Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252218
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To analyze the occurrence and distribution of high-level microsatellite instability (MSI-H) in precancerous lesions and histological subtypes of endometrial cancer, to compare the concordance rate between mismatch repair...To analyze the occurrence and distribution of high-level microsatellite instability (MSI-H) in precancerous lesions and histological subtypes of endometrial cancer, to compare the concordance rate between mismatch repair protein deficiency (dMMR) and MSI-H, to investigate the incidence of minimal microsatellite shift in the development of endometrial cancer, and to explore potential solutions for accurate MSI-H diagnosis. A total of 848 endometrial lesion samples that underwent molecular typing at the Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University from January 2023 to January 2024 were collected, including 93 cases of atypical endometrial hyperplasia (AEH) and 755 cases of endometrial carcinoma. Microsatellite status, MMR protein expression, and gene mutations (MMR, POLE, etc.) were analyzed by histology, IHC, and NGS. Microsatellite status was determined by calculating the MSI-score based on 34 microsatellite loci. An MSI-score<0.3 was defined as microsatellite stable (MSS),≥0.3 as microsatellite instability-high (MSI-H), and 0.3±0.05 as the equivocal range. Simultaneously, a visualization graph was established for minimal microsatellite shift analysis and identification. The 848 lesions included 93 cases of AEH, 442 cases of low-grade endometrioid carcinoma (G1-G2), 143 cases of high-grade endometrioid carcinoma (G3), 20 cases of clear cell carcinoma, 20 cases of carcinosarcoma, 16 cases of mixed adenocarcinoma, 12 cases of dedifferentiated/undifferentiated carcinoma, and 102 cases of other types (including 94 serous carcinomas, 6 mesonephric-like adenocarcinomas, and 2 gastric-type mucinous adenocarcinomas). The results showed that the incidence of dMMR in AEH was 4.3%, and MSI-H was 3.2%, significantly lower than the 24.9% and 23.0% in endometrial cancer, respectively (<0.001). All the 102 cases of other types, including serous carcinoma, were pMMR/MSS. The overall concordance rate between dMMR and MSI-H was 90.6%, but it varied between 75% and 100% across different stages and histological subtypes. In molecular subtyping, the concordance rate was 75% for AEH and carcinosarcoma, 87.5% for dedifferentiated/undifferentiated carcinoma, 91.5% for high-grade endometrioid carcinoma, and 100% for other high-grade carcinomas, while the POLE-mutated subtype had the lowest concordance rate of 66.7%, significantly lower than the 93.1% overall concordance rate for the MSI-H subtype (<0.001). In MSI-H cases, up to 84.5% of endometrial cancer cases exhibited minimal microsatellite shift in at least one locus, with 67.8% showing shifts in≥3 loci. Through analysis of 34 microsatellite loci and visualization, 20 cases (11.5% of 174 MSI-H cases) were identified as borderline (MSI-score=0.3±0.05), considered diagnostically challenging. Among these, MLH1-/PMS2- co-loss accounted for 12/20 cases, with half (6/12) harboring MLH1 mutations; isolated MSH6 loss accounted for 6/20 cases, with 5 of these harboring MSH6 mutations. The 20 minimal shift MSI-H cases shared all pathological features of typical MSI-H endometrial cancer. The incidence and distribution of MSI-H show significant differences across histological subtypes between endometrial precancerous lesions and endometrial carcinomas. The overall concordance between dMMR and MSI-H is good, but varies across different disease stages, histological types, and molecular subtypes. Minimal microsatellite shift is commonly detected in MSI-H cases, and some cases are difficult to interpret due to their classification within the equivocal range. Increasing the number of microsatellite loci, combined with visualization graph comparison and integration of mismatch repair protein immunophenotype and histological features, can effectively improve the accuracy of MSI-H interpretation.
Lei T, Shi YQ, Deng X
… +4 more, Wang HY, Cheng YQ, Qiang X, Li Q
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252217
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To investigate the clinicopathological and molecular genetic characteristics of uterine inflammatory myofibroblastic tumor (UIMT). A retrospective analysis was conducted on 8 patients diagnosed with UIMT at Changzhou Fi...To investigate the clinicopathological and molecular genetic characteristics of uterine inflammatory myofibroblastic tumor (UIMT). A retrospective analysis was conducted on 8 patients diagnosed with UIMT at Changzhou First People's Hospital, Changzhou Wujin Hospital of Traditional Chinese Medicine, Changzhou Second People's Hospital, and Changzhou Maternal and Child Health Care Hospital from January 2018 to July 2025, including 6 cases of non-aggressive UIMT, 1 case of aggressive UIMT and 1 case of epithelioid inflammatory myofibroblastic sarcoma (EIMS). The clinicopathological features, molecular genetic characteristics, treatment and prognosis were summarized. The patient's age was 44.5(38.5, 46.0) years old, and the tumor size was 6.35(5.05, 8.70) cm. Among the cases, one tumor was located submucosally within the uterus, four were within the uterine muscular wall, and three were subserosa. The tumors exhibited heterogeneous morphological features: non-aggressive UIMT displayed either a mucinous pattern with sparse cellularity or a dense fascicular pattern (similar to smooth muscle), with well-defined tumor margins or invasive growth; UIMT with aggressive behavior showed invasive growth, with greater cellular atypia, more mitotic figures, and necrosis. One EIMS showed invasive growth, mainly composed of epithelioid cells with focal spindle cell morphology, significant cellular atypia, active mitotic figures, and a small amount of lymphocyte and plasma cell infiltration between the epithelioid cells. Fluorescence in situ hybridization (FISH) testing detected ALK rearrangement in all eight cases. RNA next generation sequencing (NGS) indicated that all tumors were driven by ALK rearrangement. Among these tumors, EIMS harbored a novel fusion gene, KANK2::ALK. DNA NGS demonstrated that UIMT with aggressive behavior and EIMS harbored more pathogenic gene alterations, including mutations in TP53 and ATM, as well as amplification of the CCNE1 gene. Except for EIMS, immunohistochemical analysis revealed positive expression of ALK protein in 7 cases of UIMT. Immunohistochemistry also showed abnormal expression of p16 or p53 protein in EIMS and one case of UIMT with aggressive behavior. All patients underwent surgical treatment. The follow-up period ranged from 4 to 84 months. One patient with aggressive behavior of UIMT developed liver and lung metastases 4 months after the surgery. The patient was treated with the oral targeted drug crizotinib and died of multiple organ failure 18 months after surgery. UIMT is a morphologically heterogeneous neoplasm, and its biological behavior can vary from benign to highly aggressive. This type of tumor is mainly driven by ALK gene rearrangement. UIMT and EIMS that exhibit aggressive behavior typically possess a greater number of genetic alterations. The abnormal expression of p53 or p16 protein, when combined with clinicopathological parameters, can serve as indicators for predicting the adverse biological behavior of tumors.
Zhang PY, Wu CY, Wu W
… +6 more, Xie HK, Hou LK, Huang Y, Dong ZW, Li SL, Xie XF
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252216
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To investigate the clinicopathological features of tuberous sclerosis complex (TSC)-associated multifocal micronodular pneumocyte hyperplasia (MMPH) and the mutation status of TSC1/TSC2 genes. A retrospective analysis w...To investigate the clinicopathological features of tuberous sclerosis complex (TSC)-associated multifocal micronodular pneumocyte hyperplasia (MMPH) and the mutation status of TSC1/TSC2 genes. A retrospective analysis was conducted on 8 MMPH cases diagnosed at Shanghai Pulmonary Hospital Affiliated to Tongji University from September 2020 to August 2024. Clinical information and imaging findings of these cases were collected. Histopathological analysis and next-generation sequencing (NGS) were performed. Among the 8 patients, there were 4 males and 4 females, aged 44 (36, 50) years old. None of them had a definite family history of TSC. Only 1 patient presented with respiratory symptoms at the time of consultation. Four patients had TSC-related cutaneous lesions. Two had shagreen patches, 1 had hypomelanotic macules, and 1 had hypomelanotic macules combined with fibrous plaques on the scalp and angiofibromas. Three patients themselves or their first-degree relatives had a history of epilepsy. Five patients themselves or their first-degree relatives had liver/kidney cysts or a surgical history of renal angiomyolipoma. Computerized tomography scans showed multiple ground-glass nodules in both lungs, with an average diameter of 10.5 (8.5, 11.0) mm. Six cases were diagnosed via surgical resection, and 2 via transbronchial cryobiopsy. Intraoperative frozen sections of the 6 surgically resected cases were all misdiagnosed as early-stage lung adenocarcinoma (including adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive non-mucinous adenocarcinoma), but the diagnosis was corrected to MMPH postoperatively. One of these 6 cases was concurrent with a benign perivascular epithelioid cell tumor (PEComa). Microscopically, MMPH was characterized by multifocal proliferation of type Ⅱ alveolar epithelial cells, which showed bland cellular morphology without atypia or invasive growth. For the case concurrent with PEComa, clear epithelioid cells were observed growing in nests or sheets. Immunohistochemically, the proliferative epithelial cells were positive for TTF-1 and showed low expression of Ki-67. PEComa cells were positive for Melan A and MiTF. NGS showed that TSC1 mutations were detected in 6 cases, TSC2 mutation in 1 case (which also had a concurrent class Ⅲ missense mutation of BRAF G466E), and no mutation in 1 case, with an overall mutation detection ratio is 7/8. No other lung cancer-related driver-gene variations were found in any case. Follow-up data were available for 8 patients. During the follow-up, 1 patient developed scattered thin-walled lucencies in both lungs, but no pathological examination was performed. All patients had a favorable overall survival status, follow-up time was 14.0(9.5,47.0) months. MMPH is a rare, benign TSC-associated pulmonary lesion, often presenting as multiple ground-glass nodules in both lungs. It can be easily misdiagnosed as early-stage lung adenocarcinoma. The diagnosis requires a comprehensive judgment based on clinical data, imaging findings, histopathology, and TSC1/TSC2 gene mutation results.
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252215
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To investigate the diagnostic value of PRAME immunohistochemistry in the differential diagnosis between clear cell sarcoma (CCS) of soft tissue and melanoma, and its utility in routine diagnostic practice. A retrospecti...To investigate the diagnostic value of PRAME immunohistochemistry in the differential diagnosis between clear cell sarcoma (CCS) of soft tissue and melanoma, and its utility in routine diagnostic practice. A retrospective analysis was conducted on 25 CCS and 25 site-matched melanoma cases diagnosed at the Fudan University Shanghai Cancer Center from 2021 to 2025. Clinicopathologic data were collected, histologic features were assessed, and PRAME immunohistochemistry was performed. Clinicopathologic differences between the two groups were compared. The sensitivity and specificity of PRAME for differential diagnosis were evaluated. Twenty-five patients with CCS were included, aged 38.0 (31.5, 56.0) years old. Another 25 patients with melanoma were included, aged 61.0 (54.0, 72.0) years old. In each group, 11 male and 14 female patients were included. Tumors were predominantly located in the extremities and trunks in both groups. In primary or recurrent melanomas, epidermal involvement with pagetoid proliferation at the dermoepidermal junction was frequently observed, whereas epidermal involvement was usually absent in CCS. Epithelioid morphology with prominent tumor-infiltrating lymphocytes and scant fibrous collagen septa were more often observed in metastatic melanomas, whereas a mixed epithelioid-spindle pattern, paucity of tumor-infiltrating lymphocytes, and frequent fibrous collagen septa were more commonly observed in CCS. PRAME negativity was observed in 96.0% (24/25) of the CCS cases, with only one case showing 5% nuclear positivity. By contrast, PRAME positivity was observed in 88.0% (22/25) of the melanoma cases, including diffuse nuclear positivity in>50% of tumor cells in 80.0% (20/25) of cases (0.001). With the cut-off of >50% positive cells, the sensitivity and specificity of PRAME for the diagnosis of melanoma were 80.0% and 100.0%, respectively. BRAF V600E immunohistochemistry was positive only in melanoma (56.0%, 14/25). All CCS cases were molecularly confirmed to harbor EWSR1 rearrangement.No co-occurrence of EWSR1 rearrangement and BRAF V600E immunohistochemistry positivity was observed in this cohort. Diffuse PRAME nuclear positivity is highly specific for diagnosing melanoma. It is particularly useful in biopsy specimens from recurrent lesions, needle biopsy specimens from metastatic lesions with inconspicuous pigmentation, biopsies of small primary lesions, and ulcerated specimens lacking an epidermal component. Therefore, PRAME immunohistochemistry is especially practical for community-hospital laboratories and interpreting biopsy specimens with limited tissue.
Wei YY, Zheng LM, Pan XY
… +7 more, Yu TP, Zhang JY, Gong J, Yu T, Chen XQ, Zhou Q, Chen N
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252214
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To investigate the clinicopathological characteristics of IDH-mutant adult-type diffuse gliomas. Adult-type diffuse gliomas with IDH1 (R132) or IDH2 (R172) mutation confirmed by Sanger sequencing and 1p/19q FISH testing...To investigate the clinicopathological characteristics of IDH-mutant adult-type diffuse gliomas. Adult-type diffuse gliomas with IDH1 (R132) or IDH2 (R172) mutation confirmed by Sanger sequencing and 1p/19q FISH testing were collected at the West China Hospital of Sichuan University between January 2021 and June 2025. The correlations among patient sex, age, lesion location, IDH mutation type, tumor type, and WHO grade were retrospectively analyzed. Among the 1 301 patients, 722 (55.5%) were male and 579 (44.5%) were female, with a male-to-female ratio of 1.25∶1.00. The patient age was 41 (33, 51) years. There were 9 patients (0.7%) aged≤18 years, 1 140 (87.6%) aged 19-55 years, and 152 (11.7%) aged>55 years. There were observed in 1 271 cases (97.7%) of supratentorial tumor and 17 cases (1.3%) of infratentorial tumor, while the location was unknown in 13 cases (1.0%). IDH1 (R132) mutations were identified in 1 244 cases, with R132H being the most common (1 211 cases, 93.1%), while non-R132H IDH1 mutations were detected in 33 cases (2.5%) and IDH2 mutations in 57 cases (4.4%). Among the 1 301 cases, 711 cases (54.7%) were astrocytoma, with WHO grades 2, 3, and 4 comprising 364 cases (51.2%), 116 cases (16.3%), and 231 cases (32.5%), respectively. Oligodendrogliomas accounted for 590 cases (45.3%), with WHO grade 2 in 372 cases (63.1%), and WHO grade 3 in 218 cases (36.9%). Patient sex was associated with WHO grade (=0.078, =0.014), but not age, location, tumor type, or IDH mutation type. Male patients outnumbered females across all grades, with the proportion of males increasing with higher tumor grades. Patient age was associated with IDH mutation type and tumor type (=-0.072, 0.199, =0.001), but not location or WHO grade. Compared to patients>18 years, those≤18 years were more likely to harbor non-R132H IDH1 mutations, whereas IDH2 mutations were observed only in patients>18 years. Patients over 65 years exhibited exclusively IDH1 R132H mutation. The proportion of oligodendroglioma patients increased with age (=0.199, =0.001). Tumor location was associated with IDH mutation type and tumor type (=0.118, -0.077,<0.05), but not with WHO grade. Compared to supratentorial tumors, non-R132H IDH1 mutations were significantly more common in infratentorial tumors (=74.285, =0.001), while IDH2 mutations rarely occurred infratentorially. Oligodendrogliomas were rarely found in infratentorial locations. IDH mutation type was associated with tumor type (=0.118, =0.001), but not with WHO grade. The incidence of non-R132H IDH1 mutations was significantly higher in astrocytoma than oligodendroglioma. The proportion of IDH2 mutations was significantly higher in oligodendrogliomas than astrocytoma (=50.661, <0.001). IDH mutations predominantly occur in adults, with an average age range of 25-55 years, although there are also rare pediatric cases. IDH-mutant gliomas are most located in the supratentorial region, particularly in the frontal lobe, and predominantly with IDH1 R132H mutation. Patients aged >65 years exclusively exhibit IDH1 R132H mutations. Compared to supratentorial tumors, non-R132H IDH1 mutations are significantly more frequent in infratentorial tumors. IDH2-mutant gliomas almost exclusively occur in adults and in supratentorial locations, with a significantly higher proportion in oligodendrogliomas than astrocytoma.
Duan ZJ, Yang JJ, Feng J
… +5 more, Ma Z, Zhang XF, Hu ZJ, Xiang L, Qi XL
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252213
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To investigate the clinicopathological and genetic characteristics of papillary glioneuronal tumor (PGNT) and to reclassify cases according to the integrated pathologic-molecular diagnosis with the 2021 World Health Orga...To investigate the clinicopathological and genetic characteristics of papillary glioneuronal tumor (PGNT) and to reclassify cases according to the integrated pathologic-molecular diagnosis with the 2021 World Health Organization (WHO) classification of tumors of central nervous system (CNS). Six tumors diagnosed as PGNT at the Sanbo Brain Hospital, Capital Medical University from January 2010 to August 2025 were collected. Their clinical, imaging, histopathological, and molecular data were retrospectively analyzed. Comprehensive profiling was conducted using hematoxylin and eosin staining, immunohistochemistry, targeted next-generation sequencing, RNA sequencing, and DNA methylation analyses. All tumors were located in the supratentorial cerebral hemispheres. Among the 6 patients, there were 4 males and 2 females, aged 17.0 (10.0, 25.5) years old. Histology revealed a characteristic papillary structure. In four cases, focal and sheet-like neurocytic cells were observed in interpapillary regions, meanwhile two cases showed scattered suspicious ganglion or neuronal cells. Mitoses were rare. The case 4 exhibited focal anaplasia features within the tumor. The papillary-forming cells showed diffuse immunoreactivity for GFAP, OLIG2, S-100, and SOX10. Cells in the interpapillary areas exhibited diffuse or partial synaptophysin positivity, with focal and diffuse positivity for NeuN and calretinin in four cases. The Ki-67 proliferation index was mostly<5% (only one case showed a focal increase to 8%). All cases were negative for IDH1-R132H, H3K27M, and BRAF V600E. Cases 3 to 6 harbored SLC44A1::PRKCA fusions. Cases 1 and 2 had KIAA1549::BRAF and STRIP2::BRAF fusions, respectively. Based on the integrated pathologic-molecular diagnosis, the cases 3 to 6 were definitively classified as PGNT, CNS WHO grade 1, while the case 4 showed focal anaplasia. By integrated with DNA methylation profiling, the case 1 and 2 were reclassified as low-grade glioma/low-grade glioneuronal tumor, not elsewhere classified. The 6 patients underwent craniotomy with gross total or subtotal tumor resection. One of them also received local radiotherapy. At the last follow-up (July 2025), all patients were alive without recurrence or progression. The overall survivals were 105, 50, 66, 64, 12, and 6 months, respectively. PGNT is a rare glioneuronal tumor characterized by a biphasic pattern with pseudopapillary glial architectures and interpapillary neuronal components. The presence of focal and sheet-like NeuN-positive neurocytic cells in the interpapillary regions is a significant diagnostic clue for PGNT. Integrated pathologic-molecular analysis is essential for accurately classifying supratentorial papillary glioneuronal tumors. Classic PGNTs are molecularly defined by recurrent PRKCA fusions, while BRAF-altered cases warrant reclassification.
Yuan ML, Liu Q, Shi XY
… +6 more, Zhou ZY, Shi Y, He ZC, Ping YF, Chang ZJ, Bian XW
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252212
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To investigate the expression pattern of cell cycle-related and expression-elevated protein in tumor (CREPT) in vascular endothelial cells of glioma and to elucidate its mechanism in regulating angiogenesis. Based on si...To investigate the expression pattern of cell cycle-related and expression-elevated protein in tumor (CREPT) in vascular endothelial cells of glioma and to elucidate its mechanism in regulating angiogenesis. Based on single-cell sequencing data from human glioma samples, CREPT expression patterns across different cell types were analyzed. Immunohistochemistry and immunofluorescence staining were used to examine its expression and distribution in glioma tissues. The correlation between CREPT expression and micro-vessel density (MVD) in glioblastoma was evaluated. Gene set enrichment analysis (GSEA) was performed to assess CREPT's impact on endothelial cell functions. A CREPT-knockdown hCMEC model was established. Tube formation assays were conducted to evaluate CREPT's effect on angiogenic capacity. The Gilovis database was used to analyze the correlation between CREPT and vascular endothelial growth factor A (VEGFA), and to validate their expression patterns in different glioblastoma regions, which was further confirmed using immunohistochemistry. Western blot was also performed to detect changes in the expression of adhesion junction proteins and downstream signaling molecules. CREPT was specifically expressed in glioma vascular endothelial cells, and the micro-vessel density (MVD) in the group with high CREPT expression was significantly higher than that in the group with low CREPT expression (=2.083, <0.05). GSEA showed that CREPT was involved in regulating endothelial cell tube formation and adhesion junction functions. The tube-forming ability of hCMEC was significantly inhibited by knockdown of CREPT (=12.99, <0.05). Using differential expression analysis and clinical sample validation, it was revealed that both CREPT and VEGFA were upregulated in regions such as pseudopalisading necrosis (=7.513, 0.05;=9.461,<0.001), and their expression levels were positively correlated (=0.36, <0.05). After CREPT knockdown, the expression of VEGFR2 was markedly decreased (=12.74, <0.05). CREPT is specifically expressed in glioma vascular endothelial cells. It also enhances the tube-forming capacity of glioma vascular endothelial cells and promotes tumor angiogenesis by regulation of the VEGFA-VEGFR2 signaling pathway. These findings provide a novel potential target for anti-angiogenic therapy in glioblastoma.
Zhonghua Bing Li Xue Za Zhi
· 2026 Jun · PMID 42252210
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Genome-wide DNA methylation profiling, a high-throughput epigenomic technology, systematically examines the methylation status of CpG sites across the genome to generate "methylation fingerprints" that reflect cellular o...Genome-wide DNA methylation profiling, a high-throughput epigenomic technology, systematically examines the methylation status of CpG sites across the genome to generate "methylation fingerprints" that reflect cellular origins and developmental states. This technique has emerged as a transformative tool in the diagnosis of central nervous system (CNS) tumors. This article introduces the principles of this technology, along with its significant applications and major limitations in the diagnosis of CNS tumors. It proposes that current pathological diagnosis of CNS tumors should adopt an integrated diagnostic model centered on the pathologist, emphasizing that methylation profiling serves as an adjunctive tool rather than a replacement. Any methylation-derived result must be interpreted within the comprehensive context of clinical, radiological, histopathological, and molecular data. In the future, with advances in explainable artificial intelligence, multi-omics integration, and international standardization efforts, this technology is expected to evolve from a "revolutionary tool" into an "intelligent assistant" deeply integrated with pathological diagnosis.