Virchows Archiv最新文献

The lack of standardized reporting in placental pathology limits research scalability and clinical application despite consensus-based criteria like the Amsterdam Criteria. This study presents the development and implementation of a comprehensive Standardized Structured Reporting (SSR) tool for placental pathology. Utilizing the LogicNets© platform, the tool incorporates the Amsterdam Criteria, Freedman placental phenotype classification system, and consensus recommendations on placental examination. Development involved collaboration with placental pathology experts, literature review, and iterative feedback from pathologists to address reporting inconsistencies and ensure practicality. The SSR tool integrates evidence-based standards for examining and phenotyping the placenta, including structured gross and microscopic analyses. It introduces control mechanisms for severity grading and phenotype assignment, enabling precise assessment of placental lesions, even in multiple births. Organized into sections-Demographics, Macroscopy, Microscopy, and Group and Phenotype-it efficiently records and analyzes data. Additional functionalities include automated calculations of gross placental features, built-in controls, and versatile documentation of microscopic observations. The tool is designed for seamless integration into clinical workflows. Implementing the SSR tool could enhance placental pathology reporting quality, completeness, and consistency, facilitating large-scale analyses. Discrete data capture enables robust research, potentially improving the clinical utility and understanding of placenta-mediated diseases. However, further validation is required before widespread adoption. Embracing SSR could standardize placental examination, improve clinical interpretation, and advance research in placental pathology for enhanced utility in both research and clinical care.

Foveolar-type gastric adenoma with raspberry-like appearance (FGA-RA) is a rare subtype of Helicobacter pylori-naïve gastric neoplasm characterized by its small, reddish, polypoid morphology. This study aimed to clarify the molecular basis of its epithelial phenotype and the superficial capillary proliferation characteristic of FGA-RA's reddish appearance by examining alterations in mucin gene expression and angiogenesis-related pathways using spatial transcriptomic profiling and immunohistochemistry. Formalin-fixed, paraffin-embedded tissue from a representative case of FGA-RA was analyzed using the Visium spatial transcriptomics platform (10 × Genomics). Spatial gene mapping revealed diffuse MUC5AC expression throughout the tumor epithelium, consistent with a foveolar phenotype. Notably, MUC17-typically restricted to intestinal enterocytes-was aberrantly coexpressed with MUC5AC in the superficial tumor layer, while MUC2 was absent, suggesting skewed differentiation toward absorptive enterocytes without goblet cell lineage. To validate these findings, immunohistochemical staining for MUC5AC and MUC17 was performed on six biopsy specimens from genetically validated FGA-RA cases harboring the characteristic KLF4 mutation, five of which showed overlapping superficial expression of both MUC5AC and MUC17. Spatial transcriptomic analysis also demonstrated elevated VEGFA expression in tumor and inflammatory cells, and FLT1 expression in superficial stromal endothelial cells. This expression pattern correlated with vascular markers and may contribute to the prominent capillary proliferation seen in FGA-RA. FGA-RA exhibits a distinctive mucin profile reflecting incomplete intestinal differentiation due to KLF4 dysfunction. The characteristic raspberry-like morphology may be a consequence of VEGF-driven angiogenesis induced by chronic stimulation of a superficially compromised epithelium, suggesting that this unique appearance arises from sequential epithelial and stromal alterations orchestrated by KLF4 mutation.

Anaplastic thyroid carcinoma (ATC) represents one of the most aggressive human malignancies, characterized by rapid progression, early metastasis, and dismal prognosis. The emergence of immune checkpoint blockade targeting the PD-1/PD-L1 axis has revolutionized the therapeutic landscape for several cancers, including ATC, where traditional treatments have shown limited efficacy. This review provide a comprehensive overview of the biological, pathological, and clinical significance of PD-L1 in ATC, highlighting its diagnostic, prognostic, and therapeutic implications. A review of the literature was performed, encompassing molecular studies, immunohistochemical analyses, and clinical trials evaluating PD-L1 expression, its molecular correlates, and its predictive value for immunotherapy response in ATC. PD-L1 is expressed in a substantial proportion of ATCs, with positivity rates ranging from 20% to over 80% depending on the antibody clone, scoring method, and positivity threshold. Its expression correlates with oncogenic drivers such as BRAF^V600E and TP53 mutations, and with an inflamed tumor microenvironment rich in CD8⁺ T cells and interferon-γ signatures. Although the prognostic value of PD-L1 remains controversial, its predictive value for immune checkpoint inhibitor (ICI) response is well established. Prospective trials demonstrated that only PD-L1-positive ATCs respond to single-agent ICI therapy, while combination regimens with kinase inhibitors yield benefit even in PD-L1-low tumors. PD-L1 expression defines a biologically and clinically relevant subset of ATCs with distinct immune features and therapeutic vulnerabilities. Standardizing PD-L1 testing and integrating it with molecular and microenvironmental biomarkers will be essential to refine patient selection for immunotherapy and combination strategies, improving outcomes.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. Its association with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is unclear. Using Taiwan's National Health Insurance Research Database (NHIRD), we analyzed the relationship between iCCA and CKD/ESRD. Molecular alterations were explored through whole-exome sequencing (WES) and Archer FusionPlex in 24 surgical specimens from 22 CKD/ESRD patients. Aristolochic acid (AA)-related DNA adducts were quantified using liquid chromatography/mass spectrometry. NHIRD showed iCCA incidence was 15.35, 26.77, and 34.14 per 100,000 person-years in the general population, CKD, and ESRD patients, respectively. ESRD patients under 65 years had the highest iCCA incidence rate ratio (7.37, P < 0.0001). CKD/ESRD was an independent risk factor (adjusted OR 1.57, P < 0.0001). WES revealed recurrent TP53 (33%), LRP1B (21%), BAP1 (21%) mutations, CDKN2A/B deletion (25%), and FGFR3::TACC3 or SLMAP::ROS1 fusions in single cases. COSMIC SBS22a-associated mutations occurred in 15 cases (68%), more frequent in ESRD-associated tumors (P = 0.05). AA-related DNA adducts were detected in 9 cases (41%), predominantly in ESRD patients (89%). The correlation between SBS22a mutations and dA-AL-I burdens was weak, and canonical T>A transversions were rare in driver mutations. In conclusion, a subset of CKD-/ESRD-associated iCCAs in Taiwan shows molecular and chemical evidence of AA exposure. However, the modest correlation between AA adducts and SBS22a signatures and the paucity of T>A transversions in driver genes suggests that AA acts as a contributory rather than causal factor, possibly synergizing with aging and liver disease-related mutagenic processes.

Consensus conferences in medicine are frequently conducted to formulate recommendations primarily relating to contentious areas in the diagnosis and management of disease and in the assessment of prognostic markers. While these conferences have the potential to provide recommendations that will be of benefit to both the patient and relevant professional group, there are potential pitfalls which can bias results. Of interest, there is an opinion that experts cannot be relied on to reach a reliable consensus on facts relating to their own area of expertise. Even with the best intentions, little consideration is usually given to issues which could lead to the endorsement of recommendations that may not be evidence-based and/or supported by the profession. The potential for bias may result from the selection process for choosing conference participants, the choice of topics nominated for discussion, and the formulation of questions presented to the audience for voting. Bullying, peer pressure, social influence, confirmation bias, communal reinforcement of incorrect concepts, and a desire to conform and achieve acceptance within a peer group may all influence the consensus process, thus limiting the validity of results. It is the responsibility of the conference organizers to ensure that proposed conferences are relevant, objective, evidence-based, and likely to produce meaningful results. It is also incumbent on journal editors and peer reviewers to ensure that the published proceedings report novel, meaningful recommendations that advance the profession and/or improve patient outcomes.

SMARCB1 (INI1) is a tumor suppressor gene essential for chromatin remodeling and transcriptional regulation. Loss of SMARCB1 expression defines a heterogeneous group of mostly aggressive neoplasms collectively termed SMARCB1/INI1-deficient tumors. A rare subset of these tumors exhibits yolk sac tumor (YST)-like morphology, causing significant diagnostic challenges as they can be misclassified as true germ cell tumors. We report a case of SMARCB1-deficient carcinoma with YST-like differentiation arising in the inguinal region of a 40-year-old man. The patient presented with an inguinal mass and elevated serum alpha-fetoprotein. Needle biopsy and excision specimens at an outside facility were considered consistent with a germ cell tumor, specifically a YST. He was initially treated with standard chemotherapy and had a suboptimal response. Our review of the histopathologic and immunophenotype studies verified YST-like features except for complete loss of SMARCB1 expression. Fluorescence in situ hybridization failed to identify isochromosome 12p or 12p amplification, further supporting a somatic origin. Next generation sequencing (NGS) by a commercial laboratory showed SMARCB1 deletion, microsatellite stable status, low tumor mutation burden, and an NGS-based algorithm predictive of a germ cell tumor with 99% probability, a result we consider inaccurate. This case highlights the need to consider SMARCB1-deficient carcinoma in the differential diagnosis of extra-gonadal tumors with YST-like features, especially in cases with atypical clinical presentation or resistance to standard germ cell tumor regimens. The inguinal region of young males appears to be one of the favored sites for these tumors. Furthermore, NGS-based algorithms may fail to accurately classify such tumors.

The objective of this study was to analyze the diagnostic role of HEG homolog 1 (HEG1) in cancers affecting the serosal cavities. HEG1 protein expression by immunohistochemistry was analyzed in 534 specimens (341 effusions and 193 surgical specimens). Effusions consisted of 151 tubo-ovarian carcinomas, 59 breast carcinomas, 44 mesotheliomas, 37 lung carcinomas, 29 uterine corpus and cervical carcinomas, 17 gastrointestinal carcinomas and 4 genitourinary carcinomas. Surgical specimens consisted of 139 tubo-ovarian carcinomas, 42 mesotheliomas, 7 multicystic mesothelial proliferations and 5 papillary mesothelial tumors. HEG1 expression was found in 43/44 (98%) mesothelioma effusions and 39/42 (93%) surgical mesothelioma specimens, as well as all multicystic and papillary mesothelial tumors. HEG1 was infrequently expressed in breast carcinoma (4/59; 7%), lung carcinoma (2/37; 5%) and cervical/uterine carcinoma effusions (3/29; 10%), but was often detected in tubo-ovarian carcinoma effusions (80/151; 53%) and surgical specimens (99/139, 71%). HEG1 was additionally consistently expressed by reactive mesothelial cells in effusions and in endothelial cells in surgical specimens. HEG1 had sensitivity of 95% for diagnosing malignant mesothelioma in all studied specimens, with a specificity of 38% in the differential diagnosis from tubo-ovarian carcinoma and 93% in the differential diagnosis from non-tubo-ovarian carcinomas. Of 179 HEG1-positive carcinomas, 172 expressed the epithelial marker claudin-4. In conclusion, HEG1 is a highly sensitive marker of both benign and malignant mesothelial cells. It shows high specificity in the differentiation of mesothelioma from lung or breast carcinoma but is of little value in differentiating mesothelioma from tubo-ovarian carcinoma. The potential role of HEG1 as vascular marker merits further research.

Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) is characterized by solid basaloid morphology, geographic necrosis, and shadow cells, often associated with CTNNB1 mutations and aberrant β-catenin expression, exhibiting aggressive behavior. However, high-grade endometrial carcinomas with similar solid basaloid/geographic necrosis (SB-GN) features may overlap diagnostically with PiMHEC. This study aimed to investigate the clinicopathological and molecular characteristics of endometrial carcinomas with SB-GN and compare them with PiMHEC. Eighteen endometrial carcinomas with SB-GN (including 6 PiMHECs) were diagnosed in Fudan University Shanghai Cancer Center. Histopathological, immunohistochemical, and molecular features based on next-generation sequencing were reviewed. In our cohort, recurrence/metastasis occurred early (median: 5 months; range: 0-21). Most cases had classic basaloid tumor cells with solid growth pattern. Spindle-shaped cells or tumor cells with more cytoplasm were occasionally observed. Twenty-eight percent of patients had squamous differentiation and 33% had shadow cells. In solid components, aberrant β-catenin expression was observed in 77.8% of cases. Eighty-three percent harbored CTNNB1 exon 3 mutations (frequent co-mutations: PTEN, ARID1A, PIK3CA). Molecular classification revealed 28% MMR-deficient, 22% POLE-mutated, 6% p53-abnormal, and 44% no specific molecular profile (NSMP). Endometrial carcinomas with SB-GN showed no significant differences compared to PiMHECs, except for higher PR positivity in solid components (58.3% vs. 0%, p = 0.046). Endometrial carcinomas with SB-GN represent a distinct and aggressive tumor group characterized by solid growth pattern, prominent necrosis, frequent basaloid morphology, high rates of CTNNB1 mutations, and aberrant β-catenin staining. Our results demonstrate that endometrial carcinomas with SB-GN and PiMHECs share similar clinicopathologic and molecular profiles, supporting a unified biological spectrum.

Cancer progression is driven by the accumulation of genetic variants, with technological advances increasing their detection. Precise variant interpretation is essential for clinical decision-making, necessitating robust quality assurance programmes. However, variability in interpretation can influence clinical outcomes. This study examines factors contributing to interpretation variability across French laboratories and evaluates the role of EQA schemes in enhancing consistency. Five-year data from the Gen&Tiss EQA programme (2018-2023) focusing on pathogenicity and actionability was analysed. Forty-four participants evaluated 75 variants in colon, lung, and melanoma cancer, while 17 evaluated 50 variants in ovarian cancer. The criteria included the entity responsible for post-analysis, MTB consultations, access to the private French OncoGenetics (FrOG) germline variant database, laboratory activity levels, type of institution, and interpretation complexity. Over the study period, laboratory performance improved significantly, with annual increases of 2.6% in multiparametric pathogenicity and 6.3% in actionability. Laboratories with dedicated somatic genetics services achieved the highest pathogenicity scores. While MTB consultations had inconsistent effects on variant interpretation, access to FrOG database was associated with higher pathogenicity scores in the ovarian programme. Additionally, higher laboratory activity correlated with improved interpretation accuracy, and increased interpretation complexity was linked to lower pathogenicity scores. These findings highlight structural factors affecting interpretation, but further investigation is needed at the individual level to inform policy and training strategies.

The epididymis frequently exhibits a broad spectrum of non-neoplastic epithelial and stromal alterations that may mimic neoplastic or obstructive processes in orchiectomy specimens. Existing data are mostly derived from single-institution series. This multi-institutional study aimed to provide a comprehensive, contemporary, multi-institutional analysis of the prevalence, spectrum, and clinicopathological associations of epididymal morphological variations in a large orchiectomy cohort. This retrospective study included 1,528 orchiectomy specimens from multiple academic centers. All hematoxylin and eosin-stained slides containing epididymal tissue were systematically reviewed using a standardized protocol. Morphological features assessed included atrophy, intranuclear inclusions, lipofuscin pigment, cribriform hyperplasia, Paneth cell-like metaplasia, nuclear atypia, clear cell change, smooth-muscle proliferation, vascular and duct ectasia, myxoid change, calcification, hematoma, and inflammation. Associations with underlying testicular pathologies were analyzed statistically. 66% (1004/1528) were performed for testicular neoplasms, which were predominantly germ cell tumors derived from germ cell neoplasia in situ (87.5%, 878/1004). The most common epididymal alterations were lipofuscin pigment (49.9%, 762/1528), intranuclear inclusions (40.3%, 616/1528), atrophy (35.4%, 541/1528), and duct ectasia (35.3%, 539/1528). Non-tumoral cases more frequently exhibited atrophy (58.4%, 306/524 vs. 23.4%, 235/1004), duct ectasia (45.2%, 237/524 vs. 30.1%, 302/1004), inflammation (21.9%, 115/524 vs. 2.7%, 27/1004), and hematoma (5.9%, 31/524 vs. 0.2%, 2/1004) (p < 0.0001 for all). Tumoral cases showed higher rates of cribriform hyperplasia (28.5%, 286/1004 vs. 16.4%, 86/524), Paneth cell-like metaplasia (12.4%, 124/1004 vs. 1.9%, 10/524), nuclear atypia (21.9%, 220/1004 vs. 17.2%, 90/524), and clear cell change (21.7%, 218/1004 vs. 14.3%, 75/524) (all p ≤ 0.03). Several features, including atrophy, lipofuscin pigment, cribriform hyperplasia, clear cell change, and calcification, showed significant variation across tumor subtypes. Non-neoplastic epithelial and stromal alterations of the epididymis are common and histologically diverse, often co-occurring and varying by underlying testicular pathology. Awareness of these patterns is essential to avoid misinterpretation, especially in oncologic settings. This study provides the largest contemporary dataset to date, offering a robust histopathological framework for epididymal assessment in routine surgical pathology practice.