Deepika Sirohi

Objectives: Atypical intraductal proliferation (AIP) is an intraductal proliferation in which histologic features are more atypical than high-grade prostatic intraepithelial neoplasia but fall short of diagnostic criteria of intraductal carcinoma. We performed a retrospective review of patients with AIP and low-grade or no invasive cancer and correlated with follow-up and Decipher scores. Methods: Prostate biopsies from 2016 to 2022 with AIP and no invasive carcinoma, Grade Group 1 (GG1, Gleason score 3 + 3 = 6) prostatic adenocarcinoma, or Grade Group 2 (GG2, Gleason score 3 + 4 = 7) prostatic adenocarcinoma were identified. Patients with concomitant intraductal carcinoma and/or ≥ GG3 were excluded. Decipher testing, PTEN staining, and subsequent biopsy/prostatectomy data were obtained from the medical record. Adverse features at prostatectomy were defined as ≥GG3, ≥pT3a, pN1, intraductal carcinoma, or Gleason pattern 5. Results: There were 51 biopsies with AIP and no invasive cancer ( n = 5), GG1 ( n = 10), or GG2 ( n = 36) from 2016 to 2022. Of 18 patients who underwent subsequent biopsy, 6 (33%) had increase in Grade Group. Of 14 patients who underwent prostatectomy, 10 (71%) showed at least one adverse feature at prostatectomy. Twelve patients (10 GG2, 2 GG1) had Decipher testing. The median Decipher for the 10 GG2 biopsies was 0.53, corresponding to intermediate Decipher risk. The median Decipher for the 2 GG1 biopsies was 0.40, corresponding to low Decipher risk. Conclusions: AIP in the absence of other high-risk features at biopsy may be a harbinger of subsequent adverse pathology on follow-up. AIP is an entity that may require more frequent active surveillance in the absence of other high-risk features.

ERBB2 (HER2) fluorescence in situ hybridization (FISH) guides therapy selection for solid tumors, including breast and gastric cancers. While laboratory technologists typically perform the initial enumeration of HER2 FISH, laboratories differ in the extent of pathologist review, ranging from full slide reassessment to review of representative captured images. By performing a retrospective analysis of ∼10,000 HER2 FISH cases scored using breast and gastric criteria, the objective was to define decision boundaries at which technologists' and pathologists’ interpretations converge, enabling a data-driven approach to triaging HER2 FISH sign-out. Results showed that agreement between technologists' and pathologists’ interpretations was highest when technologists’ counts were well beyond the diagnostic cutoffs for the HER2/CEP17 ratio and the number of HER2 signals per cell. Conversely, cases near diagnostic thresholds showed increased discordance, emphasizing the need for full review of the FISH slide in this subset. Individual technologists differed in their percent discordance with pathologists’ final results; however, this was not explained by case volume (experience) alone and did not consistently improve over time. In summary, distinct HER2 FISH technologists HER2/CEP17 ratio and HER2 signal number per cell values were identified where concordance with pathologists results exceeded 99%, suggesting cases in these ranges may require only limited pathologist slide review, potentially allowing for more efficient triaging and sign-out of HER2 FISH.

Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a histologically distinctive renal neoplasm arising in patients with end-stage renal disease, in which the molecular underpinnings remain incompletely characterized. In this study, 14 ACD-RCC tumors from 13 patients underwent comprehensive targeted next-generation sequencing with copy-number analysis. All tumors had classic histologic features characterized by solid sieve-like and cystic growth with abundant eosinophilic cytoplasm, predominantly high nucleolar grade (13/14), and variably present calcium oxalate crystals (10/14). By sequence analysis, single-gene alterations were relatively infrequent and heterogenous, with no recurrent alterations within the cohort; though several alterations identified were occasionally recurrent across studies on literature review (eg, KMT2C , SETD2 , FANCA , and FAT1) . Copy-number analysis identified 3 patterns of chromosomal alterations: gain-predominant (n=7), loss-predominant (n=4), and near-euploid (n=3) subgroups. Gain-predominant tumors harbored recurrent gains of chromosomes 3, 7, 16, 17, and 20, whereas loss-predominant tumors showed recurrent losses of chromosomes 6, 9, 14, 19, and 21. The near-euploid group had relatively fewer chromosomal copy-number alterations. Notably, comparison with publicly available The Cancer Genome Atlas papillary renal cell carcinoma (PRCC, TCGA-KIRP) data demonstrated overlapping gains of chromosomes 7, 16, 17, and 20 with the gain-predominant ACD-RCC. In addition, a paired ACD-RCC and synchronous PRCC from the same patient in our cohort displayed highly similar arm-level copy-number profiles, differing only by an additional gain of chromosome 3q in the ACD-RCC. In summary, ACD-RCC demonstrates recurrent arm-level chromosomal alteration patterns despite heterogenous gene-level findings. The gain-predominant tumors show substantial molecular overlap with PRCC, supporting genomic similarity between these entities despite distinct histomorphology. Together, these findings also suggest that copy-number patterns may represent a useful molecular framework for understanding heterogeneity within ACD-RCC.

This report describes two unique gonadal serous carcinomas, one low-grade serous carcinoma (LGSC) of the ovary and one serous carcinoma of the scrotum each harboring novel PAK gene fusions. The first patient with ovarian LGSC was identified to have a PTPRM::PAK1 fusion, identifying PTPRM as a novel fusion partner for PAK1 . The second patient with high-grade papillary serous carcinoma of the scrotum contained a DLG1::PAK2 fusion. Neither fusion was detected by DNA next-generation sequencing (NGS), highlighting the importance of RNA-based methodologies in identifying gene fusions. Overexpression of PAK1 and PAK2 has been reported in ovarian malignancies, correlating with tumor progression and reduced patient survival, while the significance of the unique fusions reported here warrants further consideration in relation to tumorigenesis and clinical implications.

Background: Immunohistochemical (IHC) features of clear cell renal cell carcinomas (CCRCC) have historically been defined by morphologically selected tumours, but aberrant staining patterns that may confound the diagnosis are common. Recent studies have described the prognostic significance of architectural patterns in CCRCC and have proposed grading schemes based on morphology. We investigate a cohort of molecularly verified CCRCC to evaluate their IHC profiles and correlate with architectural patterns and key driver molecular alterations. Methods: Renal cell carcinomas (RCCs) sequenced at our institution between January 2015 and June 2024 by NGS assay were reviewed to identify CCRCCs based on VHL alterations and/or 3p loss. Architectural patterns were classified into low grade (LG) (nested, cystic), intermediate grade (IG) (tubular, tubulopapillary, alveolar), and high grade (HG) (fused nests/solid sheets, rhabdoid, sarcomatoid, low‐grade spindled, pleomorphic tumour giant cells), based on findings from recent studies and scored based on highest‐grade pattern. IHC staining for CA9, KER7, PAX8, and CD10 were reviewed for percent staining (focal 25% or less, moderate 26%–50%, diffuse greater than 50%). Correlation of aberrant staining with primary/metastatic status, architectural patterns, and molecular alterations was analysed. Results: 125 cases of molecularly verified CCRCC were identified and 108 cases with concurrent IHC met inclusion criteria, including 54 primary and 54 metastatic tumours. KER7 positivity was more common in primary vs. metastatic tumours (45% vs. 13%, P = 0.001), in tumours with LG/IG architectural patterns (67% LG and 67% IG vs. 17% HG, P = 0.002) and in PBRM1 wild type (WT) tumours (84% PBRM1 WT vs. 16% PBRM1 mutated, P = 0.021). Negative CA9 staining occurred only in metastatic tumours (15%). PBRM1 mutated tumours were more likely to be KER7‐/CA9+/PAX8‐, while BAP1 mutated tumours were more likely to have higher‐grade architectural patterns and lack CD10 expression. Conclusions: In this cohort of molecularly verified CCRCCS, positive KER7 staining was seen in 30% of tumours with diffuse strong staining in 16%. The IHC profiles correlated with both morphological features and genetic alterations.

Extrauterine presentation of Mullerian adenosarcoma is rare and thought to either arise from endometriosis or from spread from a primary uterine or ovarian origin. When accompanied by sarcomatous overgrowth, particularly when the epithelial components are limited or obscured, these tumors can be challenging to recognize as adenosarcomas and may be misdiagnosed as primary pelvic or retroperitoneal sarcomas. Diagnostic molecular testing could be valuable but also misleading, if not interpreted in the right context, as some retroperitoneal sarcomas exhibit alterations that can have overlapping molecular alterations with Mullerian adenosarcoma, such as MDM2 amplification in liposarcomas. In this report, we describe three Mullerian adenosarcomas with extrauterine presentation, all exhibiting extensive sarcomatous overgrowth and MDM2 amplification. These tumors underscore the critical importance of integrating clinical history, comprehensive tissue sampling, detailed morphologic evaluation, and molecular analysis to establish an accurate diagnosis.

A clinical algorithm originally proposed by van Nederveen et al. recommends that succinate dehydrogenase B immunohistochemical testing (SDH IHC) be performed on all pheochromocytomas and paragangliomas to screen for SDH deficiency, with abnormal staining (loss) referred to genetic counselors for confirmatory testing. However, the interpretation of SDHB IHC is challenging, with frequent partial staining or weak diffuse expression. This study sought to better characterize atypical SDHB IHC staining patterns in patients with genetically confirmed germline pathogenic or likely pathogenic variants involving SDH subunit ( SDHx ) genes. The cohort was identified from patients with known SDHx germline pathogenic or likely pathogenic variants within the familial cancer assessment and paraganglioma clinic of an academic tertiary medical center. Fifty-seven SDH-related tumors were identified (paraganglioma, pheochromocytoma, renal cell carcinoma, gastrointestinal stromal tumor, and seminoma) and stained with the SDHB immunohistochemical stain (polyclonal anti-SDHB antibody, Sigma Aldrich, HPA002868). Fourteen control specimens were identified from similar tumors. Stained slides were analyzed by a subspecialty genitourinary pathologist and a medical student completing a postsophomore fellowship in pathology. Twenty-eight of 57 tumors (49%) showed aberrant retained staining, divided into 4 observable staining patterns: fine granular staining/blush (9/28 abnormally staining tumors), focal retention (15/28), retained staining weaker than internal control (2/28), and retained staining either equal to internal control or without internal control present (2/28). We recognize the clinical utility of SDHB IHC as an affordable, but nuanced, method for screening for SDHx pathogenic or likely pathogenic variants and recommend subsequent genetic testing for any amount of abnormally lost staining.