Virchows Archiv最新文献

{"title":"Baseline retinoblastoma transcriptional corepressor 1 (Rb1) functional inactivation is a pre-requisite but not sufficient for small-cell histological transformation in epidermal growth factor receptor (EGFR) mutant lung adenocarcinomas post-tyrosine kinase inhibitor therapy.","authors":"Aruna Nambirajan, Amber Rathor, Hemavathi Baskarane, Anju Gs, Sachin Khurana, Somagattu Sushmitha, Aparna Sharma, Prabhat Singh Malik, Deepali Jain","doi":"10.1007/s00428-025-04054-0","DOIUrl":"10.1007/s00428-025-04054-0","url":null,"abstract":"<p><p>Small-cell transformation is an uncommon mechanism of tyrosine receptor kinase inhibitor (TKI) resistance in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas. This study aims to assess the dynamic changes in the molecular landscape and Rb1 functional status in EGFR-mutant lung adenocarcinomas transforming to small-cell carcinomas post-treatment with EGFR-TKIs. This is an ambispective study (2019-2023) wherein the baseline and post-TKI biopsies of EGFR-mutant lung adenocarcinomas with small-cell transformation were subject to Rb1 immunohistochemistry and 72-gene targeted panel next-generation sequencing. Rb1-deficiency was defined as Rb1 protein loss or Rb1^retained/p16^high/Cyclin-D1^low protein expression profile with RB1 mutations. A cohort of EGFR-mutant lung adenocarcinomas without small-cell transformation was included for Rb1 status comparison. Small-cell transformation was diagnosed in 9 patients (10%, 9/84) on their post-TKI biopsy. All their tested baseline adenocarcinoma (n = 7) and post-TKI small-cell carcinoma (n = 9) samples were Rb1-deficient, with additional TP53 (11/11) and PTEN mutations (2/11). Eighteen paired samples from 9 patients without small-cell transformation revealed Rb1-deficiency in one patient (1/9) only. Baseline functional inactivation of Rb1 is nearly universal in EGFR-mutant adenocarcinomas transforming to small-cell carcinomas post-EGFR TKI suggesting that Rb1 loss is prerequisite for small-cell transformation. However, it is likely not sufficient as not all adenocarcinomas with baseline Rb1 loss transform into small-cell carcinomas. Except for TP53 and PTEN, recurrent mutations in other common oncogenes tested were not detected at baseline or at progression. Within the limitation of a small sample size, specific molecular events that drive small-cell transformation remain unclear.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"639-648"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469316","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":"Hybrid granular cell tumor/perineurioma: a report of two rare cases with PIK3CA mutations.","authors":"Ani Toklu, Gauri Panse, George Jour, Konstantinos Linos, Jeffrey M Cloutier, Carina A Dehner","doi":"10.1007/s00428-025-04089-3","DOIUrl":"10.1007/s00428-025-04089-3","url":null,"abstract":"<p><p>Hybrid peripheral nerve sheath tumors (PNSTs) are rare mesenchymal neoplasms with dual differentiation, most often combining two of the three main PNST types: schwannoma, neurofibroma, and perineurioma. Recognized by the WHO since 2013, these tumors can also exhibit fewer common combinations, such as hybrid granular cell tumor/perineurioma. We herein report two rare cases of hybrid granular cell tumor perineurioma with molecular analysis. Both tumors presented as dermal to subcutaneous, well-circumscribed lesions composed of a combination of spindled and granular cell components. By immunohistochemistry, the granular cells were positive for S100, SOX10, and CD68, while the perineurial cells were highlighted by EMA and GLUT1 stains. Subsequent molecular testing revealed pathogenic mutations involving PIK3CA in both cases. Our study expands on the clinical and pathologic spectrum and provides the first molecular data on these unusual neoplasms. Further, we provide a comprehensive review of the literature of all previously reported cases and briefly discuss relevant differential diagnoses and their molecular features.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"597-604"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754560","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":"EPM2 AIP1 immunohistochemistry as a surrogate of promoter methylation analysis in endometrial carcinoma.","authors":"Sonia Gatius, Marta Vaquero, Oliver Scheiber, Ana Velasco, Dolors Cuevas, Karl Kashofer, Maria Santacana, Núria Eritja, Sigurd Lax, Xavier Matias-Guiu","doi":"10.1007/s00428-025-04132-3","DOIUrl":"10.1007/s00428-025-04132-3","url":null,"abstract":"<p><p>Mismatch repair (MMR) status in endometrial carcinoma (EC) is crucial for diagnosis, prognosis, treatment, and Lynch syndrome pre-screening. MLH1 loss is the most frequent cause of MMR deficiency and usually by promoter hypermethylation. We tried to confirm the role of EPM2 AIP1 immunohistochemistry as a surrogate of MLH1 promoter methylation in EC. Case series from two different institutions were analyzed by comparable methods using immunohistochemistry for MMR proteins and EPM2 AIP1, and pyrosequencing for MLH1 methylation. In the first series of 70 cases, concordance was 100%, after reassessing three cases with methylation scores close to cut-off, by tumor cell enrichment. In the second series of 29 MLH1-deficient ECs, concordance was 96.5%, while in the control group of 30 MMR-proficient EC, one MLH1-positive case was EPM2 AIP1-negative. EPM2 AIP1 immunoreactivity was qualitatively superior in curettages and biopsies compared to hysterectomy. We conclude that EPM2 AIP1 immunohistochemistry is a good surrogate for MLH1 promoter methylation analysis, cost-effective with short turnaround time, but needs attention regarding preanalytical handling, normal tissue contamination, or low tumor percentage.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"511-522"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence-answer to letter VIAR-D-25-00371.","authors":"Marit Bernhardt, Benjamin Aretz, Glen Kristiansen","doi":"10.1007/s00428-025-04216-0","DOIUrl":"10.1007/s00428-025-04216-0","url":null,"abstract":"","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"721-722"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostatic amyloidosis: pathological features of an underdiagnosed condition.","authors":"José A Ortiz-Rey, Jorge Sánchez-Ramos, Samer Abdulkader-Sande, David Muñoz-Raya, José Aguayo-Arjona, Alfonso Fernández-Costas, Carolina Gómez-de María, Lourdes Liste-Tizón, Edgar J Escalona-Canal, Sergio Raposeiras-Roubín, Rafael J Cobas-Paz, Pilar San Miguel-Fraile, Enrique Cespón-Outeda, María Cespón-Fernández","doi":"10.1007/s00428-024-04014-0","DOIUrl":"10.1007/s00428-024-04014-0","url":null,"abstract":"<p><p>Amyloidosis is a rare disease that can affect genitourinary organs but the involvement of the prostate has been documented in a limited number of cases. We have reviewed morphologic and immunohistochemical features of prostate biopsies or surgical specimens in which an initial diagnosis of amyloidosis was made. Prostatic amyloidosis was diagnosed in 25 patients, 21 of them were needle biopsies (1.16% of these ones). Amyloid was observed inside vessel walls (25 cases) and the stroma (3). No significant differences in the number of affected biopsy samples between patients with and without cardiac amyloidosis were found. In prostatectomies, amyloid was visualized in all the regions of the prostate, being more abundant in the periphery and the posterolateral tissue. Three patients with abundant amyloid in the prostatectomy did not have cardiac amyloidosis. Immunohistochemically prostatic amyloid was positive for transthyretin and P amyloid (24 cases). A amyloid, kappa, and lambda chains were negative. The genetic analysis revealed transthyretin wild-type amyloidosis. Immunohistochemistry was not conclusive in one case of immunoglobulin light chain amyloidosis. In conclusion, prostate amyloidosis is an infrequent finding characterized by the deposition of amyloid inside small vessel walls, and less often in the stroma. It occurs mainly in the periphery of the gland. Amyloid deposits are often subtle and overlooked but relevant as this may be the first sample in which systemic amyloidosis is diagnosed. Immunohistochemistry can be used to subtype amyloid, although there are limitations when confronted with immunoglobulin light chain amyloidosis. Most cases have corresponded to wild-type transthyretin amyloidosis.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"629-637"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883100","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":"Correction to: Succinate dehydrogenase defcient renal cell carcinoma frequently expresses GATA3 and L1CAM.","authors":"Ankur R Sangoi, Sean R Williamson, Murat Oktay, Anthony J Gill, Kiril Trpkov, Farshid Siadat, Fiona MacLean, Laurence A Galea, Dilek Ertoy Baydar, Caglar Cakir, Yasemin Yuyucu Karabulut, Deniz Baycelebi, Ganime Coban, Banu Sarsik, Busra Yaprak Bayrak, Levente Kuthi, Boglarka Posfai, Aysha Mobeen, Sambit K Mohanty, Xulang Zhang, Mohammed A Alghamdi, Liang Cheng, Michelle S Hirsch, Mahmut Akgul","doi":"10.1007/s00428-025-04194-3","DOIUrl":"10.1007/s00428-025-04194-3","url":null,"abstract":"","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"723-724"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144709001","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":"Tumor-infiltrating plasma cells are a prognostic factor in penile squamous cell carcinoma.","authors":"P J Stenzel, A Thomas, M Schindeldecker, S Macher-Goeppinger, S Porubsky, A Haferkamp, I Tsaur, W Roth, K E Tagscherer","doi":"10.1007/s00428-024-04013-1","DOIUrl":"10.1007/s00428-024-04013-1","url":null,"abstract":"<p><p>Penile cancer (PeCa) is a rare disease with poor prognosis in the metastatic stage. Neither effective adjuvant nor palliative therapeutic options are available. Research efforts in this field have so far failed to establish robust predictors of survival. To identify prognostic targets in PeCa, the current project focused on characterizing the tumor microenvironment (TME). A study cohort of 93 men with PeCa was used for the construction of a tissue microarray and immunohistochemical staining for CD3, CD4, CD8, CD20, CD56, CD138, FoxP3, and PD-L1. The quantity and spatial distribution of tumor-infiltrating immune cells were analyzed using digital image analysis. PD-L1 staining of tumor and immune cells was manually scored (combined positivity score (CPS)). T cells, T helper cells, cytotoxic T cells (CTLs), and regulatory T cells were detected in > 90% of PeCa and B cells in 88%, plasma cells in 85%, and NK cells in 23%. Approximately 50% of the PeCa samples were PD-L1 positive. In the univariate survival analysis, high PD-L1 CPS, plasma cells, CTLs, and B cells were significantly associated with favorable overall survival (OS), and the latter two with adverse recurrence-free survival. In multivariate analysis, plasma cells remained a significant factor for favorable OS (p = 0.04). In this study, the immune cells in the TME, especially plasma cells, were favorably associated with patient survival compared to other established prognostic factors in PeCa. Contemporarily, plasma cells have been discussed in the light of contributing to responses to modern immunotherapies. The results of this study support this notion.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":"687-699"},"PeriodicalIF":3.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial heterogeneity of FGFR2b in gastric cancer: a comparative analysis of primary tumors and peritoneal dissemination.","authors":"Haruki Ogawa, Hiroyuki Abe, Koichi Yagi, Yoshifumi Baba, Yasuyuki Seto, Tetsuo Ushiku","doi":"10.1007/s00428-025-04233-z","DOIUrl":"https://doi.org/10.1007/s00428-025-04233-z","url":null,"abstract":"<p><p>Gastric cancer with peritoneal dissemination (PD) confers poor prognosis and limited treatment options. FGFR2b-targeted therapy has emerged as a potential approach for FGFR2b-positive tumors. However, the expression and amplification status of FGFR2b in PD remains poorly characterized. This study aimed to investigate FGFR2b expression and gene amplification in matched primary tumors and PD tissues from gastric cancer patients, and to evaluate their association with established biomarkers including HER2, CLDN18, and PD-L1. Immunohistochemistry (IHC) for FGFR2b was performed on matched primary and PD tissues from 84 patients. FGFR2 FISH was conducted in IHC-positive cases. FGFR2b expression was detected in 7.1% (6/84) of primary tumors and 4.8% (4/84) of PD samples. Expression was highly heterogeneous; only one case was FGFR2b-positive in both primary and PD tissues. FGFR2 amplification was found in 6 of 10 IHC-positive samples, and not observed in IHC-negative samples. FGFR2b status showed no significant correlation with HER2, CLDN18, or PD-L1. FGFR2b expression in gastric cancer is spatially heterogeneous and discordant between primary tumors and PD. It may be preferable to test both primary tumor and PD tissue, if available, to better identify candidates for FGFR2b-targeted therapy. FGFR2b represents a potential therapeutic target for a subset of PD-positive gastric cancers lacking other biomarker expression.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970885","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":"Immunohistochemical evaluation of CREM in CREB-rearranged mesenchymal tumors and their mimics.","authors":"Shogo Nishino, Hirokazu Sugino, Yasuhito Arai, Natsuko Hama, Tatsuhiro Shibata, Shuhei Osaki, Seiichi Yoshimoto, Yasushi Yatabe, Taisuke Mori, Akihiko Yoshida","doi":"10.1007/s00428-025-04207-1","DOIUrl":"https://doi.org/10.1007/s00428-025-04207-1","url":null,"abstract":"<p><p>Fusion genes between the FET (EWSR1/FUS) and CREB (CREB1, ATF1, CREM) families characterize many tumor types, including mesenchymal entities. Herein, we tested the diagnostic utility of CREM (C-terminus) immunohistochemistry using 51 CREB-rearranged mesenchymal tumors and 159 tumors of 14 mimicking entities. Staining was considered positive if nuclear staining of moderate or strong intensity was observed in at least 10% of the tumor cells. Among the 51 CREB-rearranged tumors, CREM was at least focally positive in 39 tumors (76.5%), diffusely (≥ 50%) positive in 31 tumors (60.8%), and diffuse strong staining was observed in 23 tumors (45.1%). Diffuse strong reactivity was observed in nearly all angiomatoid fibrous histiocytoma (11 of 12 tumors), intracranial FET::CREB mesenchymal neoplasms (2 of 2 tumors), and unclassifiable sarcomas (2 of 2 tumors, including 1 case with SMARCA2::CREM). However, the positivity was more limited in clear cell sarcoma (15 of 20 tumors), keratin-positive malignant FET::CREB tumors in the abdomen (5 of 8 tumors), and gastrointestinal neuroectodermal tumors (4 of 7 tumors). Two separately evaluated CRTC1-rearranged tumors (CRTC1::TRIM11 and CRTC1::SS18) demonstrated diffuse strong positivity. Among the 159 tumors in the comparison cohort, CREM was at least focally positive in 33 (20.8%) tumors, diffusely positive in 19 tumors (11.9%), and diffusely and strongly positive in 5 tumors (3.1%). CREM demonstrated moderate sensitivity and specificity for the diagnosis of CREB-rearranged mesenchymal tumors as a whole cohort, and its overall utility in predicting CREB fusion is limited. However, CREM staining may be useful in a few specific contexts, such as when angiomatoid fibrous histiocytoma is suspected.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970882","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":"Langerhans cell sarcoma is a clinically, biologically, and prognostically heterogeneous \"malignant\" histiocytosis: a systematic review of 88 cases from the literature.","authors":"Annalisa Dezzani, Chiara Punziano, Emilio Berti, Arturo Bonometti","doi":"10.1007/s00428-025-04230-2","DOIUrl":"https://doi.org/10.1007/s00428-025-04230-2","url":null,"abstract":"<p><p>Malignant histiocytoses are rare histiocytic neoplasms that exhibit aggressive clinical and histopathological features. One of these entities, Langerhans cell sarcomas (LCS), shares some histopathological features with Langerhans cell histiocytosis but is distinguished by its overtly malignant cytologic features. The literature on LCS is mostly limited to short reports and a few reviews, while a complete revision of its nosology is lacking. This study aims to fill this gap in the knowledge on LCS, explore potential prognostic factors, and propose a clinical subclassification for better patient stratification, which could guide future treatment investigations. A systematic review of the literature was conducted following PRISMA guidelines. From each included patient, a complete set of clinical and pathological features was collected. Descriptive and association statistics, as well as survival analysis, were performed using R Studio. A cohort of 88 patients was analyzed, the majority being adult males with multisystem pictures often involving skin and lymph nodes. pERK pathway gene mutations were reported in around half. Overall prognosis was poor, even though the association with another hematological neoplasm displayed a significant negative prognostic impact (p = 0.0017). Moreover, in primary cases, a significant difference was observed dividing patients into single system vs multisystem (p = 0.012). Despite treatment modalities being highly heterogeneous, statistical analyses provided insights into the relevance of treating patients according to disease spread (e.g., treating localized masses with surgery alone leads to frequent complete remission, p = 0.0002). This study provides an extensive analysis of LCS nosology and prognostic factors, underscoring the importance of distinguishing LCS from LCH and other histiocytoses, as well as adopting a unified system to define disease spread and guide therapeutic management.</p>","PeriodicalId":23514,"journal":{"name":"Virchows Archiv","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970924","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}