Faculty Bibliography

Bodies have continuous reticular networks, comprising collagens and other extracellular matrix components, through all tissues and organs. We recently validated fluid flow through human interstitium and demonstrated that they are filled with hyaluronic acid by staining with biotinylated hyaluronic acid binding protein. Their continuity across tissue boundaries (skin and subcutis), and between organs (colon and mesentery) and along vessels (within adventitia) and nerves (within perineurium) has been demonstrated in this manner. We aim to evaluate the continuity of interstitium within human pancreas and beyond into adjoining tissues. Tissue blocks of histologically normal pancreas from nine pancreatectomy specimens were sectioned in parallel for staining with hematoxylin and eosin, Picrosirius red, and biotinylated hyaluronic acid binding protein. Also, specimens of invasive pancreatic cancer were assessed for interstitial tumor invasion. Picrosirius red ensheathes all microscopic units of the endocrine and exocrine pancreas, including acini, islets, and ducts, adventitia of blood vessels and perineurium, and into adjacent duodenum. Interstitial spaces within the fibrous tissue are filled with hyaluronic acid by staining and are also continuous through all microscopic structures of the pancreas, into adjoining duodenum and along vessels (within adventitia) and nerves (within perineurium). Invasive carcinoma is seen spreading through pre-existing interstitial spaces. Interstitium of the human pancreas is continuous within and beyond the pancreas. This continuity suggests the capacity to be a route of molecular, microbiome, and cellular trafficking and communication. In particular, it is a route of cancer spread.

Lymph nodes (LNs) containing only acellular mucin are considered negative for metastasis in treated colorectal cancers (CRCs). However, no data exist on how to stage these LNs in untreated CRCs. We collected 63 untreated CRC cases with LNs containing only acellular mucin from 27 US institutions and 23 additional cases from the Dutch Nationwide Pathology Databank. The practice patterns of pathologists in handling such cases, as well as the clinicopathologic features of these cases were analyzed. The survival of the study group was compared to two control groups:102 pN0 and 76 pN1 untreated CRC cases. US and Dutch pathologists demonstrated similar practice patterns in assigning the pN stage and in the use of additional studies. Tumors in the study group were more likely to be located in the right colon, exhibit mucinous features, and be mismatch repair deficient compared to tumors in the pN0 and pN1 control groups. Compared to the pN1 control group, the study group showed significantly lower frequencies of lymphovascular invasion, local recurrence, and distant metastasis. No patient in the study group died of CRC, similar to the pN0 group. In contrast, the pN1 group had a significantly higher risk of CRC-related death. These findings suggest that LNs containing only acellular mucin in untreated CRCs should be interpreted as negative and staged as pN0, in line with current practice in neoadjuvant-treated CRCs.

OBJECTIVE:Identify how surgical resection of pancreatic ductal adenocarcinoma (PDAC) affects systemic minimal residual disease (MRD). METHODS:Pancreatic tumors were generated by orthotopic implantation of tumor cells into the pancreas of immunocompetent mice. Tumor resection was carried out via distal pancreatectomy and splenectomy. Liver metastases and microenvironment immune changes were analyzed in resected vs. non-resected mice. RESULTS:Resection was accompanied by proliferative expansion of liver metastases and an increase in hepatic metastatic burden. Postoperative immune changes predominantly manifested as a time-dependent increase in eosinophils and decrease in neutrophils. The postoperative hepatic eosinophilia was protective of further metastatic progression. The parenchymal findings were detectable in the circulation, and the trends observed in the mouse model modeled those seen in PDAC patients postoperatively. CONCLUSION/CONCLUSIONS:Collectively, we describe a preclinical resection model that offers a means to investigate MRD. Using this model, we delineated effects of surgical resection on metastatic outgrowth and uncovered a protective link between the postoperative hepatic eosinophilia and further metastatic progression.

Rituximab (RTX) is a monoclonal anti-CD20 antibody widely used to treat B-cell neoplasms and autoimmune conditions. RTX has recently been linked to an enteropathy characterized by diarrhea, malabsorption, and hypogammaglobulinemia, closely resembling common variable immunodeficiency (CVID) enteropathy. We present the first dedicated histopathologic assessment of RTX-associated CVID-like enteropathy. Study inclusion criteria were the presence of diarrhea, weight loss, or other gastrointestinal (GI) symptoms in the setting of current/prior RTX use and associated hypogammaglobulinemia. Twenty-two patients (15M:7F; mean age at biopsy/resection, 63.4y) across 9 tertiary medical centers met inclusion criteria and had small bowel (N=20) and/or colon (N=17) specimens (biopsies/resections) available for review; 71.4% of specimens dated from ≤5y of last RTX dose. Cases were systematically evaluated by GI pathologists at each institution. Key histologic features in the small bowel included sparse/absent lamina propria plasma cells (N=10, 50%), intraepithelial lymphocytosis (N=12, 60%), villous atrophy (N=11, 55%), increased crypt apoptotic bodies (N=6, 30%), and active inflammation (N=5, 25%). Common features in the colon included sparse/absent plasma cells (N=7, 41.2%), increased crypt apoptotic bodies (N=7, 41.2%), active inflammation (N=5, 29.4%), and intraepithelial lymphocytosis (N=4, 23.5%). Goblet cell loss was appreciated in small bowel and/or colon specimens from 2 patients. Follow-up biopsies (interval, 2m-4y) were available for 7 patients and largely recapitulated the histology of the index specimens, though 1 patient demonstrated improvement in villous blunting and intraepithelial lymphocytosis. In summary, the histologic spectrum of post-RTX CVID-like enteropathy encompasses lamina propria plasma cell depletion, increased crypt apoptotic bodies, small bowel villous atrophy, and goblet cell loss. While the underlying pathophysiology remains uncertain, the clinicopathologic picture may reflect post-RTX B-cell/plasma cell impairment. Although histologic findings may be subtle and variable, pathologists should be aware of this entity and should seek a history of RTX use in patients whose biopsies exhibit these CVID enteropathy-like features.

BACKGROUND:To improve outcomes for patients with pancreatic ductal adenocarcinoma, a complete resection is crucial. However, evidence regarding the impact of microscopically positive surgical margins (R1) on recurrence is conflicting due to varying definitions and limited populations of patients with borderline-resectable and locally advanced pancreatic cancer. Therefore, we aimed to determine the impact of the resection margin status on recurrence and survival in patients with pancreatic ductal adenocarcinoma stratified by local tumor stage. METHODS:We performed a retrospective cohort study on patients with nonmetastatic pancreatic ductal adenocarcinoma undergoing pancreatectomy at a high-volume academic center (2012-2022). R1 was subclassified into microscopic invasion of the margin (R1 direct) or carcinoma present within 1 mm but not directly involving the margin (R1 <1 mm). Overall survival and time to recurrence were assessed by log-rank test and multivariable Cox regression. RESULTS:Of 472 included patients, 154 (33%) had an R1 resection. Of those 50 (32%) had R1 <1 mm and 104 (68%) R1 direct. The most commonly involved margin was the uncinate (41%) followed by the pancreatic neck (16%) and vascular margins (9%). Overall, a stepwise shortening of time to recurrence and overall survival was observed with an increasing degree of margin involvement (median time to recurrence: R0 39.3 months, R1 <1 mm 16.0 months, and R1 direct 13.4 months, all comparisons P < .05). Multivariable analyses confirmed the independent prognostic value of R1 direct across all surgical stages. CONCLUSION/CONCLUSIONS:The resection margin status portends an independent prognostic value. Moreover, this association persists in patients with borderline-resectable and locally advanced pancreatic cancer. Increasing the R0-resection rate is the most important potentially influenceable prognostic factor for improving surgery-related outcomes.

BACKGROUND:The American Joint Committee on Cancer (AJCC) eighth edition is based on pancreatic intraepithelial neoplasia-derived pancreatic ductal adenocarcinoma (PDAC), a biologically distinct entity from intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer. The role of nodal disease and the AJCC's prognostic utility for IPMN-derived pancreatic cancer are unclear. This study aimed to evaluate the prognostic role of nodal disease and the AJCC eighth-edition N-staging for IPMN-derived pancreatic cancer. METHODS:Upfront-surgery patients with IPMN-derived PDAC from four centers were stratified according to the AJCC eighth-edition N stage. Disease characteristics were compared using descriptive statistics, and both overall survival (OS) and recurrence-free survival (RFS) were evaluated using log-rank tests. Multivariable Cox regression was performed to determine the prognostic value of N stage for OS, presented as hazard ratios with 95 % confidence intervals (95 % CIs). A lowest p value log-rank statistic was used to derive the optimal cutoff for node-positive disease. RESULTS:For 360 patients, advanced N stage was associated with worse T stage, grade, tubular histology, and perineural and lymphovascular invasion (all p < 0.05). The median OS was 98.3 months (95 % CI 82.8-122.0 months) for N0 disease, 27.8 months (95 % CI 24.4-41.7 months) for N1 disease, and 18.1 months (95 % CI 16.2-25.9 months) for N2 disease (p < 0.001). The AJCC N stage was validated and associated with worse OS (N1 [HR 1.64; range, 1.05-2.57], N2 [HR2.42; range, 1.48-3.96]) and RFS (N1 [HR 1.81; range, 1.23-2.68], N2 [HR 3.72; range, 2.40-5.77]). The optimal cutoff for positive nodes was five nodes. CONCLUSION/CONCLUSIONS:The AJCC eighth-edition N-staging is valid and prognostic for both OS and RFS in IPMN-derived PDAC.

INTRODUCTION/UNASSIGNED:Acute upper gastrointestinal bleeding is one of the most common medical emergencies that present to the hospital, and delineating the underlying etiology is essential to provide adequate definitive treatment. The purpose of this case report was to review the diagnosis and treatment of a rare complication known as radiation-induced hemorrhagic gastritis (RIHG) that can occur in patients with prior radiation exposure. The motivation for this study arose from the identification of a case within our institution. CASE PRESENTATION/UNASSIGNED:The study involved a review of the diagnosis and management of a patient who presented with anemia and recurrent episodes of gastrointestinal bleeding at our institution after undergoing treatment for metastatic biliary adenocarcinoma. With the advent of new therapies, we aimed to investigate the various techniques utilized to manage these patients and highlight the importance of maintaining a high index of suspicion for RIHG as a potential etiology of gastrointestinal bleeding in patients with a relevant medical history of radiation exposure. Despite the literature review, we found that there is a lack of guidelines in the approach to the management of these patients. CONCLUSION/UNASSIGNED:This case report underscores the rarity of radiation-induced gastritis and the complications that may arise from its diagnosis, including recurrent GI bleeding. Further investigation into identifying definitive treatment and creating guidelines for its management is desperately needed.

BACKGROUND:The prognostic significance of histology in ileal pouch-anal anastomosis (IPAA) remains unclear. The aim of this study was to evaluate if histologic variables are predictive of IPAA clinical outcomes and healthcare utilization. METHODS:This was a retrospective cohort study of patients with IPAA undergoing surveillance pouchoscopy at a tertiary care institution. Pouch body biopsies were reviewed by gastrointestinal pathologists, who were blinded to clinical outcomes, for histologic features of acute or chronic inflammation. Charts were reviewed for clinical outcomes including development of acute pouchitis, chronic pouchitis, biologic or small molecule initiation, hospitalizations, and surgery. Predictors of outcomes were analyzed using univariable and multivariable logistic and Cox regression. RESULTS:A total of 167 patients undergoing surveillance pouchoscopy were included. Polymorphonuclear leukocytes (odds ratio [OR], 1.67), ulceration and erosion (OR, 2.44), chronic inflammation (OR, 1.97), and crypt distortion (OR, 1.89) were associated with future biologic or small molecule initiation for chronic pouchitis. Loss of goblet cells was associated with development of chronic pouchitis (OR, 4.65). Pyloric gland metaplasia was associated with hospitalizations (OR, 5.24). No histologic variables were predictive of development of acute pouchitis or surgery. In an exploratory subgroup analysis of new IPAA (<1 year), loss of goblet cells was associated with acute pouchitis (OR, 14.86) and chronic pouchitis (OR, 12.56). Pyloric gland metaplasia was again associated with hospitalizations (OR, 13.99). CONCLUSIONS:Histologic findings may be predictive of IPAA outcomes. Pathologists should incorporate key histologic variables into pouchoscopy pathology reports. Clinicians may need to more closely monitor IPAA patients with significant histologic findings.

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.