Journal of Pathology Clinical Research最新文献

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) constitutes an exceptionally rare histological subset of uterine mesenchymal neoplasms. While most cases have benign clinical behavior, a subset of UTROSCTs exhibits clinically aggressive behavior characterized by recurrence and metastasis. Here, we present a cohort of 25 UTROSCT cases molecularly confirmed by recurrent fusion gene detection, including ESR1::NCOA3 (n = 12), GREB1::NCOA1 (n = 6), ESR1::NCOA2 (n = 3), GREB1::NCOA2 (n = 2), GREB1::SS18 (n = 1), and GREB1::CTNNB1 (n = 1). Notably, six cases (6/25, 24%) demonstrated recurrence/metastasis: two cases showed intrauterine recurrence (harboring ESR1::NCOA3 and GREB1::NCOA1 fusions), while four developed extrauterine metastases (carrying ESR1::NCOA3, ESR1::NCOA2, GREB1::NCOA1, and GREB1::NCOA2 fusions), with one fatality. To dissect the biological basis of UTROSCT aggressiveness, we performed integrated clinicopathologic, immunohistochemical, and molecular profiling. Multivariate analysis identified tumor size >5 cm, FIGO stage IB, and lymphovascular space invasion (LVSI) as independent predictors of recurrence/metastasis, whereas histologic features, proliferation index, and fusion gene subtypes lacked prognostic significance. Multi-omics analysis of primary versus metastatic tumors revealed striking copy number variations (CNVs) exclusively in metastatic lesions. Specifically, heterozygous losses of SMARCB1 (2/4 metastatic cases) and ATRX (1/4 metastatic cases) were identified; both play critical roles in chromatin remodeling. These genetic alterations were conspicuously absent in primary tumors, suggesting their potential role in metastatic progression. Our findings represent the first demonstration of CNV-driven oncogenic evolution in UTROSCTs, particularly implicating SWI/SNF complex dysregulation in metastatic competence.

The World Health Organization (WHO) Classification of Tumours: A Living Evidence Gap Map by Tumour Type (WCT EVI MAP) project aims to develop Evidence Gap Maps of the available evidence, primarily to inform the WHO Classification of Tumours. The project, covering all tumour types, faces the challenge of reviewing a huge number of studies by reviewers from multiple backgrounds. The aim was to develop a decision tree (DT) diagram for classifying study designs reporting on tumour pathology studies, in order to support the decision-making process when assigning evidence levels across various disciplines. A modified consensus process, incorporating stakeholder workshops, was conducted in three phases: (1) development of the initial DT diagram draft (literature review and expert evaluation); (2) iterative reviews with project partners; and (3) testing the advanced DT diagram version with several sets of references to refine critical points. A total of 368 records were used for training throughout the entire process. Consensus was achieved when classifications could categorise studies consistently without causing discordance in new example sets. A DT diagram and its Glossary of Operational Definitions with 27 decision nodes and 26 categories were developed. The DT diagram is organised into six sections: WCT EVI MAP selection criteria, evidence synthesis, basic research related studies, descriptive studies, observational and experimental studies, and diagnostic test studies. The DT diagram is a valuable tool for the project's needs, successfully integrating diverse disciplinary perspectives for classifying evidence in tumour pathology research according to study design. It lays the foundation for future advancements in evidence mapping and classification within tumour pathology and related disciplines.

Reply to Yang et al.

We thank the authors for their interest in our recent paper ‘Myeloid sarcoma shows a high frequency of mutations activating the MAPK/ERK pathway and association with clonal hematopoiesis’ [1], which appeared in the September issue of The Journal of Pathology, Clinical Research. In their letter to the Editor, Dr. Yang and his colleagues raise some important issues, which point the way for further studies on myeloid sarcoma (MS) and its development [2]. These include subclonal mutations in the MAPK pathway, the association with clonal hematopoiesis and the importance of the microenvironment.

Nevertheless, we want to clarify a few points raised by Dr. Yang and colleagues concerning our results. They state that the frequent subclonal nature of many MAPK/ERK mutations in our MS samples suggests they may not be the universal founding oncogenic event. Although we agree with this statement in principle, since activating mutations of NRAS, KRAS and/or BRAF were observed in only 53% of our MS cases and other acquired mutations, namely NPM1, mutated in 38% of cases, are alternative candidate drivers, we want to point out that NRAS/KRAS mutations constitute minor, subclonal events in only 2/18 cases. In case 27, the bone marrow showed a KRAS mutation with 7% variant allele frequency (VAF), which was present at 2% and 3% VAF, respectively, in the two MS from this patient. In case 31, the NRAS mutation was present in the bone marrow at 28% VAF and at only 0.4% VAF in the MS. In these cases, the MAPK/ERK mutations most likely represent a subclone and are not responsible for MS development. In the remaining 15/18 cases with NRAS/KRAS mutations; however, these showed a high VAF (mean 41.7%, range 19–92%). In the cases with available pre-transplant bone marrow (BM) biopsy, the majority of NRAS/KRAS mutations were acquired in MS or showed a significant increase in VAF in the MS in comparison to the BM biopsy. In some cases with mutations in other genes with higher VAF, this is indicative of a bi-allelic event rather than subclonality of the RAS mutation, as for example in case 33 with a TP53 mutation with 83% VAF and the EZH2 mutation in case 18 with 89% (scrotal) and 99% (penis) VAF, respectively, in two different locations. In summary, the high VAFs and the frequent de novo acquisition of NRAS/KRAS mutations in many MS cases, together with the clear evidence for upregulation of the MAPK/ERK signaling cascades (supplementary material, Figure S3 in our paper [1]) detected by comparative gene expression profiling clearly point to a role in MS development, although functional studies will be necessary to corroborate these findings. Of interest is case 10, which showed acquired identical mutations of BRAF and KRAS in both MS samples, but not in the BM. Given the fact that both

Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and tertiary lymphoid structures (TLSs) has not yet been sufficiently described. We examined whole tissue sections histopathologically for TLSs and immunohistochemically for CD20 and CD138. The B-cell immunoscore (B-IS) divided the cohort into five categories based on the expression of these two B-cell/plasma cell markers (CD20 and CD138, respectively). Patients with fewer TLSs had worse overall survival (OS) [hazard ratio (HR) = 2.17; 95% CI: 0.94–5; p = 0.069]. A significant association was identified between a high TLS diameter and the presence of a lymphocytic infiltrate [odds ratio (OR) = 2.2442; 95% CI: 1.1022–4.55; p = 0.0208]. Patients with low B-IS (HR = 1.89, 95% CI: 1.18–3.03, p = 0.008), a low number of CD20⁺ cells in the tumor center (HR = 1.67, 95% CI: 1.04–2.7, p = 0.035), and a low number of CD20⁺ cells at the tumor invasion front (HR = 1.69, 95% CI: 1.06–2.78; p = 0.028) had significantly worse OS. High B-ISs were strongly associated with a mutated p53 profile detected by immunohistochemistry (OR = 4.76, 95% CI: 1.32–25, p = 0.011), low T-cell immunoscores (OR = 0.49; 95% CI: 0.23–1.03; p = 0.051), and brisk lymphocytic infiltration (OR = 2.0417, 95% CI: 1.01–4.76; p = 0.037). High CD20⁺ cell counts at the invasion front were associated with histological grade 3 disease (OR = 2.44, 95% CI 1.15–5.26, p = 0.015). An association was also observed between low B-IS and mutations in KMT2D (OR 0.31, 95% CI: 0.07–1.21, p = 0.057) and EGFR (OR = ∞, 95% CI: 0.86–∞, p = 0.053). In conclusion, high numbers of tumor-infiltrating B cells within TLSs represent a favorable prognostic marker in pSCC. These findings emphasize the need to identify novel microscopic prognostic markers during pathological assessment to guide early and appropriate therapeutic strategies.

Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12–63 years (median 44). Twenty-eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0–1/10 high-power fields, HPF). A single patient with distant metastasis harboured a solid-predominant tumour showing nuclear grade 2–3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan-TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2–30% of tumour cells), and all were HER2 negative or low (0–1+). Ki-67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6-NTRK3 dual-fusion; 3 NTRK3 break-apart). In the metastatic case, RNA sequencing confirmed canonical ETV6-NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) – RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow-up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6-NTRK3 rearrangement with diffuse pan-TRK/S100 positivity. A solid-predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK-inhibitor therapy in advanced disease.

Adult diffuse gliomas with FGFR3-TACC3 (F3T3) fusion are rare and highly heterogeneous central nervous system (CNS) tumors. Current research on the biological behavior of these tumors is limited, especially regarding whether histopathologically low-grade tumors are indolent or represent early-stage high-grade tumors, thereby posing challenges for grading. In this single-center study of 17 patients with adult F3T3 fusion diffuse gliomas (F3T3 gliomas), both low- and high-grade F3T3 gliomas presented distinctive recurrent histopathological features, such as oligodendrocyte-like cells, branched vessels and frequent calcifications. Molecularly, TERT promoter mutations and 7+/10− chromosomal alterations were common; one patient with recurrent glioma with histopathological features of polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had additional CDK4 and MDM2 amplifications. Methylation profiling of 3 samples revealed varied results. A patient whose tumor had histopathological features consistent with PLNTY and a methylation subtype classified as the mesenchymal subtype of glioblastoma (GBM) experienced tumor recurrence 8 months after surgery. After 5–62 months of follow-up, seven patients relapsed, and six died; the primary tumors of the three patients with recurrence presented histopathological characteristics of low-grade glioma (LGG). GBM patients had worse overall survival than LGG patients (p = 0.035) but similar progression-free survival (p = 0.47), indicating that LGG patients may experience recurrence. For adults with tumors with histopathological features of PLNTY, further molecular and methylation analyses are needed for grading. If TERT promoter mutations are present, even with a PLNTY methylation profile, these tumors can still exhibit the biological behavior of high-grade gliomas.

The field of gynecologic pathology is undergoing a transformative change. The translation of molecular findings from large-scale genomic studies into clinical practice has been facilitated by robust surrogate assays, particularly immunohistochemistry (IHC). These tools provide scalable molecular proxies with short turnaround times, enabling molecular subclassification and conclusive prognostic biomarker studies. This commentary highlights how prognostic markers now refine diagnoses in challenging borderline areas, where an abnormal result can help exclude benign or precursor entities. However, the utility of these markers is highly context-dependent, modified by histotype and molecular subtype. Furthermore, the confident diagnosis of rare entities and the study of their precursors have been advanced by defining specific molecular and IHC profiles, opening new avenues for research and therapy. The integration of morphology with molecular features is increasing the robustness of diagnoses and dictating oncology management as never before.

Bone and soft tissue sarcomas are a diagnostic challenge due to their histological complexity, variety, and mutational heterogeneity. This has led to continued refinements in classification and diagnostic criteria, presented and soon to be updated by the WHO. This commentary features articles published in this journal and elsewhere that have ultilised pan-sarcoma datasets and artificial intelligence-based classifiers. A notable entry is the DKFZ Sarcoma Classifier, which is based on methylation profiles and available for use via a commercial platform. This work has created hope that one day a comprehensive sarcoma classifier will be available, though it is also a reminder of the many challenges apparent in studying rare cancer types.

Inter-observer concordance data for the HER2 category as assessed by a group of 16 specialist breast pathologists on 50 diagnostic core biopsies was compared with that produced by digital image analysis (DIA) using the HER2 APP, CE2797 (VP APP; Visiopharm, Hoersholm, Denmark). Comparing pathologists' consensus scores and DIA scores, 36 cases (73.5%) agreed. Fleiss' kappa statistic was 0.433 (indicative of moderate agreement). Cohen's weighted kappa was used to compare the scores of individual raters to consensus scores; for all 50 cases the kappa scores had a range between 0.412 and 0.854; the VP APP was ranked 12th of 17 raters (kappa score 0.638 indicating substantial agreement). Results for HER2-low cases (N = 44) showed a kappa score range of 0.295 to 0.823; the VP APP ranked 12th of 17 (score 0.535 indicating moderate agreement). For high agreement cases the kappa score range was 0.664 to 1.000 for all HER2 scores (N = 24) and the VP APP scored 0.916 (indicating almost perfect agreement). For the HER2-low scores (N = 20), the kappa score range was 0.506–1.000 and the VP APP scored 0.860 (almost perfect agreement). DIA of the proportions of tumour cells showing expression within each of the HER2 categories demonstrated that the majority of cases showing a low level of agreement between pathologists showed heterogeneity and/or a level of expression close to a cut-point for decision making. This study demonstrates that the VP APP produces results that are extremely well-aligned to those of expert pathologists in cases with good overall agreement, and in difficult cases its reproducibility will outperform that of the visual scorer. The results also suggest that use of the VP APP has the potential to reduce the proportion of cases referred for gene amplification testing by reducing the number of cases incorrectly classified as HER2 2+.