Virchows Archiv最新文献

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.

Adenosquamous carcinoma is an uncommon cervical malignancy which is composed of a morphologically recognisable malignant squamous and glandular component. In the current 5th edition WHO Classification of Female Genital Tumours, adenosquamous carcinoma of the cervix is regarded as a high-risk human papillomavirus (HPV)-associated neoplasm. However, in recent years, there have been occasional reports of cervical HPV-independent adenosquamous carcinomas. We report a series of 5 cervical HPV-independent adenosquamous carcinomas in women aged 45 to 68 years; 4 of 5 patients were postmenopausal. The percentage of the squamous component ranged from 10 to 90%. In all cases, the glandular component was gastric-type. All tumours exhibited negative/non-block-type staining with p16 and were also negative for HPV on molecular testing. Molecular testing (4 of 5 cases) revealed no recurrent variants. However, in individual cases, pathogenic or likely pathogenic variants were present in BRAF, CDK12, RB1, FGFR2, FGFR3, BRCA1, KRAS, CDKN1A, CDKN2A, TP53, and STK11. In addition, deletions of CDKN2A/CDKN2B and TP53 were present in 1 case. The tumours were advanced stage at diagnosis: stage IIB (1 case), IIIC1 (2 cases), and IVB (2 cases). Our findings suggest that cervical adenosquamous carcinoma should be classified into HPV-associated and HPV-independent types and this should be reflected in updated WHO Classifications.

Up to 10% of small cell lung carcinomas do not express any neuroendocrine markers and are characterized by an expression of the transcription factor POU2F3. Recently, few cases of poorly differentiated carcinomas harboring POU2F3 expression have been described in the breast, cervix, and bladder. Herein, we report the morphological, immunohistochemical, and molecular characterization of two primary cutaneous POU2F3-expressing small cell carcinomas. The cases arose in the temple and on the occipital region in a 92-year-old woman and a 78-year-old man respectively. Microscopic examination revealed in both cases a large and ulcerated poorly differentiated neoplasm infiltrating the full thickness of the dermis with extension into the subcutaneous tissues in case #1. The tumors harbored solid and trabecular growth patterns and were composed of poorly differentiated highly mitotic cells. Immunohistochemical investigation revealed diffuse pancytokeratin positivity while no expression of cytokeratin 20, chromogranin A, synaptophysin, CD56, or INSM1 was detected. Diffuse nuclear expression of POU2F3 was observed. Transcriptomic analysis revealed a SBS7 mutation signature related to UV-induced DNA damages in one case and evidenced an expression profile similar to the one observed in POU2F3-expressing small cell lung cancers in both. Methylation analysis confirmed the proximity of the two cases with other skin cancers. To conclude, we report herein the first description of primary cutaneous small cell carcinoma POU2F3 subtype.

Mixed yolk sac tumors (YST) with carcinoma or carcinosarcoma (Ca/CS) of the uterus and ovary represent exceptionally rare and aggressive malignancies with poorly characterized genetic drivers. Through an integrated clinicopathologic and molecular analysis of nine cases using immunohistochemistry, fluorescence in situ hybridization, and targeted next-generation sequencing, we identified recurrent somatic driver mutations in TP53 (8/9), PIK3CA (3/9), and PTEN (2/9), and absence of i(12p), confirming their somatic origin. Multi-region sequencing revealed that YST and Ca/CS components share truncal mutations yet harbor divergent genetic alterations, supporting a model of clonal origin and lineage-specific evolution. Therapeutically, we identified a high frequency of actionable alterations, including homologous recombination repair (HRR) gene mutations (4/9), HER2 amplification or low expression (7/9), and biomarkers for immunotherapy (positive PD-L1 in 3/9, TMB > 10 mutations > 10 /Mb in 2/9). Consistent with these findings, two patients derived profound clinical benefit from matched PARP inhibitors or anti-HER2 antibody-drug conjugate. Our findings definitively establish the somatic and clonal nature of these mixed tumors and provide a compelling rationale for molecularly guided treatment.

Microsatellite instability (MSI), caused by impaired mismatch repair (MMR), has gained prominence as a biomarker predicting response to immune checkpoint inhibitors in various cancers. MSI-high (MSI-H) tumours exhibit widespread instability across multiple microsatellite loci and are well-characterized. In contrast, low-level microsatellite instability (MSI-L)-marked by instability at a low number of loci-is poorly understood and its biological relevance remains controversial. MSI-L has often been grouped together with microsatellite stable (MSS) tumours, given the lack of consistent molecular distinctions. However, some studies, particularly in colorectal and gastric cancers, have reported that MSI-L correlates with distinct clinical and molecular features, including poorer prognosis, increased tumour mutational burden (TMB) following chemotherapy, and better response to platinum/5-fluorouracil-based neoadjuvant chemotherapy. Notably, these associations frequently involve instability at dinucleotide repeat markers, hinting at a specific subset of MSI-L. Moreover, recent data provide initial evidence that MSI-L may be associated with subtle alterations of genes involved in DNA damage tolerance pathways. This review aims to clarify the current understanding of MSI-L by (a) comparing diagnostic methods and their influence on MSI-L classification, (b) summarizing clinical and molecular associations of MSI-L specifically in gastric and colorectal cancer, (c) highlighting new aspects regarding potential mechanisms underlying MSI-L, focusing on the particular unstable marker and a possible role of the DNA damage tolerance pathways, and (d) discussing whether MSI-L, particularly defined by dinucleotide repeat instability, may serve as a marker for therapeutic vulnerability.

Choriocarcinoma (CHC) is an aggressive tumor that expresses Nectin-4, which makes it a potential target for enfortumab vedotin (EV). However, only a few cases have been analyzed so far, and the correlation between Nectin-4 and clinical-pathological features has never been investigated. Twenty-one testicular CHCs were collected and stained for Nectin-4. Cytoplasmatic expression was positive in 17/20 primary CHCs (4/20: moderate expression). Membrane expression was positive in 16/20 primary CHCs (5/20: moderate expression). Cytoplasmatic expression was associated with higher % of CHC (p = 0.028) and β-HCG serum levels (p = 0.007); moderate/strong cytoplasmatic expression was associated with younger age (p = 0.0039). The only post-chemotherapy and metastatic CHC showed the highest membrane expression (H-score: 155), especially if paired with its primary (H-score: 33). The Nectin-4 stain was primarily confined to syncytiotrophoblasts rather than to cytotrophoblasts/intermediate trophoblasts. These findings confirm that testicular CHC expresses Nectin-4 and may be potentially targetable with EV. Future studies are needed to verify whether metastasis and chemotherapy up-regulate Nectin-4 and increase the sensitivity to EV, and whether the absence of Nectin-4 expression by cytotrophoblasts (the proliferative population of CHC) influences its potential efficacy.