Hemangioblastomatosis of the central nervous system without von Hippel–Lindau Disease: a case report

Summary We report a very rare case of hemangioblastomatosis in a patient without von Hippel–Lindau disease (VHL). A 50-year-old woman had a history of surgical procedures for total removal of a cerebellar hemangioblastoma (HB). Twenty-one years after the last operation, she developed communicating hydrocephalus; computed tomographic (CT) scans of the brain showed no recurrence of HB in the posterior fossa. Subsequently, she underwent placement of a ventriculo-peritoneal shunt. One year later, she was readmitted because of progressive numbness and pain in the left lower limb. Magnetic resonance imaging (MRI) showed multiple Gd-enhancing tumors around the brain stem, in the cerebellum, and in the cervical and thoracolumbar regions of the spine. She underwent surgical removal of the tumors in the cerebellum and spinal cord. Although the extirpated tissues were histopathologically verified HB with less than 1% MIB-1 labeling index, surgery was followed by external beam radiation therapy with doses of 40 Gy to the whole brain, 10 Gy to the posterior fossa and 30 Gy to the whole spine. However, she subsequently developed quadriparesis and became bedridden.     

Pazopanib therapy for cerebellar hemangioblastomas in von Hippel–Lindau disease

von Hippel-Lindau (VHL) disease is a genetically acquired multisystem tumor syndrome of the viscera and central nervous system (CNS). The most common tumors associated with this disease are histologically benign, slow-growing CNS hemangioblastomas affecting the retina, cerebellum, brainstem, spinal cord or nerve roots. With mean age at diagnosis of 30 years, CNS hemangioblastomas are usually the first manifestation of the disease. Ongoing clinical and radiological surveillance is required, with symptomatic lesions necessitating treatment. As tumor growth is inevitable during the lifetime of most VHL patients, and the multiplicity of tumors may preclude surgical cure, the search for effective therapies is ongoing. Here we provide the first report demonstrating clinical and radiological anti-tumor response using pazopanib, a small molecule multi-receptor tyrosine kinase inhibitor, in a patient with treatment-refractory VHL-associated CNS hemangioblastoma. Treatment initiation with daily oral pazopanib (800 mg/day) resulted in significant neurologic improvement and radiologic tumor volume reduction.     

Incidence of first primary central nervous system tumors in California, 2001–2005

We examined the incidence of first primary central nervous system tumors (PCNST) in California from 2001–2005. This study period represents the first five years of data collection of benign PCNST by the California Cancer Registry. California’s age-adjusted incidence rates (AAIR) for malignant and benign PCNST (5.5 and 8.5 per 100,000, respectively). Malignant PCNST were highest among non-Hispanic white males (7.8 per 100,000). Benign PCNST were highest among African American females (10.5 per 100,000). Hispanics, those with the lowest socioeconomic status, and those who lived in rural California were found to be significantly younger at diagnosis. Glioblastoma was the most frequent malignant histology, while meningioma had the highest incidence among benign histologies (2.6 and 4.5 per 100,000, respectively). This study is the first in the US to compare malignant to benign PCNST using a population-based data source. It illustrates the importance of PCNST surveillance in California and in diverse communities.     

Incidence and survival for childhood central nervous system tumours in Australia, 1983–2016

Journal of Neuro-Oncology - Atypical (WHO grade II) and malignant meningiomas (WHO Grade III) are a rare subset of primary intracranial tumors. Given their relatively high recurrence rate after...     

A novel missense mutation (N78D) in a family with von Hippel–Lindau disease with central nervous system haemangioblastomas, pancreatic and renal cysts

von Hippel–Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations in the VHL tumor suppressor gene. In a family with VHL, we identified a novel missense mutation (N78D), which affects a fully conserved residue in the VHL protein. Interestingly, several other missense mutations reported at same codon in the VHL protein that might be associated with a low risk of renal cell carcinoma (RCC) but not pheochromocytoma appear to be associated with a VHL type 1 phenotype. At the moment, RCC is present in none of the affected mutation carriers in the family described here. In contrast to other missense changes at codon 78, the change in our VHL family is predicted to have a mild effect on VHL function, which apparently is insufficient to cause predisposition to RCC. Our findings suggest that the risk of RCC in VHL is attributable to the severity of the amino acid substitution at this particular codon in the VHL protein.     

Primary central nervous system tumor treatment and survival in the United States, 2004–2015

Journal of Neuro-Oncology - Brain tumor treatment and survival information is generally limited in large-scale cancer datasets. We provide a clinical investigation of current patterns of care and...     

Incidence of first primary central nervous system tumors in California, 2001–2005: children, adolescents and teens

This study used data from the California Cancer Registry to comprehensively examine first primary central nervous system tumors (PCNST) by the International Classification of Childhood Cancers (ICCC) diagnostic groups and to compare their incidence by age groups, sex, race/ethnicity, socioeconomic status and tumor behavior. The study period, 2001–2005, represents the first 5 years of benign PCNST data collection in the state. The age-adjusted incidence rates were 2.1 for malignant and 1.3 for benign per 100,000. Children younger than 5 years old had the highest incidence of malignant PCNST (2.6 per 100,000). Teens aged 15–19 had the highest incidence of benign PCNST (1.8 per 100,000). Age-specific incidence rates were nearly the same for Hispanics, non-Hispanic whites, and Asian/Pacific Islanders for malignant PCNST among children younger than 5 (2.6–2.7 per 100,000); non-Hispanic whites had the highest rates in the 5–14 year-old age group (2.5 per 100,000) and Asian/Pacific Islanders the highest among the 15–19 year old age group (2.3 per 100,000). We found no statistically significant differences in the incidence of malignant PCNST by race/ethnicity in any age group. Astrocytoma had the highest incidence for both malignant and benign histology in most age groups.     

Expression of survivin, platelet-derived growth factor A (PDGF-A) and PDGF receptor α in primary central nervous system lymphoma

Purpose Primary central nervous system lymphomas (PCNSL) are rare tumours occurring in the brain. Their biology and the factors predicting survival are not well known. This study investigated expression of the antiapoptotic protein survivin and platelet-derived growth factor A (PDGF-A) and receptor (PDGFRα) in PCNSL.Experimental design A total of 44 patients with histologically confirmed PCNSL treated between 1992 and 2004 were included in this study, and tumour specimens were investigated immunohistochemically for expression of survivin, PDGF-A and PDGFRα. Protein expression and clinical variables were analyzed statistically.Results Of the 44 tumours 43(98%) were diffuse large B-cell non-Hodgkin’s lymphomas (NHL) and one was a T-cell NHL. Around 37 (84%) of the examined PCNSL specimens showed expression of survivin, 16 (36%) of PDGF-A and 34 (77%) of PDGFRα. Tumours expressing surviving co-expressed PDGFRα frequently and PDGF-A occasionally. Expression of the above proteins was not predictive for survival in this patient group. Except for age and therapy, no other clinical variables correlated significantly with overall survival.Conclusions PCNSL express survivin and PDGFRα in the majority of investigated cases. PDGF-A is expressed less frequently. Immunohistochemical detection of these proteins does not correlate with overall survival and cannot be used as a prognostic factor.These authors have contributed equally to the study     

Incidence and survival of children and young people with central nervous system embryonal tumours in the North of England, 1990–2013

BackgroundMedulloblastoma and primitive neuroectodermal tumours (PNET) are the most common central nervous system (CNS) embryonal tumours diagnosed in childhood. Survival outcomes are worse for children diagnosed with CNS PNET compared to medulloblastoma. Less is known about survival outcomes in teenagers and young adults (TYA).MethodsData were extracted from two population-based cancer registries of children and young people (0–24 years) in the north of England for all diagnoses of medulloblastoma and CNS PNET between 1990 and 2013. Incidence and survival trends were analysed using Poisson and Cox regression.ResultsBetween 1990 and 2013, 197 medulloblastomas and 58 CNS PNET were diagnosed, age-standardised incidence rates of 3.8 and 1.5 per million, respectively. Medulloblastoma incidence decreased over time while there was no significant change in trend for CNS PNET. The overall 5-year survival rate was 54%. The risk of death was 2.4 times higher (95% confidence interval [CI] 1.6, 3.7) for patients with CNS PNET compared to medulloblastoma, after adjustment for patient characteristics. There was a 39% reduction (95% CI 0.43, 0.87) in the risk of death for patients diagnosed between 2000 and 2013 compared to 1990–1999. Risk of death did not differ for TYA (15–24 years) compared to children aged 5–9 years.ConclusionsMedulloblastoma incidence decreased over time and differences in survival between medulloblastoma and PNET emerged within the first-year post diagnosis leading to poorer outcomes for children and young adults diagnosed with PNET; however, a significant improvement in survival over time was observed.     

Pheochromocytoma in von Hippel–Lindau disease and neurofibromatosis type 1

Clinical and genetic understanding of chromaffin tumors has been greatly enhanced in the last few years. Although some pheochromocytoma genes may still be unknown, the role of RET, VHL, SDHB, SDHD and NF1 genes is unequivocal and phenotypes are also being better characterized. The loss of function of VHL and NF1 genes can lead to a variety of tumors including phechromocytoma and their mechanism of action is under intensive investigation. Many different mutations are responsible for VHL gene inactivation but only missense mutations have been described so far in families with pheochromocytoma. Because of its large size extensive mutation analysis of the NF1 gene has seldom been performed, and mutations have only been identified in about 15% of patients. Several point mutations have been found in exon 31. Differences in pheochromocytoma phenotype in VHL or NF1 are not very pronounced, but it may be of some interest to consider the two groups separately. In VHL, pheochromocytoma has an earlier onset than in sporadic forms, it is often multiple, and malignancy is less frequent. The mean age of diagnosis is 28 years, the youngest patient being 5 years old. In NF1 patients pheochromocytoma phenotype is similar to sporadic forms. The mean age of pheochromocytoma onset is 42 years; 84% of patients have solitary adrenal tumors, 9.6% have bilateral adrenal disease and 6.1% have ectopic pheochromocytomas; malignant pheochromocytomas were identified in 11.5% of the cases. The group of pheochromocytoma susceptibility genes includes, along with the tumor suppressor genes VHL and NF1, the proto-oncogene RET and the genes encoding succinate dehydrogenase subunit D and succinate dehydrogenase subunit B. Whether there is a common pathway among these different genes is still a matter of debate.     

Survival among patients with primary central nervous system lymphoma, 1973–2004

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin’s lymphoma that occurs in immunocompetent and human immunodeficiency virus (HIV) patients. Despite treatment advances, previous reports have produced conflicting information about survival trends over time. Using the Surveillance, Epidemiology, and End Results (SEER) data, 2,557 patients diagnosed with PCNSL between 1973 and 2004 were identified and classified by HIV status. Potential predictors of survival were evaluated using log-rank tests. Hazard ratios and 95% confidence intervals (CIs) were computed using a Cox proportional hazards regression model. The cohort included 1,732 (67.7%) HIV-negative patients and 825 (32.3%) HIV-positive patients. Median overall survival was 12 months (95% CI 10, 13) among HIV-negative patients. In this group, median survival increased over time, from 7.5 months (95% CI 6, 14) for patients diagnosed in the 1970s, to 14 months (95% CI 11, 20) for patients diagnosed in the 2000s. Independent predictors of mortality included older age (hazard ratio [HR] 1.03 [95% CI 1.02, 1.03]), earlier year of diagnosis (HR 0.98 [95% CI 0.98, 0.99]), male sex (HR 1.20 [95% CI 1.08, 1.34), married status (HR 0.70 [95% CI 0.63, 0.78]), and receipt of radiation therapy (HR 0.69 [95% CI 0.61, 0.77]). HIV positivity was a powerful adverse prognostic factor in the overall cohort (HR 4.55 [95% CI 4.01, 5.16]). Despite treatment advances, survival among PCNSL patients in the United States remains poor. However, in the subset of PCNSL patients who are HIV-negative, survival has improved over time.     

Population-based incidence and survival of central nervous system (CNS) malignancies in Girona (Spain) 1994–2005

The purpose of this study was to describe the incidence and survival of primary Central Nervous System (CNS) malignancies using data from the population-based cancer registry for Girona province (north-east Spain).     

Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non–small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria

BackgroundCentral nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase–positive (ALK+) non–small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.MethodsBoth studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.ResultsBaseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2–77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7–68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).ConclusionAlectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.     

Temozolomide plus rituximab in the treatment of recurrent central nervous system lymphoma： Case report and literature review

Objective  

The aim of our study was to investigate the treatment of recurrent central nervous system lymphoma.