Virchows Archiv最新文献

This study aimed to characterize the tumor microenvironment (TME) in patient-derived xenograft (PDX) models of oral squamous cell carcinoma (OSCC) and compare histological findings with primary tumors of origin (PTT). OSCC samples from five donor patients were implanted into NOD/SCID mice (PDX0) and subsequently re-implanted into new animals (PDX1), yielding three groups for analysis: PTT, PDX0, and PDX1 (n = 5 each). Histological slides with sections were stained with hematoxylin and eosin for grade analysis and subjected to immunohistochemical reactions with antibodies against SMA, CD4, CD8, CD31, CD34, Claudin-1, Vimentin, and Ki-67. Multiple comparisons were performed between samples (PTT, PDX0, and PDX1). The histological grade of PDX0 and PDX1 tumors showed instability across passages. The expression of SMA, claudin-1, vimentin, and Ki-67 was maintained, with no significant differences between PDX0 and PDX1 when compared with PTT. In contrast, the expression of CD4, CD8, CD31, and CD34 was significantly reduced in PDX0 and PDX1 tumors compared with PTT. OSCC PDX tumors may exhibit instability in the degree of differentiation compared with the donor tumors across passages, as well as alterations in certain components of the TME, including cancer-associated fibroblasts, epithelial-mesenchymal transition-related features, and cellular proliferation characteristics.

Diagnostic challenges remain in desmoid fibromatosis (DF) due to somewhat frequent β-catenin immunohistochemical negativity, risking misclassification and overtreatment. The present study evaluates the role of CTNNB1 molecular testing in optimizing diagnosis. A single-center, large retrospective analysis of 780 patients with DF was performed. The incidence of DF was higher in females, particularly within the adult demographic. 77.3% of DF cases exhibited nuclear β-catenin positivity.The majority of cases that were β-catenin nuclear negative underwent CTNNB1 exon 3 Sanger sequencing.Molecular analysis revealed that 74.1% of β-catenin negative cases harbored CTNNB1 mutations, primarily at codon 41 (p.T41A). Patients with wild-type CTNNB1 were significantly older. Notably, β-catenin IHC showed higher positivity in resected specimens (79.7%) compared to biopsies (62.0%), whereas CTNNB1 mutational detection was higher in biopsies (93.5%) than resections (76.8%). Codon 41 mutations correlated with higher β-catenin IHC positivity than codon 45 mutations. A subsequent analysis of age demonstrated that DF in the abdominal wall, retroperitoneal cavity, and trunk was more likely to occur in the adult group. Four novel mutations (p.S45_G48del, p.T41V, p.S23N, and p.G34E) were identified. CTNNB1 mutational testing is indispensable for the diagnosis of β-catenin-negative DF, especially in older patients, where IHC limitations are pronounced. Identifying CTNNB1 gene mutations provides an accurate diagnosis in challenging cases without immunohistochemical support, facilitating the development of more effective treatment strategies.

The co-expression of myeloid and B-cell antigens is characteristic of mixed-phenotype acute leukemia (MPAL)-B/myeloid. This finding can also be observed in AML with t(8;21)(q22;q22)/RUNX1::RUNX1T1, as well as in cases of AML with other RUNX1 rearrangements, copy number gains, or mutations. AML with plasmacytoid dendritic cell (pDC) differentiation (pDC-AML) containing clonally-related myeloblasts and neoplastic pDCs, are enriched for RUNX1 mutations and have been shown to exhibit B-cell marker expression. Here, we present two cases of pDC-AML with B-cell marker expression in which RUNX1 aberrations were not identified. Although previously we speculated on the role of RUNX1 in the aberrant expression of B-cell markers such in cases, the absence of RUNX1 lesions in the current cases supports the potential inherent ability of pDCs to express B-cell markers during maturation.

We assessed whether an endothelium-specific enhancer is co-amplified with MYC in postirradiation/lymphedema-associated angiosarcoma (PLAS). First, the signal pattern and diagnostic utility of MYC break-apart fluorescence in situ hybridization (FISH) were examined to distinguish PLAS from carcinoma. Next, public data were analyzed to determine the association between the MYC-co-amplified region and cell type-specific active enhancers. Six cases of PLAS were retrieved, including three with a history of breast cancer. Additionally, we retrieved 23 MYC-amplified carcinoma cases, of which seven were breast cancers. MYC break-apart FISH was performed in all cases. The MYC-co-amplified regions in angiosarcoma and other carcinomas were explored using cBioportal. Endothelium-specific active enhancers were searched using H3K4me1 and H3K27ac chromatin immunoprecipitation-sequencing data on ENCODE. MYC break-apart FISH analysis revealed selective 5' amplification in all six PLAS cases, whereas 16 of 23 carcinomas, as well as six of seven MYC-amplified breast cancers, exhibited dual-signal amplification. cBioportal data analysis revealed 5' skewing of the MYC-co-amplified region in angiosarcoma, which was not readily apparent in other carcinomas. ENCODE chromatin immunoprecipitation-sequencing data analysis revealed endothelium-specific active enhancers upstream of MYC; the cell/tissue-type-specific 3' enhancer was not conspicuous. In conclusion, MYC break-apart FISH is a useful adjunctive tool for distinguishing PLAS from carcinoma. The 5' skewing of the MYC-co-amplified region, possibly associated with an endothelium-specific active enhancer, was confirmed. Subsequent studies involving larger case series, higher-resolution genomic experiments, and single-cell epigenetic experiments are required.

Male breast cancer (MBC) is a rare disease accounting for less than 1% of all breast cancers. MBC is almost always of the estrogen receptor (ER) positive luminal subtype. Although differences have been described between male and female breast cancers, therapies for MBC are still largely extrapolated from female breast cancer (FBC). Treatment planning requires accurate prediction models. Several FBC prediction models have also been validated for MBC. Here, we validate the IHC4 + C algorithm in MBC, known to perform well for ER positive FBC. IHC4 + C combines immunohistochemical scores of ER, progesterone receptor, HER2, and Ki67, supplemented by four clinicopathologic features (age, grade, T- and Nstatus). IHC4 + C was validated in a retrospective MBC cohort of 143 patients. The algorithm performed best in MBC for the endpoint of 5-year overall survival, with C-indices between 0.72 and 0.75. Also for MBC, contributing the clinical score to IHC4 improved predictive power. A clear distinction between groups of MBC patients with good, moderate, and poor prognosis was demonstrated using Kaplan-Meier analyses and was highly statistically significant according to the Log-rank test (p = 0.001). The IHC4 + C algorithm that was originally developed for FBC patients performed well in an MBC cohort. It accurately separated patients with good, intermediate, and poor performance at high statistical significance. Development of a MBC-specific prediction tool remains desirable.

This publication presents in two parts a comprehensive comparison of the manyfold salivary gland and cutaneous adnexal tumors, investigating both striking similarities and discrepancies with respect to clinical aspects, terminology, (immune)-histology, and molecular pathology. Part I has presented basic embryology/histology and overlapping topographical aspects, followed by a first series of related tumor entities. In this second part, a further series of histologically analogous/similar tumor entities are compared, comprising secretory and microsecretory carcinoma, sialadenoma and syringocystadenoma papilliferum, adenoidcystic carcinoma, mucinous and mucoepidermoid tumors, lymphoepithelial tumors, sebaceous tumors, and further rare related tumor groups. Finally, in a synoptic comparison, general features are summarized: While tumors with follicular differentiation are lacking in salivary glands, tumors with acinar and oncocytic differentiation are lacking in the skin. In general, salivary tumors have a higher proportion of malignancy, are on average larger, are frequently more difficult to resect due to a more complex topography, and, hence, show a higher propensity for recurrence and metastases, on average with a poorer prognosis. Multifocality with or without link to hereditary tumor syndromes is not infrequent in cutaneous lesions, but is very rare in salivary tumors.

Prior studies of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) have mainly emphasized B-cell-intrinsic oncogenic mechanisms and the supportive role of T-cells. However, whether neoplastic B-cells' microenvironment can reciprocally drive T-cell clonality or even promote T-cell neoplastic evolution remains poorly understood. Prompted by an index case where MALT lymphoma evolved into composite lymphoma with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), we systematically investigated T-cell receptor (TCR) gene rearrangements in 147 consecutive MALT lymphoma cases diagnosed between 2020 and 2023. TCR clonality was assessed using EuroClonality PCR assays and validated by next-generation sequencing (NGS). Clinicopathologic correlations and histologic spatial patterns of T- and B-cell distribution were evaluated. Monoclonal TCR rearrangement was detected in 16.3% (24/147) of MALT lymphomas. Among them, TCRG rearrangements were significantly enriched in pulmonary cases (25.0%) but were absent in gastric cases (P = 0.0002). Histologically, two distinct patterns of B-T cell distribution were identified. Pattern_1 showed extensive intermingling of B- and T-cells, whereas Pattern_2 displayed relatively segregated growth with limited spatial overlap between the two lineages. Monoclonal TCR rearrangements represent a nonrandom event in a subset of MALT lymphomas, suggesting an underappreciated active role for T-cells in tumor evolution. The preferential enrichment of TCRG rearrangements in pulmonary cases compared with gastric cases highlights site-specific immune milieus shaping T-cell clonality. Together with distinct B-T spatial interaction patterns, these findings support dynamic B-T cell crosstalk and potential multilineage evolution within the MALT lymphoma microenvironment.

"Spin" - the overinterpretation of research findings - has been assessed in experimental and synthesis designs of interventional evidence. Little attention has been given to the assessment of spin in diagnostic evidence bases. Therefore, we conducted a cross-sectional study to assess for spin found within diagnostic accuracy meta-analyses published in top pathology journals. We searched PubMed for diagnostic test accuracy meta-analyses published in top 20 pathology journals from past to present. We applied published methodology to identify the presence of 10 items of actual overinterpretation and 9 items of potential overinterpretation. Authors screened and extracted relevant data from sample studies in a masked duplicate fashion to reduce extraction errors. On September 21st, 2023, we identified 207 articles from PubMed for potential inclusions. After screening, 55 abstracts and full-texts were available for full data extraction. with 80% (44/55) having positive conclusions germane to accuracy or clinical implications. Every meta-analysis contained one item of spin. Most positive conclusions in abstracts (75%; 33/44) and full-texts (79.6%; 35/44) did not adequately reflect pooled estimates while 19 (34.5%) studies employed non-recommended statistical approaches for pooling accuracy measures. Diagnostic test accuracy meta-analyses found within top pathology journals consistently overstate their conclusions. Authors should contextualize diagnostic summary effects within predetermined diagnostic performance. Further, authors should ensure that summary estimates are pooled using bivariate or hierarchical approaches that maintain threshold effects throughout meta-analytic calculations. Readers should cautiously interpret meta-analyses that fail to report sample sizes and confidence intervals of summary estimates.

While oral submucous fibrosis (OSMF) in Asia associated to betel nut usage has been extensively characterized both clinically and histologically, the effects of snus (a traditional Scandinavian oral tobacco product) use in Europe are far less well understood. With the growing popularity of snus across Europe, its impact on oral mucosal pathology has become an issue of increasing clinical relevance. In this study, 50 patients were examined, presenting with clinically detectable oral mucosal alterations, associated with habitual snus use. Clinically, the lesions typically appeared as leukoplakic, firm mucosal changes with surface corrugation. In the most severe cases, biopsies were obtained and histopathologically and immunohistochemically analyzed. This evaluation revealed lymphocytic infiltration, epithelial hyperplasia with keratinization, and varying degree of submucosal fibrosis. These findings demonstrate that snus use can induce significant pathohistological manifestations in the oral mucosa, closely analogous to those of the established potentially malignant disorder OSMF. Additional periodontal and dental effects, including gingival recession, erosions, and tooth discoloration, were also recorded. This study provides novel insights into the potential link between snus use and OSMF-like pathology and underscores the importance of vigilant clinical monitoring of affected individuals.

Microsecretory adenocarcinoma (MSAd) is a recently described, low-grade salivary gland malignancy primarily involving intraoral sites, characterized by consistent morphological and immunohistochemical features, as well as the MEF2C::SS18 fusion. This study reported five new MSAd cases and reviewed previously reported MSAd cases affecting the maxillofacial region. Most of the patients in this case series study were male, with the palate being the most affected intraoral location. All cases showed uniform histological features and immunophenotype associated with S100, SOX10, p63, AE1/AE3, and CK7 positivity, and p40, c-KIT, and calponin negativity. Focal SMA and mammaglobin expressions were observed in one case each. Perineural and vascular invasion were uncommon findings. All MSAd cases were MEF2C::SS18 fusion positive. A literature review identified 44 head and neck MSAd cases, encompassing both salivary gland and cutaneous tumors. Some previously reported MSAd cases displayed subtle variations in their histopathological and immunohistochemical characteristics, underscoring the importance of molecular fusion confirmation. Given its typically indolent behavior, MSAd patients can be managed similarly to those with other low-grade salivary gland carcinomas.