Brain Tumor Pathology最新文献

Radiotherapy remains a cornerstone of brain tumor treatment; however, its effectiveness is frequently undermined by the development of radioresistance. This review highlights the pivotal role of molecular chaperones in promoting radioresistance and explores the potential to increase radioresistance in brain cancers, particularly glioblastoma (GBM). Among chaperones, heat shock proteins (HSPs), such as HSP70 and HSP90, have been identified as key contributors to radioresistance, acting through mechanisms that include the maintenance of protein homeostasis, enhancement of DNA repair processes, and protection of cancer stem cells. Specifically, HSP70 and HSP90 are crucial in stabilizing oncogenic proteins and preventing apoptosis, thus enabling tumor survival during radiotherapy. Also, HSP27 and GRP78 are involved in the radioresistance of brain tumors mainly by suppressing cell death and enhancing tumor stem cell propagation. Emerging evidence also suggests that targeting these chaperones, in combination with radiotherapy, can enhance tumor radiosensitivity, offering promising therapeutic strategies. Recent studies have revealed novel aspects of chaperone-mediated autophagy and interaction with non-coding RNAs, providing deeper insights into the molecular mechanisms underlying radioresistance. This review also addresses the potential of combining chaperone-targeted therapies, such as HSP90 inhibitors, with radiotherapy to overcome resistance. Ultimately, understanding these mechanisms may pave the way for innovative clinical applications and personalized therapeutic approaches in brain tumor treatment.

Glioblastoma (GBM) is a primary brain tumor, characterized by rapid progression, high recurrence rates, and resistance to standard therapies. Current treatment modalities provide limited survival benefits, highlighting the need for novel therapeutic strategies. This retrospective study evaluated the efficacy of autologous formalin-fixed tumor vaccine (AFTV) in 375 patients with newly diagnosed GBM. Patients receiving AFTV therapy (n = 164) showed significantly improved progression-free survival (PFS; 14.0 months vs. 8.7 months, p = 0.03) and overall survival (OS; 32.0 months vs. 21.9 months, p < 0.01) compared with the non-AFTV group (n = 211). Subgroup analyses revealed that AFTV therapy was particularly effective in patients with wild-type IDH tumors and those negative for PD-L1 and p53 expression. In contrast, patients whose tumors were positive for both PD-L1 and p53 exhibited significantly poorer outcomes. These findings suggest that the combination of PD-L1 and p53 status may serve as a useful biomarker for predicting AFTV responsiveness, reflecting the influence of the immunosuppressive tumor microenvironment on treatment efficacy. These findings establish AFTV as a promising treatment option for GBM and highlight the importance of molecular profiling in treatment selection. Future studies should explore combining AFTV with immune checkpoint inhibitors to enhance efficacy in PD-L1-positive cases.

IDH-mutant astrocytomas exhibit a more indolent natural history and better prognosis compared to their IDH-wild type counterparts. WHO 2021 classification integrated CDKN2A/B homozygous deletion as a crucial criterion for grading these tumors, emphasizing its prognostic implications. FISH assay is commonly used to assess CDKN2A status, but guidelines for interpreting FISH results for glioma prognostication are not well-defined in the literature. We conducted an ambispective study involving 22 cases of recurrent IDH-mutant astrocytomas, including primary tumor samples. Histopathological assessments, including WHO grading and molecular profiling, were performed. Immunohistochemistry confirmed IDH mutation status, and FISH analysis evaluated CDKN2A homozygous deletion. Homozygous CDKN2A deletion was detected in only 1/22 (4.8%) of primary tumors, which was grade 3 astrocytoma, and significantly more frequent in recurrent cases, particularly in histological grade 2/3 tumors (35.3%). Patients harboring CDKN2A deletions exhibited significantly poorer overall survival, highlighting its prognostic significance. Our findings highlight the clinical relevance of CDKN2A assessment in recurrent IDH-mutant astrocytomas and its utility as a prognostic marker. We propose a selective approach to FISH testing, focusing on primary grade 3 and all recurrent cases, regardless of histology grade, to optimize diagnostic accuracy and stratification for personalized treatment strategies.

We describe a rare case of discordant lymphoma characterized by the coexistence of diffuse large B-cell lymphoma (DLBCL) in the brain and mantle cell lymphoma (MCL) in the colon, rectum, and bone marrow. A 63-year-old male patient with consciousness impairment and gait disturbance was admitted to our institution. Head computed tomography scan and contrast-enhanced magnetic resonance imaging showed a mass in the right temporal lobe and rectal wall thickening. Brain biopsy revealed DLBCL, and bone marrow and rectum biopsy showed MCL. According to a polymerase chain reaction analysis of immunoglobulin heavy-chain gene rearrangements using brain and bone marrow specimens, the two lesions were clonally unrelated lymphomas. After five cycles of R-MPV (rituximab, methotrexate, procarbazine, vincristine) therapy and three cycles of R-ESHAP (rituximab, etoposide, cytarabine, cisplatin, methylprednisolone) therapy, the patient received autologous hematopoietic stem cell transplantation using R-MEAM (rituximab, ranimustine, etoposide, cytarabine, melphalan) regimen after bridging therapy with ibrutinib. In addition, he received whole-brain irradiation at a dose of 40 Gy in 20 fractions as consolidation therapy. He did not relapse within 3 years of transplantation. To the best of our knowledge, this is the first case report of DLBCL and MCL coexistence.

Gliomas are the most common primary brain tumors in adults. However, glioblastoma is especially difficult to treat despite advancements in treatment. Therefore, new and more effective treatments are needed. The endothelial glycocalyx covers the luminal surface of the endothelium and plays an important role in vascular homeostasis. Tumor blood vessels normally have increased permeability, but some of them mimic normal cerebral blood vessels constituting the blood-brain barrier and retain drug-barrier function. Therefore, brain tumor vessels are considered to constitute the blood-tumor barrier. There are few reports on the endothelial glycocalyx in human brain tumor vessels. We aimed to visualize the endothelial glycocalyx in human brain tumor vessels and evaluate its microstructural differences in glioma vessels and normal capillaries. Surgical specimens from patients with glioma who underwent tumor resection at our institution were evaluated. We visualized the microstructures of the brain tumor vessels in human glioma specimens using electron microscopy with lanthanum nitrate. The endothelial glycocalyx was identified in the human glioma vasculature and its microstructure varied between the tumor margin and core. These variations may influence tumor angiogenesis and vascular remodeling, contributing to advancements in targeted therapies and diagnostics for human gliomas.

Tectal glioma (TG) is a rare lower grade glioma (LrGG) that occurs in the tectum, mainly affecting children. TG shares pathological similarities with pilocytic astrocytoma (PA), but recent genetic analyses have revealed distinct features, such as alterations in KRAS and BRAF. We conducted a retrospective review of cases clinically diagnosed as TG and treated at our institute between January 2005 and March 2023. Six cases were identified and the median age was 30.5 years. Four patients underwent biopsy and two patients underwent tumor resection. Histological diagnoses included three cases of PA, one case of astrocytoma, and two cases of high-grade glioma. The integrated diagnosis, according to the fifth edition of the World Health Organization Classification of Tumours of the central nervous system, included two cases of PA and one case each of diffuse high-grade glioma; diffuse midline glioma H3 K27-altered; glioblastoma; and circumscribed astrocytic glioma. Among the three patients who underwent molecular evaluation, two had KRAS mutation and one had H3-3A K27M mutation. Our results demonstrate the diverse histological and molecular characteristics of TG distinct from other LrGGs. Given the heterogeneous pathological background and the risk of pathological progression in TG, we emphasize the importance of comprehensive diagnosis, including molecular evaluation.

Primary intracranial sarcoma (PIS) is a rare and aggressive pediatric brain tumor, which is partially associated with DICER1 mutant. Although the molecular genetic characteristics of this tumor have previously been investigated, novel therapeutic targets remain unclear. Further, the lack of faithful preclinical models has hampered the development of novel therapeutic strategies. Herein, we describe a pediatric case of PIS with DICER1 mutant and describe the development of the first novel patient-derived xenograft (PDX) model of this rare tumor. Somatic genomic profiling of the tumor revealed mutations in DICER1, TP53, and ATRX. Germline analysis further revealed a pathogenic variant of DICER1, significant for the diagnosis and management of hereditary tumor predisposition syndrome. Overall, we demonstrated that the PDX model faithfully retained the phenotype and genotype of the patient's tumor, as well as the DNA methylation profile. Through high-throughput drug screening using PDX tumor cells, we found that activation of the retinoic acid receptor (RAR) signaling pathway reduced tumor cell viability. These findings indicate that the RAR signaling pathway is a potential therapeutic target for PIS in DICER1 mutant.

Double-hit lymphoma (DHL) formerly referred to high-grade B-cell lymphoma with concurrent MYC and BCL2 or BCL6 rearrangements, however, the updated 2022 World Health Organization Classification (5th edition online) excludes those with MYC and BCL 6 rearrangements from the high-grade category. DHL confined to the central nervous system (CNS), known as double-hit primary CNS lymphoma (DH-PCNSL), is rare with poorly understood clinical features. Here, we report a case of a 64-year-old man with multiple brain tumors diagnosed with DH-PCNSL who showed bone marrow (BM) infiltration early in the clinical course. The histological diagnosis was high-grade B-cell lymphoma with MYC and BCL6 rearrangements. Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed no abnormal accumulation except in the CNS. The patient received whole-brain radiotherapy following the failure of high-dose methotrexate. After completion of radiotherapy, the patient developed thrombocytopenia, and BM biopsy showed infiltration of DHL cells, which were not detected by repeated FDG-PET. This is the first report of DH-PCNSL where identical gene rearrangements were confirmed in both the resected CNS tumor and BM tissue. Patients with DH-PCNSL require careful follow-up because they may be at a potential risk of BM infiltration, which may be undetectable by FDG-PET, particularly early in the disease course.

High-grade supratentorial tumors harboring ZFTA::NCOA1/2 fusion in infants presenting with mixed histology of embryonal-appearing components resembling ependymoma and mesenchymal sarcomatous components have recently been reported as ependymoma-like tumors with mesenchymal differentiation (ELTMDs). In contrast, we describe herein a pathologically similar case with a novel ZFTA::RELA fusion in an adult. A frontal lobe lesion was resected from a 30-year-old woman and displayed mixed components on pathological examination, showing ependymoma-like and sarcomatous parts. The absence of perivascular pseudorosettes was inconsistent with a diagnosis of ependymoma. Fluorescence in situ hybridization analysis confirmed ZFTA::RELA fusion. The DKFZ methylation classifier (v12.8) did not categorize this case among established methylation classes. In addition, t-distributed stochastic neighbor embedding analysis using DNA methylation data revealed that the present case was distant from ependymomas but close to two previously reported cases of ELTMD involving ZFTA::NCOA1/2 fusion. Taken together, we concluded that this tumor should be considered under the entity of ELTMD. This represents the first description of an adult patient with ELTMD harboring ZFTA::RELA fusion analyzed by DNA methylation profiling, supporting the establishment of ELTMD as a possible new tumor type.