Coexistence of radiation-induced glioma and acute pontine infarct 40 years after radiotherapy for glioma: A case report.

We report an unusual case of radiation-induced glioma with a very long latent period. The patient had a history of brain stem glioma diagnosed 40 years earlier treated by radiotherapy. For treatment of radiation-induced glioma, radiotherapy was utilized again. Following therapy, the patient presented with an acute pontine infarct. To the best of our knowledge this may be the first report of radiation-induced glioma and radiation-induced stroke occurring within the same patient.

A brainstem mass of Müllerian type Epithelial Origin without any primary cancer source.

Brainstem tumors are rare, even rarer is a brainstem tumor containing tissues of an embryologic gynecologic origin. We report a very rare case of presence of a calcified heterogeneously contrast enhancing brainstem mass of Müllerian origin in a patient in a 38 year old female with no female genital tract cancer and past surgical history of ventriculoperitoneal (VP) shunt placement for congenital hydrocephalus. To our knowledge this is the very first and unusual case of a mass of gynecologic origin in the brainstem region especially in the setting of no history of gynecological tumor. The authors also reviewed the literature for all tumors reported for anterograde and retrograde dissemination of tumor cells through VP shunt. This case is a reaffirmation of the importance of brain tumor location and tissue diagnosis for the purpose of adjuvant treatment of neurosurgical lesions in the neurocritical care setting. It also highlights the role of catheters as potential routes of iatrogenic transmission not just in anterograde but also in a retrograde manner to the CNS, which is very unusual. This is the only second case to report retrograde flow of tumor cells from an extraneural source up the VP catheters. The authors suggest that intraperitoneal chemotherapy should be considered in the cases of known extraneural abdominal malignancies of high malignant potential with or without the presence of peritoneal infiltration in order to avoid dissemination through VP shunts.

Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry.

With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3-3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4-17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

Radiologic Features and Surgical Strategy of Hemangioblastomas with Enhanced Cyst Wall.

OBJECTIVE: Hemangioblastomas with enhanced cyst walls represent a rare radiologic presentation of hemangioblastomas with poor understandings. We aimed to summarize the clinical and radiologic features, important differential diagnosis, surgical strategy, and clinical outcome of this rare entity. METHODS: From June 2008 to March 2017, 12 patients with cystic hemangioblastomas presenting with enhanced wall thickness on MRI were treated in our department. The clinical presentations, radiologic investigations, surgical treatment, neurologic outcome, and recurrence rate were evaluated. Important preoperative differential diagnosis and surgical strategy of this entity were discussed. RESULTS: Twelve patients with cystic hemangioblastomas presenting with an enhanced cyst wall on magnetic resonance imaging were analyzed retrospectively. There were 5 male and 7 female subjects, with a mean age of 41.4 years (range, 13-78 years) and an average duration of symptoms before diagnosis of 2.23 months (range, 0.5-8.0 months). Radiologically, enhancement of both tumoral nodule and cyst were observed in 8 patients, while pure ring-enhanced cyst without typical tumoral nodule was found in 4 patients. Histopathologic examination confirmed the diagnosis of hemangioblastomas, and the enhanced cyst wall and mural nodule shared the same histopathologic pattern. Postoperative complications occurred in only 1 patient with postoperative cerebellar hemorrhage. During follow-up, 8 patients achieved favorable neurologic outcomes (Karnofsky score: 100) without recurrence; however, 4 patients experienced local tumor recurrence after the initial surgery. CONCLUSIONS: Hemangioblastomas with enhanced cyst wall possess distinctive radiologic features, and they are frequently misdiagnosed preoperatively. Favorable tumor control can be achieved only when gross total resection of both the tumor nodule and cyst wall are performed. Close follow-up is necessary because of the high recurrence rate in this subset of hemangioblastomas.

Ganglioglioma of brain stem and cervicomedullary junction: A 50years review of literature.

Gangliogliomas are rare low-grade brain tumors composed of both neoplastic glial and neuronal cell elements. The treatment modalities are relatively different in this location and hence factors affecting outcome are poorly understood. We identified 142 brain stem GG patients across 46 studies. The average age was 11.4years with significant difference b/w males and females under the age of 20 (p=0.001). 100% of tumors in the CMJ while, 72% of type I and 86% of type II tumors demonstrated contrast enhancement. 72% of type I and 86% of type II tumors demonstrated contrast enhancement. All BRAF mutation positive tumors demonstrated contrast enhancement. Medulla and pons was the most favorable location followed by medulla alone, and the CMJ. In all tumors "gross total resection" (GTR, 16%), "subtotal resection" (STR, 48%) or "partial resection" (PR, 36%) was achieved. Most subtypes II and III were partially resected (86% and 66%), while, subtype I underwent STR (66%). Only 55% of the patients were positive for the BRAF V600E mutation. The overall survival dropped from 50% at 24 to 10% at 60months, postoperatively. Through this review, we found that an early diagnosis, location, and with the imaging characteristics are vital part of the preoperative planning. Surgical resection is highly dependent on location in the brain stem with radical resection only limited to the most contrast enhancing portion of these tumors. BRAF V600E mutation status should be considered to allow the possibility of targeted therapy in case of a residual tumor and/or regrowth.

Pediatric central nervous system hemangioblastomas: different from adult forms? A retrospective series of 25 cases.

BACKGROUND: Pediatric hemangioblastomas are rare, and the clinical features, timing of surgical intervention, optimal treatment, and clinical outcomes are still unclear. METHODS: We performed a retrospective study of all patients with CNS hemangioblastomas who were treated at West China Hospital from January 2003 to March 2015. Patients under the age of 16 years were included in the study. The medical records of these patients were reviewed and statistically analyzed. RESULTS: Twenty-five children (15 females and ten males, [mean age 12.6 ± 4.7 years, range 1-16 years]) presented with hemangioblastomas. Tumors were detected in the cerebellum, brainstem, and spinal cord in 40, 28, and 32% of patients, respectively. Sixteen children (64%) had VHL syndrome. The most frequent symptoms were those related to increased intracranial pressure. The mean duration of symptoms was 1.5 ± 2.1 months. Preoperative hydrocephalus was noted in 11 children (44%). Gross total resection was achieved in all children. Clinical symptoms improved in 19 children (76%), unchanged in four children (16%), and aggravated in two children (8%), respectively. The mean follow-up was 44.5 ± 32.3 months. Five patients (20%) experienced disease progression. Using univariate analysis, both tumor-associated cysts (P = 0.027) and VHL disease (P = 0.032) were significantly related to postoperative outcomes. CONCLUSIONS: Pediatric hemangioblastomas have many different clinical features compared with adult cases. A high degree of suspicion for VHL disease should be raised in pediatric hemangioblastomas. Despite many challenges involved, surgical outcomes for pediatric hemangioblastomas are favorable. Lifelong follow-up is mandatory to detect the disease progression.

Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System.

OBJECTIVE: In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. METHODS: It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. RESULTS: The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. CONCLUSION: Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.

Long-term survival of an infant with diffuse brainstem lesion diagnosed by prenatal MRI: a case report and review of the literature.

BACKGROUND: We describe a unique case of expansive diffuse brainstem lesion diagnosed prenatally by magnetic resonance imaging (MRI) with long-term survival. Findings of fetal and postpartum MRI were highly consistent with the characteristics of diffuse brainstem glioma. METHODS: Diagnosis was based on the features of MRI, and histopathology was not confirmed by biopsy. Although the prognosis of diffuse brainstem tumor is usually poor, this child was asymptomatic at birth and the neurological condition is still normal at 4 years of age without any treatment. RESULTS: During routine imaging follow-up, diameters of the expansion have remained stable, while the size of the lesion compared to the posterior fossa size has diminished. In addition to brainstem tumor, a skin lesion of the back was observed and MRI of the thoracic spine showed a large asymptomatic extradural cystic lesion suggesting an arachnoid cyst. The pontine tumor of this infant, in agreement with a few previously reported cases, suggests a subgroup of beneficial outcome of expansive diffuse brainstem lesions, particularly in the neonatal period. DISCUSSION: In this article, we discuss the prognosis and characteristics of pediatric brainstem tumors and differential diagnosis of neonatal brainstem lesions.

Radiation induced brainstem glioblastoma in a patient treated for glomus jugulare tumour.

The intensive utilisation of cranial irradiation in young individuals with benign intracranial pathologies are of particular concern because of the potential for delayed development of radiation-induced neoplasms. We present a 48-year-old man who developed a second metachronous brainstem glioblastoma 10 years following adjuvant radiotherapy for a partially resected glomus jugulare tumour. The current patient highlights the importance of judicious and individualised consideration for irradiation treatment in benign pathologies that are associated with long-term survival.

Histologically Proven Radiation-Induced Brainstem Glioma 93 Months After External Beam Radiotherapy for Pituitary Macroadenoma: Radiation Treatment Dose and Volume Correlation.

Patient is a 29-year-old with a history of recurrent growth hormone-secreting pituitary macroadenoma diagnosed 12 years prior to presentation. Eight years prior to current presentation, the patient underwent re-resection and received 50.4 Gy external beam radiotherapy (EBRT) in 28 fractions of 1.8 Gy each. Serial postradiation MRIs demonstrated regression in pituitary tumor size. Patient presented with new headaches 7.5 years after completing EBRT. Brain MRI demonstrated new FLAIR hyperintensity and contrast enhancement within the pons and medulla, corresponding to the 36 Gy isodose line of each radiation dose fraction. Differential diagnosis included radiation necrosis and radiation-induced glioma (RIG). The patient's neurologic exam worsened over the following 4 months. MRI showed progressive increase in mass effect, extent of FLAIR hyperintensity, and contrast enhancement in the brainstem. Stereotactic-assisted biopsy showed infiltrating astrocytoma with moderate atypia. A PubMed search showed this is the first case of histologically verified brainstem RIG correlated with 3-dimensional conformational radiation therapy dose and volume planning following EBRT for a pituitary adenoma. The rare occurrence of brainstem RIG after radiation therapy for pituitary tumor supports the need for long-term imaging monitoring of such patients.

Radiosurgery for radiosurgery-induced cavernous malformation.

BACKGROUND: This report describes the use of radiosurgery for the treatment of a radiosurgery-induced cavernous malformation (CM). METHODS: A 21-year-old woman underwent stereotactic biopsy of a pineocytoma and subsequent gamma knife radiosurgery (marginal 14.5 Gy, 50%) for the lesion. A T1-weighted enhanced magnetic resonance imaging one year later showed that the tumor had disappeared. After two years, she developed facial palsy and experienced mental status changes. It was found that she experienced repeated hemorrhages in that radiation field, and magnetic resonance imaging showed a CM. RESULTS: The area where the CM developed had been exposed to 5.0 ± 3.7 Gy. This value was calculated using the fused dose planning image using Leksell GammaPlan. We used gamma knife radiosurgery to treat this lesion (marginal 12.5 Gy, 50%), and believe that it is a radiation-induced CM. Five years after gamma knife radiosurgery for the CM, the CM has controlled without any new hemorrhages. CONCLUSIONS: Gamma knife radiosurgery-induced CMs are very rare, and the use of another gamma knife radiosurgery to treat this lesion has not yet been reported. We report a case of radiosurgery for CM that was induced by gamma knife radiosurgery for a pineocytoma. This report suggests that radiosurgery is a reasonable option for treating radiation-induced CM to prevent repeated hemorrhage.

Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis type 2.

Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder characterized by the development of benign tumors of the peripheral nervous system and the CNS, including schwannomas, meningiomas, and ependymomas. The gene responsible for the development of NF2 acts as a tumor suppressor gene. Stereotactic radiotherapy (SRT) or single-fraction stereotactic radiosurgery has been increasingly used in the past decades to treat benign tumors in patients with NF2. These radiotherapy methods are less invasive and can be potentially used to treat multiple tumors in a single session. The risk of inducing malignancy is unclear. Few reports exist of malignant peripheral nerve sheath tumors, meningiomas, or ependymomas occurring after SRT or stereotactic radiosurgery in patients with NF2. The authors present the first documented case of rhabdomyosarcoma following SRT for multiple NF2-associated schwannomas. Compared with patients with sporadic tumors, NF2 patients having a germline tumor suppressor gene defect may be more prone to secondary malignancies after treatment involving radiation therapy.

Intracranial malignancies occurring more than 20 years after radiation therapy for pituitary adenoma.

A 37-year-old woman developed a left third cranial nerve palsy 28 years after radiation for a nonsecreting pituitary adenoma. Imaging disclosed a left parasellar mass and a midbrain/pontine signal abnormality. Biopsy of the parasellar mass revealed a malignant sarcoma. The brainstem abnormality was presumptively diagnosed as a malignant glioma. A 63-year-old man developed a malignant astrocytoma of the left optic nerve and chiasm 23 years after partial excision and radiation of a nonsecreting pituitary adenoma. Both patients died of their malignancies. Although secondary malignancies have been described in this setting, such long latencies have not been reported.

Ocupações e neoplasias intracranianas: estudo caso-controle na região metropolitana do Rio de Janeiro, Brasil / Occupations and intracranial tumors: case-control study in the metropolitan region of Rio de Janeiro, Brazil

O aumento das taxas de incidência e mortalidade dos tumores do sistema nervoso central no Brasil e no mundo tem impulsionado a investigação de seus fatores etiológicos. As exposições ambientais, principalmente as ocupacionais, têm sido foco crescente destes trabalhos. Este estudo caso-controle de base hospitalar realizado naregião metropolitana do Rio de Janeiro, entre 1999-2002, teve como objetivo identificar as associações entre ramos de atividade econômica e ocupações referidas com as neoplasias intracranianas em adultos, segundo subtipos histológicos gliomas emeningiomas. Foi analisada a história ocupacional de 239 casos e 267 controles, pareados por freqüência de sexo e idade, utilizando as classificações por ramos de atividades econômicas e por grupos ocupacionais. Os riscos foram estimados por regressão logística. Na análise por ramo de atividade, a Agricultura apresentou OR: 2,52(IC 95 por cento: 1,15 – 5,53) para o conjunto das neoplasias cerebrais. Além disso, Saúde e Social, Administração Pública e Educação apresentaram associação positiva sem significância estatística. Quanto aos meningiomas, observou-se risco em trabalhadores das áreas de Transporte (OR: 3,14, IC 95 por cento: 1,08 – 9,19) e Bens Imóveis (OR: 2,45, IC 95 por cento: 1,17 – 5,15). Em relação aos grupos ocupacionais, os agricultores apresentaram risco significativo: OR: 2,44 (IC 95 por cento: 1,14 – 5,18). Associação direta foi evidenciada nos grupos de Transporte / Produção de Equipamentos e Forças Armadas enquanto queProfissionais Técnicos e Trabalhadores com Vendas apresentaram associação inversa. A análise para gliomas mostrou risco para Empregados de Escritório: OR: 2,33 (IC 95 por cento: 1,02 – 5,29). Os achados sugerem que trabalhadores da agricultura, militares eprofissionais de saúde apresentam risco para neoplasias intracranianas, demandando novas pesquisas para identificação de exposições específicas.

Diffuse intrinsic brainstem tumors in neonates. Report of two cases.

The authors report on 2 newborn infants with the unusual presentation of intrinsic brainstem tumors. Both nondysmorphic, full-term neonates had cranial nerve palsies and hypotonia. Diagnoses of diffuse intrinsic brainstem gliomas were made on the basis of magnetic resonance imaging, which showed large expansive, nonenhancing intrinsic pontine masses. Intrinsic pontine tumors, characteristically seen in school-age children, are most often high-grade gliomas that are almost invariably fatal. However, the microanatomy and natural history of pontine tumors in neonates are unknown. With parental consent, both newborns were treated expectantly with supportive care but died of progressive disease by 2 weeks of age. In one child, postmortem examination revealed a primary brainstem primitive neuroectodermal tumor. The authors conclude that, as in older children, neonatal intrinsic brainstem tumors may be of a highly malignant nature. The rapid tumor progression in both cases indicates that where a diagnostic procedure may pose significant risks, supportive observation can aid in distinguishing malignant from benign tumor growth.

Anaplastic glioma after high-dose proton-photon radiation treatment for low-grade skull base chondrosarcoma.

We report the case of a 63-year-old man who developed an anaplastic oligoastrocytoma of the brain stem and midbrain 13 years after postoperative high-dose proton-photon radiation therapy for a recurrent low-grade chondrosarcoma of the skull base. To our knowledge, this is the first reported case of an anaplastic glioma after proton-photon irradiation.

Fluorescence-activated cell sorting-based purification of embryonic stem cell-derived neural precursors averts tumor formation after transplantation.

The differentiation of dopaminergic (DA) neurons from mouse embryonic stem cells (ESCs) can be efficiently induced, making these neurons a potential source for transplantation as a treatment for Parkinson's disease, a condition characterized by the gradual loss of midbrain DA neurons. One of the major persistent obstacles to the successful implementation of therapeutic ESC transplantation is the propensity of ESC-derived grafts to form tumors in vivo. To address this problem, we used fluorescence-activated cell sorting to purify mouse ESC-derived neural precursors expressing the neural precursor marker Sox1. ESC-derived, Sox1+ cells began to express neuronal cell markers and differentiated into DA neurons upon transplantation into mouse brains but did not generate tumors in this site. In contrast, Sox1- cells that expressed ESC markers frequently formed tumors in vivo. These results indicate that Sox1-based cell sorting of neural precursors prevents graft-derived tumor formation after transplantation, providing a promising strategy for cell transplantation therapy of neurodegenerative disorders.

Endoscopic third ventriculostomy for hydrocephalus associated with tectal gliomas.

OBJECT: Tectal gliomas are a distinct form of pediatric brainstem tumor that present in patients with symptoms related to increased intracranial pressure due to obstructive hydrocephalus. The natural history of these lesions is often uniquely indolent. Thus, initial surgical therapies are directed at treatment of hydrocephalus, usually with ventricular shunt placement. Recently, third ventriculostomy has been used in patients with tectal gliomas, both as an initial procedure and after shunt failures. In this report the authors review their experience with the treatment of hydrocephalus in patients with tectal gliomas. METHODS: The authors reviewed 31 consecutive cases of tectal gliomas and compared the success rates of ventricular shunt placement with the success rates of endoscopic third ventriculostomy (ETV). Shunt placement procedures were associated with a significant number of malfunctions, and most patients required shunt revisions. The ETV procedure was attempted both as an initial treatment and after shunt malfunction. Overall, ETV was attempted in 18 patients and was performed successfully in all cases. At the time of follow-up evaluation, 16 patients (89%) were shunt free. CONCLUSIONS: The authors found that ETV could be performed with good long-term success both as an initial treatment and after shunt failure. Overall, ETV was found to be superior to ventricular shunt placement in the management of hydrocephalus associated with tectal gliomas.

Treatment of intramedullary hemangioblastomas, with special attention to von Hippel-Lindau disease.

OBJECTIVE: Hemangioblastomas of the central nervous system are rare vascular tumors that can occur as sporadic lesions or as component tumors of autosomal dominant von Hippel-Lindau disease. With the availability of magnetic resonance imaging, asymptomatic tumors are detected more frequently, especially among patients with von Hippel-Lindau disease, and the questions of whether and when these lesions should be treated arise. To identify surgical outcomes and the timing of surgery for intramedullary hemangioblastomas, we retrospectively analyzed data for a series of 28 consecutive patients whom we surgically treated for intramedullary hemangioblastomas in the past 10 years. METHODS: All tumors were completely removed. Functional grades, according to the McCormick scale, were determined before and after surgery and in follow-up assessments. Several clinical characteristics were correlated with changes in functional grades in follow-up assessments, compared with preoperative grades. RESULTS: Functional grades in follow-up assessments improved for 28.6% of the patients and remained unchanged for 71.4%. No patient was in worse condition, compared with preoperative status. Peritumoral edema on preoperative magnetic resonance imaging scans was correlated with significantly higher surgical morbidity rates. Four asymptomatic patients were surgically treated because of tumor or pseudocyst progression on serial magnetic resonance imaging scans. All of those patients remained asymptomatic postoperatively. CONCLUSION: Intramedullary hemangioblastomas can be removed with low surgical morbidity rates and excellent long-term prognoses. The timing of surgery for patients with von Hippel-Lindau disease and multiple lesions remains a matter of debate. On the basis of our data, we established the strategy of operating also on asymptomatic lesions that exhibit radiological progression, before significant neurological deficits occur, which are often not reversible.

The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease.

OBJECT: The goals of this study were to define the natural history and growth pattern of hemangioblastomas of the central nervous system (CNS) that are associated with von Hippel-Lindau (VHL) disease and to correlate features of hemangioblastomas that are associated with the development of symptoms and the need for treatment. METHODS: The authors reviewed serial magnetic resonance images and clinical histories of 160 consecutive patients with VHL disease who harbored CNS hemangioblastomas and serially measured the volumes of tumors and associated cysts Six hundred fifty-five hemangioblastomas were identified in the cerebellum (250 tumors), brainstem (64 tumors, all of which were located in the posterior medulla oblongata), spinal cord (331 tumors, 96% of which were located in the posterior half of spinal cord), and the supratentorial brain (10 tumors). The symptoms were related to a mass effect. A serial increase in hemangioblastoma size was observed in cerebellar, brainstem, and spinal cord tumors as patients progressed from being asymptomatic to symptomatic and requiring surgery (p < 0.0001). Twenty-one (72%) of 29 symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of 221 nonsymptomatic cerebellar tumors had tumor-associated cysts (p < 0.0001). Nine (75%) of 12 symptomatic brainstem tumors had associated cysts, compared with only four (8%) of 52 nonsymptomatic brainstem lesions (p < 0.0001). By the time the symptoms appeared and surgery was required, the cyst was larger than the causative tumor; cerebellar and brainstem cysts measured 34 and 19 times the size of their associated tumors at surgery, respectively. Ninety-five percent of symptom-producing spinal hemangioblastomas were associated with syringomyelia. The clinical circumstance was dynamic. Among the 88 patients who had undergone serial imaging for 6 months or longer (median 32 months), 164 (44%) of 373 hemangioblastomas and 37 (67%) of 55 tumor-associated cysts enlarged. No tumors or cysts spontaneously diminished in size. Symptomatic cerebellar and brainstem tumors grew at rates six and nine times greater, respectively, than asymptomatic tumors in the same regions. Cysts enlarged seven (cerebellum) and 15 (brainstem) times faster than the hemangioblastomas causing them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) and then stabilize in a period of arrested growth (quiescent phase). Of 69 patients with documented tumor growth, 18 (26%) harbored tumors with at least two growth phases. Of 160 patients with hemangioblastomas, 34 patients (median follow up 51 months) were found to have 115 new hemangioblastomas and 15 patients new tumor-associated cysts. CONCLUSION: In this study the authors define the natural history of CNS hemangioblastomas associated with VHL disease. Not only were cysts commonly associated with cerebellar, brainstem, and spinal hemangioblastomas, the pace of enlargement was much faster for cysts than for hemangioblastomas. By the time symptoms appeared, the majority of mass effect-producing symptoms derived from the cyst, rather than from the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth, and many untreated tumors may remain the same size for several years. These characteristics must be considered when determining the optimal timing of screening for individual patients and for evaluating the timing and results of treatment.