Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group.

BACKGROUND: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. METHODS: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. RESULTS: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). CONCLUSIONS: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

Clinical significance and pitfalls of human chorionic gonadotropin-related tumor markers for intracranial germinomas.

PURPOSE: Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGß, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. METHODS: We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGß, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. RESULTS: The positivity rates of serum hCGß, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGß (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGß, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively. CONCLUSION: Serum intact and total hCGs have higher detection rates than hCGß in patients with germinoma using available commercial measurement tools.

Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma.

EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations frequently observed in adult IDH-wild-type (IDHwt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDHwt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFRamp, 7+/10-, and pTERTmut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors. In addition, we addressed the question whether combinations of partial gains on chromosome 7 and partial losses on chromosome 10 exhibited a diagnostic and prognostic value similar to that of complete 7+/10-. Several such combinations proved relevant and were combined as the 7/10 signature. Our results demonstrate that EGFRamp and the 7/10 signature are closely associated with IDHwt GBM. In contrast, pTERTmut is less specific for IDHwt GBM. We conclude that, in the absence of endothelial proliferation and/or necrosis, the detection of EGFRamp is a very strong surrogate marker for the diagnosis of GBM in IDHwt diffuse astrocytic tumors. The 7/10 signature is also a strong surrogate marker. However, care should be taken to exclude pleomorphic xanthoastrocytoma. pTERTmut is less restricted to this entity and needs companion analysis by other molecular markers to serve as a surrogate for diagnosing IDHwt GBM. A combination of any two of EGFRamp, the 7/10 signature and pTERTmut, is highly specific for IDHwt GBM and the combination of all three alterations is frequent and exclusively seen in IDHwt GBM.

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.

Grading of Diffuse Astrocytic Gliomas: A Review of Studies Before and After the Advent of IDH Testing.

Estimating the malignancy level of tumors is key to management, and has been part of oncology practice for the past ∼100 years. A central aspect of assessing malignancy level is based on histological "grading"-a process in which a pathologist evaluates microscopic features of a tumor and interprets those findings in light of large prognostic studies. For the diffuse astrocytic gliomas, there have been many such studies over the past century and these have proven useful in estimating prognosis for patients. With the advent of molecular genetics, molecular diagnostic testing has been added to histological evaluation in the armamentarium of the pathologist, and the recent World Health Organization (WHO) Classification of Tumors of the Central Nervous System encourages testing for isocitrate dehydrogenase (IDH) gene status in the classification of diffuse astrocytic gliomas. The present review catalogues a large series of diffuse astrocytic glioma grading studies over the past few decades, and compares the prognostic value of such grading schema before and after the emergence of IDH testing. The review concludes that novel approaches to diffuse astrocytic tumor grading are required in the era of IDH testing.

Genomic characterization of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.

Temozolomide Treatment for Pediatric Refractory Anaplastic Ependymoma with Low MGMT Protein Expression.

The benefit of postoperative chemotherapy for anaplastic ependymoma remains unknown. We report two pediatric patients with refractory anaplastic ependymoma treated with temozolomide (TMZ). We did not detect O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation in tumor samples; however, MGMT protein expression was low. With TMZ treatment, one patient had a 7-month complete remission; the other, stable disease for 15 months. Three other patients did not respond to TMZ; two had high and one low MGMT expression, and two showed no MGMT promoter methylation. These findings suggest that TMZ may be effective for pediatric refractory anaplastic ependymoma with low MGMT protein expression.

Brainstem oligodendroglial tumors in children: two case reports and review of literatures.

PURPOSE: There is little information on pediatric oligodendroglial tumor located in the brainstem because of its rarity. METHODS: Here, we present two pediatric cases of pontine oligodendroglial tumors with radiological findings atypical for diffuse intrinsic pontine glioma. RESULTS: The first patient was an 8-year-old boy. Brain magnetic resonance imaging (MRI) demonstrated diffuse high-intensity changes in the pons, left middle cerebellar peduncle, and part of the left cerebellar hemisphere on T2-weighted and fluid-attenuated inversion recovery images, with an enhanced spot lesion in the left cerebellar hemisphere. The pathological diagnosis was anaplastic oligodendroglioma, and we identified a mutation in histone H3.3 in the tumor specimen. He succumbed to massive disseminated relapse 7 months from diagnosis despite local radiation therapy. The second patient, a 2-year-old girl, was diagnosed with oligoastrocytoma. Brain MRI revealed a large mass in her rostral pons extended to the fourth ventricle with obstructive hydrocephalus. The tumor recurred with intracranial dissemination 56 months post-surgery. CONCLUSIONS: Pediatric brainstem oligodendroglial tumors can include histone H3.3-mutated tumors and have a tendency to disseminate throughout the neuroaxis at the time of relapse.

Malignant transformation of germinoma 14 years after onset: Favorable efficacy of oral etoposide.

We report the case of a 19-year-old woman with a highly malignant intracranial germ cell tumor (GCT) that developed 14 years after treatment for neurohypophyseal germinoma. Magnetic resonance imaging (MRI) showed a large neurohypophyseal mass and a synchronous lesion in the pineal region. Plasma α-fetoprotein was elevated to 3038 ng/mL. Although the tumor shrank and tumor marker levels normalized after chemotherapy and craniospinal irradiation, treatment was switched to oral etoposide for the residual tumor because of adverse events. MRI after oral etoposide introduction showed additional tumor shrinkage for 27 months after the onset of the second tumor. To the best of our knowledge, this is the longest interval between germinoma onset and the development of highly malignant recurrent GCT to be reported in the English-language literature. Oral etoposide prevented regrowth of the GCT, which has a poor prognosis, and decreased the size of the residual tumor.

Prognostic prediction of glioblastoma by quantitative assessment of the methylation status of the entire MGMT promoter region.

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is reported to be a prognostic and predictive factor of alkylating chemotherapy for glioblastoma patients. Methylation specific PCR (MSP) has been most commonly used when the methylation status of MGMT is assessed. However, technical obstacles have hampered the implementation of MSP-based diagnostic tests. We quantitatively analyzed the methylation status of the entire MGMT promoter region and applied this information for prognostic prediction using sequencing technology. METHODS: Between 1998 and 2012, the genomic DNA of 85 tumor samples from newly diagnosed glioblastoma patients was subjected to bisulfite treatment and subdivided into a training set, consisting of fifty-three samples, and a test set, consisting of thirty-two samples. The training set was analyzed by deep Sanger sequencing with a sequencing coverage of up to 96 clones per sample. This analysis quantitatively revealed the degree of methylation of each cytidine phosphate guanosine (CpG) site. Based on these data, we constructed a prognostic prediction system for glioblastoma patients using a supervised learning method. We then validated this prediction system by deep sequencing with a next-generation sequencer using a test set of 32 samples. RESULTS: The methylation status of the MGMT promoter was correlated with progression-free survival (PFS) in our patient population in the training set. The degree of correlation differed among the CpG sites. Using the data from the top twenty CpG sites, we constructed a prediction system for overall survival (OS) and PFS. The system successfully classified patients into good and poor prognosis groups in both the training set (OS, p = 0.0381; PFS, p = 0.00122) and the test set (OS, p = 0.0476; PFS, p = 0.0376). Conventional MSP could not predict the prognosis in either of our sets. (training set: OS; p = 0.993 PFS; p = 0.113, test set: OS; p = 0.326 PFS; p = 0.342). CONCLUSIONS: The prognostic ability of our prediction system using sequencing data was better than that of methylation-specific PCR (MSP). Advances in sequencing technologies will make this approach a plausible option for diagnoses based on MGMT promotor methylation.

Duration between onset and diagnosis in central nervous system tumors: impact on prognosis and functional outcome.

BACKGROUND: The initial presentation of central nervous system (CNS) tumors in children frequently mimics other more common and less serious conditions, resulting in diagnostic difficulty and a prolonged time to diagnosis. Yet whether early diagnosis contributes to better life prognosis and functional outcome has not been elucidated. Only a few such reports have originated from Japan, where neuroimaging techniques are the best in the world. We examined the time to diagnosis, the so-called prediagnostic symptomatic interval (PSI), and its impact on prognosis and functional outcome in children with CNS tumors. METHODS: We reviewed the records of 127 patients aged <15 years with CNS tumors, who were treated at our two institutions between November 1993 and October 2011. RESULTS: The median age at diagnosis was 7.2 years (range, 3 weeks-14.9 years). The male-to-female ratio was 63:64. Median PSI was 1.5 months (0-36 months). Overall survival and progression-free survival did not differ significantly between the groups, regardless of whether the PSI was longer than the median PSI. The PSI was significantly longer in patients with long-lasting clinical signs after the initial treatment than in patients with temporary symptoms only at onset. Both univariate and multivariate analysis showed that high histological grading was statistically correlated with short PSI. CONCLUSIONS: A short PSI was significantly associated with high-grade tumors. Earlier diagnosis did not lead to better life prognosis, but possibly to better functional outcome in children with CNS tumors.

Rapidly Progressing Intramedullary Spinal Cord Abscess: A Case Report.

Intramedullary spinal cord abscess is a rare and severe infectious disease characterized by devastating neurological deficits. We report a case of cervical intramedullary spinal cord abscess in a 74-year-old diabetic male with a 3-day history of neck pain and weakness in the right lower extremity. Magnetic resonance imaging revealed a ring-shaped contrast lesion in C3-C6 of the cervical spinal cord with extensive edema. Further, 1 day after admission, he became comatose (Glasgow Coma Scale E1VtM1), and a computed tomography head scan revealed hydrocephalus. Despite emergency ventricular drainage, the patient's level of consciousness remained unchanged. Magnetic resonance imaging performed 1 day after surgery revealed bilateral intracranial extension of the abscess into the thalamus and caudate nucleus. The patient died 19 days after admission. Our report is the first case of extensive brain abscess development over a short period. Based on our experience, prompt administration of antibiotics and emergency abscess drainage of the cervical cord (and ventricular drainage, if necessary) are recommended in cases of neurological deterioration in patients with cervical intramedullary spinal cord abscess.

Double-hit primary central nervous system lymphoma with histogenetically proven bone marrow infiltration: a case report and a review of the literature.

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.

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Successful Treatment of a CNS Tumor with BCOR Internal Tandem Duplication: A Case Report.

A central nervous system (CNS) tumor with BCL-6 co-repressor (BCOR) internal tandem duplication (CNS tumor with BCOR ITD) is a rare tumor classified as an embryonal tumor by the World Health Organization classification (5th edition), and the prognosis is generally poor. A successfully treated case is reported, and its treatment is discussed. A five-year-old boy presented with a one-month history of headache and vomiting. Magnetic resonance imaging showed a well-demarcated, left-frontal tumor without perifocal edema. The patient underwent complete resection without a neurological deficit. Anti-BCOR antibody showed strong immunoreactivity in tumor nuclei, and the tumor was diagnosed as a CNS tumor with BCOR ITD. The patient received craniospinal irradiation (CSI) comprising 23.4 Gy, followed by a boost to the primary site to a total dose of 30.6 Gy in daily fractions of 1.8 Gy. The chemotherapy comprised four cycles of vincristine, cyclophosphamide, and cisplatin with peripheral blood stem cell rescue. The clinical course was uneventful throughout the treatment, the tumor has not recurred for four years, and no neurological impairment was reported. CSI and multiagent chemotherapy were effective for a CNS tumor with BCOR ITD.

Miliary Tuberculosis during R-MPV Therapy in an Elderly Patient with Primary Central Nerve System Lymphoma: A Case Report.

Most elderly patients with tuberculosis (TB) have previously been infected with Mycobacterium tuberculosis, which remains dormant in the body for decades and may reactivate when their immunity declines due to underlying diseases. Elderly cancer patients are at a high risk for TB, and the treatment of TB reactivation in these patients is challenging. Among cancer patients, the incidence of TB reactivation is the highest in lymphoma patients. However, the impact of chemotherapy on TB reactivation in lymphoma patients is unknown. We report the case of an immunocompetent elderly patient with primary central nervous system lymphoma (PCNSL) having no prior history of TB, who developed miliary TB during multiagent chemotherapy consisting of rituximab, high-dose methotrexate, procarbazine, and vincristine (R-MPV therapy). Retrospectively, the chest computed tomography showed calcification of the pleura, suggesting that the patient had a latent tuberculosis infection (LTBI) and developed miliary TB from the reactivation of TB triggered by the R-MPV therapy. Our case emphasizes that when chemotherapy is administered to patients with PCNSL, interferon-gamma release assay (IGRA) should be performed if there are findings on chest examination suggestive of LTBI, such as pleural calcification, and if IGRA is positive, chemotherapy should be given concurrently with LTBI treatment.

Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma.

BACKGROUND: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome. METHODS: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). RESULTS: Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values < .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value < .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. CONCLUSIONS: HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.

Primary intramedullary spinal cord pilocytic astrocytoma with anaplasia in an adult: illustrative case.

BACKGROUND: Primary intramedullary spinal cord (IMSC) pilocytic astrocytoma (PA) with anaplasia is extremely rare. OBSERVATIONS: A 50-year-old man presented to our hospital with numbness of the left posterior rib region, back, and bilateral lower limbs. Contrast-enhanced T1-weighted magnetic resonance imaging (MRI) revealed an intramedullary lesion at T2-T3 with no contrast enhancement. The patient opted for conservative treatment. Eighteen months after the first consultation, the patient presented with slowly progressive numbness of the bilateral upper limbs, paraparesis, and dysuria, with rapid deterioration over the following 3 months. T1- and T2-weighted MRI revealed expansion of the intramedullary lesion, which extended from C7 to T5, and syringomyelia at C5-C6. Contrast-enhanced T1-weighted MRI revealed an enhancing intramedullary lesion at C7-T5. Open biopsy and C5-T5 laminectomy were performed for diagnosis and decompression. PA with anaplasia was diagnosed based on pathological and immunohistochemical findings. The patient received postoperative radiotherapy and chemotherapy. LESSONS: Rapidly progressive IMSC PA with a change in contrast enhancement is extremely rare in adults. PA may undergo a spontaneous malignant transformation during its natural clinical course. In this case, the change in contrast enhancement may have been associated with the malignant transformation of the PA.

True anaplastic oligoastrocytoma with dual genotype: illustrative case.

BACKGROUND: The revised fourth edition of the World Health Organization classification of central nervous system tumors was published in 2016. Based on this classification, one of the infiltrating glioma entities named "oligoastrocytoma/anaplastic oligoastrocytoma" is discouraged. It is proposed that these mixed gliomas should be classified as diffuse astrocytoma/anaplastic astrocytoma or oligodendroglioma/anaplastic oligodendroglioma when analyzing their genetic alteration. OBSERVATIONS: A 78-year-old female underwent brain computed tomography (CT) because of a traffic accident. Cranial CT revealed a brain tumor in the left temporoparietal lobe; therefore, she was hospitalized. She underwent awake craniotomy. After the operation, she was treated with only local radiotherapy; the authors could not prescribe temozolomide, because she had had levetiracetam-induced pancytopenia. The remaining tumor neuroradiologically disappeared, and she was alive 40 months after the operation without tumor recurrence. LESSONS: Histopathologically, this tumor was diagnosed as an anaplastic oligoastrocytoma with a distinct dual phenotype of astrocytoma and oligodendroglioma components. Genetically, these two components revealed astrocytoma and oligodendroglioma genotypes, respectively. Therefore, the authors considered the integrated diagnosis of the temporal tumor as a true anaplastic oligoastrocytoma with a dual genotype. Interestingly, this case also included an area composed of spindle to oval neoplastic cells that revealed intermediate genetic alterations between astrocytomas and oligodendrogliomas.

Role of proliferative marker index and KBTBD4 mutation in the pathological diagnosis of pineal parenchymal tumors.

Pineal parenchymal tumors (PPTs) are clinically rare and a biopsy is often required for a definitive diagnosis. To improve the accuracy of histological assessment of PPTs, we examined the proliferative capacity of PPT cells and investigated DICER1 expression and KBTBD4 mutations. This study included 19 cases of PPTs [3 pineocytomas (PCs), 10 PPTs of intermediate differentiation (PPTID), and 6 pineoblastomas (PBs)]. Immunohistochemistry for Ki-67, PHH3, and DICER1, as well as Sanger sequencing analysis for KBTBD4 mutations, was performed using formalin-fixed paraffin-embedded tissue specimens that were resected during surgery. Tumor cell proliferation was quantified using an image analysis software. For the PHH3 and MIB-1 indices, a significant difference was observed between the PPTIDs and PBs (P < 0.05). Loss of DICER1 was not specific for PB; 0/3 PCs (0.0%), 2/9 PPTIDs (22.2%), and 2/4 PBs (50.0%). KBTBD4 mutations were detected in 1/3 PCs (33.3%), 6/9 PPTIDs (66.7%), and 0/4 PBs (0.0%). Thus, combined application of the proliferative marker index and KBTBD4 mutation analysis may be useful for the differential diagnosis of PPTs. Furthermore, detection of KBTBD4 mutations using Sanger sequencing analysis may support the diagnosis of PPTID.