Virchows Archiv最新文献

This study aims to describe the pathologic features and biomarker profiles of a large microinvasive breast carcinoma (MiBC) cohort diagnosed on biopsy (CNB) and compare these findings with corresponding tumors on excision. Out of 263 MiBC, approximately half of the DCIS cases were classified as high-grade. On CNB, ER, PR, and HER2 were positive in 166/226 (73%), 124/225 (55%), and 48/174 (28%) of the tested cases, respectively. Excision specimens from 132 cases revealed invasive carcinoma in 52/132 (39%), MiBC in 31/132 (23%), DCIS only in 35/132 (27%), LCIS only in 4/132 (3%), and benign findings in 10/132 (8%). The concordance rates between CNB and excision were initially 100% for ER (40/40), 95% for PR (38/40), and 90% for HER2 (26/29). While routine retesting of ER/PR may not be necessary in cases of MiBC on CNB, selective repeat HER2 testing should be considered when larger tumors are present on excision.

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.

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.

We describe the case of a 41-year-old woman undergoing hysteroscopic resection of a submucosal uterine mass, histologically consistent with a cellular leiomyoma. Immunohistochemistry showed diffuse cyclin D1 expression, an unexpected finding in leiomyomas and typically seen in high-grade endometrial stromal sarcomas. Targeted RNA sequencing revealed a novel HMGA2::PLCZ1 fusion transcript, not previously described in leiomyomas or other tumors. Given the known role of HMGA2 in regulating cyclin D1 transcription, this mechanism may plausibly account for the aberrant immunoprofile, although cyclin D1 expression has not been systematically evaluated in cellular leiomyomas. This case brings forward two key considerations: (i) cyclin D1 expression may, in rare cases, reflect HMGA2 rearrangements in leiomyomas; (ii) cyclin D1 positivity alone should not prompt misdiagnosis of high-grade endometrial stromal sarcoma, particularly in fragmented hysteroscopic specimens. To our knowledge, this is the first report of an HMGA2::PLCZ1 rearrangement, expanding the molecular spectrum of uterine smooth muscle tumors. This case also emphasizes the biological link between HMGA2 activation and cyclin D1 overexpression, providing new insights into the molecular mechanisms underlying uterine smooth muscle tumorigenesis.

Venous invasion (VI) is a well-established prognostic factor in distal extrahepatic bile duct carcinomas (DBDCs), yet its histologic features have not yet been systematically evaluated. We retrospectively analyzed hematoxylin and eosin-stained slides from 325 surgically resected DBDCs to assess VI and to classify the patterns of VI as destructive, biliary intraepithelial neoplasia (BilIN)-like, or conventional. VI was identified in 101 (31.1%) DBDCs and was associated with larger tumor size (P = 0.014), higher T and N categories (all, Ps < 0.001), poorer differentiation (P = 0.015), sclerosing macroscopic type (P = 0.001), and perineural (P = 0.002) and lymphovascular (P < 0.001) invasions. Among DBDCs with VI, the BilIN-like pattern of VI was most common (61, 60.4%), followed by the destructive (46, 45.5%), and conventional (39, 38.6%) patterns. Of the DBDCs with VI, 36 (35.6%) showed multiple VI patterns. The destructive pattern was associated with higher T category (P = 0.001) and duodenal invasion (P = 0.010). The patients with DBDCs with destructive VI pattern had shorter recurrence-free survival (RFS) (P < 0.001) than those with non-destructive VI pattern. The destructive pattern remained as a poor prognostic factor of RFS (P = 0.007) in multivariable analysis. VI in DBDC displays distinct histologic patterns, and specifically the destructive VI pattern associated with aggressive clinicopathologic features and poorer outcomes. Recognition of VI patterns may enhance prognostic assessment and guide postoperative management in patients with resected DBDC.

Antibody-mediated rejection (AMR) presents a rare but complex challenge following liver transplantation, characterized by histopathologic features lacking specificity. The 2016 Banff Working Group criteria aimed to standardize AMR diagnosis, focusing on histologic findings and C4d staining interpretation. Our retrospective analysis of 463 liver transplant recipients between 2017-2023 identified 13 donor specific antibody (DSA)-positive cases (2.8%) with matched liver biopsy available: 3 (23.1%) were classified as definite AMR, 7 (53.8%) as suspicious, and 3 (23.1%) as indeterminate. The incidence of AMR was found to be only 0.6%. 7 of these 13 cases were clinically treated as mixed AMR and T cell mediated rejection (TCMR), and 4 cases were treated as TCMR. Four cases treated as AMR/TCMR responded well, and no subsequent rejection episodes occurred during the follow-up period (20.3-96.5 months). Three patients failed to respond and expired after biopsy (6 days to 2.5 months), an outcome attributable to other complications in addition to liver dysfunction. Of note, among the cases classified as "definite" according to the Banff criteria, two cases had an h-score of 1. This discordance between h-score and C4d staining suggests diagnostic challenges in current practice, highlighting the necessity for C4d immunostaining in all allograft biopsies with microvasculitis to prevent misdiagnosis. Although integrated evaluation of DSA positivity, histologic pattern of injury, and C4d staining was generally reliable for distinguishing definite/suspicious categories from the indeterminate group, this study argues for further refinement of diagnostic criteria to enhance the accuracy of AMR detection and improve patient outcomes in liver transplantation.

Chromophobe thyroid carcinoma (CTC) is a rare thyroid carcinoma with distinct morphology, often occurring in patients with tuberous sclerosis complex (TSC). The molecular drivers remain poorly understood. We report two additional CTC cases and review the literature including genetic query. Patient 1, an 11-year-old boy, had a 10.3-cm bilateral thyroid mass with tumoral capsular and vascular invasion. Microscopically, the tumor showed trabecular and nested growth, prominent cell membranes, raisinoid nuclei, eosinophilic granular cytoplasm, and perinuclear halos resembling chromophobe renal cell carcinoma. The tumor expressed thyroid markers (TTF-1, PAX-8, thyroglobulin) and renal cell markers (colloidal iron, parvalbumin, CD117) with peripheral mitochondrial accentuation by anti-mitochondrial staining. A somatic TSC2 p.Y1650Cfs*4 frameshift mutation was identified. Patient 2, a 24-year-old woman, had a 3.8-cm infiltrative, angioinvasive right lobe tumor with similar morphology and marker expression and positive lymph nodes. Molecular analysis showed somatic TSC2 c.2071dupC p.R691Pfs*12 and TSC2 c.2353C > T p.Q785* mutations. A cBioPortal query (2285 cases) found TSC1 alterations in 2% and TSC2 in 1%, mostly deletions, enriched in poorly differentiated and anaplastic thyroid carcinomas. Literature review identified seven CTC cases; 42.8% had TSC association and 42.8% showed locoregional recurrence. Median follow-up of 36 months showed all patients alive. Common morphologic and immunophenotypic features were consistent; 85.7% exhibited vascular invasion. None harbored common mutations like BRAF p.V600E and RAS. CTC is a distinct, rare thyroid carcinoma often linked to TSC or TSC mutations, characterized by unique morphology and immunophenotype.

Intra-adrenal (historically "pheochromocytoma") and extra-adrenal paragangliomas (PPGLs) represent a unique subset of non-epithelial neuroendocrine neoplasms that feature remarkable biological diversity with significant diagnostic complexity. Over the past decade, advances in molecular genetics, biomarker discovery, and integrative tumor classification have transformed our understanding of PPGL pathobiology and redefined the pathologist's role in their diagnosis and clinical management. This review outlines the current multidisciplinary approach to PPGLs, emphasizing practical diagnostic strategies, germline susceptibility testing, and evolving concepts in molecular risk stratification. Pathologists are now central to identifying heritable disease through a thorough morphology assessment and molecular immunohistochemistry, interpreting germline variants of uncertain significance, and integrating genomic and biochemical data into diagnostic reports that inform clinical management. Traditional morphology-based scoring systems such as PASS and GAPP have demonstrated limited prognostic reliability, leading to their replacement by dynamic, multidimensional models that combine histopathological, clinical, biochemical, and molecular features. The 5th edition of the WHO Classification of Endocrine and Neuroendocrine Neoplasms recognizes all PPGLs as malignant non-epithelial (paraneuronal) neuroendocrine neoplasms with variable metastatic potential, underscoring the importance of cell proliferation (Ki67, mitotic count), and accurate biomarker profiling-including SDHB, FH/2SC, CAIX, and molecular cluster-specific markers-to guide the dynamic risk assessment and genetic counseling. By taking into account common daily practice challenges, this review summarizes the evolving pathology practice in PPGLs, highlights the role of biomarkers in the diagnostic workup of these neoplasms, and provides practical pitfalls in the distinction of metastatic disease from germline susceptibility-related multifocal PPGL. It also expands on a modern framework for pathology practice rooted in dynamic risk assessment and integrative endocrine oncology principles.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms encompassing both well differentiate neuroendocrine tumors (NETs), and poorly differentiated neuroendocrine carcinomas (NECs). This classification is supported by distinct histological, clinical, and molecular profiles. NETs are typically slow-growing and hormone-producing, with organoid architecture and frequent associations with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) disease. In contrast, NECs are highly malignant, rapidly proliferating tumors characterized by mutations in adenocarcinoma-driver genes and in addition to TP53 mutations and RB1 inactivation, without hereditary links to endocrine tumor syndomes. Recent WHO classifications introduced site-specific grading systems, including NET G3 in the digestive, urogenital, gynecological and head and neck organs. There is growing evidence of progression from NET G1 to G3 with occasionally NEC-like features via acquired TP53 mutations. Advances in transcription factor profiling related to hormonal expression, molecular alterations resulted in further subtyping especially in pancreatic, pulmonary, and pituitary NETs. These tools support more precise treatment strategies. Genomic studies focusing on pancreatic NETs highlighted mutations in MEN1, DAXX, ATRX, and targets in mTOR pathway. NECs display higher tumor mutation burdens and harbor various actionable alterations. Approximately 5-10% of NETs are associated with hereditary syndromes, though recent findings suggest germline pathogenic variants, which were present in additional 5% of apparently sporadic NETs and NECs, requiring further study. An integrated histological, molecular, and clinical approach is essential to improve the classification, prognostication, and management of NENs, while recognizing the distinct biology of individual subtypes.

Gastric neuroendocrine neoplasms (gNENs) encompass all the spectrum of NENs including neuroendocrine carcinomas (gNECs), mixed neuroendocrine/non-neuroendocrine neoplasms (gMiNENs) and neuroendocrine tumors (gNETs). Differently from other digestive sites, gNETs are subclassified according to the clinicopathologic setting in which they arise, with important prognostic implications. Since gastric endoscopic biopsies represent a high-volume daily activity in both referral and community hospitals, pathologists should be increasingly aware of this disease. This will allow to correctly identify the different entities and, when present, their precursor lesions, giving useful information to clinicians for the best patient management. This review paper aims to provide morphologic, immunophenotypic, and, when necessary, molecular criteria for the correct diagnosis and subtyping of gNENs. In addition, a simplified prognostic classification schema of enterochromaffin-like (ECL)-cell NETs is proposed, based on gastrin serum levels and the status of gastric acid secretion.