Montgomery, Elizabeth Anne

7533 Background: Ciltacabtagene autoleucel (cilta-cel) shows benefit for patients (pts) with relapsed/refractory multiple myeloma (RRMM). A recently recognized uncommon adverse reaction, IEC-EC is characterized by severe/persistent diarrhea typically 1–3 months post CAR-T cell infusion. Here we summarize incidence and features of IEC-EC in clinical trials of cilta-cel for RRMM. Methods: 483 pts across RRMM studies (CARTITUDE-1, -2, -4, and CARTIFAN-1) were evaluated for evidence of IEC-EC. The clinical picture and nomenclature for IEC-EC were described in the real-world setting after infusion of most pts. As such, retrospective analysis was performed to identify cases consistent with IEC-EC, defined as prolonged (≥3 weeks) and severe (≥grade 3) diarrhea after cilta-cel infusion, without clear infectious etiology. Correlative biomarker analyses included peripheral CAR-T cell expansion/persistence, immune cell composition, and cytokines/inflammatory markers. Centralized pathomorphological review and immunohistochemical analysis of available biopsies was conducted. Results: Across RRMM studies, 6/483 (1.2%) pts demonstrated the clinical picture of IEC-EC, presenting 12–214 days after receiving cilta-cel (median onset 67 days post infusion). Best response was CR/sCR for all subjects. Pts received therapies including steroids (4/6). Four pts experienced symptom resolution within 123–227 days; 2 had persistent symptoms until death (causes: multiorgan failure and COVID19). Pts with IEC-EC had lower levels of B cells and higher levels of CAR+ T cells and inflammatory cytokines (eg, IL-6) at onset compared to a GI symptom-free control group at comparable time; while all cilta-cel–treated pts experienced B cell depletion, pts with IEC-EC had more prolonged deficiency. Histological analyses of GI biopsies from 5 pts with IEC-EC revealed plasma cells, normally present in the GI tract, were absent. CAR-T cells were detected and localized to the lamina propria and were not observed juxtaposed with epithelia, making it unlikely direct damage to epithelia was caused by CAR-T cells. Histologic damage was greater in the small intestine (predominantly duodenum) than the colon. Conclusions: Retrospective analysis of cilta-cel trials identified a low IEC-EC incidence (1.2%). Findings support a reactive mechanism involving plasma cell depletion and immune dysregulation rather than direct CAR-T cell cytotoxicity and highlight the importance of upper endoscopy to identify injury patterns in the small intestine that may be less pronounced in the colon. Although the pathophysiology is not fully defined, increased awareness and earlier diagnosis may improve understanding of management and enhance likelihood of IEC-EC reversibility.

Several reports describing a rare primary liver tumor with histologic features reminiscent of follicular thyroid neoplasms have been published under a variety of descriptive terms including thyroid-like, solid tubulocystic, and cholangioblastic cholangiocarcinoma. Although these tumors are considered to represent histologic variants, they lack classic features of cholangiocarcinoma and have unique characteristics, namely immunoreactivity for inhibin and NIPBL::NACC1 fusions. The purpose of this study is to present clinicopathologic and molecular data for a large series of these tumors to better understand their pathogenesis. We identified 11 hepatic tumors with these features. Immunohistochemical and NACC1 and NIPBL fluorescence in situ hybridization assays were performed on all cases. Four cases had available material for whole-genome sequencing (WGS) analysis. Most patients were adult women (mean age: 42 y) who presented with abdominal pain and large hepatic masses (mean size: 14 cm). Ten patients had no known liver disease. Of the patients with follow-up information, 3/9 (33%) pursued aggressive behavior. All tumors were composed of bland cuboidal cells with follicular and solid/trabecular growth patterns in various combinations, were immunoreactive for inhibin, showed albumin mRNA by in situ hybridization, and harbored the NIPBL::NACC1 fusion by fluorescence in situ hybridization. WGS corroborated the presence of the fusion in all 4 tested cases, high tumor mutational burden in 2 cases, and over 30 structural variants per case in 3 sequenced tumors. The cases lacked mutations typical of conventional intrahepatic cholangiocarcinoma. In this report, we describe the largest series of primary inhibin–positive hepatic neoplasms harboring a NIPBL::NACC1 fusion and the first WGS analysis of these tumors. We propose to name this neoplasm NIPBL:NACC1 fusion hepatic carcinoma.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society’s Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible “predysplastic lesions” with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial “serrated epithelial change” encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

INTRODUCTION: Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. METHODS: In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1–6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. RESULTS: One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. DISCUSSION: In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.

AimsCellular schwannoma is a specific subtype of schwannoma, prone to misinterpretation as a malignant neoplasm. Involvement of the intracranial compartment by these tumours is extremely rare. We aim to characterise this clinicopathological subgroup.Methods and resultsWe identified a total of 20 cellular schwannomas with predominant intracranial involvement. The mean age of the patients at the time of surgery was 37 years (range = 16–81), with a slight female predominance (1.5:1 ratio). The most common sites were the eighth (n = 8) and fifth (n = 6) cranial nerves. Three tumours involved the anterior cranial fossa/olfactory groove, and a single case involved the glossopharyngeal nerve. All tumours met established criteria for cellular schwannoma, and were composed of interlacing fascicles of spindle cells lacking Verocay bodies with minimal Antoni B pattern and variable chronic inflammation and foamy histiocytes. Rare findings included haemosiderin deposition (n = 6), necrosis (n = 4), brisk mitotic activity (>10 mitoses per 10 high‐power fields) (n = 2), focal epithelioid morphology (n = 2), myxoid areas (n = 2), neuroblastoma‐like pattern (n = 1) and granular cells (n = 1). Immunohistochemical stains demonstrated expression of Schwann cell markers (S100 protein, SOX10, collagen IV) and preserved H3 K27 trimethylation in all cases tested. Fourteen patients had postoperative follow‐up, ranging from 2 months to 21 years (mean = 66 months). In patients with follow‐up, local recurrence/persistence developed in six cases; five tumours were initially incompletely resected. No metastatic disease or deaths were reported.ConclusionsIntracranial cellular schwannomas share morphological and immunophenotypical features with cellular schwannomas at others sites may demonstrate locally aggressive growth but appear to lack metastatic potential.

AimsGastric heterotopia (GH) has been described throughout the gastrointestinal tract. However, the colorectal region is an extremely rare location for it. We describe the clinicopathological features of GH of the colon, rectum and anus.Methods and resultsWe identified 33 cases in 20 males and 13 females (median age = 54 years; range = 4 months–73 years). Sites included the rectum (n = 26), anus (n = 4), ileocaecal junction (n = 1), ascending colon (n = 1) and descending colon (n = 1). Presenting symptoms (n = 27) included haematochezia (41%) and altered bowel habits (4%); 15 patients (55%) were asymptomatic. On colonoscopy (n = 31), all appeared as solitary lesions (median size = 6.5 mm, range = 2–55 mm), either as polyps (61%), raised erythematous patches (23%), an ulcer (10%), within a rectal diverticulum (3%) or a haemorrhoid (3%). Patients were managed by polypectomy. One with an associated carcinoma in the area of GH underwent resection. No morbidity related to GH itself was reported following excision. Histologically, heterotopic gastric mucosa was oxyntic (85%), mixed oxyntic and non‐oxyntic (12%) and not specified (3%) types. In five patients a pyloric gland adenoma (PGA) arose from heterotopic gastric mucosa, two of which contained a focus of invasive adenocarcinoma. One case had associated surface foveolar‐type low‐grade dysplasia. Another had associated adenocarcinoma arising from the heterotopic mucosa. One example harboured Helicobacter pylori organisms.ConclusionsWe highlight the features of GH in the distal GIT – the ‘outlet patch’. Association with PGA, surface dysplasia and adenocarcinoma suggests that lower tract GH can undergo neoplastic transformation.

Gastric polyps are found in 1% to 4% of patients undergoing gastroscopy. The vast majority are sporadic, but some gastric polyps indicate an underlying syndrome. Gastric polyps can manifest in each of the gastrointestinal polyposis syndromes, including the recently described gastric adenocarcinoma and proximal polyposis of the stomach syndrome. In addition, gastric polyps occur in Lynch syndrome and in a few rare conditions that are not primarily gastrointestinal. While some of these syndromes are clearly associated with an increased risk of gastric cancer, others are not. Interestingly, even in disorders with a well-established risk of gastric cancer, the neoplastic potential and the precursor status of these gastric polyps are not always clear. Although rare, recognition of syndromic gastric polyps is important for individual patient management. These conditions also serve as important models to study gastric homeostasis and gastric tumorigenesis.