler, Bruker) of MRN and HGDN within their native cirrhotic microenvironment in FFPE explant specimens from three patients. Fifteen regions of interest spanning background cirrhosis (n = 2), MRN (n = 3), HGDN (n = 4), and the HGDN–cirrhotic interface (n = 6) underwent exploratory differential expression and gene set enrichment analyses; because MRN and HGDN derived from different patients, lesion class and donor could not be separated. MRN showed a quiescent regenerative program characterized by HGFAC upregulation, depletion of inflammatory and immunoglobulin transcripts, and no significant upregulation of canonical hepatocellular carcinoma markers. HGDN showed PZP, DEPP1, and CDHR5 upregulation and enrichment of interferon signaling. Spatially, HGDN separated into a metallothionein-enriched core and an MHC-I/interferon-enriched interface expressing HLA-B, HLA-C, and IFI6, a pattern that bulk profiling would be expected to obscure; the core–interface distinction persisted when analysis was restricted to a single patient. In this pilot cohort, morphologically defined regenerative and premalignant hepatocellular nodules showed distinct transcriptional profiles, providing preliminary, hypothesis-generating molecular support for a difficult morphologic distinction. These observations, including the MHC-I/interferon-enriched dysplastic interface, identify candidate targets for validation in larger cohorts with paired lesions.
A prior analysis of medical residency match outcomes from 2008 to 2017 found a major decline in the percentage of filled pathology residency positions that were taken by senior medical students from United States (US) allopathic medical schools (MD seniors). Consequently, recruitment efforts were initiated, such as the College of American Pathologists' (CAP) Pathologist Pipeline Initiative, which began in year 2019 or 2020. The goal of this study is to determine if there has been a recent change in the percentage of offered pathology residency positions that were filled by MD seniors. Main Residency Match (MRM) data from year 2008 to 2026 were analyzed and graphed. The percentage of offered pathology residency positions that were filled by MD seniors peaked at 65.0% in year 2010, bottomed at 32.4% in 2021, and is 41.5% in 2026. Out of 15 major medical specialties, pathology had the 3rd lowest percentage of offered residency positions that were filled by MD seniors in 2026. Out of 10 major medical specialties which offer post-graduate year-1 (PGY-1), but not PGY-2, residency positions, pathology had the 3rd lowest percentage. For either list, otolaryngology and family medicine had the highest (88.1%) and lowest (27.2%) percentages, respectively. In conclusion, since 2021 there has been an upward trend in the percentage of offered pathology residency positions that were filled by MD seniors in the MRM, yet the current percentage is relatively low compared to other major medical specialties.
Site-of-origin immunohistochemistry is widely used in the evaluation of metastatic carcinoma, but lineage-associated markers are neither completely sensitive nor entirely specific. This review examines diagnostically important patterns of immunophenotypic discordance, with emphasis on aberrant marker expression and loss of expected lineage-associated proteins. Biological mechanisms include dedifferentiation, lineage plasticity, metastatic selection, intratumoral heterogeneity, and treatment-associated reprogramming, whereas fixation, decalcification, antibody clone, assay conditions, staining interpretation, and limited sampling may create analytical or interpretive pseudodiscordance. Particular attention is given to PAX8; GATA3, TRPS1, and SOX10; TTF-1 and Napsin A; CDX2 and SATB2; and NKX3.1, PSMA, PSA, and PSAP. The review also outlines a practical approach to conflicting results based on reassessment of morphology, verification of technical credibility, use of limited complementary panels, comparison with prior material, and clinicoradiologic correlation. Molecular tissue-of-origin profiling may provide ancillary diagnostic support when clinicopathologic findings remain unresolved. Comprehensive genomic profiling serves a distinct treatment-oriented role by identifying potentially actionable molecular alterations. Overall, discordant immunophenotypes should modify diagnostic probability rather than determine site of origin in isolation.
