Addition of cribriform pattern 4 and intraductal prostatic carcinoma into the CAPRA-S tool improves post-radical prostatectomy patient stratification in a multi-institutional cohort.

AIMS: Pre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we analyse the additional prognostic impact of CC/IDC observed in prostatectomies using Cancer of Prostate Risk Assessment post-surgical (CAPRA-S) stratification. METHODS: A retrospective cohort of treatment-naïve radical prostatectomy specimens from three North American academic institutions (2010-2018) was assessed for the presence of CC/IDC. Patients were classified, after calculating the CAPRA-S scores, into low-risk (0-2), intermediate-risk (3-5) and high-risk (6-12) groups. Kaplan-Meier curves were created to estimate biochemical recurrence (BCR)-free survival. Prognostic performance was examined using Harrell's concordance index, and the effects of CC/IDC within each risk group were evaluated using the Cox proportional hazards models. RESULTS: Our cohort included 825 prostatectomies (grade group (GG)1, n=94; GG2, n=475; GG3, n=185; GG4, n=13; GG5, n=58). CC/IDC was present in 341 (41%) prostatectomies. With a median follow-up of 4.2 years (range 2.9-6.4), 166 (20%) patients experienced BCR. The CAPRA-S low-risk, intermediate-risk and high-risk groups comprised 357 (43%), 328 (40%) and 140 (17%) patients, and discriminated for BCR-free survival (p<0.0001). For CAPRA-S scores 3-5, the addition of CC/IDC status improved stratification for BCR (HR 2.27, 95% CI 1.41 to 3.66, p<0.001) and improved the overall c-index (0.689 vs 0.667, analysis of variance p<0.001). CONCLUSION: The addition of CC/IDC into the CAPRA-S classification significantly improved post-radical prostatectomy patient stratification for BCR among the intermediate-risk group (CAPRA-S scores 3-5). The reporting of CC and IDC should be included in future prostate cancer stratification tools for improved outcome prediction.

Aggressive prostatic adenocarcinoma with urothelial-like morphology, with frequent CK7/CK20/HMWK expression and occasional diffuse neuroendocrine features: A clinicopathologic study of 12 cases.

INTRODUCTION: Prostatic adenocarcinoma can occasionally display urothelial carcinoma morphology, which prompts immunohistochemistry (IHC) studies to determine its lineage. Typically, prostate cancer is characterized by the lack of cytokeratin (CK) 7, CK20 and high molecular weight keratin (HMWK) expression, as opposed to bladder cancer. METHODS: We report a series of 12 prostatic adenocarcinoma cases with unusual urothelial-like morphology, diagnosed at two academic institutions in Toronto between 2018 and 2023, and analyzed by immunohistochemistry for prostatic, urothelial, and neuroendocrine marker expression. We collected patient age, androgen deprivation therapy (ADT) status, tumour site, histomorphology, Grade group (GG) and results of genetic testing. RESULTS: The median age of the 12 patients included in this case series was 75.5 years (range 41-85). A history of prostatic cancer was noted in 7/12 (58%) patients. Five of nine (56%) patients had elevated serum PSA level at diagnosis. Six of eleven (55%) patients had prior ADT. Tumour sites were prostate (n = 6), bladder (n = 3), liver metastases (n = 2), and lung metastasis (n = 1). GGs of the primary tumours were GG3 (n = 1) and GG5 (n = 8). The observed urothelial-like morphology was diffuse in ten cases, and focal in two cases. CK7 was strong/diffuse in 8/11 tested cases, and focal weak in one case. CK20, HMWK, p63 and GATA3 were patchy/focal/weak/moderate in 3/6, 4/7, 4/8 and 2/9 cases, respectively. Ten (83%) cases were positive for at least one prostatic marker; eight (67%) cases had loss/weak staining of at least one prostatic marker. AR loss was seen in 2/7 (29%) cases. Seven of ten (70%) cases had diffuse/strong expression of at least one neuroendocrine marker. No trend was evident between prior ADT/AR status and any IHC result. Molecular analyses for DNA damage repair (DDR) genes (n = 6) demonstrated one ATM deletion (bladder). In addition, one TMPRSS2:ERG fusion (lung metastasis) was identified. CONCLUSION: This series comprises high-grade and/or metastatic prostatic adenocarcinoma cases with distinctive urothelial-like morphology and frequent aberrant CK7/CK20/HMWK expression. Their histomorphology, highly suggestive of an urothelial origin, represents a diagnostic pitfall that can lead to considerable management repercussions. The fact that a high proportion of the reported cases had loss/weak expression of at least one of the tested prostatic-specific markers, and occasionally a diffuse positivity for neuroendocrine markers highlights the importance of (1) clinical history and (2) utilization of broad IHC panels to correctly diagnose such unusual prostate cancer cases.

AI improves accuracy, agreement and efficiency of pathologists for Ki67 assessments in breast cancer.

The Ki-67 proliferation index (PI) guides treatment decisions in breast cancer but suffers from poor inter-rater reproducibility. Although AI tools have been designed for Ki-67 assessment, their impact on pathologists' work remains understudied. 90 international pathologists were recruited to assess the Ki-67 PI of ten breast cancer tissue microarrays with and without AI. Accuracy, agreement, and turnaround time with and without AI were compared. Pathologists' perspectives on AI were collected. Using AI led to a significant decrease in PI error (2.1% with AI vs. 5.9% without AI, p < 0.001), better inter-rater agreement (ICC: 0.70 vs. 0.92; Krippendorff's α: 0.63 vs. 0.89; Fleiss' Kappa: 0.40 vs. 0.86), and an 11.9% overall median reduction in turnaround time. Most pathologists (84%) found the AI reliable. For Ki-67 assessments, 76% of respondents believed AI enhances accuracy, 82% said it improves consistency, and 83% trust it will improve efficiency. This study highlights AI's potential to standardize Ki-67 scoring, especially between 5 and 30% PI-a range with low PI agreement. This could pave the way for a universally accepted PI score to guide treatment decisions, emphasizing the promising role of AI integration into pathologist workflows.

Idiopathic gigantomastia in a patient on polypharmacy.

Gigantomastia is an uncommon benign condition characterized by massive breast enlargement. It is most often due to hormonal imbalance secondary to puberty or pregnancy, or induced by a pharmacological agent but can also be idiopathic. Herein, we report a rare case of idiopathic gigantomastia in a 46-year-old female on antiepileptic multiple-drug therapy who underwent total bilateral mastectomy to relieve associated pain.

Circulating levels of lipocalin-2 are associated with fatty pancreas but not fatty liver.

Lipocalin-2 (LCN-2), a peptide with diverse expression pattern, has been identified as a biomarker of various diseases as well as a factor contributing to inflammatory responses associated with excess adiposity and ensuing metabolic disorders. Although the inter-relationship between LCN-2 and excess adiposity is increasingly recognized, little is known about the inter-relationship between LCN-2 and ectopic fat deposition. The present study aimed to investigate the associations between LCN-2 and fatty pancreas as well as fatty liver. In addition, the associations between LCN-2 and pro-inflammatory cytokines were studied. Magnetic resonance imaging was used to quantify intra-pancreatic fat deposition and visceral-to-subcutaneous fat volume ratio whereas magnetic resonance spectroscopy was used to quantify liver fat deposition. Fasting venous blood was analyzed for LCN-2, C-C motif chemokine ligand 2, interleukin-6, leptin, tumor necrosis factor-α, glycated hemoglobin, glucose, and insulin. Binary logistic regression and linear regression analyses were conducted. Three statistical models were built to adjust for demographics, comorbidities, levels of glycated hemoglobin, insulin resistance, and abdominal fat distribution. A total of 79 individuals were studied, of whom 20 had fatty pancreas, 14 had fatty liver, and 4 had both. Lipocalin-2 was significantly associated with fatty pancreas in all the adjusted models (p = 0.014 in the most adjusted model) but was not significantly associated with fatty liver in any of the studied models. Lipocalin-2 was significantly associated with interleukin-6 and tumor necrosis factor-α, in both the unadjusted and adjusted models. Leptin and C-C motif chemokine ligand 2 were not significantly associated with LCN-2 in any of the studied models. These findings suggest that LCN-2 is a potential biomarker of fatty pancreas, independent of abdominal fat distribution, insulin resistance, and other covariates. The role of LCN-2 in intra-pancreatic fat deposition and related low-grade inflammation warrants further investigations.

Associations between intra-pancreatic fat deposition and circulating levels of cytokines.

While a plethora of studies have been conducted to investigate the associations between pro-inflammatory cytokines and obesity, the inter-relationship between pro-inflammatory cytokines and intra-pancreatic fat deposition (IPFD) has been poorly investigated. In the present study, circulating levels of C-C motif chemokine ligand 2 (CCL2), interleukin-6 (IL-6), leptin, and tumor necrosis factor-alpha (TNFα) were measured in 90 individuals after acute pancreatitis (AP) as well as 21 healthy non-obese individuals. Magnetic resonance imaging was used to quantify IPFD and visceral-to-subcutaneous fat volume ratio by two independent raters. Linear regression analyses were performed to investigate the associations between IPFD and each cytokine, adjusting for demographic, metabolic, and pancreatitis-related factors, as well as abdominal fat distribution. In healthy non-obese individuals, IPFD was not significantly associated with any of the studied cytokines in both the unadjusted and adjusted models. In individuals after AP, IPFD was significantly associated with leptin in the models adjusted for age and sex (ß = 0.063 [95% confidence interval: 0.007, 0.119], P = 0.026); age, sex, visceral-to-subcutaneous fat volume ratio, glycated hemoglobin, and pancreatitis-related factors (ß = 0.056 [95% confidence interval: 0.000, 0.111], P = 0.049). Also, IPFD was significantly associated with TNFα in the unadjusted model (ß = 0.102 [95% confidence interval: 0.002, 0.202], P = 0.045) and the model adjusted for age, sex, visceral-to-subcutaneous fat volume ratio, glycated hemoglobin, and pancreatitis-related factors (ß = 0.128 [95% confidence interval: 0.034, 0.223], P = 0.008). The associations between IPFD and IL-6, CCL2 were not statistically significant, in both the unadjusted and adjusted models. These findings indicate that leptin and TNFα are associated with IPFD independent of abdominal fat distribution and other covariates in individuals after AP. The role of IPFD in low-grade inflammation warrants further investigations.