Background Differentiating central nervous system (CNS) germinomas from other germ cell tumors (GCTs) is diagnostically challenging. EZHIP (EZH Inhibitory Protein, encoded by CXorf67) and H3K27me3 (trimethylated histone H3 at lysine 27) are widely used in diagnosing posterior fossa group A (PFA) ependymomas, their expression in germinomas remains poorly characterized. Methods We performed a clinico-pathological and immunohistochemical (IHC) analysis of 126 CNS GCT cases. Expression of EZHIP, H3K27me3, SALL-4, OCT3/4, and PLAP was evaluated in paraffin-embedded tissues. Results In GCTs of the CNS, both pure germinomas and the germinoma component in NGGCTs, EZHIP was positive in 95.1% (97/102) of cases, loss of H3K27me3 was observed in 98.0% (100/102), SALL-4 was expressed in 100% (82/82), OCT3/4 in 98.9% (96/97), and PLAP in 96.9% (94/97). In contrast, none of the non-germinomatous components of the CNS GCTs showed EZHIP positivity (0/24), while loss of H3K27me3 was found in such components in only 12.5% of the tumors. Both markers exhibited statistically significant differential expression (P < 0.01 for each). For diagnosing germinomas, EZHIP expression demonstrated a sensitivity of 95.1% and specificity of 100%, whereas H3K27me3 loss had a sensitivity of 98.0% and specificity of 87.5%. Conclusion EZHIP expression and loss of H3K27me3 staining are good markers for recognition of pure germinomas and of germinoma components in mixed germ cell tumors as such and can be used for discriminating those from non-germinomatous components of the CNS GCTs.

Myxopapillary ependymoma (MPE) is a rare spinal tumor that remains undercharacterized in systematic investigations. Accurate distinction from histologic mimics in the conus-cauda-filum terminale region is challenging. This study aimed to describe the clinicopathologic features and outcomes of a large single-center MPE cohort, evaluate the diagnostic utility of HOXB13 immunohistochemistry (IHC), and explore the molecular profiles of atypical cases through methylation clustering. HOXB13 IHC was performed on 45 MPEs, 44 spinal ependymomas (SEs), and 35 other nonependymal spinal tumors. Fourteen atypical cases (MPEs with weak HOXB13 or high-level involvement, and HOXB13-positive SEs) were analyzed by DNA methylation microarray with t-SNE and random forest clustering. HOXB13 expression was semiquantitatively graded (0 to 2). Strong positivity was seen in 97.8% (44/45) of MPEs, but only 4.5% (2/44) of SEs and 11.4% (4/35) of nonependymal tumors. Sensitivity and specificity for MPE diagnosis were 97.8% and 92.4%. Methylation clustering showed strong HOXB13 expression aligned with the MPE methylation class (EPN_MPE). Notably, 3 typical MPEs were misclustered due to fresh hemorrhage, stromal sclerosis, or dural components, whereas 2 HOXB13-strong lumbar SEs fell into the EPN_MPE class. MPE patients had 100% 10-year overall survival and 75% progression-free survival (PFS), but PFS was significantly shorter than that of SE patients ( P < 0.01). HOXB13 is a highly specific and sensitive IHC marker for MPE. Histologic artifacts can interfere with methylation-based classification, emphasizing the need for tissue quality assessment and microdissection when indicated. HOXB13 IHC is a simple, reliable diagnostic tool that improves accuracy when added to routine IHC panels.

H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and EGFR-mutant. H3F3B, another gene encoding histone H3.3 in addition to H3F3A, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of H3F3B-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with H3F3B-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic H3F3B p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that H3F3B-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. PPM1D and NF1 were frequently mutated in H3F3B-mutant DMGs. Survival analysis showed that H3F3B-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, H3F3B mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between H3F3B-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.

Key point:IRM appears promising and well tolerated as first-line therapy for newly diagnosed PCNS DLBCL in a small pilot cohort; these hypothesis-generating results require confirmation in larger prospective studies. Background:Primary diffuse large B-cell lymphoma of the central nervous system (PCNS DLBCL) is a rare, aggressive lymphoma with rising incidence in elderly patients. Bruton tyrosine kinase (BTK) inhibitors show promise in recurrent/refractory cases, warranting exploration in newly diagnosed disease. Methods:This single-center pilot study evaluated the safety/efficacy of ibrutinib, rituximab, and high-dose methotrexate (IRM) in nine newly diagnosed PCNS DLBCL patients (2018-2019). Treatment included 4 cycles of IRM induction, consolidation (HSCT or 2 additional IRM cycles), and maintenance therapy (ibrutinib/lenalidomide). Results:After induction, overall response rate (ORR) was 100% (complete response [CR]: 77.8%, partial response [PR]: 22.2%). Post-consolidation, CR increased to 88.9%. At a median follow-up of 77.6 months, 5-year overall survival (OS) and progression-free survival (PFS) rates were both 77.8%, with 8 patients in sustained CR and one progression. No treatment-related deaths occurred; grade ≥3 adverse events were rare (2 neutropenia, 2 anemia, 1 gastrointestinal bleeding). Conclusion:In this small pilot cohort, IRM showed promising activity and tolerability as first-line therapy for PCNS DLBCL. These descriptive findings warrant confirmation in larger prospective trials (#ChiCTR1900027811).

Our previous research demonstrated that TERT and concurrent PIK3CA mutations predict worse overall survival in patients with poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma. However, the molecular mechanism underlying the synergistic oncogenic operations of the two oncogenes is unclear. This study aimed to explore further the effect of TERT and PIK3CA co-mutation on the malignant biological phenotype of thyroid carcinoma and its possible mechanism. PIK3CA E545K mutation plasmid was transfected into thyroid anaplastic cancer cell line (C643) with TERT promoter mutation, then CCK-8 and transwell invasion assays were used to investigate the ability of cell proliferation and invasion, respectively. RT-qPCR and western blot were performed to detect the expression of PIK3CA, TERT, GABPA and GABPB1. GABPA/GABPB1 siRNA plasmid was transfected with C643 cells, then the ability of cell proliferation and invasion were identified. We also detected the expression of PIK3CA and TERT. C643 cells carry TERT promoter mutation C228T. Concurrent PIK3CA E545K and TERT mutation markedly enhanced the proliferation and invasion of C643 cell in vitro, with significantly increased mRNA/protein expression of PIK3CA, TERT, GABPA and GABPB1. Knocking down GABPA markedly inhibited cell proliferation. Knocking down of GABPB1 significantly decreased the proliferation and invasion of C643 cells, with much lower expression of PIK3CA and TERT. TERT and PIK3CA co-mutations promote the proliferation and invasion of thyroid anaplastic carcinoma cells and may be caused by up-regulating the expression of GABPA and GABPB1.

MicroRNA-20a-5p (miR-20a-5p) has been shown to function as a tumor promoter factor in several cancers. However, its role in small cell lung cancer (SCLC) remains unclear. In this study, we have made an attempt to measure the tumor tissue levels of miR-20a-5p in patients with SCLC using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The biological function of miR-20a-5p in SCLC cells was investigated in vitro and in vivo studies, including cell proliferation, migration assays and tumorigenicity in nude mice. Meanwhile,we conducted the luciferase reporter assay to verify the biological relationship between miR-20a-5p and CCNG2. The expression of miR-20a-5p was significantly upregulated in human SCLC compared to that in normal tissues. Kaplan-Meier analysis indicated that patients with high expression of miR-20a-5p are closely related with the shorter survival of SCLC. Further, multivariate analysis showed that miR-20a-5p was an independent prognostic factor. Increasing miR-20a-5p expression promotes the proliferation, migration and invasion of the NCI-H446 cells in vitro and in vivo. Dual-luciferase reporter gene assay demonstrated that miR-20a-5p directly targets CCNG2. These findings suggest that miR-20a-5p levels might be a novel diagnostic and prognostic marker of SCLC. Inhibiting miR-20a-5p could be a promising therapeutic strategy for SCLC.

temozolomide are the primary treatment options when complete surgical resection is risky. Some studies on targeted drugs and cellular immunotherapy, such as Imipridone ONC201 and the IDO1 inhibitor Indoxi-mod are in the early phases of clinical activity. In addition, the use of immunotherapy is being trialed as an option. Chimeric antigen receptor T-cell therapy and immune-modulating antibodies are also under research. Our patient, despite surgical resection followed by con-current chemoradiotherapy, experienced rapid regrowth of the tumor, which lead to her demise 6 months after surgery.

A 29-year-old man presented with intermittent headache for 3 months. Cranial magnetic resonance imaging showed a nodular, hemorrhagic mass measuring 57 × 56 × 51 mm located in the right frontal region. The mass showed heterogeneously isointense T2-weighted and hypointense T1-weighted image signals with heterogeneous contrast enhancement using gadolinium (Figure 1). The patient underwent systemic examinations during which no other specific abnormalities were found. Gross total resection was performed by a right frontal approach. During the operation, the right frontal gyrus was found to be swollen. The tumor was located below the right frontal cortex, and adhered tightly to the cerebral falx (Box 1). Access at https://isn-slidearchive.org/?col=ISN&fol=Archive&file=BPA-22-10-243.svs Histopathological examination revealed a densely cellular malignant tumor involving meninges (Figure 2A). The tumor exhibited a poorly differentiated and somewhat primitive appearance. There was a heterogeneous population of small round cells, spindle cells and ovoid cells arranged in fascicular and storiform patterns. The tumor cells exhibited obvious atypia, with scattered pleomorphic cells. Mitoses were frequent (10 mitoses/mm2) (Figure 2B). Some of the tumor cells had prominent eosinophilic cytoplasmic globules (Figure 2C). Reticulin stain revealed a dense pericellular network among tumor cells (Figure 2D). By immunohistochemistry, tumor cells were diffusely positive for vimentin and negative for GFAP, OLIG2 and synaptophysin. They expressed diffusely p53 and showed loss of expression for ATRX (Figure 2E) and H3 K27me3 (mosaic loss) (Figure 2F). INI1 protein expression was retained, whereas H3G34R, H3G34V, EMA, SSTR-2, CD34, STAT-6, SOX-10, SMA, Desmin and Myogenin were negative. The Ki-67 proliferation index was 80%. Next-generation sequencing revealed that the tumor harbored mutations of DICER1 (c.5438A>G, p.E1813G mutation and c.4458dup, p.Ser1487IIefsTer5 mutation, with mutant allele frequencies of 45.1% and 49.3% respectively), while H3.1/H3.3 and IDH1/2 were wild-type. In addition, the tumor also harbored NF1 nonsense mutation (c.6211C>T p.Gln2071Ter p.Q2071*), ARID1B missense mutation (c.6565C>G p.Pro2189Ala), ATRX splicing mutation (c.6505-1G>C), and TP53 nonsense mutation (c.517G>A p.Val173Met p.V173M), as well as copy gain of FGFR3, NOTCH1, and SDHA. Primary intracranial sarcoma, DICER1-mutant. DICER1-mutant primary intracranial sarcoma, a very rare tumor recently added to the 2021 WHO classification of central nervous system (CNS) tumors, harbors pathogenic DICER1 mutations and a distinctive DNA-methylation profile [1]. The DICER1 gene, located at 14q32.2, encodes a ribonuclease essential in the production of microRNAs and its mutations have been shown to interfere with its ability to process RNAs. The tumor primarily occurs in children, with a median age of 6 years and has been associated primarily with DICER1 tumor predisposition syndrome, but also with neurofibromatosis type 1 [1]. The prognosis remains unknown because of limited clinical data collected to date. Here, we report a very unusual case occurring in an adult, with no indications of DICER1 tumor predisposition syndrome. This tumor was initially considered a possible H3 G34-mutant diffuse hemispheric glioma or embryonal CNS tumor according to histological features indicative of a malignant high grade tumor with a somewhat primitive appearance, negative for OLIG2, with loss of ATRX expression and strong p53 expression [2]. Given the complete lack of expression of glial (GFAP and OLIG2) markers, while vimentin was diffusely positive in the tumor cells and reticulin stain showed a dense pericellular network, consideration was also given to other diagnoses including malignant peripheral nerve sheath tumor, solitary fibrous tumor or an undifferentiated sarcoma. The final diagnosis of “DICER1-mutant primary intracranial sarcoma” was made after confirming that this tumor harbored DICER1 mutations. In addition to DICER1 mutations, the tumor also showed disruptions of p53 signaling due to a TP53 mutation, chromatin remodeling due to a ATRX mutation, and NOTCH signaling due to a NOTCH1 mutation, as well as the activation of the MAPK signaling pathway due to alterations in NF1 and FGFR3, which are frequent in DICER1-mutant primary intracranial sarcoma [1, 3]. The exact histogenesis of primary intracranial sarcoma, DICER1-mutant is at present unknown. Its relationship to DICER1-associated sarcoma occurring at extracranial anatomical sites including lung, uterus, kidney, and others also remains to be determined. Our patient received radiotherapy after surgery, but unfortunately suffered from tumor recurrence after 3 months and died after 9 months. Leiming Wang analyzed the data, reviewed the pathological diagnosis and wrote the manuscript. Yukui Wei provided essential material and analyzed the clinical data. Lianghong Teng reviewed the pathological diagnosis and the manuscript. All authors approved the final version of the manuscript. This work was supported by the Beijing Nova program (Z201100006820149) and Beijing Hospitals Authority Clinical Medicine Development of Special Funding (ZYLX202113). The authors declare no conflict of interest. The study was approved by the ethics committee of Xuanwu Hospital, Capital Medical University, Beijing, China, and was conducted in full compliance with all principles of the Helsinki Declaration. I confirm that my article contains a Data Availability Statement even if no data is available (list of sample statements) unless my article type does not require one (e.g., Editorials, Corrections, Book Reviews, etc.).

Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort ( n = 1362) and a validation cohort ( n = 340), and tested on an internal testing cohort ( n = 289) and two external cohorts ( n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.

目的:了解和评价北京市不同医院病理科结直肠癌病理报告规范性程度及诊断差异，寻找解决方法。方法:通过结直肠癌规范化病理报告调查问卷、结直肠癌及相关癌前病变病理答题及上传结直肠癌取材报告3部分综合评估。结果:本次质控项目完整完成所有问卷的有54家，其中三甲医院34家，三乙医院15家，二甲医院5家。一共有42家医院病理科（77.8%，42/54）使用了规范化报告，在规范化报告要求的14项诊断指标中，所有单位均报告了结直肠癌组织学类型及肿瘤浸润深度；90%以上的单位均报告了肿瘤部位，且使用三径描述肿瘤大小，报告中均描述了切缘及脉管受累情况；但仍有62.2%的病例未报肿瘤出芽情况，22.7%的病例未报告神经侵犯情况。所有病例中，90.1%的病例均使用免疫组织化学方法检测了错配修复（MMR）蛋白缺失的状态；使用PCR及二代测序检查微卫星不稳定（MSI）状态的病例占比分别为7.1%及6.1%，同时检测MMR和MSI的病例数占比9.2%。结直肠癌及相关病变的病理诊断答题结果显示，对于绒毛管状腺瘤伴高级别异型增生、无蒂锯齿状病变、幼年性息肉的诊断正确率分别为85.2%、79.6%及90.7%。直肠乙状结肠交界处大息肉的内镜黏膜切除术（EMR）切除标本，诊断、浸润癌级别、浸润深度、肿瘤出芽级别、脉管癌栓状况、基底切缘加侧切缘状况正确率分别为98.2%、94.4%、72.2%、85.2%、88.9%、90.7%。升结肠癌根治标本，诊断、环周切缘、肿瘤出芽级别、脉管癌栓（血管及淋巴管癌栓）、神经侵犯及癌结节正确率分别为96.3%、57.4%、72.2%、20.4%、53.7%、87.0%。54家参评单位中，45家单位上传的3份不同部位及分期的结直肠癌取材报告均为规范格式的取材报告。结论:北京市各级医院病理科大多数均已具备了结直肠癌规范化取材和报告的能力，然而部分医院仍需进一步加强室内质控，减少科室内报告水平的差异，提高科室整体水平。格式化报告的推广及针对本次质控问题组织统一的业务学习可能是解决目前问题的有效方案。

目的 探讨TERT(telomerase reverse transcriptase)基因启动子对中枢神经系统孤立性纤维性肿瘤(solitary fibrous tumors of the central nervous system,CNS SFT)预后的影响.方法 采用Sanger测序法检测61例CNS SFT和20例胸膜孤立性纤维性肿瘤(solitary fibrous tumors,SFT)中TERT启动子突变.采用Kaplan-Meier法分析各项指标与预后的相关性.Cox比例风险回归模型分析预后影响因素.结果 81例样本中有8例样本检测到TERT突变,其中7例突变位点均为C228T,1例检测到少见位点突变C216T.生存分析显示,TERT启动子突变与患者无进展生存期(progression-free survival,PFS)无关(P=0.469).CNS SFT比胸膜SFT更易复发(P=0.002).多因素分析显示,肿瘤发生部位及有无坏死是SFT独立预后因素(HR=4.294,95％CI=1.163～15.845,P=0.029;HR=5.887,95％CI=1.322～26.255,P=0.020).结论 TERT 启动子突变对 CNS SFT 及胸膜SFT缺乏明确的预后价值,组织学特征是判断其预后的最佳指标.

Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.

High-altitude hypoxia may disturb the metabolic modulation and function of both adipose tissue and liver. The endoplasmic reticulum (ER) is a crucial organelle in lipid metabolism and ER stress is closely correlated with lipid metabolism dysfunction. The aim of this study is to elucidate whether the inhibition of ER stress could alleviate hypoxia-induced white adipose tissue (WAT) lipolysis and liver lipid accumulation-mediated hepatic injury. A rat model of high-altitude hypoxia (5500 m) was established using hypobaric chamber. The response of ER stress and lipolysis-related pathways were analyzed in WAT under hypoxia exposure with or without 4-phenylbutyric acid (PBA) treatment. Liver lipid accumulation, liver injury, and apoptosis were evaluated. Hypoxia evoked significant ER stress in WAT, evidenced by increased GRP78, CHOP, and phosphorylation of IRE1 alpha, PERK. Moreover, Lipolysis in perirenal WAT significantly increased under hypoxia, accompanied with increased phosphorylation of hormone-sensitive lipase (HSL) and perilipin. Treatment with 4-PBA, inhibitor of ER stress, effectively attenuated hypoxia-induced lipolysis via cAMP-PKA-HSL/perilipin pathway. In addition, 4-PBA treatment significantly inhibited the increase in fatty acid transporters (CD36, FABP1, FABP4) and ameliorated liver FFA accumulation. 4-PBA treatment significantly attenuated liver injury and apoptosis, which is likely resulting from decreased liver lipid accumulation. Our results highlight the importance of ER stress in hypoxia-induced WAT lipolysis and liver lipid accumulation.

The characteristics of H3.3 G34-mutant gliomas in adults have yet to be specifically described. Thirty adults with H3.3 G34-mutant diffuse gliomas were retrospectively reviewed for clinical and pathologic information. Molecular profiling using next-generation sequencing was performed in 29 of the 30 H3.3 G34-mutant patients with 1 patient lacking available tumor samples, as well as 82 IDH/H3 wild-type adult diffuse glioma patients. The age at diagnosis of H3.3 G34-mutant diffuse gliomas was significantly younger than IDH/H3 wild-type gliomas (24 vs. 57 y, P <0.001). Overall, 19 of the 30 patients were diagnosed of glioblastoma with the primitive neuronal component, and 8 were glioblastoma. The molecular profiling analysis revealed higher frequencies of Olig-2 loss of expression, TP53 mutation, ATRX mutation, PDGFRA mutation, and MGMT promoter methylation ( P <0.05) in H3.3 G34-mutant gliomas than IDH/H3 wild-type gliomas. No TERT promoter mutation and only 1 case of EGFR amplification were detected in the H3.3 G34-mutant cohort, the frequencies of which were significantly higher in the IDH/H3 wild-type cohort. A dismal prognosis was observed in H3.3 G34-mutant patients comparing to IDH/H3 wild-type cohort (overall survival: 14 vs. 22 mo; P =0.026). Univariate and multivariate analyses showed that the extent of resection and TP53 mutation were independently affecting prognosis. The distinct pathologic and molecular features of H3.3 G34-mutant diffuse gliomas in adult patients demonstrated the clinical importance of detecting H3.3 G34R/V mutations. The dismal prognosis of this rare high-grade glioma disease we reported here would further promote the investigation of dedicated therapeutic strategies.

Glioma has a specific CpG island methylator phenotype (G⁃CIMP), which is closely related to isocitrate dehydrogenase (IDH) mutation. A hypermutation is present at recurrence in temozolomide⁃treated gliomas, and O6⁃methylguanine⁃DNA methyltransferase (MGMT) promoter methylation levels can help predict the risk of hypermutation to inform clinical decision. Whole genome DNA methylation analysis has become an effective auxiliary method for the classification of central nervous system tumors. This article reviews the research progress of DNA methylation analysis in glioma and discusses its clinical significance.

AbstractBackgroundNeuroendocrine carcinomas of the gastrointestinal tract (GI‐NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI‐NECs.MethodsComprehensive genomic analysis using whole‐exome sequencing was performed on 143 formalin‐fixed, paraffin‐embedded samples of surgically resected GI‐NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors.ResultsIn total, 143 GI‐NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty‐three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI‐NECs showed distinct genetic alterations from their lung counterparts and non‐neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low‐density lipoprotein receptor‐related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT‐β‐catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI‐NECs harbored putative clinically relevant alterations, and non‐gastric location andRB1bi‐allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI‐NECs first gain clonal mutations inTP53,RB1,NOTCH1andAPC, followed by subsequent whole‐genome doubling (WGD) and post‐WGD clonal mutations inLRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb‐b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations.ConclusionsGI‐NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI‐NECs.

目的 探讨筛状神经上皮肿瘤的临床病理特征与鉴别诊断.方法 回顾性分析1例筛状神经上皮肿瘤患者的临床病理特征、免疫组织化学染色及分子病理学特征,并复习相关文献.结果 患者男性,11个月时出现恶心、呕吐,头颅CT提示第四脑室占位性病变,行第四脑室肿瘤部分切除术,术后11个月肿瘤复发,MRI见第四脑室不规则巨大囊实性混合肿块,再次行第四脑室及脑干病损切除术.镜下见肿瘤细胞成筛状、腺管状及乳头状浸润性生长,局灶伴坏死.免疫组化染色显示肿瘤细胞CK、EMA弥漫阳性,SMARCB1表达缺失,E-cadherin阴性,二代测序检测证实SMARCB1基因7号外显子杂合性缺失,诊断:筛状神经上皮肿瘤.结论 筛状神经上皮肿瘤是一种SMARCB1缺失的非横纹肌样罕见肿瘤,具有独特的神经病理学和临床特征,需要与脉络丛癌、不典型畸胎样/横纹肌样瘤鉴别.

目的 研究甲状腺乳头状癌经典型、滤泡亚型和高细胞亚型3种病理亚型特征性的声像图特征.方法 回顾性分析进行手术且手术病理为甲状腺乳头状癌经典型、滤泡亚型和高细胞亚型的病历资料,统计患者的一般资料及病灶的声像图特征(结构、回声、形态、边缘、局灶性强回声),从而研究3种亚型特有的声像图特征.结果 395名患者中282人为单病灶病例(71.4％),113人为多病灶病例(28.6％).纳入研究结节411个,经典型乳头状癌结节352个,滤泡亚型结节48个,高细胞亚型结节11个.滤泡亚型的病例多灶发生率(45.8％)最高,其次是经典型(31.5％)和高细胞亚型(9.1％),差异具有统计学意义(P=0.03).在声像图特征的统计中,3种亚型与声像图特征的关联性分析显示局灶性强回声(P=0.039)和纵横比(P=0.036)的差异具有统计学意义.结论 3种甲状腺乳头状癌病理亚型的局灶性强回声和纵横比特征具有一定的差异性.

Objective:To analyze the clinical features and mutation of myeloid differentiation factor 88 (MYD88) L265P in patients with diffuse large B-cell lymphoma (DLBCL) of central nervous system (CNS).Methods:The clinicopathological materials of 45 cases of DLBCL of CNS were retrospectively collected in Xuanwu Hospital, Capital Medical University from September 2014 to February 2017. The clinicopathological data were retrospectively analyzed, combined with immunohistochemistry, EB virus in situ hybridization, imaging and medical history. The mutation of MYD88 L265P gene was detected by pyrosequencing and its clinical significance was analyzed. Results:The age of the patients ranged from 42 to 82 years [(57.6±8.8) years], including 24 males and 21 females. Totally 93.3% (42/45) of the patients had supratentorial tumours, which were single or multiple. The cerebral hemisphere (31/45, 68.9%) was the most common involved site, and 21 cases (21/45, 46.7%) had multiple lesions. Histologically, DLBCL in the CNS showed diffuse infiltration of tumor tissue, some of which grew around blood vessels in a "sleeve" arrangement. CD 20 and CD 79a were diffusely and strongly positive. Thirty-nine cases (39/45, 86.7%) were non-germinal center B cell (non-GCB) subtype and 6 cases (6/45, 13.3%) were germinal center B cell (GCB) subtype. MYD88 L265P mutation was found in 64.4% (29/45) patients. There was statistically significant difference between non-GCB type (71.8%, 28/39) and GCB type DLBCL (1/6, P=0.017). Compared with the operation/biopsy group without chemotherapy, operation+chemotherapy, biopsy+chemotherapy, operation/biopsy+chemotherapy+stem cell transplantation can improve the survival and prognosis ( HR=0.05, 95% CI 0.01-0.33 , P=0.002; HR=0.04, 95% CI 0.01-0.36 , P=0.004; HR=0.01, 95% CI 0.00-0.17 , P=0.001; respectively). Conclusions:DLBCL of the CNS is aggressive tumor with poor prognosis, the clinical manifestations are complex and diverse, and the diagnosis is challenging. MYD88 L265P is a common and specific gene mutation in primary CNS lymphoma(PCNSL), which is of great significance in the diagnosis and treatment of lymphoma. The MYD88 L265P mutation was more frequently detected in non-GCB than GCB subtype. Chemotherapy can improve the survival rate of PCNSL patients. If chemotherapy achieves complete remission and autologous hematopoietic stem cell transplantation is performed, there may be a chance of long-term survival.