Virchows Archiv最新文献

VGLL3 (encoding the mammalian Vestigial-like 3 transcriptional cofactor) has emerged as a fusion partner in hybrid nerve sheath tumors and in rare spindle cell rhabdomyosarcomas (RMS) of the head and neck. We herein describe a new EP300::VGLL3 RMS and review/update reported cases (total: 6) to reappraise their outcome. All six reported EP300::VGLL3 fusion RMS cases originated exclusively in the tongue musculature of adult males at a median age of 48 years (range, 36-59). Nonradical surgery was the initial treatment in most cases, followed by variable re-excisions in most. Incomplete adjuvant chemotherapy was given to one patient. No metastases were recorded, and all patients with follow-up were disease-free at last follow-up (12, 34, 36, and 48 months). Histologically, all tumors displayed bland spindled to ovoid plump cells lacking clear-cut rhabdomyoblastic features and disposed into fascicular and storiform patterns. The tumor margins were infiltrating with entrapment of skeletal muscle fibers. Overtly malignant cytology, brisk mitotic activity, necrosis, lymphovascular, and perineural invasion were absent. Immunohistochemistry was consistently positive for desmin (6/6), and variably myogenin (6/6), myoD1 (4/4), and SMA (5/6). Fusion breakpoints were identical among all cases (EP300ex31::VGLL3ex2). Given their indolent course after local excision alone, the noncommitted term EP300::VGLL3-fused rhabdomyoblastic tumor might be more appropriate for these tumors than the original RMS terminology to avoid overprognostication/overtreatment that the "rhabdomyosarcoma" label would imply. Reporting more cases is mandatory to elucidate the full anatomic and biological spectrum of this morphologically, anatomically, and genetically unique entity.

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.

Steroid-associated osteonecrosis of the femoral head (SONFH) is closely related to ischemia after corticosteroid treatment as well as the subsequent inflammatory response and oxidative stress. This study examined the temporal and spatial expression of high mobility group box 1 (HMGB1) and peroxiredoxin 4 (PRDX4) in SONFH lesions using immunohistochemistry. Tissue samples from SONFH patients undergoing total hip arthroplasty were compared with those from osteoarthritis (OA) controls. The expression of PRDX4 was significantly reduced in SONFH and was inversely correlated with the oxidative DNA damage marker 8-Hydroxy-2'-deoxyguanosine (8-OHdG). Notably, PRDX4 is strongly expressed in osteoblasts and chondrocytes within callus tissue at the necrotic-viable bone interface, implicating its role in promoting repair through the suppression of oxidative stress. In contrast, most SONFH cases exhibit nuclear-to-cytoplasmic translocation of HMGB1, consistent with its function as a damage-associated molecular pattern (DAMP) that drives inflammatory responses. These findings indicate that HMGB1 acts as an inflammatory mediator during the early phase of SONFH, whereas PRDX4 functions as an oxidative stress regulator during the repair process. Together, these molecules appear to act in a complementary manner to orchestrate the transition from inflammation to tissue regeneration. Their expression dynamics may serve as potential factors for disease progression and reparative activity, while therapeutic strategies targeting HMGB1 signaling or augmenting the expression of PRDX4 may represent promising avenues for intervention.

Metabolic renal cell carcinomas (RCC) deficient in succinate dehydrogenase (SDH) or fumarate hydratase (FH) are rare but clinically significant entities formalized in the last WHO classification. Their recognition typically starts from morphology and is corroborated by targeted immunohistochemistry (IHC) and, where appropriate, molecular and germline testing. In routine practice, however, implementation may be uneven. Hence, we conducted a nationwide, web-based survey (made by 25 items) among members of the Italian Study Group of Uropathology (GIUP) to map real-world awareness, diagnostic pathways, and test availability across Italian centers. Twenty-one pathologists responded; 18/21 (85.7%) reported dedicated uropathology practice with heterogeneous seniority (≤ 5 years, 28.6%; 5-10 years, 19.0%; 10-20 years, 14.3%; > 20 years, 38.1%). Despite substantial renal-tumor workloads (12/20, 57.1% handled > 100 cases in the previous 5 years), direct exposure to metabolic RCCs remained limited (FH-deficient ≥ 1 case, 11/21, 52.4%; SDH-deficient ≥ 1 case, 9/21, 42.9%). Suspicion was predominantly morphology-led: for SDH-deficient RCC, morphology ranked first in 16/21 (76.2%) with the commonest sequence morphology > age > number of lesions (76.2%); for FH-deficient RCC, morphology was top-ranked in 19/21 (90.5%). Key morphologic cues were mixed architectural patterns/papillary elements/macronucleoli for FH-deficient RCC, and eosinophilic cytoplasm with solid-alveolar architecture for SDH-deficient RCC. IHC mirrored these priorities (FH top for FH-deficient, 85.7%; SDHB top for SDH-deficient, 76.2%), whereas 2-succinocysteine (2SC) was rarely available (1/21, 4.8%). Critically, this FH-loss-only workflow can miss non-truncating FH variants (FH immunoreactive but enzymatically inactive) tumors, contributing to under-recognition. Molecular testing would be requested in all suspected cases by 12/21 (57.1%); among selective users, equivocal IHC was the leading trigger (6/8, 75%). Overall, metabolic RCC recognition in Italy is primarily morphology-driven but constrained by uneven access to confirmatory IHC, particularly 2SC, and to molecular assays. The findings argue for harmonized diagnostic algorithms, regional reference laboratory networks, and routine involvement of molecular tumor boards, supported by targeted educational initiatives (including curated digital slide repositories), to standardize practice and improve patient pathways from morphologic suspicion to genetic counselling and tailored surveillance.

HER2-low and -ultralow breast cancer have recently emerged as distinct theranostic subcategories within the HER2 spectrum, prompting reassessment of traditional HER2-negative immunohistochemistry scores (0, 1+ , and 2+ without amplification). This study reclassifies, according to this new categorization, a cohort of 367 patients who have never received chemotherapy and have non-metastatic triple-negative breast cancer (TNBC). We evaluated its association with their clinicopathological features and prognosis. HER2 0 tumors were reclassified as HER2-null (no staining) or HER2-ultralow (≤10% faint, incomplete membrane staining). HER2 1+ or 2+ (non-amplified) tumors were defined as HER2-low. Overall, 38.4%, 37.6% and 24.0% of TNBC samples were reclassified as HER2-null, -ultralow and -low, respectively. HER2-ultralow tumors were more frequently associated with the presence of tertiary lymphoid structures (p = 0.0259) and BRCA1 promoter methylation (p = 0.0439) than HER2-low tumors. Moreover, compared with HER2-null samples, HER2-ultralow tumors were of smaller size (p = 0.0167) and lower stage and grade (p = 0.0066 and p = 0.0364, respectively). Conversely, age, lymph node involvement, histology, molecular apocrine or basal-like phenotypes, PIK3CA and PTEN status, immune infiltrates, assessed using T-cell (CD3), B-cell (CD20) and macrophage (CD163) markers, and PD-L1 expression in tumor or stromal cells were not associated with the HER2-ultralow status. The survival analysis (median follow-up = 10.3 years) showed that relapse-free survival was not influenced by the HER2 status. Despite some significantly different clinicopathological features, there is no solid evidence to support HER2-ultralow, HER2-low and HER2-null cancers as individual TNBC clinical-molecular entities. Particularly, assigning TNBC samples to the HER2-null, -ultralow and -low categories did not bring any additional prognostic value.

The reliable diagnosis of one of the many types of B-cell lymphoma (BCL) currently requires an integrated approach comprising morphological expertise, immunophenotyping, and inclusion of clinical data, but may also incorporate flow cytometry, cytogenetics, and clonality analysis. In recent years, several studies have elucidated the mutational landscape of BCL, which may also serve as a complementary diagnostic tool. We have developed a custom next-generation sequencing panel for application in the routine diagnosis of BCL based on available literature and our diagnostic questions. We applied this panel to 160 cases of BCL or with this differential diagnosis (DD) in our routine workflow to gain further diagnostic support or on clinical request. Evaluable results were obtained in all but two cases of the entire cohort. Diagnostically informative molecular genetic profiles were identified in 72% of the evaluable cases. Focusing on 21 challenging cases with the DD of Burkitt lymphoma (BL) and the germinal center B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL), we detected at least one mutation in all cases, and in 18/21 (86%) cases, panel sequencing provided significant decision guidance. In conclusion, although morphology and immunohistochemistry remain the backbone of diagnosis, panel sequencing provided substantial diagnostic assistance in many cases. It has been particularly useful in providing additional arguments to clarify the clinically important DD between BL and DLBCL in challenging cases.

Proliferative verrucous leukoplakia (PVL) is a rare yet aggressive oral potentially malignant disease (OPMD) with the greatest rate of malignant transformation. Its pathophysiology is poorly understood despite much histopathological and molecular research. Particularly, Telomerase reverse transcriptase (TERT) promoter mutations at C228T and C250T have been linked to many epithelial malignancies; however, their significance in PVL is yet unknown in the Indian population. The aim of this study was to assess frequency of TERT promoter mutations (C228T, C250T) and rs2853669 single nucleotide polymorphism (SNP) in PVL, oral leukoplakia (OL), oral squamous cell carcinoma (OSCC) and healthy controls. 120 fresh frozen tissue specimens (30 each of OL, PVL, OSCC and controls) were tested for presence of C228T and C250T mutation in TERT promoter gene region and SNP at rs2853669, using Sanger sequencing on genomic DNA. TERT C228T mutation was found in 6.7%, 0% and 20% cases in PVL, OL and OSCC group (p = 0.03) respectively. TERT C250T mutation was present only in OSCC group (6.7% cases). None of the two mutations were present in controls. Both the mutations were mutually exclusive of each other. A significant association was found between rs2853669 SNP and epithelial dysplasia in OL, specifically with CC genotype (p = 0.04). Molecular signature of PVL shows limited evidence of TERT promoter mutations. The findings of this study suggest that the genetic underpinnings of PVL are distinct from those commonly observed in other forms of cancerous lesions.

We report a case of GALT-associated carcinoma, a rare morphological variant of colorectal adenocarcinoma characterised by cystic glands containing eosinophilic material, set within dense lymphoid stroma with germinal centres. Since its first description in 1999, only 26 cases have been documented. Its association with lymphoid tissue, the presence of intraepithelial lymphocytes, and the absence of goblet cells led to the hypothesis that it may originate from M-cells located in the dome epithelium of gut-associated lymphoid tissue, hence the alternative term "dome-type carcinoma". Through detailed histological, immunohistochemical, ultrastructural and molecular analyses of our case, supported by a comprehensive literature review, we found no evidence supporting M-cell differentiation: intraepithelial B lymphocytes were absent, GP2 immunostaining was negative and ultrastructural features were inconsistent with M-cell morphology. Nevertheless, the lesion's pushing growth pattern, lack of high-risk histopathological features and indolent behaviour justify its recognition as a distinct morphological subtype of colorectal cancer.

Reactive and clonal proliferations of histiocytes (macrophages/dendritic cells) represent a broad spectrum of disorders, which can affect virtually any organ of the body. The clinical spectrum ranges from benign, localized and self-limiting manifestations to severe multi-system disease. Hemophagocytic lymphohistiocytosis (HLH) is a frequently life-threatening, systemic hyperinflammatory process triggered by massive cytokine release by activated, reactive macrophages. Familial and secondary forms of HLH are discerned. Histiocytoses are clonal inflammatory myeloid disorders characterized by proliferations of mature histiocytes/macrophages and dendritic cells with recurrent kinase-activating mutations which result in constitutive activation of the ERK signaling pathway. Although traditionally subclassified according to the phenotype of the lesional cells, the clonal cells can show significant plasticity, and the occurrence of mixed histiocytoses is increasingly recognized. This is in part due to their derivation from a myeloid progenitor cell and explains the frequent association with clonal hematopoiesis or overt myeloid neoplasms in adults. At the joint Workshop of the Chinese Society of Hematopathology, the European Association for Haematopathology and the Society for Hematopathology on histiocytic/dendritic cell proliferations, neoplasms, and their mimics in Hefei, China, April 2024, in sessions 1 and 2 a total of 8 cases of HLH, 9 cases of reactive histiocytic proliferations and 40 cases of histiocytoses were submitted and reviewed by the panel. The latter included cases of LCH, indeterminate cell histiocytosis, Erdheim Chester disease, juvenile xanthogranuloma, Rosai Dorfman disease, multicentric reticulohistiocytosis, ALK-positive histiocytosis, and mixed histiocytoses. The present report summarizes important findings and open questions arising from discussing the workshop cases.

Adenoid cystic carcinoma (ACC) is the second most common malignancy of salivary glands with a poor long-term prognosis. The presence of mutually exclusive t(6;9)/MYB::NFIB and t(8;9)/MYBL1::NFIB chromosomal translocations has been used as diagnostic markers for ACC. In this study, we report a non-MYB/MYBL1 fusion gene NFIB::PHACTR2 in a palate ACC of a 66-year-old male. The excised 1.7 cm partially encapsulated tumor featured focal invasion into the adjacent mucinous minor salivary glands. By light microscopy, the tumor showed cribriform and tubular patterns with obvious perineural and intraneural invasion. The findings remind us that salivary gland tumors without MYB/MYBL1 fusion genes could still be ACC if they have a rearrangement involving genes adjacent to MYB/MYBL1 genes.