Virchows Archiv最新文献

POU2F3 defines tuft cell-like carcinomas, yet POU2F3-driven neuroendocrine neoplasia in the urinary bladder remains incompletely characterized and can morphologically mimic basaloid carcinomas. We report a case of an octogenarian woman with a diverticular bladder tumor composed of conventional high-grade urothelial carcinoma juxtaposed with a sharply demarcated basaloid component. Although the basaloid component lacked classical small-cell morphology and showed scant conventional neuroendocrine marker expression, it was diffusely POU2F3-positive, underscoring a potential diagnostic pitfall with human papillomavirus (HPV)-associated basaloid squamous cell carcinoma. Both components showed concordant aberrant tumor-suppressor immunoprofiles (p53 overexpression and Rb loss), and high-risk HPV RNA in situ hybridization (RNAscope) was negative. This case expands the recognized morphologic spectrum of bladder neuroendocrine carcinoma to include POU2F3-defined non-small cell neuroendocrine carcinoma with basaloid architecture, supporting the practical value of incorporating POU2F3 into immunohistochemical panels for poorly differentiated basaloid bladder tumors.

Germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) cause early-onset autoimmunity, lymphoproliferation, and immune dysregulation. Enteropathy is frequent, but longitudinal histopathological data remain limited. We report the clinical course and histological evolution of autoimmune enteropathy in an infant with a previously described STAT3 GOF mutation (c.2144C > T, p.Pro715Leu). Over 29 months, four endoscopies with duodenal biopsies conducted during different treatments revealed progressive villous atrophy and persistent inflammation despite clinical remission under Janus kinase (JAK) inhibitor therapy. Immunohistochemical staining showed consistent STAT3 expression, whereas phosphorylated STAT3 (pSTAT3) markedly decreased in epithelial and lamina propria lymphocytes under JAK inhibition. Additionally, initially altered goblet cell morphology normalized. This case demonstrates that JAK inhibitor therapy can induce clinical remission and reduce tissue pSTAT3 despite ongoing histological inflammation, supporting its role as targeted treatment in STAT3 GOF syndrome. The potential relevance of goblet cell restoration in STAT3 GOF-associated enteropathy is highlighted.

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.

Mucoepidermoid carcinoma (MEC) of the thyroid gland (TMEC) is exceptionally rare, with poorly understood histogenesis and molecular characteristics. This report describes a unique case of incidentally detected TMEC, accompanied by a comprehensive molecular characterization. A 60-year-old woman, during follow-up for diffuse large B-cell lymphoma, was detected to have a metabolically active lesion involving the thyroid gland. Resection revealed an infiltrative tumor composed of squamoid cells with focal gland formation and intracytoplasmic lumina. An adjoining focus of the infiltrative follicular subtype of papillary thyroid carcinoma (PTC) was also noted. Immunopositivity for CK19, p63, PAX8, and thyroglobulin and negativity for CD10 confirmed the diagnosis of mucoepidermoid carcinoma associated with PTC. MAML2 fusion was absent. Next-generation sequencing (NGS) revealed pathogenic/likely pathogenic variants involving genes previously documented in PTC. Post-recovery, the patient developed a third malignancy, squamous cell carcinoma involving the esophagus. The case has an unusual presentation, occurring in conjunction with two other metachronous malignancies. Co-existent PTC, immunopositivity for thyroid-differentiation markers, and the genetic profile confirm a squamoglandular metaplasia of follicular cells as the origin. The absence of MAML2 fusion questions its WHO categorization as a "salivary gland-type carcinoma." Detailed molecular profiling, while contributing to a better understanding of the pathogenesis of this enigmatic neoplasm, also helped decipher potentially actionable genetic variants.

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.