Vision-language foundation models have shown great promise in computational pathology but remain primarily data-driven, lacking explicit integration of medical knowledge. We introduce knowledge-enhanced pathology (KEEP), a foundation model that systematically incorporates disease knowledge into pretraining for cancer diagnosis. KEEP leverages a comprehensive disease knowledge graph encompassing 11,454 diseases and 139,143 attributes to reorganize millions of pathology image-text pairs into 143,000 semantically structured groups aligned with disease ontology hierarchies. This knowledge-enhanced pretraining aligns visual and textual representations within hierarchical semantic spaces, enabling a deeper understanding of disease relationships and morphological patterns. Across 18 public benchmarks (over 14,000 whole-slide images) and 4 institutional rare cancer datasets (926 cases), KEEP consistently outperformed existing foundation models, showing substantial gains for rare subtypes. These results establish knowledge-enhanced vision-language modeling as a powerful paradigm for advancing computational pathology.

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, exhibits marked clinical heterogeneity driven by poorly understood molecular mechanisms. Identifying the molecular characteristics of different RMS subtypes and the molecular pathways influencing the RMS treatment response and recurrence is an urgent clinical need. Here, we perform deep proteomic profiling of 19 RMS tumors (8 alveolar [ARMS], 11 embryonal [ERMS]) and matched normal tissues, integrating bioinformatics with functional validation to delineate subtype-specific pathways, therapy resistance drivers, and actionable targets. ARMS tumors are characterized by ubiquitination pathway activation (UBE2R2, UBE2J2), while ERMS exhibits spliceosome dysregulation. Chemo- and radio-resistant tumors both show significant enrichment in the ribosome pathway. Relapsed cases show phosphonate and phosphinate metabolism pathway enrichment, suggesting metabolism reliance. Unsupervised clustering reveals ribosome- and glycolysis-driven subtypes with distinct metabolic dependencies. Functional studies implicate MED18─a core component of the Mediator complex─in mediating therapy resistance possibly via promoting DNA damage repair. Our study establishes proteomics as a tool to decode RMS heterogeneity, proposing subtype-tailored strategies targeting ubiquitination, splicing, and metabolism.

Despite Phosphoenolpyruvate carboxykinase 2 (PCK2) has attracted growing attention as a potential biomarker in cancer research, its role in medulloblastoma (MB) remains unclear. This research aims to evaluate PCK2 as a novel biomarker for groups 3 and 4 MB and to investigate its associations with prognosis and the tumor immune microenvironment. Five cohorts were extracted to identify characteristic genes associated with MB molecular subtypes through gene differential expression analysis and machine learning techniques. Kaplan-Meier survival analysis, alongside univariate and multivariate COX regression analyses, was employed to investigate the relationship between PCK2 expression and clinical significance. Immunohistochemistry was used to detect PCK2 expression in MB samples. ROC analysis was performed to verify the specificity of PCK2. MCP-counter, CIBERSORT, and ssGSEA were used to explore the correlation of tumor-infiltrating immune cells according to PCK2 expression. Immunofluorescence was performed to testify the co-expression patterns across PCK2, CD206 and PD-L1 in MB tissues. PCK2 is increasingly expressed in Group 3 MB and could serve as an independent poor prognostic indicator for MB patients. PCK2 correlates with immune infiltrates and immunosuppression. Furthermore, PCK2 exhibits a positive correlation with M2-type macrophage infiltration and is co-expressed with CD206 and PD-L1 in MB tissues. Our study demonstrates that PCK2 may serve as a reliable biomarker for differentiating Group 3 from Group 4 MB and could potentially play a role in immunotherapy-related mechanisms.

Rare cancers comprise 20-25% of malignancies (over 70% in pediatric oncology) but face major diagnostic challenges due to limited expert availability. While pathology vision-language models show promising zero-shot capabilities for common cancers, their performance on rare cancers remains limited. Existing multi-instance learning (MIL) methods rely solely on visual features, overlooking cross-modal knowledge and compromising interpretability critical for rare cancer diagnosis. To address this, we propose PathPT, a framework that exploits vision-language foundation models through spatially-aware visual aggregation and task-specific prompt tuning. PathPT converts WSI-level supervision into fine-grained tile-level guidance, preserving tumor localization and enabling cross-modal reasoning. Across eight rare and three common cancer datasets-spanning 56 subtypes and 3958 WSIs, PathPT consistently outperforms state-of-the-art methods under data-scarce settings. It achieves substantial gains in both subtyping accuracy and cancerous region grounding ability, providing a scalable, interpretable AI solution to improve rare cancer subtyping with limited access to specialized expertise.

Accurate prediction of the recurrence risk of localized primary gastrointestinal stromal tumors (GISTs) after complete surgical resection is crucial for determining adjuvant treatment and surveillance strategies. Traditional risk-stratification schemes often exhibit heterogeneity and may not provide sufficient prognostic information. Therefore, the authors' objective was to develop a pathomics nomogram that integrates digital pathology and machine-learning algorithms to improve predictive accuracy. The authors enrolled 421 eligible participants (253 in the training cohort, and 168 in the external validation cohort) from four medical centers. Four distinct machine-learning methods were evaluated, and the one that demonstrated optimal performance in the validation cohort was selected to develop the pathomics model. Subsequently, stepwise multivariate Cox regression analysis was performed to construct a machine-learning-based pathomics nomogram (the MLPNom). The MLPNom exhibited superior predictive performance compared with traditional risk criteria (concordance index values: training cohort, 0.892; validation cohort, 0.964). The time-dependent area under the curve values for the MLPNom were notably higher than those for traditional risk criteria (5-year area under the curve values: training cohort, 0.919; validation cohort, 0.959). Calibration curves and Brier scores confirmed the excellent calibration of the MLPNom. Decision curve analysis further underscored the utility of the MLPNom in clinical decision making for GISTs. Furthermore, the MLPNom identified three distinct prognostic subgroups that retained their significance after stratification based on diverse clinicopathologic factors. The MLPNom demonstrates robust discrimination and calibration in predicting recurrence-free survival in localized primary gastric and small intestinal GISTs after complete surgical resection. This may complement traditional risk criteria and aid in selecting patients for adjuvant imatinib therapy.

体质错配修复缺陷综合征（constitutional mismatch repair deficiency syndrome，CMMRD）是一种常染色体隐性遗传肿瘤易感综合征，由4种错配修复基因（MLH1、PMS2、MSH2和MSH6）之一的双等位基因胚系致病性变异引起。CMMRD非常罕见，患者在儿童时期发生肿瘤的风险很高，以脑肿瘤和胃肠道肿瘤最多见。4个错配修复基因中以PMS2和MSH6突变占主导地位。CMMRD相关肿瘤常表现为超高突变（≥100 Muts/Mb）、错配修复缺陷以及微卫星不稳定性。CMMRD的基因型-表型存在一定的相关性，与PMS2和MSH6相比，MLH1和MSH2基因变异的肿瘤更具侵袭性、外显率更高、癌症发病更早和预后更差。由于临床表现的多样性及基因变异的复杂性，CMMRD相关肿瘤的诊断存在诸多挑战，进一步开发可重复性好、可及性强、灵敏和特异性的检测方法对及早识别患者及携带者，改善预后具有重要的临床意义。

A 12-year-old Chinese adolescent girl presented with a 2-month history of left nipple bleeding. Physical examination revealed bloody and brownish nipple discharge. Ultrasonography identified a 1 mm solid mass within a dilated duct, and MRI showed heterogeneous enhancement. Surgical exploration revealed a well-defined, medium-textured mass within the duct, which was completely excised. Histopathological analysis confirmed an intraductal fibroadenoma with stromal infarction and hemorrhage, explaining the nipple discharge. Postoperatively, the patient recovered well without recurrence during a 12-month follow-up. Fibroadenoma, the most common benign breast lesion in adolescents, arises from estrogen-sensitive intralobular fibroblasts and may involve ductal structures, as in this case. Spontaneous infarction of intraductal fibroadenoma is exceptionally rare and can present with bloody discharge, necessitating differentiation from other intraductal lesions such as ductal adenoma and intraductal papilloma. This case highlights the importance of timely diagnosis and management of breast lesions in adolescents, emphasizing the need to distinguish between physiological changes and pathological conditions. The report also discusses the etiology of spontaneous infarction in intraductal fibroadenoma and its clinical implications, contributing to the understanding of this rare presentation in pediatric patients.

OBJECTIVE:Estrogen receptor-positive (ER-positive) platinum-resistant recurrent epithelial ovarian cancer (PROC) patients following second-line platinum-based chemotherapy failure face the dilemma of limited therapeutic options. We aimed to evaluate the efficacy and safety of letrozole plus anlotinib for these patients. METHODS:We conducted a single-arm phase 2 study (NCT04720807) evaluating letrozole plus anlotinib in ER-positive PROC patients following second-line platinum-based chemotherapy failure. Patients received oral anlotinib 10 mg daily (days 1-14, q21d) and continuous oral letrozole 2.5 mg. Treatment was continued until disease progression, death, intolerant toxicity, or patient withdrawal. The primary endpoint was the objective response rate (ORR) according to RECIST version 1·1 and the GCIG criteria. RESULTS:Between January 2021 and December 2023, 30 patients were assessed for eligibility, and 27 patients were enrolled. The median age was 62 years (range 50-79). Seven patients achieved a partial response, while no patients showed a complete response, resulting in an ORR of 25·9 % (95 % CI, 11·8 %-46·6 %). The disease control rate was 74·1 % (95 % CI, 53·4 %-88·1 %). The median progression-free survival was 4·57 months (95 % CI, 4·07-9·66). Most adverse events were Grade 1-2 and manageable. Patients with a primary platinum-free interval exceeding 6 months, lower baseline CA-125 levels (<500 IU), or higher ER expression levels (≥ 25 % stained positive for ER) showed a statistically significant treatment benefit. CONCLUSION:The combination of letrozole plus anlotinib demonstrated promising efficacy and manageable toxicity in the treatment of ER-positive PROC patients following second-line platinum-based chemotherapy failure.

Abstract Objective This study aimed to compare the expression of lymphoid enhancer factor 1 (LEF1) and β-catenin in basal cell adenoma (BA), desmoid-type fibromatosis (DF), and pancreatic solid pseudopapillary neoplasm (SPN) to evaluate their diagnostic utility in tumors associated with the WNT/β-catenin signaling pathway harboring the mutation of CTNNB1 gene 3 exon. Methods Eighty tumor patients, including 26 BAs, 30 DFs, and 24 SPNs, were analyzed. Immunohistochemical staining was identified positive (nuclear staining of LEF1 and β-catenin in > 50% of tumor cells). The diagnostic rate of LEF1 alone, β-catenin alone, and their combination were compared for each tumor type and all patients. Results Compared to β-catenin, when LEF1 alone was used for diagnosis, the diagnostic rate increased by 46.16% for BA, 16.67% for SPN, and 11.25% for all patients, but decreased by 23.34% for DF. The combined use of β-catenin and LEF1 significantly increased the diagnostic ratio in BA (46.16%), SPN (16.67%), and all patients (21.25%), but only marginally in DF (3.33%). In terms of all WNT pathway tumors with CTNNB1 gene mutation encompassed by our study, statistical analysis revealed no significant difference between LEF1 alone and β-catenin alone. However, their combined application was highly significant (P = 0.001) . Conclusion While β-catenin is commonly used as a marker for WNT pathway tumors, its variable expression and localization can be challenging for diagnosis. Our study emphasizes the importance of LEF1 as a complementary marker to β-catenin in diagnosing BA, DF, SPN, and other WNT pathway tumors activated by exon 3 CTNNB1 gene mutation. The combined use of LEF1 and β-catenin enhances diagnostic accuracy and may help the identification of these tumor types.

Background:Malignant peripheral nerve sheath tumors (MPNST) are a severe complication of neurofibromatosis type 1 (NF1). The median age at diagnosis is 47.1 years in the general population, whereas NF1-associated cases present significantly earlier, at 33.9 years. The incidence is 1.46 per million in the general population and 0.56 per million in children, with a higher occurrence in late adolescence. Case report:A 3-year-old girl was referred for a recurrent soft-tissue mass in her left wrist. Imaging suggested a neurofibroma. After excision, pathological analysis and genetic testing revealed a germline NF1 mutation, confirming Neurofibromatosis type 1 (NF1), along with somatic mutations in NF1 and deletions in CDKN2A. Pathology confirmed malignant Triton tumor (MTT). She received six cycles of ifosfamide and doxorubicin, followed by a second excision, which showed persistent tumor activity. Positron emission tomography-computed tomography (PET-CT) scans revealed reduced metabolic activity at the tumor site, suggesting a partial response to treatment. The patient is currently undergoing oral MEK inhibitor-targeted therapy. Conclusion:This case highlights the challenges associated with MPNST in pediatric NF1. Both surgery and chemotherapy have been shown to enhance outcomes. Ongoing monitoring is crucial, and additional research on MEK inhibitors and genetic profiling is imperative for tailoring treatment strategies.

Abstract Objectives Lymphocyte activation gene 3 (LAG3), an inhibitory receptor in T‐cell activation, is a negative prognostic factor. However, its impact on tumours has yet to be comprehensively elucidated on a pan‐cancer scale. Thus, we aim to reveal its role at the pan‐cancer level. Methods We performed IHC staining on a retrospective cohort of 370 patients. Then we assessed the prognostic effect of LAG3 using Kaplan–Meier survival analysis and multivariate Cox regression analysis. In pan‐cancer analysis, we constructed competing endogenous RNA and protein–protein interaction networks, conducted gene set enrichment analysis and identified correlations between LAG3 gene expression and various factors, including clinical characteristics, tumour purity, mutations, tumour immunity and drug sensitivity across 33 cancer types. Results LAG3 was expressed higher in normal kidney tissues than in tumours. A high level of LAG3 gene expression was an independent prognostic factor for OS (HR = 6.60, 95% CI = 2.43–17.90, P < 0.001) and PFS (HR = 3.44, 95% CI = 1.68–7.10, P < 0.001). In pan‐cancer analysis, LAG3 exhibited robust correlations with survival and tumour stages in various cancers. Moreover, LAG3 was strongly associated with immune‐related genes, proteins and signalling pathways. LAG3 gene expression was positively associated with increased infiltration of activated immune cells and decreased infiltration of several resting cells. LAG3 gene expression was associated with tumour mutation burden and microsatellite instability in multiple cancers. Conclusion High LAG3 gene expression was an independent risk factor in kidney neoplasms. It also functioned as a biomarker for prognosis, TIME and immunotherapy efficacy in the pan‐cancer dimension.

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

Dedicator of cytokinesis 8 (DOCK8) deficiency represents a primary immunodeficiency with a wide range of clinical symptoms, including recurrent infections, atopy, and increased malignancy risk. This study presents a case of a 6-year-old girl with DOCK8 deficiency, characterized by severe, treatment-resistant herpetic infections who was successfully treated with siltuximab and glucocorticoids. The successful use of siltuximab in achieving remission highlights the pivotal role of interleukin-6 (IL-6) in DOCK8 deficiency pathogenesis and suggests that IL-6 modulation can be critical in managing DOCK8 deficiency-related viral infections, which may inform future therapeutic strategies for DOCK8 deficiency and similar immunodeficiencies.

The classification of TFEB-altered renal cell carcinoma (RCC) has been revised to include TFEB-rearranged RCC and TFEB-amplified RCC in the 2022 World Health Organization (WHO) Classification of Tumors of the Urinary System. Given the wide spectrum of TFEB-altered RCC in terms of morphology and clinical behavior, an accurate diagnosis is challenging yet crucial, particularly in aggressive cases. Moreover, the concurrence of TFEB gene rearrangement and amplification/gene copy number (GCN) gains was also observed, but there was limited knowledge of these cases. We presented three TFEB-rearranged RCC cases, one TFEB-amplified RCC case, and one case of concomitant TFEB-rearranged and -amplified RCC, comparing the similarities and differences among these three subgroups. Furthermore, we summarized the clinicopathological and molecular features of TFEB-rearranged RCC concomitant with TFEB amplification/GCN gains from the literature and the present study. TFEB-altered RCCs exhibit significant heterogeneity in morphology and clinical behavior while displaying similar immunohistochemical profiles, including positive staining for Melan-A, PAX8, and CD117, and negative staining for CK7. A typical biphasic “rosette-like” morphology has been observed in a proportion of TFEB-rearranged RCC concomitant with TFEB amplification/GCN gains, which has been noted in TFEB-rearranged RCC, but not in cases with only TFEB amplification. Notably, TFEB-rearranged RCCs concomitant with TFEB amplification/GCN gains tend to be aggressive, in contrast to the often indolent nature of TFEB-rearranged cases, irrespective of the extent of TFEB gene copy increase. Therefore, a TFEB FISH assay is essential for unclassified RCC cases that exhibit melanocytic marker expression, and fluorescent signals should be counted and interpreted acurrately.

Epidermoid cyst of the spleen is a rare disease, and relatively few cases were reported by literatures. Most published case reports provided inadequate information on the impact of splenic epidermoid cyst on tumor markers. A 32-year-old woman with a giant splenic epidermoid cyst was reported, for whom the serum concentration of a collection of tumor markers (CA19–9, CEA, CA125, CA242, and CA50) increased abruptly accompanied by left upper abdominal pain for 5 days. After comprehensive preoperative examination and multidisciplinary team discussion, we ruled out any concurrent malignancy and a laparoscopic total splenectomy was performed, during which the splenic cyst spontaneously ruptured unexpectedly. After surgery, the elevated serum tumor marker levels decreased sharply until reaching normal range 3 months later. Learning from the case, we conclude that interval monitoring of serum tumor markers is of critical value for patients with splenic epidermoid cyst. Abrupt elevation of tumor marker levels and abdominal pain may serve as signs of cyst rupture, which is strongly indicative of surgical intervention as soon as possible. Total removal of the splenic cyst is strongly suggested considering the recurrence and malignant potential of the splenic epidermoid cyst.

Background: Pyroptosis is a programmed death mode of inflammatory cells, which is closely related to tumor progression and tumor immunity. Clear cell renal cell carcinoma (ccRCC) is the major pathological type of renal cell carcinoma (RCC) with poor prognosis. Many theories have tried to clarify the mechanism in the development of ccRCC, but the role of pyroptosis in ccRCC has not been well described. The main purpose of this study is to explore the role of pyroptosis in ccRCC and establish a novel prognosis prediction model of pyroptosis-related molecular signatures for ccRCC. Methods: In the present study, we made a systematical analysis of the association between ccRCC RNA transcriptome sequencing data from The Cancer Genome Atlas (TCGA) database [which included 529 ccRCC patients who were randomized in a training cohort (n=265) and an internal validation cohort (n=264)] and 40 pyroptosis-related genes (PRGs), from which four genes (CASP9, GSDME, IL1B and TIRAP) were selected to construct a molecular prediction model of PRGs for ccRCC. In addition, a cohort of 114 ccRCC patients from Shanghai Eastern Hepatobiliary Surgery Hospital (EHSH) was used as external data to verify the effectiveness of the model by immunohistochemistry. Moreover, the biological functions of the four PRGs were also verified in ccRCC 786-O and 769-P cells by Western blot (WB), CCK-8 cell proliferation, and Transwell invasion assays. Results: The model was able to differentiate high-risk patients from low-risk patients, and this differentiation was consistent with their clinical survival outcomes. In addition, the four PRGs also affected the ability of cell proliferation and invasion in ccRCC. Conclusion: The prediction model of pyroptosis-related molecular markers developed in this study may prove to be a novel understanding for ccRCC.