Virchows Archiv最新文献

{"title":"Perforin-2 is overexpressed in Kikuchi-Fujimoto disease.","authors":"Kirill A Lyapichev, L Jeffrey Medeiros, Narittee Sukswai, Siok Bian Ng, Salwa S Sheikh, Samir Amr, Noula D Shembade, Joseph D Khoury","doi":"10.1007/s00428-025-04046-0","DOIUrl":"https://doi.org/10.1007/s00428-025-04046-0","url":null,"abstract":"<p><p>Kikuchi-Fujimoto disease (KFD) is a self-limited lymphadenopathy characterized by subcortical necrosis and paracortical proliferation of lymphocytes, histiocytes and plasmacytoid dendritic cells with abundant apoptosis. The etiology of KFD remains unknown. Perforin-2 is a highly conserved transmembrane molecule capable of forming pores following intercellular interaction with bacteria and erythrocytes. Perforin-2 is also essential for the activation of type I interferon-induced JAK/STAT signaling and elimination of virus infection. Herein, we hypothesized that perforin-2 or macrophage-expressed gene 1 (MPEG1) protein function is dysregulated in KFD, resulting in an exaggerated immune response, possibly following exposure to an unknown infectious agent. Twelve cases of KFD were the study group. We isolated total RNA from fixed, paraffin-embedded whole tissue sections. We also assessed primary human B-cells and 4 cases of reactive follicular hyperplasia as controls. Perforin-2 mRNA levels were assessed by quantitative real-time PCR (qRT-PCR). We found that perforin-2 mRNA expression was significantly upregulated in 11 of 12 (92%) KFD cases as compared with control samples. These results suggest that expression of perforin-2 is dramatically upregulated in KFD cases. Increased levels of perforin-2 likely explain the abundant apoptosis in KFD. These data also support the hypothesis that upregulation of perforin-2 may be part of the host immune reaction to an unknown infectious agent that is the trigger for KFD.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nodular fasciitis: a case series unveiling novel and rare gene fusions, including two cases with aggressive clinical behavior.","authors":"Carla Saoud, Abbas Agaimy, Robert Stoehr, Michael Michal, Scott Kuan-Wen Wang, Srinivas Mandavilli, Gregory W Charville, Konstantinos Linos","doi":"10.1007/s00428-025-04040-6","DOIUrl":"https://doi.org/10.1007/s00428-025-04040-6","url":null,"abstract":"<p><p>Nodular fasciitis is a benign myofibroblastic tumor characterized by rapid growth and spontaneous regression. While nodular fasciitis is typically an indolent process, rare cases with benign morphologic features have developed metastases. Conversely, nodular fasciitis with malignant histologic features and benign clinical course have also been reported. In this study, we present seven nodular fasciitis cases with novel USP6 gene fusion partners, in addition to two cases with rare fusions that displayed aggressive clinical behavior. The cohort comprised five females and four males with a median age of 36 years (range 13-59). Tumors were located in the forearm (n = 3), thigh (n = 2), and shoulder, abdominal wall, chest wall, and oral cavity (one each), ranging from 1.4 to 24.0 cm in size (median, 2.2 cm). Except for the clinically aggressive cases, patients presented with painless masses of varying onset from days to months. Of the clinically aggressive cases, one patient presented with a slowly growing subfascial thigh/hip mass over nine years, leading to erosion of the femur and pelvis; the other presented with a painful subfascial thigh mass of several months' duration. Histologically, all cases, including the clinically aggressive ones, showed conventional nodular fasciitis features without nuclear pleomorphism or atypical mitotic figures; one case with aggressive clinical behavior exhibited focal infarction-type necrosis. Break-apart FISH analysis using USP6 flanking probes failed to detect USP6 rearrangement in two cases (false negatives) and was inconclusive in one case. Next-generation RNA sequencing identified USP6 fusions in all cases. The clinically aggressive cases showed fusions with COL1A1 (exon 1) and PPP6R3 (exon 1), while novel fusions were identified in the remaining cases including EIF4A1 (exon 1), FILIP1L (exon 2), NF1 (exon 33), OMD (exon 1), PFN1 (exon 1), RLIM (exon 1), and SETD5 (exon 1). Six patients underwent surgical resection; three were managed conservatively, with two experiencing spontaneous tumor resolution. Of the clinically aggressive cases, one patient had progression of the tumor with erosion of the underlying bone, and the second patient developed local recurrence at 14 months and lung metastasis at 19 months, ultimately dying of disease at 22 months. The remaining patients showed no recurrence or metastasis. Our findings expand the spectrum of USP6 gene fusion partners in nodular fasciitis and, for the first time, report cases with conventional morphology exhibiting aggressive behavior, including death. These observations raise the question of whether a subset of deep lesions with conventional nodular fasciitis histology but unusual clinical features, such as large tumor size, represents malignant nodular fasciitis or alternatively a nodular fasciitis-like myofibroblastic sarcoma.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prognostic value of the tumor-stroma ratio compared to tumor-infiltrating lymphocytes in triple-negative breast cancer: a review.","authors":"Layla Andour, Sophie C Hagenaars, Barbara Gregus, Anna Mária Tőkes, Zsófia Karancsi, Rob A E M Tollenaar, Judith R Kroep, Janina Kulka, Wilma E Mesker","doi":"10.1007/s00428-025-04039-z","DOIUrl":"https://doi.org/10.1007/s00428-025-04039-z","url":null,"abstract":"<p><p>Previous literature extensively explored biomarkers to personalize treatment for breast cancer patients. The clinical need is especially high in patients with triple-negative breast cancer (TNBC) due to its aggressive nature and limited treatment modalities. This review aims to evaluate the value of tumor-infiltrating lymphocytes (TILs) and tumor-stroma ratio (TSR) as prognostic biomarkers in TNBC patients and assess their clinical potential. A literature search was conducted in PubMed, Embase, Emcare, Web of Science, and Cochrane Library. Papers comparing survival outcomes of TNBC patients with low/high or negative/positive TSR and immune cells were included. The most frequently mentioned subgroups of TILs were selected and reported in this review. Data from 43 articles on TILs and eight articles on TSR were included. Among TNBC patients, high CD8 expression was generally associated with better survival. Notable, the poor survival outcomes were related to high intra-tumoral PD-L1 expression, whereas high stromal PD-L1 expression more often was correlated with favorable outcomes. For the TSR, a high amount of stroma in the primary tumor of TNBC patients was consistently associated with worse survival. This review highlights that a high number of CD8-positive T-cells is a promising prognostic factor for TNBC patients. PD-L1 expression analyzed for intra-tumoral and stromal expression separately reports strong but contrasting information. Finally, the TSR shows potential to be an important prognostic marker, especially for TNBC patients. Utilizing both biomarkers, either on itself or combined, could enhance clinical decision-making and personalization of treatment.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in gastric adenosquamous carcinoma.","authors":"Yijin Gu, Zebing Liu, Xia Sheng, Lei Dong, Chen Chen, Haimin Xu, Zhongyu Wang, Benyan Zhang, Qiyun Li, Yuechen Wang, Yu Yang, Qi Peng, Lingyan Zhu, Fei Yuan, Chaofu Wang, Anqi Li","doi":"10.1007/s00428-025-04044-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04044-2","url":null,"abstract":"<p><p>Primary gastric adenosquamous carcinoma (GASC) is a rare tumor that exhibits aggressive behavior and currently lacks standardized therapeutic recommendations. Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) and positive PD-L1 expression confer sensitivity to immune checkpoint inhibitors; however, their statuses in GASC remain uncertain. In this study, clinical features, MMR/MSI status, MLH1 methylation, two T-cell markers, and PD-L1 expression of 30 GASC cases were collected from three institutions. Additionally, 196 gastric adenocarcinomas (GACs) were collected for comparison. The median age of GASC patients was 62 years, with 76.7% being males, and 56.7% at stage III. dMMR/MSI-high with MLH1 hypermethylation was observed in 33.3% GASCs, and was significantly associated with older age, female, distal location, larger size, deeper tumor invasion, and higher CD3 and CD8 densities and PD-L1 expression. Both glandular and squamous components of all dMMR GASCs showed loss of MLH1 and PMS2 expression. No significant difference in overall survival was observed between dMMR and mismatch repair proficiency (pMMR) GASC patients, while inferior overall survival was observed in pMMR GASC treated with surgery alone compared to those receiving chemotherapy. When comparing to GAC, GASC exhibited clinicopathological features indicative of more aggressive behavior (larger size, poorly tumor differentiation, deeper tumor invasion and more lymph node metastases). A significantly higher frequency of dMMR was found in GASC (33.3%) than that in GAC (16.3%). This study offers a comprehensive perspective on the clinicopathological features of GASC, emphasizing a subset of GASC associated with dMMR and MLH1 hypermethylation. Immunotherapy might be a promising strategy for GASC.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulator of interferon genes (STING) immunohistochemical expression in fumarate hydratase-deficient renal cell carcinoma: biological and potential predictive implications.","authors":"S Marletta, L Marcolini, A Caliò, S Pedron, P Antonini, F M Martelli, L Stefanizzi, G Martignoni","doi":"10.1007/s00428-025-04041-5","DOIUrl":"https://doi.org/10.1007/s00428-025-04041-5","url":null,"abstract":"<p><p>Fumarate hydratase (FH)-deficient renal cell carcinoma is an aggressive neoplasm driven by inactivating mutations of the FH gene, which cause metabolites like S-(2-succinyl)cysteine (2SC) to accumulate and trigger cascades supporting malignant transformation. Although in preclinical models the c-GAS-STING pathway is activated by fumarate metabolites, its role in humans has not been explored yet. Eleven FH-deficient renal cell carcinomas, including primary neoplasms and metastases, were retrieved and evaluated for clinical-pathological features and immunohistochemical expression of FH, 2SC (commercially available), and STING. The in-house collection accounted for 0.2% of the 2011-2023 renal cell carcinomas cohort (5/2210). Eight-on-ten cases with available follow-up behaved aggressively (local recurrence/distant metastases). All tumors revealed FH staining loss and strong and diffuse 2SC immunolabeling. At least focal STING expression was detected in most primary tumors (9/11, 82%), often (78%) in a wide percentage of cells (≥ 30%). Notably, significant STING expression was observed in all but two aggressive renal neoplasms, with one of the remaining showing increased staining in its hepatic localization, and in 86% (6/7) of neoplasms significantly expressing PD-L1. In our series, (i) FH-deficient renal cell carcinoma represents 0.2% of in-house cases; (ii) combining FH loss and positive 2SC staining now commercially available is useful in primary and secondary tumors, supporting this latter marker's safe routine adoption; and (iii) a significant STING labeling (≥ 30%) in most of the samples, especially in those behaving aggressively and expressing PD-L1, provides novel insights regarding the molecular basis of FH-deficient renal cell carcinomas, proposing STING as a potential predictive marker.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coccoid Helicobacter pylori in patients with obesity: an immunohistochemical study.","authors":"Chen Mayer, Daniel Hillel, Iris Barshack, Michael Schvimer","doi":"10.1007/s00428-025-04042-4","DOIUrl":"https://doi.org/10.1007/s00428-025-04042-4","url":null,"abstract":"<p><p>Helicobacter pylori (HP) is a Gram-negative bacterium that infects approximately fifty percent (50%) of individuals worldwide. The coccoid form of HP, a dormant state with altered morphology, has been associated with persistent infections and antibiotic resistance. This study aimed to investigate the prevalence of the coccoid form of HP in patients living with obesity. Sleeve gastrectomy specimens from obese patients and gastric biopsies from non-obese individuals were analyzed. Immunohistochemistry (IHC) staining and histopathological examination were performed to identify and quantify the coccoid forms of HP. Statistical analysis was conducted to compare the results between the two groups. The study included 53 obese patients and 62 non-obese individuals. The percentage of coccoid forms of HP was significantly higher in obese patients compared to non-obese individuals (median 50% vs. 10%, p < 0.001). Type of gastritis was also significantly different between the groups. Obese patients exhibited a higher prevalence of the coccoid form of HP in their gastric mucosa. This finding suggests that the gastric microenvironment in obesity may favor the formation of the coccoid form, potentially impacting the colonization and pathogenicity of HP. The higher prevalence of the coccoid form in obese patients has important clinical implications, as it is more resistant to antibiotics and difficult to eradicate. Alternative treatment strategies may be necessary to effectively manage HP infections in this population. Furthermore, the presence of the coccoid form may increase the risk of HP-associated diseases in obese individuals. Further research is needed to elucidate the underlying mechanisms and explore novel treatment approaches for HP infection in the context of obesity.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EWSR1::CREM rearranged intra-abdominal malignant epithelioid neoplasm: two new cases of an emerging entity with clinicopathological characteristics and histological pitfalls.","authors":"Mariam Rusidzé, François Poumeaud, Béatrice Akiki, Thibaud Valentin, Gwenaël Ferron, Anne Ducassou, Daniel Pissaloux, Solène Evrard, Pierre Brousset, Sophie Le Guellec, Philippe Rochaix","doi":"10.1007/s00428-025-04034-4","DOIUrl":"https://doi.org/10.1007/s00428-025-04034-4","url":null,"abstract":"<p><p>The EWSR1::CREM rearranged intra-abdominal malignant epithelioid neoplasm is an emerging tumor, with only a few publications describing it to date. Here, we report two new cases of this highly aggressive tumor, primarily involving the peritoneal surface. The tumors presented as a widespread diffuse peritoneal lesion associated with a 4-cm pelvic mass in a 28-year-old woman (Case 1) and as a 10-cm intra-abdominal mass infiltrating the stomach with multiple hepatic metastases in a 53-year-old woman (Case 2). The tumors shared predominant epithelioid morphology with minimal nuclear polymorphism. One of them additionally harbored spindle and rhabdoid cell populations. Both tumors displayed immunoreactivity for pan-cytokeratins, EMA, and CD99, and variable positivity for MUC4, progesterone and estrogen receptors, pan-NTRK, and synaptophysin. This misleading histology and immunophenotype give rise to a wide spectrum of differential diagnoses and highlight the crucial role of RNA sequencing in diagnostic accuracy and thus in appropriate therapeutic approaches.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epstein-Barr virus status drives morphological and molecular intra-tumour heterogeneity in gastric cancer: insights from a case report and literature review.","authors":"Irene Gullo, Maria Luísa Sacramento, Rui Morais, Yongsoo Kim, Paul P Eijk, Ana Mafalda Rocha, Diana Baptista, João Santos-Antunes, Bauke Ylstra, Fátima Carneiro","doi":"10.1007/s00428-025-04035-3","DOIUrl":"https://doi.org/10.1007/s00428-025-04035-3","url":null,"abstract":"<p><p>This case report describes a rare case of bi-phenotypic gastric cancer with two distinct, but clonally related, histological components. The first component, associated with Epstein-Barr virus (EBV) infection, exhibited the morphological features of gastric carcinoma with lymphoid stroma, suggesting that EBV, as an effective immunogenic factor, may trigger a prominent immune response within the tumour microenvironment. The second component, which was EBV-negative, displayed tubular/papillary morphology and features of increased biological aggressiveness, such as high-grade areas and lymphatic invasion. Immunohistochemical and molecular studies confirmed that, despite the differing morphologies and immunophenotypes, both components were clonally related, with the EBV-negative area showing more complex DNA aberrations, reminiscent of chromosomally instable (CIN) lesions. This case describes clonally related EBV-positive and -negative components within a single gastric cancer, contributing to a better understanding of EBV role in tumour heterogeneity and progression and highlights the impact of EBV loss on tumour behaviour.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MAPK1IP1L::TFE3-rearranged renal cell carcinoma: a novel fusion adding to the differential diagnosis of oncocytic renal neoplasms.","authors":"Anne V Cheng, Douglas J Wu, Lisa Aviva Friedman, Emily Chan, Sean R Williamson, Laurence A Galea, Ankur R Sangoi","doi":"10.1007/s00428-025-04031-7","DOIUrl":"https://doi.org/10.1007/s00428-025-04031-7","url":null,"abstract":"<p><p>Beyond the more common TFE3 fusion partners PRCC, ASPSCR1, and SFPQ, additional less common fusion partners of TFE3-rearranged renal cell carcinoma (RCC) have been described. Herein, we present an example of TFE3-rearranged renal cell carcinoma harboring fusion partner MAPK1IP1L, a rare rearrangement with only one other reported tumor found in the literature. The currently reported TFE3-rearranged RCC demonstrates unique histological features compared to the previously reported tumor including dense eosinophilic cytoplasm and nuclear pseudoinclusions (corroborated by electron microscopic evaluation), with features not typically seen in other TFE3-rearranged RCCs. Recognizing this novel fusion may be important in the identification, classification, and development of potential therapeutic agents of kidney tumors in the future.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ötzi's perimortem skin changes.","authors":"Jochen Weber, Joachim Wahl, Marco Samadelli, Albert Zink","doi":"10.1007/s00428-025-04036-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04036-2","url":null,"abstract":"","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}