Portosinusoidal Vascular Disorder: A Heretofore Unrecognized Manifestation of Sickle Cell Disease?

Portosinusoidal vascular disorder (PSVD) is a recently proposed histopathologic entity that encompasses a spectrum of often subtle hepatic microvascular lesions and related microarchitectural abnormalities. Clinical manifestations may arise years after histologic diagnosis and include extrahepatic portal vein thrombosis and portal hypertension. While the histopathologic features of PSVD have been associated with numerous clinical conditions, most notably prothrombotic/vasculopathic disorders, PSVD has not yet been described in sickle cell disease. This gap is striking given the central role of microvascular dysfunction in sickle cell disease and well-described patterns of hepatic injury and dysfunction in this population. This case series is the first to explore the prevalence and pathogenesis of PSVD in sickle cell disease. Forty-one diagnostically adequate liver biopsies from patients with sickle cell disease were identified across the archives of 5 tertiary medical centers. All biopsies exhibited at least 1 histopathologic feature associated with PSVD (mean 3.8 features/case). Overall, 90.2% of patients met the criteria for a diagnosis of PSVD based on the presence of specific histopathologic and/or clinical findings. Immunohistochemical stains for von Willebrand factor, CD34, and glutamine synthetase were performed on 36 cases (87.8%). Aberrant (centrilobular sinusoidal) CD34 and von Willebrand factor staining was present in 97.2% and 86.1% of cases, respectively. Glutamine synthetase reactivity was at least mildly decreased in zone 3 hepatocytes in 52.8% of cases. We posit that chronic erythrocyte sickling results in dysfunction and remodeling of the portal microvasculature, culminating in regression of zone 3 hepatocytes. The presence of PSVD may explain, at least in part, the hepatic dysfunction observed in this patient population. These patients may also benefit from extended clinical surveillance for portal hypertension and other complications. While subtle and prone to overdiagnosis, the features of PSVD should be carefully considered when interpreting liver biopsies from patients with sickle cell disease.

Crohn's Disease Features in Anastomotic Biopsies from Patients With and Without Crohn's Disease: Diagnostic and Prognostic Value.

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn's disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Relation between mismatch repair status, chemoresponse, survival and anatomic location in gastroesophageal adenocarcinoma.

BACKGROUND: It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location. METHODS: We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis. RESULTS: In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94). CONCLUSION: Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.

Morphologic alterations post trimodal therapy in muscle-invasive urothelial carcinoma: understanding the impact of post-treatment changes on the pathological interpretation and their potential clinical correlates.

While surveillance biopsies play a critical role in management of patients with muscle invasive bladder cancer (MIBC) treated with trimodal therapy (TMT), their assessment is often confounded by pronounced post-treatment changes. The aim of this study was to characterize these morphologic alterations and their clinical implications. A single-center retrospective analysis of surveillance transurethral resection of bladder tumor (TURBT) samples was undertaken, assessing for post-treatment morphologic changes in non-neoplastic and neoplastic tissue, as well as the correlation between these changes and cancer recurrence and cancer-specific survival. The cohort consisted of 73 patients with 56 males (76.7%), with a median age of 72 years and stage cT2 in 84.9%. The median follow-up was 28 months (4-207 months), with 34 patients (46.6%) dead during follow-up. A wide spectrum of morphologic characteristics was documented in all post-TMT TURBTs, with most common features including fibrosis (63.0%), inflammation (56.2%), and epithelial denudation (45.2%). Presence of fibrosis inversely correlated with cancer-specific death (n = 68, p = 0.027). Among the 18 cases with residual MIBC, 12 cases (66.7%) showed morphologic changes in the neoplastic cells that deviated from usual morphology of urothelial carcinoma. Presence of these changes was enriched in patients with subsequent disease recurrence (n = 18, p = 0.05). Secondary pathology review identified two cases (2.7%) with diagnostic discrepancy, both due to omission of in situ component. Post-treatment changes in post-TMT TURBTs must be recognized to avoid diagnostic misinterpretation and accurately guide patient management. Also, poor cellular preservation and severe cytologic changes in the residual carcinoma are not associated with a better prognosis.

Impact of Programmed Death-ligand 1 Expression on Oncological Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Radiation-based Therapy.

Background: No biomarkers are recommended for patients undergoing radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC). Objective: We aim to evaluate the predictive role of programmed death-ligand 1 (PD-L1) expression on the oncological outcomes of patients treated with RT for MIBC. Design setting and participants: A single-center retrospective analysis of tumor specimens collected through transurethral resection (TURBT) from 104 MIBC patients, implemented in a tissue microarray and stained with the SP263 PD-L1 clone (Ventana Medical Systems, Tucson, AZ, USA), was conducted. Two reviewers measured the PD-L1 H-score for tumor and immune cells. Intervention: RT (maximal TURBT followed by radiation and concurrent chemotherapy when eligible). Outcome measurements and statistical analysis: Logistic and Cox regression models were used to predict 3-mo complete response (CR) and overall survival (OS) after RT, respectively. Results and limitations: A total of 88 (85%) patients had cT2 disease and 39 (37.5%) had high immune cell PD-L1 expression. A CR was achieved in 68 (65%) patients. On the multivariable analysis (MVA), a higher clinical stage (p = 0.02) and a low immune cell PD-L1 H-score (p = 0.02) were associated with a decreased CR after RT. The median time to death was 43 mo (95% confidence interval 20-66). On Cox MVA, a high immune cell PD-L1 H-score (p = 0.0017) was associated with better OS, independently of performance status (p = 0.0005) or tumor stage (p = 0.0013). A high tumor cell PD-L1 H-score was not an independent predictor of CR or OS. Limitations of the study include the retrospective design. Conclusions: MIBC patients with high PD-L1 expression on immune cells appear to have better oncological outcomes following RT. Our results may aid in patient stratification for future clinical trial design. Patient summary: In this report, we evaluated the role of programmed death-ligand 1 (PD-L1) expressed on tumor and immune cells in the tumor microenvironment for patients treated with a bladder-sparing regimen. We found that PD-L1 overexpression on immune cells is able to predict a better response to radiation-based therapy.

An integrated virtual pathology education platform developed using Microsoft Power Apps and Microsoft Teams.

The transition towards digital pathology and an extensive selection of video conferencing platforms have helped provide continuity to education even during the COVID-19 pandemic. Innovative approaches for pathology education, will likely persist beyond the pandemic, as they have powerful didactic potential. While there is a wide selection of software for use as educational tools, an environment to access all resources with ease is clearly lacking. In this technical note, we highlight our customized educational applications built using a low-code approach. Our applications, developed with Microsoft Power Apps, serve both educational and examination purposes and are launched using Microsoft Teams. Building applications using a low-code approach has made our applications very specific to our use and enabled daily distanced education. Combined with existing features on Teams, such as file sharing, meeting scheduling, and messaging, the applications serve as a unique and customizable pathology educational platform.