Objective: To investigate the diagnostic and prognostic value of CSPG4 and SFRP1 expression in esophageal basaloid squamous cell carcinoma (EBSCC). Methods: EBSCC cases in pathological diagnostic reports from Zhongshan Hospital, Fudan University from 2001 to 2023 were collected. Three senior pathologists independently reviewed the slides, and 81 cases of EBSCC and 55 conventional esophageal squamous cell carcinomas (ESCC) with consistent diagnoses were collected. Immunohistochemical staining for CSPG4 and SFRP1 was performed. The sensitivity and specificity of CSPG4 and SFRP1 expression in diagnosing EBSCC, as well as their correlation with prognosis, were analyzed. Results: Among the 81 EBSCC and 55 conventional ESCC cases, there were no significant differences in patient gender, age, or surgical resection time (P>0.05). The expression levels of CSPG4 and SFRP1 were significantly higher in EBSCC than in conventional ESCC (P<0.001), with no significant differences across different invasive layers (P>0.05). The receiver operating characteristic (ROC) curve for CSPG4 had an area under the curve (AUC) value of 0.952, with an optimal H-score cutoff of 75, showing a sensitivity of 92.6% and a specificity of 89.1% for diagnosing EBSCC. For SFRP1, the ROC curve had an AUC value of 0.880, with an optimal H-score cutoff of 1.5, showing a sensitivity of 81.5% and a specificity of 94.5%. When combined, CSPG4 and SFRP1 achieved a sensitivity of 80.2% and a specificity of 100% for diagnosing EBSCC. Among the 79 EBSCC cases with follow-up data, 17.7% showed high expression of both CSPG4 and SFRP1, 17.7% showed high CSPG4 but low SFRP1 expression, 13.9% showed low CSPG4 but high SFRP1 expression, and 50.6% showed low expression of both molecules. Compared to patients with low expression of both CSPG4 and SFRP1, those with high CSPG4 and low SFRP1 expression had the worst prognosis (disease-free survival: P=0.190; overall survival: P=0.031), particularly in stage Ⅰ-Ⅱ patients (disease-free survival: P=0.031; overall survival: P=0.013). Conclusions: CSPG4 and SFRP1 are primarily expressed in EBSCC. The combined application of immunohistochemical staining for these two markers can serve as a molecular indicator for the differential diagnosis and prognostic prediction of EBSCC.

Objective: To assess the utility of histopathological and immunohistochemical characteristics in identifying POLE-mutated (POLEmut) endometrial carcinoma (EC). Methods: A total of 1 541 EC cases that underwent molecular classification at Peking University Third Hospital from January 2018 to December 2024 were included. Cases were categorized into POLEmut and non-POLEmut groups (including p53-abnormal, mismatch repair-deficient, and no specific molecular profile subtypes). A comparative analysis of histopathological features, mismatch repair (MMR) protein expression, and p53 immunostaining patterns was performed. A multivariable logistic regression-derived prediction model for POLEmut status was developed and internally validated. Results: POLEmut tumors showed significantly higher frequencies of prominent peritumoral lymphocytes (PTLs) and tumor-infiltrating lymphocytes (TILs), high-grade nuclei, bizarre nuclei, clear cytoplasm, and ambiguous morphology compared with non-POLEmut tumors (all P<0.05). Multivariable analysis identified severe PTLs/TILs infiltration, high-grade nuclei, ambiguous morphology, and clear cytoplasm as independent positive correlates for POLE mutation status, while aberrant p53 expression and MMR protein loss were negative correlates. The scoring system showed robust discrimination, with an area under the curve (AUC) of 0.867 in the training set (n=1 319) and 0.873 in the test set (n=222). At the ≥3- point cutoff, it provided a sensitivity of 80.8%, specificity of 66.3%, and negative predictive value (NPV) of 96.3% in the test set. Calibration analysis indicated good overall performance (Brier score=0.045), though local miscalibration was observed in intermediate-and low-risk subgroups. Conclusions: This POLEmut scoring system achieves high sensitivity and high NPV for initial screening of POLEmut EC. Despite a relatively low positive predictive value requiring confirmatory sequencing, it effectively enriches candidates needing POLE gene sequencing in resource-limited settings. Future multicenter validation is warranted to assess its clinical utility.

Objective: To study the clinicopathological features and key differential diagnosis of clear cell adenocarcinoma (CCA) of the urinary tract. Methods: A retrospective analysis was performed on the clinicopathological data, immunophenotypes, and molecular test results of patients with pathologically confirmed primary CCA of the urinary tract at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China from December 2015 to September 2024. This study was supplemented by a review of the relevant literature. Results: Nine patients were included (1 male and 8 females), age 57.0 (44.5, 61.0) years old. The main symptoms were urinary tract irritation and hematuria. Th lesions were in the urethra of 5 patients and in the bladder in 4 patients. Macroscopically, the tumors were cauliflower-like, with edema and firm consistency. Microscopically, they showed mostly papillary/tubular-cystic structures, with solid sheet-like arrangements. The tumor cells showed clear or eosinophilic cytoplasm, moderate to high nuclear grade, prominent nucleoli, and frequent mitotic figures. The tumor cells also exhibited strong expression of PAX8, CK7, and HNF1-β, various positivity of Napsin A and P504s, and partial expression of SOX17, CK20, and GATA3. The Ki-67 index ranged from 30% to 70%, and p53 showed a heterogeneous expression pattern. The cells were negative for p63 and the renal cell carcinoma marker (RCC). Among the 7 cases subject to urine fluorescence in situ hybridization (FISH) testing, 5 cases showed abnormal centromeric signals. One case underwent next-generation sequencing (DNA-seq) and harbored a nonsense ARID1A mutation. Two patients underwent radical surgery, 3 total urethrectomy, and 4 palliative surgery. Four patients received postoperative chemotherapy. The follow-up ranged from 9 to 58 months: 3 patients had tumor recurrence while 2 died. Conclusions: CCA of the urinary tract is a rare and aggressive malignancy. Its histological morphology resembles that of ovarian CCA. The diagnosis should be based on a combination of morphological features and immunophenotype. It is recommended to use PAX8, CK7, HNF1-β, and Napsin A as a core immunohistochemical panel, while testing SOX17 can also help.

Objective: To study the clinicopathological features, immunophenotype, diagnosis, and prognosis of TSC/mTOR mutation-associated renal cell carcinoma with leiomyomatous stroma (M/TSC-RCC-LMS). Methods: Nine cases of molecularly confirmed M/TSC-RCC-LMS were collected at the Affiliated Hospital of Qingdao University (7 cases) and No. 971 Hospital of the People's Liberation Army, Qingdao, China (2 cases) between December 2011 and August 2024. Histological evaluation, immunohistochemical staining, and molecular analysis were performed, along with literature review. Results: Among the 9 patients, 1 was male and 8 were female, with their ages 48(35,55) years. Eight cases were detected during routine physical examinations, while 1 case presented with painless gross hematuria. All 9 cases were located within the renal parenchyma, presenting nodular masses with tumor diameters 2.0(1.4,2/7) cm. The lesions were well-circumscribed. The tumors were solid, grayish-white, grayish-yellow or grayish-red in color, and soft in consistency, while one case showed cystic-solid characteristics. All 9 cases exhibited thick fibromuscular pseudocapsules. In 8 cases, smooth muscle components within the capsule were observed extending into the tumor, dividing the neoplastic tissue into nodular and clustered patterns. The tumor cells were primarily arranged in tortuous, elongated branching tubular structures, with focal areas showing small amounts of delicate papillary structures containing fibrovascular cores. They also had abundant cytoplasm that was pale-staining or mildly eosinophilic, occasionally clear. The nuclei were round or irregular in shape, with some showing conspicuous nucleoli. All the 9 cases showed patchy to diffusely strong expression of CK7 (70%-100%). Carbonic anhydrase Ⅸ (CAⅨ, 6/9) and CD10 (membranous positivity, 8/9) demonstrated variable extent and intensity of expression. Glycoprotein nonmetastatic melanoma protein B (GPNMB) showed diffusely moderate to strong positivity in 7 of the 9 cases. The 9 cases were all negative for α-methylacyl-CoA racemase (AMACR), TFE3, TFEB, TCEB1, HMB45, and Melan A, with Ki-67 proliferative index ranging from 1% to 10%. Whole exome sequencing revealed mTOR gene mutations in 5 cases, concurrent TSC2 and mTOR mutations in 1 case, a TSC2 mutation in 1 case, and germline TSC1 mutations in 2 cases. Follow-up of the cases ranged from 6 to 159 months. All patients were alive at the end of the follow-up, with no recurrence or metastasis. Conclusions: M/TSC-RCC-LMS exhibits unique morphological and immunophenotypic characteristics. The tumor cells exhibit abundant pale or mildly eosinophilic cytoplasm, forming elongated, tortuous branching tubules accompanied by stromal smooth muscle components. These are typically morphological features of this renal cell carcinoma subtype. The contribute to the diagnosis and differential diagnosis of the tumor diffusely strong positivity of CK7 and the positivity of GPNMB. This type of renal cell carcinoma often demonstrates indolent biological behaviors with favorable prognosis and is expected to be newly classified as an independent subtype of renal cell carcinoma.

Objective: To explore the clinicopathological features, immunophenotype, molecular characteristics, and prognosis of primary malignant solitary fibrous tumor (MSFT) of the kidney. Methods: The clinicopathological data of four renal MSFT cases diagnosed at the Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China and one case at the Ningbo Clinical Pathology Diagnostic Center, Ningbo, China between 2015 and 2025 were collected. The clinical features, histomorphology, and immunohistochemical characteristics were analyzed. Fluorescence in situ hybridization (FISH) and RNA-based next-generation sequencing were performed. Follow-up and review of relevant literature were conducted. Results: Among the five patients, three were male and two were female, aged 70(61,71) years. The tumors were all found during routine physical examinations. Four cases (cases 1, 3, 4, and 5) occurred in the left kidney, and one case (case 2) first occurred in the left kidney and recurred in the right kidney 5 years later. Four cases had a single lesion with a maximum diameter of 6.0-19.0 cm, and one case (case 5) had 2 lesions with maximum diameters of 2.0 cm and 4.0 cm, respectively. Histologically, three cases (cases 1, 2, and 5) were de novo MSFT, one case (case 5) was morphologically similar to synovial sarcoma with spindle cells arranged densely in bundles, one case (case 1) had sheets of epithelioid tumor cells, and one case (case 2) had alternating myxoid and spindle cell areas, with sparse tumor cells in the myxoid areas and dense tumor cells in the spindle cell areas. Two cases (cases 3 and 4) were classic solitary fibrous tumor (SFT) with dedifferentiation, and the dedifferentiated components were high-grade undifferentiated sarcoma. In the typical SFT areas, tumor cells were alternately dense and sparse, with collagenized areas and rare mitotic figures, while branching or hemangiopericytoma-like structures were also present. In the dedifferentiated areas, tumor cells were spindle-shaped or epithelioid with conspicuous nucleoli. Necrosis was seen in all three de novo MSFT cases (cases 1, 2, and 5) and one dedifferentiated case (case 4). The mitotic figures in three de novo SFT cases and two dedifferentiated areas were 4 to 10 per 10 HPF. No heterologous differentiation was found in any of the five cases. According to the Demicco risk classification, four cases were of moderate risk, and one case (case 4) was of high risk. Four cases showed diffuse expression of STAT6, while one case (case 3) showed partial expression. CD34 was diffusely positive in 3 cases, partially positive in one case (case 4) and negative in one case (case 1). Only one of the 5 cases expressed CKpan which was focally positive. PAX8, desmin, BCOR, S-100 protein, Melan A and HMB45 were all negative. H3k27Me3 expression was retained. FISH showed no SYT (SS18, 18q11) rearrangements in two cases (cases 4 and 5), and no MDM2 amplification in one case (case 5). RNA sequencing in four cases detected NAB2::STAT6 gene fusion, all of which were NAB2ex6::STAT6ex16 fusion subtypes. Follow-up data were available for four cases, with the follow-up period of 11-30 months. Among the 4 cases, one case had liver metastasis 3 months after surgery, and one case of left renal MSFT (moderate risk) had right renal recurrence 5 years after surgery. The other two had no recurrence or metastasis. Conclusions: Renal MSFT with moderate to high-risk is rare, shows a wide morphological spectrum and needs to be differentiated from various tumors. Extensive sampling, careful morphological observation, immunohistochemical staining and molecular detection of NAB2::STAT6 fusion are helpful for the diagnosis. It appears to have aggressive biological behaviors.

Neoadjuvant therapy has become one of the standard treatment modalities for various solid tumors. Accurate assessment of pathological response after neoadjuvant therapy is crucial to the guidance of subsequent treatment strategies and the determination of patient prognosis. Currently, expert consensus on pathological evaluation of neoadjuvant therapy efficacy has been well-established for tumors such as breast cancer and non-small cell lung cancer. However, the significant heterogeneity and multifocality of prostate cancer pose unique obstacles to establishing a standardized system for the pathological assessment for neoadjuvant hormonal therapy (NHT), The current status and challenges of pathological assessment for NHT response in prostate cancer are reviewed in this article, and the clinical value of predictive biomarkers is explored. The overarching goals are the optimize of patient stratification and the advance of precision medicine for prostate cancer.

The treatment landscape for treating NSCLC and SCLC has been shaped by significant advances in imaging, radiotherapy technology, tumor biology, and systemic therapy. This review evaluates the role of radiotherapy in contemporary lung cancer management, drawing on evidence from key prospective trials conducted in the past 2 decades.

To examine the risk factors for open conversion during minimally invasive colorectal surgery and to investigate the impact of open conversion on short- and long-term prognosis.

Second primary cancers (SPCs) pose an increasingly significant clinical challenge for survivors of hematologic malignancies, attributed to improved therapeutic outcomes and prolonged survival. The development of SPCs is influenced by a complex interplay of treatment-related factors, genetic susceptibility, immune dysregulation, and microenvironmental remodeling. This narrative review summarizes the epidemiological patterns of SPCs in survivors of hematologic malignancies and discusses the underlying biological mechanisms, including therapy-induced genomic instability, clonal hematopoiesis, inflammatory signaling, and alterations in the bone marrow microenvironment. Furthermore, we review current surveillance strategies and emerging biomarkers for early detection and risk stratification. Additionally, we discuss the potential contributions of integrated multi-omics approaches, tumor microenvironment profiling, and precision medicine strategies to SPC monitoring and prevention. Lastly, we outline future directions for clinicians and researchers, emphasizing the necessity for personalized surveillance programs, translational biomarker validation, and multidisciplinary management strategies to mitigate SPC risk in long-term survivors.

Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC.

ABBV-368 is a humanized monoclonal antibody that targets the costimulatory receptor OX40. Here, we investigate a treatment strategy with ABBV-368 combined with the investigational toll-like receptor 9 agonist tilsotolimod, the programmed cell death 1 inhibitor budigalimab, and nab-paclitaxel in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). To our knowledge, this is the first clinical study in this setting to investigate chemotherapy combined with three immunotherapy agents, aiming to overcome failure of prior immune checkpoint inhibition and chemotherapy.

To date, no radioimmunotherapy (RIT) regimen has been approved by US Food and Drug Administration for the treatment of pancreatic cancers. Highly desmoplastic and immune-desert phenotypes of pancreatic cancer remain two major hurdles that attenuate the efficacy of conventional treatment (radiotherapy and chemotherapy) and immunotherapeutic (immune checkpoint inhibitors and chimeric antigen receptor T cells).

Atezolizumab plus bevacizumab (Atez/Bev) has become the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, reliable biomarkers to predict therapeutic response remain lacking.

The tumor microenvironment (TME), composed of tumor cells together with stromal cells, immune cells, vascular networks, and other components, constitutes a complex ecosystem that plays a decisive role in tumor initiation, progression, metastasis and therapeutic response. Traditional pathological diagnosis mainly relies on pathologists manually examining H&E-stained tissue sections under the microscope, a method that not only suffers from substantial interobserver variability but also has relatively low analytical efficiency. With the rapid development of computational pathology, the integration of whole-slide imaging technology and deep learning algorithms has provided powerful tools for characterizing tumor microenvironment. These techniques enable automated characterization of cellular, spatial and molecular heterogeneity within the tumor microenvironment, providing integrated insights that advance precision diagnostics and improve prediction of therapeutic response and patient outcomes. Based on a comprehensive review of existing research, this paper highlights recent advances in deep learning-driven recognition of panoramic TME features from H&E slides and their clinical applications and further discusses both the translational potential and current limitations of this technology in oncology research and clinical applications.

Human solid tumors such as hepatocellular carcinomas (HCC) establish a complex immunosuppressive tumor microenvironment (TME) that undermines the efficacy of existing immunotherapies such as chimeric antigen receptor T (CAR T) cell therapy. To advance immunotherapy for HCC, it is crucial to delineate the molecular mechanisms that drive TME formation and immune evasion.

In this issue of Developmental Cell, Wu et al.1 identify that invasion of ovarian cancer cell spheroids into the mesothelium is critically aided by apical constriction of mesothelial cells. Experimentally, integrin adhesions linked invasion and constriction, while computational modeling revealed that these cell behaviors are explainable by active wetting theory.