Kerper, Allison L.

Abstract Background: Pancreatic cancer is a frequently fatal disease that is often diagnosed at a late stage associated with a poor prognosis and an increasing impact on cancer related mortality. Despite advances, chemotherapy remains the mainstem of therapeutic interventions for this disease and most of the currently identified molecular alterations are not currently targetable. Therefore, novel biomarkers and strategies are necessary to impact patient outcomes. Claudin-18.2 (CLDN18.2) is a splice variant of the Claudin 18 family and is a component of tight junctions, which seal the paracellular spaces of epithelial and endothelial cells. CLDN18.2 is frequently retained in malignant gastric tissue and overexpressed in pancreatic and gastroesophageal adenocarcinomas. CLDN18.2 overexpression at the message and protein levels has been observed in pre-clinical studies involving pancreatic cancer cell lines and in tumors from pancreatic cancer patients. The goal of this study was to obtain a deeper understanding of CLDN18.2 positivity and CLDN18.2 expression and the associated clinical prevalence, prognostic implications, patient clinical characteristics and relationship with other biomarkers in pancreatic ductal adenocarcinoma (PDAC) patient samples. Design: This was a single institution/reference laboratory based retrospective study including as many as 320 patients, in which CLDN18.2 positivity as defined by ≥ 75% of the tumor cells expressing moderate to strong membranous staining was examined. The goals were to evaluate CLDN18.2 in tumor samples by immunohistochemistry for prevalence in pancreatic adenocarcinoma patients. Claudin 18.2 expression was assessed by the Ventana (43-14A) Class I IVD that was purchased from Ventana/Roche Diagnostics. In addition to prevalence, CLDN18.2 was evaluated with respect to the clinicopathological features of patients, patient prognosis, adjusted for clinical covariables, response to treatments and relationship to patient demographics, tumor grade and disease status. Patient information has been obtained from electronic medical records and research database to establish clinical course (survival status, metastatic sites, etc.) along with patient demographics. Conclusions: CLDN18.2 is a novel potentially actionable biomarker in patients with advanced and metastatic pancreatic adenocarcinoma. This study provides important clinical information regarding CLDN18.2 expression in these patients that is important to consider when evaluating biomarkers in these patients. Funding for the study was provided by Astellas Pharma Global Development, Inc. Citation Format: Allison Kerper, Robert H. Getzenberg, Rondell P. Graham. Real world clinical characteristics of claudin 18.2 expression in patients with pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5915.

Primary pulmonary myxoid sarcoma (PPMS) and thoracic angiomatoid fibrous histiocytoma (AFH) are rare neoplasms with EWSR1 fusions and overlapping morphology. Both tumor types often show epithelial membrane antigen expression, but AFH characteristically co-expresses desmin. We encountered a case of PPMS with the unexpected finding of patchy, strong anaplastic lymphoma kinase (ALK) (previously reported in AFH) and synaptophysin expression. We evaluated a cohort of PPMS and thoracic AFH with systematic morphologic comparison and surveyed for aberrant expression of ALK and synaptophysin. Medical records and slides were reviewed for 16 molecularly confirmed cases of PPMS (n=5) and thoracic AFH (n=11). Each case was scored for morphologic characteristics typical of PPMS and/or AFH. ALK, synaptophysin, chromogranin, desmin, and epithelial membrane antigen immunostains were performed on cases with available tissue. AFH and PPMS cases showed similar age at presentation and long-term tumor behavior. Almost all cases of PPMS and AFH had a fibrous pseudocapsule and lymphoid rim. All PPMS had myxoid stroma and reticular growth pattern, but these features were also present in a subset of AFH. Synaptophysin expression was present in 6 of 11 AFH and 1 of 5 PPMS; all tested cases were negative for chromogranin (n=15). One case of AFH and 1 case of PPMS showed focally strong coexpression of synaptophysin and ALK. AFH and PPMS show considerable clinicopathologic overlap. When supportive, the immunohistochemical findings described may aid in diagnosis before molecular confirmation. PPMS and AFH may be morphologic variants of the same clinicopathologic entity, which can show more immunophenotypic variability than previously reported.

Context.— Nuclear protein in testis (NUT) carcinoma is an aggressive carcinoma defined by NUTM1 gene rearrangement. Diagnostic challenges include morphologic overlap with poorly differentiated squamous cell carcinoma, small cell carcinoma, thoracic SMARCA4-deficient undifferentiated tumor, and other small round blue cell tumors. Objective.— To comprehensively study the immunohistochemistry (IHC) features of a large cohort of NUT carcinomas. Design.— Fifty-seven NUT carcinoma cases were identified from 2012–2022, including 38 thoracic/mediastinal, 13 head and neck/sinonasal, and 6 from other sites. Pathology reports and available slides were reviewed. Comprehensive IHC studies were performed on available cases. Results.— Keratin stains showed variable positivity and were entirely negative in 15% (8 of 55) of cases. p40 was only positive in 65% (24 of 37) of cases, implying inferior sensitivity when compared to p63 (87% sensitivity, 20 of 23 cases) and other squamous cell markers. Neuroendocrine markers were focally/weakly positive in few cases; however, INSM1 was positive in 54% (7 of 13) of cases, indicating a possible diagnostic pitfall. TTF-1 was mostly negative with focal positivity in 26% (10 of 38) of cases. Occasional CD34 (15%, 3 of 20 cases) and CD99 (21%, 3 of 14 cases) positivity could also cause potential diagnostic confusion. S100, desmin, CD45, and SALL4 were rarely positive. BRG1 and INI1 were retained in all cases. Ki-67 proliferative index was high (median, 60%). PD-L1 was negative in all tested cases. Conclusions.— This comprehensive IHC study demonstrates the immunohistochemical spectrum of NUT carcinoma. The findings can help narrow the differential diagnosis and recognize potential pitfalls.