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ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.Results Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

Background Small cell neuroendocrine carcinoma of the prostate (SCNECP) is a rare, aggressive subtype of prostate carcinoma. Most SCNECP arise from conventional prostate adenocarcinoma (CPAC) treated with androgen deprivation therapy (ADT). Case presentations We identified four cases of CPAC treated with ADT, which evolved to SCNECP with liver metastasis. The average interval between the diagnosis of CPAC and SCNECP was 102 months (range: 12 to 168). Histologically, the tumors showed nests of cells with high nuclear:cytoplasmic ratios, granular chromatin, and frequent mitoses. All cases were synaptophysin, chromogranin, and AE1/AE3 positive, with a Ki-67 labeling index ≥70%. NKX3.1 was negative in all but one case and TTF-1 was positive in half. Weak ERG positivity by IHC was seen in one case which also demonstrated the TMPRSS2-ERG gene rearrangement; all other cases were negative for ERG by IHC. Serum prostate specific antigen (PSA) levels were normal to near-normal in all. The median interval between the diagnosis of SCNECP and death was 3.25 months (range: 0.75 to 26). Conclusions Our case series highlights the importance of considering a prostate primary, even in the setting of normal PSA levels and loss of prostate markers, when diagnosing neuroendocrine carcinoma in the liver. Further, we emphasize the significance of diagnosing SCNECP that metastasizes to the liver, as it portends a particularly dismal prognosis.

(Arch Pathol Lab Med. 2025;149:904-912; doi: 10.5858/ arpa.2024-0435-OA) In 2021, the US Preventive Services Task Force published updated recommendations for colorectal cancer screening guidelines to align with those published by the American Cancer Society, which lowered the age for initial screening colonoscopy to age 45 in 2018.1,2 This change has led to increased numbers of colorectal polypoid lesions being diagnosed, with most being epithelial in origin; these have become one of the most encountered specimens in pathologists' day-to-day practice. MATERIALS AND METHODS Case Selection and Clinicopathologic Data This study was conducted in accordance with the Institutional Review Board at the University of Rochester Medical Center (Rochester, New York) and Beth Israel Deaconess Medical Center (Boston, Massachusetts). Follow-up information and survival status (measured in months) were obtained through the electronic medical record. Additional reasons for colonoscopy included a prior history of colorectal polyps (33%, 162 of 490), a family history of colon cancer or polyps (8%, 39 of 490), a known genetic syndrome (5%, 26 of 490), a history of inflammatory bowel disease (4%, 20 of 490), a positive Cologuard or fecal immunochemical test result (1%, 6 of 490), and surveillance for a prior history of lower gastrointestinal malignancies (1%, 5 of 490).

Colorectal lesions with neural differentiation encompass various entities, often presenting with overlapping histologic or immunohistochemical profiles. Most research has focused on single entities, lacking a comprehensive comparative analysis of these lesions. To characterize and compare colorectal lesions with neural differentiation. This study retrospectively examined cases of neural or neural-related colorectal lesions diagnosed between 2004 and 2020 across 2 institutions, analyzing clinical, histologic, and endoscopic features. The cohort included 634 lesions from 593 patients (269 males and 324 females; mean age, 57 years; range, 13-85 years). Most patients were asymptomatic (83%, 490 of 593) and had solitary lesions (92%, 545 of 593), predominantly polypoid or nodular (96%, 610 of 634). Common types included benign fibroblastic polyp/perineurioma (n = 231 of 634, 36%), mucosal Schwann cell hamartoma (n = 203, 32%), and ganglioneuroma (n = 146, 23%), mostly centered in the mucosa (99%, P < .001) of the left colon (n = 318, P < .001). In contrast, granular cell tumors (n = 31, 5%) often involved the submucosa (n = 26, 84%; P < .001) of the cecum and ascending colon (n = 23, 74%; P < .001). Rare lesions like schwannoma (n = 13 of 634, 2%) and neurofibroma (n = 5 of 634, 1%) were found in various sites. A subset of patients (n = 48, 8%) had synchronous and/or metachronous lesions. Of these, 23 (48%) had genetic evidence of a syndromic manifestation (P < .001), with multiple ganglioneuromas in Cowden syndrome (n = 16) being the most common scenario. This is the largest comparative study of neural colorectal lesions, highlighting lesion types' association with colon segments and histologic layers. Multifocal presentations, though rare, are usually linked to genetic syndromes.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production. Glutathione has pleiotropic functions in different organs. Here the authors specifically examine deletion of a glutathione synthetic enzyme in the liver of adult mice and show that lack of glutathione affects lipid abundance through repressing NRF2.

BackgroundPeritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs.ObjectiveThe goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs.MethodsWe performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence.ResultsWe identified 217 patients with localized LAMNs. Median age was 59 years (11–95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0–271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5–47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence.ConclusionsThis multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.

Abstract Objectives To systematically evaluate gynecologic malignancies (adnexal or uterine) causing gastrointestinal (GI) signs (eg, mass on colonoscopy) or symptoms (eg, bloody stools) clinically mimicking a GI primary malignancy. Methods The archives of 2 institutions were retrospectively reviewed for gynecologic malignancies clinically manifesting as colonic lesions. For each case, available radiologic, endoscopic, and histologic findings were recorded. Results We identified 16 cases: 13 biopsies and 3 resections. The masses were localized in the rectosigmoid (14 cases [88%]), right (1 case [6%]), and transverse (1 case [6%]) colon. Gastrointestinal-type complaints included abdominal pain, weight loss, hematochezia, and obstruction; 1 case was asymptomatic and found during screening colonoscopy. Nine patients (56%) had no known prior gynecologic malignancy, and in only 2 of these patients was there some clinical suspicion of a noncolonic primary malignancy. Most cases (13 [81%]) were serous carcinoma, usually high-grade adnexal or primary peritoneal. Six cases (38%) directly extended into the colon, and 7 (44%) metastasized; route of spread was unclear in the others. Only 1 case (6%) showed mucosal involvement, and none showed desmoplasia or dirty necrosis. Four of the 13 serous carcinomas (31%) showed psammoma bodies. Conclusions Advanced gynecologic malignancies, most commonly serous carcinoma, can rarely manifest as GI lesions. Clues to noncolonic origin on biopsy include lack of colonic mucosal involvement/dysplasia, desmoplasia, or dirty necrosis.

Objectives: Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. Methods: All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. Results: Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%o, respectively. Conclusions: HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold. Key Words: HER2; Gastric cancer; Gastroesophageal cancer; Esophageal cancer; Immunohlstochemlstry; Biopsy; Resection

Abstract Objectives Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. Methods All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. Results Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. Conclusions HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.

Microscopic colitis (MC) includes lymphocytic colitis (LC) and collagenous colitis (CC). Microscopic changes are required to establish these diagnoses. While criteria exist, interobserver variability has been reported previously. This has not been evaluated in the context of subspecialty signout (SSSO) or a consensus conference. We identified 133 colon biopsies diagnosed as LC, CC, MC, or normal but with mild changes insufficient for MC. All predated the introduction of SSSO at our institution. They were independently reviewed by three gastrointestinal (GI) pathologists. Cases lacking independent consensus were reviewed by the same pathologists in consensus conference to establish a final diagnosis. Individual diagnoses were compared with the consensus diagnoses, and consensus diagnoses were compared with original diagnoses made by GI and non-GI pathologists. Consensus diagnoses were normal (n = 34), LC (n = 57), and CC (n = 42). “Normal” was the diagnosis most commonly agreed upon independently (27/34 cases, P = 0.0073 versus LC, P = 0.0172 versus CC). The reviewing pathologists independently agreed with 80%, 80%, and 94% of consensus diagnoses (κ = 0.70, 0.69, and 0.91). The group consensus agreed with the diagnoses in 49 of 58 (84%) cases originally signed out by non-GI pathologists (κ = 0.77) and in 44 of 57 (77%) cases originally signed out by GI pathologists (κ = 0.63). Good interobserver agreement exists for MC, though whether GI subspecialty training improves agreement remains unclear. Group consensus may aid in diagnosis of difficult/borderline MC cases.