Clear cell papillary renal cell carcinoma (CCPRCC) was recently included in the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia as a subtype of RCC that is morphologically, immunohistochemically, and genetically distinct from both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma. In our clinical practice we have observed tumors with overlapping histologic features of CCPRCC and CCRCC; therefore, our aim was to describe the morphologic, immunohistochemical, and clinical characteristics of these tumors. We examined a large series of consecutive nephrectomies diagnosed as CCRCC and found 37 tumors with morphologic overlap between CCRCC and CCPRCC, identifying 2 patterns. Pattern 1 tumors (N=19) had areas diagnosable as CCRCC admixed with foci having a prominent linear arrangement of nuclei away from the basement membrane imparting a resemblance to CCPRCC; however, other morphologic features commonly seen in CCPRCC (such as branching acini and cystic spaces with papillary tufts) were not typical and, when present, were focal or poorly developed. Pattern 2 (N=18) tumors had 2 discrete areas, one area with an appearance strongly resembling CCPRCC and the other with higher grade nuclei and features diagnosable as CCRCC, sometimes including rhabdoid differentiation, sarcomatoid differentiation, necrosis, and high-stage disease. Four (21%) of the pattern 1 tumors had grade 3 nuclei in the CCRCC-like areas, and 4 were high stage (pT3a). Of the 16 immunostained pattern 1 tumors, all expressed cytokeratin 7 (CK7) at least focally in the CCPRCC-like areas, strongly and diffusely in 9 (56%) cases; 12 (75%) showed negative to focal and/or weak CK7 expression in the CCRCC-like areas. CD10, α-methylacyl-CoA-racemase, high–molecular-weight cytokeratin, and carbonic anhydrase IX (CA IX) had no significant differential expression between these foci. No cup-like staining pattern was seen with CA IX. Two (11%) patients with pattern 1 tumors developed metastases, and 1 (5%) subsequently died of disease. Eleven (61%) pattern 2 cases had the International Society of Urological Pathology grade 3 nuclei in the CCRCC-like areas, and 7 (39%) were grade 4 (4 of these cases had rhabdoid features; 1 was also sarcomatoid). Of the 16 immunostained pattern 2 tumors, 8 (50%) showed strong diffuse CK7 expression in the CCPRCC-like areas, and 9 (56%) showed complete lack of CK7 expression in the CCRCC-like areas. CD10, α-methylacyl-CoA-racemase, and high-molecular-weight cytokeratin did not have significant differential expression. Membranous expression of CA IX, typically strong and diffuse, was identified in both the CCPRCC-like and CCRCC-like areas in all cases tested (with a cup-like pattern at least focally in the CCPRCC-like areas of 10 [63%] pattern 2 cases). Five (28%) patients with pattern 2 tumors had distant metastases, 3 (17%) of whom subsequently died of disease. Renal cell carcinomas with areas resembling both CCRCC and CCPRCC occur. Some can have high-grade and high-stage foci, and aggressive clinical outcomes are seen. Given this malignant potential, we would presently diagnose such cases as CCRCC. These 2 patterns of renal neoplasia underscore the need for caution in diagnosing CCPRCC on limited sampling, reserving the diagnosis for those tumors that strictly fulfill both morphologic and immunohistochemical criteria.

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary system and is ranked the sixth most diagnosed cancer in men worldwide. Around 70–75% of newly diagnosed UC manifests as the non-muscle invasive bladder cancer (NMIBC) subtype, which can be treated by a transurethral resection of the tumor. However, patients require life-long monitoring due to its high rate of recurrence. The current gold standard for UC diagnosis, prognosis, and disease surveillance relies on a combination of cytology and cystoscopy, which is invasive, costly, and associated with comorbidities. Hence, there is considerable interest in the development of highly specific and sensitive urinary biomarkers for the non-invasive early detection of UC. In this review, we assess the performance of current diagnostic assays for UC and highlight some of the most promising biomarkers investigated to date. We also highlight some of the recent advances in single-cell technologies that may offer a paradigm shift in the field of UC biomarker discovery and precision diagnostics.

Background/aims: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones. Methods: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off. Results: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ ² =5.25; p=0.022), compared with clinicopathological features alone. Conclusions: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.

Tissue pathogens are commonly encountered in histopathology and cytology practice, where they can present as either benign mimickers of malignancy or true malignancies. The aim of this review is to provide a timely synthesis of our understanding of these tissue pathogens, with an emphasis on pertinent diagnostic conundrums associated with the benign mimickers of malignancy that can be seen with viral infections and those which manifest as granulomas. The oncogenic pathogens, including viruses, bacteria, and parasites, are then discussed with relationship to their associated malignancies. Although not exhaustive, the epidemiology, clinical manifestations, pathogenesis, and histological findings are included, along with a short review of emerging therapies.

273 Background: The Decipher 22-gene genomic classifier (GC) has been shown to predict for metastasis and survival in predominantly Caucasian and African-American men from Western cohorts. There is however little data on the clinical utility of GC in Asian prostate cancer (PCa). We investigated if GC prognosticates for metastasis-free survival (MFS) in an Asian cohort of localized PCa. Additionally, we performed comparative genomic analyses between our Asian patients and non-Asian cases from a large Decipher GRID database (Veracyte, San Francisco, CA). Methods: We used a cohort of PCa patients who were treated at a single institution from East Asia between 2006 to 2021. Patients underwent active surveillance or radical prostatectomy (RadP) and/or radiotherapy (RT) +/- hormonal therapy (HT). The GC assay (Decipher Biosciences, CA) was performed on diagnostic biopsies, following central review of the Gleason’s grade (GG) and tumor cellularity by an expert GU pathologist. MFS was the primary endpoint for survival analysis. Comparative analyses of 273 gene-signatures were performed against the full and a propensity-score matched (PSM) cohort identified from the Decipher GRID database. Adjusted p-values from Wilcoxon tests were used to select from these signatures. Results: We profiled 126 unique patient tumors, comprising of 19 (15.1%) NCCN-defined low-/favorable intermediate-, 22 (17.5%) unfavorable intermediate-, 34 (27.0%) high-, and 51 (40.5%) very high-risk groups. 24 (19.0%) patients had RadP as primary treatment, 98 (77.8%) had RT +/- HT, while 4 (3.2%) underwent active surveillance or HT alone. Using the GC, 70 (55.6%), and 56 (44.4%) were stratified as low/intermediate- (≤0.6) and high-risk ( > 0.6), respectively. GC high-risk was significantly associated with an inferior MFS than GC low/intermediate-risk ( HR 5.22 [95% CI:1.08–25.3], P = 0.04). Comparison between our Asian and the full unmatched GRID cohort (N = 80,703) revealed a lower proportion of ERG+ PCa (14% vs 41%, P < 0.001) and a higher proportion of PAM50 basal subtypes (41% vs 30%, P < 0.001), as well as a lower T-cell exclusion (median 0.080 vs 0.097; P < 0.001) and angiogenesis (-0.37 vs -0.08; P < 0.001) signature scores. These trends were also observed when comparing with the PSM-subset (N = 630; 5:1 ratio for NCCN, GG, age at diagnosis, and assay quality score). Interestingly, both high angiogenesis and T-cell exclusion signatures were associated with a worse MFS ( HR not available due to no events for low angiogenesis, P = 0.0015 by log-rank test; HR 5.12 [1.03–26.5], P = 0.046, respectively). Conclusions: We validated the Decipher 22-gene GC for prognostication of MFS in a predominantly high-risk PCa cohort. We also identified several gene expression signatures that were significantly different between Asian PCa and other cohorts. These observations may have implications for customizing treatment recommendations to an Asian population.

Objective: To develop an automated detection tool for Helicobacter pylori (HP) microorganisms (HPOrg) and intestinal metaplasia (IM) identification on gastric biopsy specimens on hematoxylin and eosin (H&E) whole-slide images (WSIs), incorporating background histopathologic features. Methods: A total of 180 H&E gastric biopsy WSIs, archived at the Department of Anatomical Pathology, Singapore General Hospital, were used to train, validate, and test (60:20:20) a decision support tool. Eighty WSIs displayed non-HP inflammation; 100 were annotated for HP-associated gastritis, HPOrg, and IM. A 2-stage model was employed—a Vision Transformer–based model filtered artifacts after stain normalization, and then a Graph Attention Network component aggregated patch-level features, giving a prediction for each of 6 tissue sections within each WSI, with a majority vote determining the final WSI prediction. Results: A total of 776 636 patches were used for training/validation and testing. The optimized model showed HPOrg classification (precision: 0.604, F1-score: 0.617, and top 10 micro F1-score: 0.714) and IM classification (precision: 0.905, F1-score: 0.861, and top 10 micro F1-score: 1.0). The macro average F1-score was 0.739, section-level precision was 0.981, and the F1-score was 0.945. The WSI-level precision achieved was 1.0, with a F1-score of 0.96. Conclusions: We demonstrate a 2-stage model to detect HP and IM in gastric biopsy specimens, considering background inflammation, which more closely reflects real-world clinical diagnosis.