Virchows Archiv最新文献

Cervical squamous cell carcinoma (SCC) is classified by the World Health Organization based on its association with human papillomavirus (HPV) into HPV-associated (HPVA) and HPV-independent (HPVI) categories. HPVI SCCs can be p53 wild-type or p53 abnormal, the latter harboring a driver alteration in TP53 and portending worse survival. Recent developments have expanded the spectrum of squamous intraepithelial lesions (SILs) in the cervix. In the HPVA category, seborrheic keratosis-like lesions are now established as having an aetiological association with HPV42, a common low-risk HPV type. Papillary immature metaplasia, a further low-risk HPVA lesion, also falls into this category. More recently, potential HPVI squamous precursor lesions have been described; these form a wide morphologic spectrum and are difficult to diagnose, with the use of p16, p53, and HPV testing mandatory. When these ancillary tests are used, the HPVI SILs, similar to their invasive counterparts, stratify into p53 abnormal and p53 wild-type categories. Different genomic alterations are seen within the two groups, supporting their neoplastic nature. In this review, we provide a historical perspective and comprehensive description of all cervical SILs, with a focus on emerging entities and premalignant lesions, and appraise the terminology used over past years and that recently proposed for new entities. Key clinical, colposcopic, and morphologic features, differential diagnosis, treatment, follow-up, and prognosis are discussed. Special attention is paid to ancillary studies that assist in resolving differential diagnoses and their interpretation in light of recent scientific publications and international guidelines. We also discuss the clinical impact of a pathologic diagnosis of HPVA versus HPVI SILs.

This retrospective study of 650 Chinese Pilocytic astrocytoma (PA) patients aimed to define age-related distinctions and prognostic factors. Demographic, imaging, histopathological, and genetic data were analyzed. Pediatric PAs more commonly arose in the posterior fossa and exhibited larger size, exuberant vasculopathy, pilomyxoid features, brisk mitotic activity, and dispersed histological patterns. In contrast, adult PAs were more frequently supratentorial and demonstrated higher rates of calcification, hemosiderin, necrosis, inflammation, and compact patterns. Molecularly, pediatric patients harbored more frequent BRAF translocations, while BRAF V600E mutations and non-BRAF alterations were more common in adults. Among 564 patients (86.8%) with a median follow-up duration of 60 months (range, 2-182 months). Tumor progression occurred in 79 patients (14.0%), and 16 patients (2.8%) died. Kaplan-Meier analysis showed that tumors located in the optic pathway/midline and spinal cord, along with certain histological features (such as lack of calcification and hemosiderin, presence of pilomyxoid changes, exuberant vasculopathy, and brisk mitoses), had significantly poorer outcomes. BRAF alterations predicted more favorable progression-free survival (PFS). Patients undergoing gross-total or near-total resection (GTR/NTR) had superior outcomes, and unexpectedly, those with partial resection had shorter PFS than those with biopsy alone. Multivariable Cox regression confirmed GTR/NTR and low mitotic activity as independent predictors of improved PFS. No significant survival differences were observed by age group. Pediatric and adult PAs differ in histopathology and BRAF alterations, suggesting different prognosis. GTR/NTR and low mitotic activity independently predict improved PFS, highlighting the need for integrated diagnostic approaches.

Most thyroid lesions are of epithelial origin characterized by a papillary and/or follicular pattern. However, lesions involving plasma cells or plasmacytoid cytomorphology that mimic plasma cells can rarely be encountered in the thyroid gland. Thyroid lesions involving true plasma cells include benign entities such as chronic lymphocytic thyroiditis and neoplasms including plasmacytoma. Thyroid lesions that present with plasmacytoid features include medullary thyroid carcinoma. Rendering the correct diagnosis may be difficult due to the rarity of these lesions, overlapping cytomorphologic features, and challenges selecting the appropriate ancillary studies. This review discusses those thyroid entities showing plasmacytoid cell features and emphasizes their relevance to the recent Bethesda system for reporting thyroid cytopathology and WHO classification of endocrine tumors.

CIC-rearranged sarcomas represent a distinct rare pathological entity within the spectrum of undifferentiated small round cell sarcomas. This single institution retrospective study investigates the histopathological, molecular, and clinical characteristics of a cohort of 14 CIC-rearranged sarcomas. These tumors were diagnosed in eight male and six female patients, with the age at initial diagnosis ranging from 8 to 67 years and a mean age of 23.7 years. Among the patients, three novel locations of CIC::DUX4 sarcomas were detected in the mesentery, pancreas, and pterygopalatine fossa. Genetically, we identified 12 cases as CIC::DUX4 sarcomas and two as sarcomas with CIC gene rearrangement detected by break-apart fluorescence in situ hybridization only. The most common gene translocation had a breakpoint located in exon 20 of the CIC gene and exon 1 of the DUX4 gene; this alteration was found in 83% of all CIC::DUX4 cases we identified. We also performed DNA methylation analysis on seven cases, which was proven to be a reliable method with high sensitivity for clustering CIC-rearranged sarcomas.

Digital pathology (DP) and artificial intelligence (AI) promise faster, more accurate cancer diagnostics, yet patient views remain undocumented. We explored perspectives of patient representatives on DP and AI implementation. A two-hour moderated roundtable with six Flemish cancer-patient advocates was recorded, transcribed and analyzed using reflexive thematic analysis. Participants anticipated improved accuracy, shorter turnaround times and stronger inter-laboratory collaboration. Trust in AI was high when algorithms were trained on diverse datasets and pathologists retained final responsibility. Clinical validity outweighed full algorithmic transparency, though ongoing explainability research was encouraged. Explicit mention of AI in reports was considered unnecessary if quality assurance was demonstrable. Privacy worries focused on potential insurer misuse rather than pseudonymized cloud transfer. Representatives requested future tools that translate technical reports into lay language and suggested questions to support shared decision-making. Patient representatives were generally supportive of the introduction of AI in pathology, provided that algorithms are clinically validated, trained on representative datasets, and deployed under clear professional oversight. Their comments specifically highlight expectations regarding human-AI collaboration, data governance, auditability, and communication about AI use. These AI-focused insights can help laboratories, vendors, and regulators align development and implementation with patient priorities.

Accurate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) scoring is crucial to identify patients for HER2-directed therapy; however, validated HER2 scoring guidelines are lacking for non-breast/gastric solid tumors. We investigated concordance in IHC scores from independent pathologists using three different scoring algorithms in non-gastric/breast solid tumors. Whole-slide scans of HER2-stained tumor samples from DESTINY-PanTumor02 (NCT04482309) and a commercial pan-tumor sample set were scored by three independent, board-certified pathologists using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) scoring algorithms for gastric (reference) and breast cancers, and a clinical trial-based algorithm for endometrial cancers (evaluated for endometrial tumors only). The pathologists evaluated 488 samples from multiple solid tumor types. Mean positive percentage agreement (PPA; across pathologists) between the breast and gastric algorithms was higher for samples scored as IHC 3 + or IHC 0 compared with IHC 2 + or IHC 1 + . Inter-pathologist PPA for each algorithm was greatest in samples scored as IHC 3 + and IHC 0. The majority of inter-pathologist pairwise comparisons had Cohen's κ coefficient values > 0.4 when using the gastric or breast algorithm to determine IHC scores, indicating at least moderate agreement between pathologists; Cohen's κ coefficient values were generally lower (range 0.17-0.43) for the endometrial algorithm. ASCO/CAP scoring algorithms for gastric and breast cancer were comparable for identifying HER2 IHC 3 + tumors; lower concordance was observed for IHC 2 + /1 + tumors. These findings highlight a real-world issue of inter-pathologist variability and emphasize a need for greater awareness of best scoring practices.

Gastric mesenchymal tumors with GLI2 gene fusions are extremely rare, and only two cases, both with PTCH1::GLI2, have been reported. Here, we describe a third case involving a 47-year-old man. The tumor, measuring 4.5 cm in size, was distributed throughout the gastric wall transmurally with an infiltrative growth pattern. It had two spindle cell components, one arranged in tight bundles and the other in a loose reticular to vague fascicular pattern, and an epithelioid component lacking glandular formation. Immunohistochemically, CAM5.2 showed focal positivity in all components, SMA was positive in both spindle cell components, whereas desmin was positive only in the former. No recurrence was observed over 5 years. RNA sequencing identified a PTCH1::GLI2 fusion with GLI1, GLI2, and PTCH1 upregulation. The breakpoint was identical to those in the previously reported cases. Taken together, these findings suggest that PTCH1::GLI2 fusion may define a distinctive subtype of gastric mesenchymal tumors within the GLI1/GLI2-altered spectrum.

Lung cancer is typically classified based on morphological characteristics and immunoprofile. When histologic differentiation is difficult, immunohistochemical staining serves as a valuable diagnostic tool. Although most cases show distinct marker expression patterns, rare instances exhibit co-expression of both TTF-1 and p40. Moreover, for this particular subtype of non-small cell lung cancer (NSCLC), no clear demarcation is provided in the World Health Organization (WHO) classification system. In this study, we first conducted a comprehensive literature review to summarize previously reported cases and constructed survival curves for this rare subtype. Subsequently, we collected four additional cases of lung cancer exhibiting this uncommon co-expression pattern, along with four cases of adenosquamous carcinoma (ASC) for comparative analysis, aiming to further characterize their distinguishing clinicopathological features. Whole-exome sequencing (WES) was performed to establish a comprehensive mutational landscape of these tumors. Lung cancers with co-expression of TTF-1 and p40 exhibit a poorer prognosis compared with conventional adenocarcinoma (ADC) and squamous cell carcinoma (SCC). TP53 represents the most frequently mutated gene in this subtype. Notably, SYNE1, TMEM132C, and TNN were identified as characteristic mutations, defining a distinct mutational profile that sets this rare subtype apart from both SCC and ADC. Our findings highlight that NSCLC with diffuse co-expression of TTF-1 and p40 probably constitutes a distinct clinicopathological subtype with rapid clinical progression and poor prognosis, defined by unique morphological characteristics, a biphenotypic immunoprofile, and specific molecular alterations.

Homologous recombination deficiency (HRD) testing may be used to stratify ovarian carcinoma (OC) patients for PARP inhibitor therapy. In the Netherlands, different NGS-based assays are used to assess genomic instability as a hallmark of HRD. We evaluated the uniformity of HRD testing. Firstly, interlaboratory assessments of 10 tumors were performed in 8 centers. 71 out of the 77 (92%) successful tests were concordant. Results were more consistent in OC with a pathogenic variation (PV) or promoter methylation of a homologous recombination repair (HRR) gene (97%) than in those without (87%). Secondly, concordance between BRCA1/RAD51C promoter methylation and HRD was assessed in 244 samples without a PV in HRR genes. BRCA1/RAD51C promoter methylation was present in 38 out of 100 (38%) samples classified as HRD, and absent in all (n = 144) non-HRD samples (p < 0.001). Lastly, pathology reports from 765 HRD tests were reviewed to evaluate routine diagnostics. Testing was successful in 695 (91%) cases. HRD detection rates were higher in high-grade serous OC compared to other histological subtypes (49% versus 12%, p < 0.001). The five HRD assays varied significantly in HRD detection rates in high-grade serous OC. The results support the applicability of genomic instability analyses to assess HRD, while also highlighting the need to improve harmonization across different assays when HRD is used for therapeutic decision making.

A translational gap exists in Burkitt leukemia (B-AL) and Burkitt lymphoma (B-Ly) regarding miRNAs associated with clinicopathological features and outcome. The aim of this study was to evaluate differential miRNA expression in a single-center series of pediatric B-AL/B-Ly. Expression profiles of 800 miRNAs in 33 B-AL/B-Ly samples were evaluated using the NanoString nCounter System. Further validation was performed by qPCR utilizing miRNA-specific TaqMan assays. Significantly expressed miRNAs in B-AL/B-Ly were evaluated in silico to identify predicted targeted cancer-related pathways. Analysis of miRNAs deregulated in B-AL/B-Ly compared to normal control lymphoid tissue (NCLT) identified a consistent set of differentially expressed miRNAs, including miR-494-3p, miR-4286, and miR-19a-3p among the higher expressed miRNAs and miR-150-5p, miR-450b-5p, and miR-342-3p among the lower expressed miRNAs in B-AL/B-Ly compared to NCLT (FC > 1.5, p-adj < 0.05). In silico, the main predicted cancer-related signaling pathways targeted by these miRNAs included the MAPK, PI3K-Akt, JAK-STAT, VEGF, TP53, Fas, TGF-β, and MYC signaling pathways (p-adj < 0.05). B-AL and B-Ly segregated into two major miRNA clusters with sets of significantly overexpressed miRNAs (miR-223-3p, miR-451a, miR-150-5p, miR-144-3p, miR-142-3p, and miR-15a-5p) and lower expressed miRNAs (miR-494-3p, miR-4286, miR-1915-3p, miR-125b-5p, and miR-100-5p) in B-AL compared to B-Ly (FC > 1.5, p-adj < 0.05). Notably, significant downregulation of miR-10a-5p (FC > 1.5, p-adj < 0.05) was observed in the unfavorable outcome group. In summary, new miRNA signatures of relevance in B-AL and B-Ly could be recognized in this study. Studies in larger cohorts are required to further validate these findings.