Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene.
We have identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system (CNS) malignant rhabdoid tumor (a subset of primitive neuroectodermal tumors, or PNET) and choroid plexus carcinoma. Various hereditary tumor syndromes, including Li-Fraumeni syndrome, Gorlin syndrome, and Turcot syndrome, have been linked to increased risk of developing CNS PNETs and choroid plexus tumors. Malignant rhabdoid tumors of the CNS and kidney show loss of heterozygosity at chromosome 22q11. The hSNF5 gene on chromosome 22q11 has recently been identified as a candidate tumor-suppressor gene in sporadic CNS and renal malignant rhabdoid tumors. We describe a family in which both affected and some unaffected family members were found to have a germline splice-site mutation of the hSNF5 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue shows loss of the wild-type hSNF5 allele, in keeping with a tumor-suppressor gene. These findings suggest that germline mutations in hSNF5 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors in infancy. (+info)
The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched.
Defects in a developmental signaling pathway involving mammalian homologues of the Drosophila segment polarity gene, patched (ptc) and its ligand, sonic hedgehog (shh), contribute to tumor formation in several tissues. Recently, a subset of medulloblastoma, the most common malignant brain tumor in children, was found to contain somatic mutations in the human ptc gene. In addition, basal cell nevus syndrome (BCNS), or Gorlin syndrome, which is characterized by developmental anomalies and a predisposition to skin and nervous system malignancies, is associated with germ-line mutation of ptc. Targeted disruption of both alleles of ptc in mice results in embryonic lethality. However, ptc+/- mice survive and develop spontaneous cerebellar brain tumors, suggesting that ptc may function as a tumor suppressor gene. Therefore, we investigated ptc+/-mice as a model for human medulloblastoma. We report that 14% of ptc+/- mice develop central nervous system tumors in the posterior fossa by 10 months of age, with peak tumor incidence occurring between 16 and 24 weeks of age. The tumors exhibited several characteristics of human medulloblastoma, including expression of intermediate filament proteins specific for neurons and glia. Full-length ptc mRNA was present in all tumors analyzed, indicating that there was no loss of heterozygosity at the ptc locus. Nucleotide sequence of ptc mRNA from four tumors failed to identify any mutations. However, a comparison of the normal ptc sequence from C57BL/6 and 129Sv mice did reveal several polymorphisms. High levels of glil mRNA and protein were detected in the tumors, suggesting that the shh/ptc pathway was activated despite the persistence of ptc expression. These data indicate that haploinsufficiency of ptc is sufficient to promote oncogenesis in the central nervous system. (+info)
Ependymoma with extensive lipidization mimicking adipose tissue: a report of five cases.
Lipomatous ependymoma is a recently described entity and only 3 cases of this variant have been reported in the literature. We report 5 cases of this rare variant of ependymoma. Patients age ranged from 4 years to 45 years and, interestingly, all of them were males. Two tumors were supratentorial in location, 2 in the fourth ventricle and 1 was intramedullary. Microscopically all of them showed the classical histology of ependymoma along with lipomatous differentiation. The lipomatous component was composed of cells with a large clear vacuole pushing the nucleus to the periphery and giving a signet ring cell appearance. This component demonstrated positivity for GFAP and S-100 protein thereby confirming its glial lineage. Three of the 5 tumors were high grade (WHO-grade III), had a high MIB-1 labelling index (MIB-1 LI) and showed recurrence on follow-up. However, 2 were low grade (WHO grade II) and patients are free of disease till the last follow up. (+info)
Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation.
PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement. (+info)
In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial. (+info)
Unusual imaging appearance of an intracranial dermoid cyst.
Intracranial dermoid cysts have characteristic CT and MR imaging findings that generally make preoperative diagnosis straightforward. Enhancement of uncomplicated intradural dermoid cysts on CT or MR studies has been reported but is rare. We present a case of a posterior fossa dermoid cyst that was not only hyperattenuating on CT scans but also contained a mural nodule with clear evidence of enhancement on MR images. (+info)
Anterior transpetrosal approach for pontine cavernous angioma--case report.
A 58-year-old male patient presented with headache and unsteady gait. Magnetic resonance imaging revealed hemorrhage from a pontine cavernous angioma. The patient experienced stepwise aggravation of symptoms due to repeated hemorrhages. We decided to surgically remove the pontine cavernous angioma through an anterior transpetrosal approach, since the angioma and hematoma were located near the ventrolateral surface of the pons. The brain stem was incised at a site caudal to the trigeminal nerve and the hematoma and angioma were totally removed. No additional neurological deficits were observed following surgery. Brain stem cavernous angiomas are usually removed via a trans-fourth ventricle or lateral suboccipital approach. However, these approaches may not be appropriate if the angioma is located ventrally to the pons. We propose that the anterior transpetrosal approach is the method of choice for ventrally located pontine cavernous angioma. (+info)
MRI findings in a case of a superficial siderosis associated with an ependymoma.
We present the imaging findings of superficial siderosis of the central nervous system associated with an ependymoma of the posterior fossa in a patient who presented with progressive bilateral sensorineural hearing loss and cerebellar ataxia. The ependymoma was a homogeneous well-defined mass of the fourth ventricle without hydrocephalus. Secondary siderosis due to chronic bleeding from the ependymoma appeared as linear hypointensity delineating the surface of the cortex, thin and subtle on spin-echo T2-weighted images, thick and obvious on gradient-echo T2-weighted images. (+info)