Virchows Archiv最新文献

Primary laryngeal lymphoma is a rare diagnosis, accounting for less than 1% of all laryngeal tumors. Approximately 100 cases have been reported in the English-language literature. A variety of lymphoma classifications have been described, including diffuse large B-cell lymphoma, NK/T-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, and peripheral T-cell lymphoma. To our knowledge, follicular lymphoma involving the larynx has been rarely reported. We report a case of a 74-year-old woman who presented with a 1-year history of hoarseness refractory to semi-occluded vocal tract (SOVT) therapy and was diagnosed with follicular lymphoma involving the false vocal fold. At presentation, the patient felt well and did not have any B symptoms. Initial computed tomography (CT) scan of the neck did not show any lesions, but a subsequent videolaryngostroboscopy revealed a small lesion in the false vocal folds. The lesion was surgically excised, and histological evaluation revealed features consistent with a diagnosis of follicular lymphoma. Herein, we present a rare case of primary follicular lymphoma of the larynx and describe its histological and immunophenotypic characteristics. Furthermore, we conducted an extensive review of the English-language literature and discuss comparable published cases.

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, with the majority of cases driven by genetic alterations that activate the MAPK signaling pathway. The BRAF V600E mutation is the most frequent alteration, while BRAF fusions are relatively rare but increasingly recognized as oncogenic drivers. These fusions typically involve the loss of BRAF's autoinhibitory N-terminal domain, leading to constitutive MAPK pathway activation. Here, we report a novel SORBS2::BRAF fusion in a case of PTC, further expanding the spectrum of BRAF alterations in thyroid cancer. A 32-year-old male was incidentally found to have a left thyroid nodule during a routine physical examination. Follow-up examinations revealed changes in the nodule's characteristics, prompting fine-needle aspiration biopsy, which identified atypical follicular epithelial cells suggestive of papillary thyroid carcinoma. Histopathological examination confirmed the diagnosis, and next-generation sequencing (NGS) revealed a novel in-frame fusion between SORBS2 exon 18 and BRAF exon 9. The resulting fusion protein retains the BRAF kinase domain while replacing its autoinhibitory domains with those of SORBS2. RT-PCR and Sanger sequencing confirmed the presence of the SORBS2::BRAF fusion. Quantitative PCR profiling of MAPK transcriptional output genes (DUSP6, CCND1, ETV4, c-Myc, and c-FOS) revealed marked upregulation in the tumor versus adjacent normal tissue, providing functional evidence for pathway activation. The SORBS2::BRAF fusion has not been previously reported in PTC or any other tumor type. Given the deletion of BRAF's inhibitory domain, this fusion likely acts as a tumor driver through constitutive activation of the MAPK pathway. This case underscores the importance of molecular diagnostics in identifying rare genetic alterations and highlights the need for further research into targeted therapies for BRAF fusion-driven cancers. The discovery of this novel fusion expands our understanding of the molecular landscape of PTC and provides a foundation for future therapeutic development.

Psoriasis and eczema are chronic inflammatory skin diseases with overlapping histopathological features, which often lead to diagnostic uncertainty even among experienced dermatopathologists. To address this challenge, we developed a computer-assisted diagnostic framework that combines the Virchow foundation model, pretrained on 1.5 million whole-slide images, with multi-instance learning (MIL) to classify psoriasis and eczema from digitized histopathology slides. Using an internal dataset (n = 40) and an external validation cohort (n = 40), equally balanced between both conditions and annotated by board-certified dermatopathologists, our best-performing configuration (Virchow + CLAM) achieved 85% accuracy, a macro-averaged F1 score of 0.80, and an AUC of 0.81 on the external cohort. This substantially outperformed baseline convolutional neural networks, which reached 61% accuracy, and models relying solely on pretrained feature extractors without MIL, which achieved an average accuracy of 68.8%. In a reader study on the same external cohort, individual dermatopathologist accuracies ranged from 47.5 to 70.0%, with a majority-vote consensus accuracy of 62.5%; our method outperformed both the average individual reader and the consensus under histology-only conditions. Furthermore, the model generates attention heatmaps that provide supportive visual context by highlighting regions associated with model predictions. Importantly, this study is designed as a methodological proof-of-concept conducted under controlled, histology-only conditions and is not intended for direct clinical deployment. Rather than demonstrating clinical readiness, it illustrates the potential of domain-specific foundation models combined with MIL for addressing diagnostically challenging inflammatory dermatoses.

This study examined the prognostic significance of tumor budding (TB) and poorly differentiated clusters (PDCs) in 232 patients with primary cutaneous melanoma (CM). Through retrospective analysis and Cox regression models, TB-3 and ulceration were identified as independent prognostic factors for overall survival, while AJCC stage IV and PDCs were associated with progression-free survival. Additionally, factors such as ulceration, vascular invasion, lymph node metastasis, TB-3, PDCs, non-brisk tumor-infiltrating lymphocytes (TILs), and Breslow thickness were significantly linked to prognosis. A nomogram developed from these findings demonstrated strong predictive accuracy (AUC = 0.839). The results suggest that incorporating TB and PDCs into the current CM staging systems could enhance risk stratification and clinical decision-making.

Spindle cell mesenchymal neoplasms comprise a heterogeneous group of tumors, with recent molecular advances uncovering novel pathogenic mechanisms. We report the case of a 22-year-old woman presenting with progressive dyspnea. A computed tomography (CT) scan revealed a solid mass located in the right cardiophrenic angle. Histological examination showed a spindle cell neoplasm composed of medium-sized, elongated cells with scant eosinophilic cytoplasm, arranged in storiform and whorled patterns. Immunohistochemical staining was negative for lineage-specific markers. Fluorescence in situ hybridization (FISH) detected an EWSR1 gene rearrangement in 15% of the neoplastic cells, and RNA sequencing demonstrated a novel EWSR1::HOXB8 fusion. This case highlights the relevance of EWSR1-driven fusions in spindle cell mesenchymal neoplasms and emphasizes the need for further exploration into their clinical and biological behavior. After 5 months of chemotherapy, the patient showed moderate clinical improvement.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor characterized by spindle cells with myofibroblastic differentiation, accompanying chronic inflammatory cells, and the hallmark genetic signature of mainly ALK or ROS1 rearrangements. Here, we report a lung IMT in a 45-year-old female demonstrating a unique meningothelial-like pattern, equivocal ALK expression (negative for clone 5A4 and positive for clone ALK1), negative ALK rearrangement by FISH, and the presence of the TPM3::ALK fusion. To our knowledge, this is the first reported case of lung IMT displaying meningothelial-like whorls, with a particular focus on differential diagnosis.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an aggressive and molecularly heterogenous cancer with poorly defined treatment strategies. We aimed to (i) assess whether RB1 immunohistochemistry alone can prognostically stratify LCNEC, (ii) determine whether adding p53, p16 and/or cyclin D1 immunohistochemistry to RB1 improves prognostic stratification, and (iii) perform a systematic review of RB1 status as a predictive marker for guiding chemotherapy regimen selection for LCNEC. A tissue microarray containing 59 archival pure pulmonary LCNEC resections was used for immunohistochemistry. Recurrence free survival (RFS) and disease specific survival (DSS) data were retrospectively assessed. Tumor responses to platinum etoposide versus other chemotherapy regimens were used in a pooled analysis with published study data. RB1 loss on immunohistochemistry was identified in 58% of cases. Among the tumors with RB1 loss, 94% had mutant-pattern p53. In multivariable analyses, retained RB1 was independently associated with longer disease-free survival of patients with advanced stage disease (HR 0.27, 95% CI 0.11-0.64, P = 0.0031). The addition of p53, p16 or cyclin D1 for subgrouping did not improve prognostic stratification. Prior studies on association of RB1 status with differential response to chemotherapy regimens had contrasting results. Overall, we find that RB1 loss assessed via immunohistochemistry is a poor prognostic factor for advanced stage LCNEC, and therefore may aid in identification of carcinomas likely to have small cell carcinoma-like behavior.

KDM6A is a critical part of the COMPASS-like complex. KDM6A deficiency may result in EZH2 dependency. KDM6A deficiency was analyzed by immunohistochemistry on a tissue microarray containing 14,814 samples from 153 different tumor entities and 76 different normal tissue types. In normal tissues, KDM6A staining was ubiquitously seen in nuclei. In tumors, KDM6A deficiency occurred in 58 of 153 tumor categories. KDM6A deficiency predominated in urothelial carcinomas (17.3-42.0%) and was seen in 4-10% of gastric, pancreatic, prostatic, and gallbladder adenocarcinomas, serous endometrial carcinomas, squamous cell carcinomas, papillary renal cell carcinoma, hepatocellular carcinomas, malignant melanomas, and ovarian serous high-grade carcinomas. Reduced or absent KDM6A expression was associated with advanced pT stage (p = 0.0233), high grade (p = 0.0002), and distant metastasis (p = 0.0152) in breast cancer, nodal metastasis in squamous cell carcinomas (p = 0.0498), advanced pT stage (p = 0.0002), nodal metastasis (p = 0.0112), and mismatch repair deficiency (dMMR; p = 0.0147) in colorectal adenocarcinoma, and with dMMR (p = 0.0033) in gastric adenocarcinoma. KDM6A deficiency was significantly more common in tumors from males (4.3%) than from females (1.9%; p < 0.0001). In summary, KDM6A deficiency predominates in urothelial neoplasms but also occurs in many further tumor entities. Whether KDM6A deficient cancers are susceptible to EZH2 inhibitors remains to be seen.