Keishi Horiguchi

Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors

The human Ras association domain family 1A (RASSF1A) gene, recently isolated from the lung and breast tumor suppressor locus 3p21.3, is highly methylated in primary lung, breast, nasopharyngeal and other tumors, and re-expression of RASSF1A suppresses the growth of several types of cancer cells. Epigenetic inactivation of RASSF1A by promoter hypermethylation is also important in the development of several human cancers. The methylation status of the promoter region of RASSF1A was analysed in primary brain tumors and glioma cell lines by methylation-specific polymerase chain reaction. In primary brain tumors, 25 of 46 (54.3%) gliomas and five of five (100%) medulloblastomas showed RASSF1A methylation. In benign tumors, only one of 10 (10%) schwannomas and two of 12 (16.7%) meningiomas showed RASSF1A methylation. The RASSF1A promoter region was methylated in all four glioma cell lines. RASSF1A was re-expressed in all methylated cell lines after treatment with the demethylating agent 5-aza-2′-deoxycytidine. Methylation of the promoter CpG islands of the RASSF1A may play an important role in the pathogenesis of glioma and medulloblastoma.

Pineal parenchymal tumor of intermediate differentiation with cytologic pleomorphism

We report a case of pineal parenchymal tumor in a 33‐year‐old man incidentally detected by radiological examination. The MRI showed an unhomogeneously enhanced, small tumor (approximately 1 cm in size) in the pineal region. A tumor specimen was obtained at endoscopic biopsy. Routine histology showed a highly cellular tumor characterized by a predominance of small cells showing high nuclear : cytoplasmic ratio and moderate nuclear atypia, pleomorphism including giant cells and an absence of pineocytomatous rosettes. Mitotic figures were rare (approximately 1 per 10 high‐power fields). Tumor necrosis was not evident. Immunohistochemically, the neoplastic cells showed positivity for neural markers (neurofilament protein, synaptophysin) and pinealocyte‐associated antibodies (PP1, PP5, PP6), but not for glial fibrillary acidic protein or S‐100. The MIB‐1 labeling index was relatively high (6.3%). Ultrastructurally, there was some evidence of pinealocytic differentiation, such as vesicle‐crowned rodlets (synaptic ribbons) and paired twisted filaments in neoplastic cells. Thus, the tumor was confirmed as a pineal parenchymal tumor of intermediate differentiation by histology, immunohistochemistry and electron microscopy. This case indicates that marked cytologic pleomorphism can occur in pineal parenchymal tumors of intermediate differentiation.

Growth of Primary and Remnant Vestibular Schwannomas: A Three-Year Follow-Up Study.

OBJECTIVE Vestibular schwannomas (VSs) are benign, slowly growing tumors. The management strategy, however, remains unclear for both primary VS and remnant VS after subtotal or partial resection. In this study, we analyzed the radiographical tumor growth to elucidate factors possibly predicting growth or regrowth of their tumors. METHODS We retrospectively analyzed the data of 76 patients with diagnoses of VS at a single tertiary academic referral center. The primary VS group consisted of 43 patients with conservative management, and the remnant VS group included 33 patients with tumor remnant after surgery. All patients were followed up with serial magnetic resonance imaging without intervention. The primary end point in this study was significant tumor growth at the end of the 3-year follow-up period. RESULTS Multivariate analysis revealed that remnant VS was less likely to grow than primary VS (odds ratio: 0.27, 95% confidence interval: 0.09-0.84). Tumor volume was correlated with tumor growth; larger tumors grew more frequently than small tumors in both primary and remnant VS groups with marginal (P = 0.05) and definite (P = 0.007) significance, respectively. The receiver operating characteristic curves plotted for tumor growth identified the optimum cutoff points of tumor volumes with greater sensitivity and specificity for remnant VS than for primary VS (sensitivity: 80% vs. 59%, specificity: 87% vs. 76%, respectively). CONCLUSIONS Small remnant VS after surgery could be conservatively managed without additional treatment, and relatively large remnant VS should be followed up with close serial imaging or might be a possible candidate for radiosurgery during the early postoperative period.

Histone H3 K27M mutations in adult cerebellar high-grade gliomas

Adult cerebellar high-grade gliomas (HGG) are rare and their molecular basis has not been fully elucidated. Although a diffuse midline glioma H3 K27M-mutant, a recently characterized variant of HGG, was reported to occasionally occur in the cerebellum, adult cases were rarely tested for this mutation; only five mutant cases have been reported to date. It currently remains unknown whether H3 K27M-mutant cerebellar gliomas share common histological features or have a uniformly dismal prognosis. In the present study, we assessed the prevalence of histone H3 K27M mutations in ten adult cerebellar HGG, identifying two H3F3A-mutant cases. One case was a 70-year-old female with a cystic lesion. Histologically, the tumor was considered to be glioblastoma; however, a part of the tumor exhibiting low proliferative activity appeared to be consistent with long-standing H3 K27M-mutant tumors in the literature. Another case was a 69-year-old male. The tumor showed a distinct circumscribed histology with minimal astrocytic differentiation, suggesting a nosological issue in the diagnosis of diffuse midline glioma. More cerebellar tumors need to be tested for H3 K27M mutations to clarify the clinical and histopathological spectra of this tumor.

Resection extent of the supplementary motor area and post-operative neurological deficits in glioma surgery

Abstract Objective The supplementary motor area (SMA) is important for the prediction of post-operative symptoms after surgical resection of gliomas. We investigated the relationships between clinical factors and the resection range of SMA gliomas, and the post-operative neurological symptoms. Methods We retrospectively studied 18 consecutive surgeries for gliomas involving the SMA proper performed in 13 patients. Seven cases were recurrence of the tumour. Clinical factors and details of specific resection of the SMA proper (resection of posterior part, medial wall) and cingulate motor area (CMA) were examined. Results Eight cases suffered new post-operative neurological deficits. Six of these eight cases had transient deficits. Permanent deficits persisted in two cases with partial weakness or paresis, after rapid improvement of post-operative global weakness or hemiplegia, respectively. The risk of post-operative neurological deficits was not associated with the resection of the posterior part of the SMA proper or the CMA, but was associated with resection of the medial wall of the SMA proper. Surgery for recurrent tumour was associated with post-operative neurological deficits. The medial wall was frequently resected in recurrent cases. Discussion The frequency of post-operative neurological symptoms, including SMA syndrome, may be higher after resection of the medial wall of the SMA proper compared with the resection of only the lateral surface of the SMA proper.

Superficial Siderosis of the Central Nervous System Caused by Hemorrhagic Intraventricular Craniopharyngioma: Case Report and Literature Review

Superficial siderosis is a rare condition caused by hemosiderin deposits in the central nervous system (CNS) due to prolonged or recurrent low-grade bleeding into the cerebrospinal fluid (CSF). CNS tumor could be one of the sources of bleeding, both pre- and postoperatively. We report an extremely rare case of superficial siderosis associated with purely third ventricle craniopharyngioma, and review previously reported cases of superficial siderosis associated with CNS tumor. A 69-year-old man presented with headache, unsteady gait, blurred vision, and progressive hearing loss. Brain magnetic resonance (MR) imaging with gadolinium revealed a well enhanced, intraventricular mass in the anterior part of the third ventricle. T2*-weighted gradient echo (GE) MR imaging revealed a hypointense rim around the brain particularly marked within the depth of the sulci. Superficial siderosis was diagnosed based on these findings. The tumor was diffusely hypointense on T2*-weighted GE imaging, indicating intratumoral hemorrhage. The lateral ventricles were dilated, suggesting hydrocephalus. [18F]fluorodeoxyglucose positron emission tomography revealed increased uptake in the tumor. The whole brain surface appeared dark ocher at surgery. Histological examination showed the hemorrhagic tumor was papillary craniopharyngioma. His hearing loss progressed after removal of the tumor. T2*-weighted GE MR imaging demonstrated not only superficial siderosis but also diffuse intratumoral hemorrhage in the tumor. Superficial siderosis and its related symptoms, including hearing loss, should be considered in patients with hemorrhagic tumor related to the CSF space. Purely third ventricle craniopharyngioma rarely has hemorrhagic character, which could cause superficial siderosis and progressive hearing loss.

Embryonal tumor with abundant neuropil and true rosettes with only one structure suggestive of an ependymoblastic rosette.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a very aggressive embryonal central nervous system (CNS) tumor, histologically featuring ependymoblastic rosettes and neuronal differentiation in a neuropil‐like background. 19q13.42 amplification was identified in ETANTR and epndymoblastoma, suggesting that these tumors constitute a single entity, called embryonal tumor with multilayered rosettes (ETMR). Here, we report a case involving a 2‐year‐old boy with a pontine embryonal tumor composed of clusters of poorly differentiated neuroepithelial cells, and smaller neuroblastic/neurocytic cells in a fibrillary and paucicellular neuropil‐like matrix, where clear ependymoblastic rosettes were not detected but only one structure suggestive of an ependymoblastic multilayered rosette was found. Fluorescence in situ hybridazation analysis revealed 19q13.42 amplification, supporting the diagnosis of ETANTR. This report indicates that rare ependymoblasic rosettes found in embryonal tumors, which are otherwise CNS primitive neuroectodermal tumors or medulloblastomas, are significant for considering the examination of 19q13.42 amplification to confirm the diagnosis of ETMR.

Microrecording and image-guided stereotactic biopsy of deep-seated brain tumors.

OBJECT Image-guided stereotactic brain tumor biopsy cannot easily obtain samples of small deep-seated tumor or selectively sample the most viable region of malignant tumor. Image-guided stereotactic biopsy in combination with depth microrecording was evaluated to solve such problems. METHODS Operative records, MRI findings, and pathological specimens were evaluated in 12 patients with small deep-seated brain tumor, in which image-guided stereotactic biopsy was performed with the aid of depth microrecording. The tumors were located in the caudate nucleus (1 patient), thalamus (7 patients), midbrain (2 patients), and cortex (2 patients). Surgery was performed with a frameless stereotactic system in 3 patients and with a frame-based stereotactic system in 9 patients. Microrecording was performed to study the electrical activities along the trajectory in the deep brain structures and the tumor. The correlations were studied between the electrophysiological, MRI, and pathological findings. Thirty-two patients with surface or large brain tumor were also studied, in whom image-guided stereotactic biopsy without microrecording was performed. RESULTS The diagnostic yield in the group with microrecording was 100% (low-grade glioma 4, high-grade glioma 4, diffuse large B-cell lymphoma 3, and germinoma 1), which was comparable to 93.8% in the group without microrecording. The postoperative complication rate was as low as that of the conventional image-guided method without using microelectrode recording, and the mortality rate was 0%, although the target lesions were small and deep-seated in all cases. Depth microrecording revealed disappearance of neural activity in the tumor regardless of the tumor type. Neural activity began to decrease from 6.3 ± 4.5 mm (mean ± SD) above the point of complete disappearance along the trajectory. Burst discharges were observed in 6 of the 12 cases, from 3 ± 1.4 mm above the point of decrease of neural activity. Injury discharges were often found at 0.5-1 mm along the trajectory between the area of decreased and disappeared neural activity. Close correlations between electrophysiological, MRI, and histological findings could be found in some cases. CONCLUSIONS Image-guided stereotactic biopsy performed using depth microrecording was safe, it provided accurate positional information in real time, and it could distinguish the tumor from brain structures during surgery. Moreover, this technique has potential for studying the epileptogenicity of the brain tumor.

Primary diffuse leptomeningeal atypical teratoid/rhabdoid tumor diagnosed by cerebrospinal fluid cytology: Case report with molecular genetic analysis

Atypical teratoid/rhabdoid tumors (AT/RT) are rare malignant neoplasms that mainly affect infants and young children, and are typically located in the cerebellar hemispheres. These tumors are histologically characterized by varying proportions of rhabdoid cells, and nuclear INI1 immunonegativity. Here, we report a case of a 15-year-old male with primary diffuse leptomeningeal AT/RT. The patient had symptoms similar to those of meningitis. Magnetic resonance imaging revealed leptomeningeal thickening. Cytological examination using cerebrospinal fluid was repeatedly performed and revealed rhabdoid cells with loss of INI1 reactivity, and shortly after, the diagnosis of AT/RT was confirmed by tissue biopsy. Multiplex ligation-dependent probe amplification analysis revealed compound heterozygous microdeletion of the SMARCB1/INI1 locus. Leptomeningeal AT/RT without primary mass is extremely rare - only four cases have been previously reported to date. To the best of our knowledge, this is the first case report of primary leptomeningeal AT/RT with detailed genetic information.

Preoperative Evaluation of Sellar and Parasellar Macrolesions by [18F]Fluorodeoxyglucose Positron Emission Tomography

OBJECTIVE Various diseases can occur in the sellar and suprasellar regions. The potential of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) for the preoperative evaluation of sellar and parasellar lesions was investigated. METHODS A total of 49 patients aged 8-82 years with sellar and parasellar macroscopic lesions (≥10 mm) underwent FDG PET. Twenty-two patients had pituitary adenomas, including 14 nonfunctioning and 8 growth hormone-secreting adenomas. Eleven patients had craniopharyngiomas, including 5 adamantinomatous and 6 squamous-papillary types. Eight patients had chordoma, 4 had meningioma, and 4 had a Rathke cleft cyst. The maximum standardized uptake value (SUVmax), and the ratio of the SUVmax in the tumor to the mean standardized uptake value in the normal cortex (T/N ratio) or in the normal white matter (T/W ratio) were calculated. The relationships between SUVmax, T/N ratio, and T/W ratio, and lesion disease were evaluated. RESULTS Uptakes of FDG, including SUVmax, T/N ratio, and T/W ratio, were lower in chordoma and Rathke cleft cyst compared with pituitary adenoma. SUVmax, T/N ratio, and T/W ratio of nonfunctioning adenoma were significantly higher than those of growth hormone-secreting adenoma. SUVmax, T/N ratio, and T/W ratio of squamous-papillary type were significantly higher than those of the adamantinomatous type of craniopharyngioma. CONCLUSIONS FDG PET is useful for the preoperative diagnosis of sellar and parasellar macrolesions. High uptake in nonfunctioning pituitary adenoma, and low uptake in chordoma are significant. The difference in FDG uptake dependent on the histologic subtype may be related to the specific genetics of the craniopharyngioma subtype.