Brachytherapy for Peripheral Retinal Capillary Haemangioblastoma in von Hippel-Lindau Disease. / Brachytherapie peripherer retinaler kapillärer Hämangioblastome beim Von-Hippel-Lindau-Syndrom.

AIM: To report our experience with 106ruthenium-brachytherapy of peripheral capillary haemangioblastomas in patients with von Hippel-Lindau disease. DESIGN: Retrospective case series. METHODS: A total of 53 haemangioblastomas, treated with 106ruthenium-brachytherapy, were included in our study. The applied radiation dose, visual outcome, angioma activity, need for vitreoretinal surgery and incidence of secondary complications such as macular oedema, secondary glaucoma, vitreous haemorrhage, and epiretinal gliosis were assessed. RESULTS: All treated eyes could be preserved. In 11 patients (20.8%), single brachytherapy did not achieve complete inactivation of the tumour. 31% developed macular oedema postoperatively. Tractional retinal detachment developed in 23.8%, and epiretinal gliosis was observed in 2.4% of patients. Vitreoretinal surgery was necessary in 50% of all treated eyes. At the end of the follow-up, 40.5% of all treated eyes achieved visual acuity (VA) of 0.6 or better, and one third reached a VA of less than 0.1. Mean irradiation dose to the tumour apex was 144 Gy. Higher apex doses correlated with better tumour control of irradiated haemanigoblastomas and lower complication rates. CONCLUSIONS: Brachytherapy of peripheral retinal capillary haemangioblastomas is an effective treatment modality. Higher irradiation doses seem to lead to more successful treatment.

Linear accelerator stereotactic radiosurgery can modulate the clinical course of Hemangioblastoma: Case series and review of the literature.

Hemangioblastomas (HB) are benign low grade vascular tumors most frequently occurring in the cerebellum, brain stem, and spinal cord. Often associated with Von Hippel Lindau disease (VHL), the lesions are often multifocal requiring complex resection and are difficult to control. Linear Accelerator (LINAC) Stereotactic Radiosurgery (SRS) has been demonstrated to provide additional tumor control. In this case series, we present our multi-center experience utilizing LINAC SRS in fourteen patients with 23 lesions. We observed a tumor control rate of 87% and found interval changes in the peritumoral enhancement to correlate with treatment outcome. In our study, SRS treatment was also well-tolerated in both cystic and noncystic patients with multifocal disease. Disease control was achieved in all but three patients post-resection and no longitudinal radiation-induced secondary malignancy was observed. SRS response correlated highly with lesion size and radiation dose. We conclude that LINAC SRS is safe and effective for patients with HB and should be considered in addition to surgery in asymptomatic, VHL patients, deep seated lesions and isolated lesions.

Leksell Radiosurgery for the 3 H Tumors: Hemangiomas, Hemangioblastomas, and Hemangiopericytomas.

Leksell stereotactic radiosurgery has proven to be effective for less common tumors encountered in the brain, including hemangiomas of the orbit or cavernous sinus, recurrent hemangiopericytomas, and both sporadic hemangioblastomas as well as those encountered in the context of von Hippel-Lindau (VHL) disease. While all three tumors are responsive to single-session radiosurgery, hemangiomas and hemangiopericytomas are the most likely to demonstrate tumor regression. Hemangiopericytomas that recur after initial resection can be lower grade or anaplastic and have both higher local as well as distant recurrence risks. Sporadic hemangioblastomas undergo Leksell radiosurgery at the time of recurrence after initial surgery. In the context of VHL, growing or recurrent tumors are treated with tumor control rates exceeding 90%. Tumor control improves with higher dose delivery, typically >15 Gy at the margin. Dose-limiting structures may include the optic apparatus for hemangiomas and brain stem locations for hemangioblastomas.

Disseminated central nervous system hemangioblastoma in a patient with no clinical or genetic evidence of von Hippel-Lindau disease-a case report and literature review.

BACKGROUND: Hemangioblastomas (HB) are benign tumors of the central nervous system (CNS) that can appear sporadic or as part of von Hippel-Lindau (VHL) disease. It is often curable with surgical resection, but upon relapse, the disease exhibits a treatment-refractory course. CASE REPORT: A patient treated for sporadic cerebellar HB relapsed 12 years post-surgery. She developed disseminated disease throughout the CNS, including leptomeningeal manifestations. Repeat surgery and craniospinal radiation therapy were unsuccessful. CONCLUSION: This case is in line with previous publications on disseminated non-VHL HB. Available treatment options are inefficient, emphasizing the need for improved understanding of HB biology to identify therapeutic targets.

Histology of hemangioblastoma treated with stereotactic radiosurgery confirms its effectiveness.

Hemangioblastoma is usually amenable to total surgical resection, but indication for surgery can be hampered by its location, multiplicity, or repeated recurrences frequently observed in patients with von Hippel Lindau disease (VHLD). Stereotactic radiosurgery (SRS) has been administered for such cases as an alternative therapeutic option with generally favorable clinical response, but the effect of SRS has not been underscored by histological examination of the treated hemangioblastoma. Here we present histology of VHLD-associated hemangioblastoma tissue resected three months after SRS because of cyst enlargement. It confirmed that hemangioblastoma cells totally disappeared after SRS with a marginal dose of 20 Gy. Furthermore, Electron microscope revealed that endothelial cells of the vascular structure disappeared while maintaining the basement membranes, and leakage of intraluminal contents was observed around the structure. We showed the SRS was effective for hemangioblastoma pathologically at least with the marginal dose of 20 Gy. Leakage of intraluminal contents from the damaged vascular structure losing the endothelial cells is one possible mechanism for the cyst enlargement, and it may be a reason of poor control rate of SRS for the cystic hemangioblastoma.

Stereotactic radiosurgery for central nervous system hemangioblastoma: systematic review and meta-analysis.

Hemangioblastomas are rare, benign, vascular tumors of the central nervous system (CNS), often associated with von-hippel lindau (VHL) disease. Current therapeutic options include microsurgical resection or stereotactic radiosurgery (SRS). With no randomized controlled studies and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. We completed a Pubmed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year progression free survival (PFS). The pooled 5-year PFS across all eligible studies was 88.4%. No difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease. Adverse events were associated with increasing marginal dose, independent of tumor volume. VHL status, sex, radiosurgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. Multiple studies show excellent tumor control at 5-year follow up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.

Hypervascular Lesions of the Cerebellopontine Angle: The Relevance of Angiography as a Diagnostic and Therapeutic Tool and the Role of Stereotactic Radiosurgery in Management. A Comprehensive Review.

BACKGROUND: The cerebellopontine angle (CPA) is a narrowed skull base area containing important cranial nerves and vessels and bordering with eloquent areas of the posterior fossa. Tumors of the CPA are a heterogeneous group and can have extradural, intradural/extra-axial, or intra-axial origins. Their vascular supply changes depending on their anatomic origin. Symptomatic, large CPA tumors require surgical resection in order to prevent irreversible, severe neurological damages. However, its tight and strategical location make surgery in the CPA very challenging and require appropriate pre-surgical planning. Pre-surgical diagnosis is of great importance as it allows us to choose the optimal management for the particular patient. This is of further significance when encountering high-risk lesions such as hypervascular tumors. Neurosurgeons should utilize every available pre-surgical diagnostic modalities as well as neo-adjuvant treatments in order to reduce such risks. METHODS: We review all reported cases of hypervascular lesions of the CPA and discuss the roles of angiography and stereotactic radiosurgery in their management. RESULTS: Three lesions of the CPA can be considered as truly hypervascular: hemangioblastomas, hemangiopericytomas and paragangliomas. All lesions share many radiological features. However, each lesion has a different anatomical origin and hence, has a characteristic vascular supply. Pre-surgical angiography can be utilized as a diagnostic tool to narrow down the differential diagnosis of a vascular CPA lesion, based on the predominant supplying vessel. In addition, pre-surgical embolization at time of angiography will narrow the associated surgical risks. CONCLUSIONS: Angiography is a crucial diagnostic and therapeutic tool, helping both in narrowing the presurgical differential diagnosis and in controlling intraoperative bleeding. Because of the high surgical risks associated with resection of vascular tumors in the CPA, noninvasive treatments, such as stereotactic radiosurgery, also may have a crucial role.

Fractionated radiotherapy in the management of benign vascular tumors.

PURPOSE: To better characterize the long-term therapeutic ratio of fractionated radiotherapy for benign vascular and lymphatic tumors. METHODS: We retrospectively reviewed 19 medical records with 13 hemangiomas, 3 hemangioblastomas, and 3 benign lymphatic tumors treated with radiotherapy at the University of Florida from 1984 to 2007 to assess clinical presentation, treatment, and outcomes. The 10 men and 9 women had a median age of 43 years (range, 2 to 74 y). Six patients underwent radiotherapy alone; 13 patients underwent radiotherapy after surgery. Median radiotherapy dose was 40 Gy (range, 15 to 63.6 Gy). Median observed follow-up was 6.2 years (range, 1.6 to 25.0 y). Disease-free survival was defined by the absence of tumor progression or death from disease. Event-free survival was defined by the absence of tumor progression, death from disease, or severe complication. RESULTS: The 5-year overall survival, disease-free survival, and event-free survival rates were 87%, 84%, and 74%, respectively. Immediately after treatment, there was 1 patient with tumor progression, 10 with stable disease, 7 with partial tumor regression, and 1 complete tumor regression. Ultimately, 3 patients experienced local tumor progression and 16 patients had long-term tumor control. Twelve patients had symptom improvement. Thirteen patients were alive with no evidence of progressive disease. Two patients were alive with symptomatic tumors. Four patients died: 2 from disease and 2 from unrelated causes. Two grade 3 and 2 grade 4 complications were noted. CONCLUSIONS: When symptomatic benign vascular and lymphatic tumors are unresectable and not amenable to radiosurgery or embolization, fractionated radiotherapy represents a viable alternative with an acceptable long-term therapeutic ratio.

Infratentorial craniospinal irradiation for von Hippel-Lindau: a retrospective study supporting a new treatment for patients with CNS hemangioblastomas.

Patients with von Hippel-Lindau (VHL) syndrome with diffuse CNS hemangioblastomas have morbidity related to their disease and require a lifetime of surgical resections. Ninety-seven percent of tumors progress, and 5-year surgery rates are 20%-60%. Stereotactic radiosurgery and fractionated radiotherapy have had limited success. For the first time, we have used infratentorial craniospinal radiation therapy (ICSRT) for VHL patients with CNS hemangioblastomas. Consecutive VHL patients treated at the National Institutes of Health with radiographic evidence of hemangioblastomas were included if they received ICSRT. Patients underwent neurologic examinations and imaging at 3- to 12-month intervals. Seven patients with 84 hemangioblastomas met eligibility criteria. ICSRT was commonly administered to 43.2 Gy in 24 fractions. Mean pre-ICSRT tumor volume was 5.48 cm(3). At a mean follow-up of 73.8 months, mean post-ICSRT tumor volume was 6.87 cm(3), and 91 tumors were identified. Complete radiographic resolution was achieved in 17.9% of lesions. Although many patients were no longer optimal surgical candidates, only 4 surgeries were needed for symptomatic lesions after ICSRT, compared with 33 prior. Acute toxicity was mild and no patient developed grade ≥1 late spinal cord toxicity according to the criteria of the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer, despite the high dose that the entire spinal cord received. Clinical and radiographic stability or resolution was demonstrated in the majority of tumors. Tumor growth rate in this study was less than reported in natural history studies, and the rate of surgical intervention was reduced. ICSRT was well tolerated, can decrease hemangioblastoma growth rate, and is a potential therapeutic option for VHL patients that warrants further investigation.

Role of fractionated external beam radiotherapy in hemangioblastoma of the central nervous system.

PURPOSE: To assess the clinical outcomes and toxicity in patients receiving fractionated external beam radiotherapy (EBRT) for hemangioblastoma of the central nervous system, treated at two Canadian radiation oncology institutions. METHODS AND MATERIALS: Between January 1980 and December 2004, the data of all patients receiving EBRT for central nervous system hemangioblastoma were retrospectively reviewed. The patient, tumor, and treatment characteristics were collected and overall survival, disease-free survival, and EBRT-related toxicities assessed. RESULTS: A total of 18 cases, 5 associated with von Hippel-Lindau disease (VHL) and 13 sporadic (non-VHL), with a total 31 lesions, were documented. These were located in the cerebellum in 20 and spinal cord in 8 patients. EBRT was delivered for recurrence in 12, adjuvantly for residual disease in 4, and definitively in 2. The EBRT schedules ranged from 50.0 to 55.8 Gy in 1.8-2.0-Gy daily fractions (n = 17), typically with parallel-opposed fields to the cerebellar target volumes and direct posterior fields for spinal disease. At a median follow-up of 5.1 years (range, 0.1-14.5), the 5-year OS rate was 69% (95% confidence interval [CI], 50-96%), decreasing to 30% (95% CI, 10-87%) at 10 years. The disease-free survival rate at 5 and 10 years was 57% (95% CI, 37-87%) and 30% (95% CI, 11-83%), respectively. The outcomes differed according to VHL status. The 5-year OS rate was 100% for those with VHL compared with 55% (95% CI, 32-95%) for those with non-VHL disease (log-rank p = 0.003), and the 5-year disease-free survival rate was 80% (95% CI, 52-100%) with VHL compared with 48% (95% CI, 26-89%) without (log-rank p = 0.036). CONCLUSIONS: Fractionated EBRT has a role in the management of extensive intracranial and/or spinal cord disease, the adjuvant treatment of residual postoperative disease, and the treatment of recurrence. More favorable outcomes were reported for VHL-associated lesions than for sporadic cases.

Angioblastoma showing aggravation after treatment with long-pulsed Nd:YAG laser (1064 nm).

Angioblastoma usually develops in infancy or early childhood on the neck or upper trunk. It is known to be slowly progressive and benign in nature, but treatment guidelines have not yet been established. Spontaneous regression has been occasionally documented, and treatment with pulsed dye laser, excision, high-dose steroids, and interferon alpha have been successful in individual patients. Our patient experienced partial response to interferon alpha injection, and for further treatment, long-pulsed Nd:YAG laser (1064 nm) treatment was performed. However, unexpectedly, the tumor was rapidly aggravated. We report this occurrence to increase awareness of trauma-induced aggravation phenomena in angioblastoma.

[Retinal angiomatosis. Ocular manifestation of von Hippel-Lindau disease]. / Angiomatosis retinae. Okuläre Manifestation des Von-Hippel-Lindau-Syndroms.

Von Hippel-Lindau disease (VHL disease) is a rare multisystem disorder of autosomal dominant inheritance with high penetrance. Inactivation of the VHL-protein leads to an increased expression of hypoxia induced growth factors. Predilection sites for tumor growth are the retina, the central nervous system and various visceral organs. Retinal capillary hemangioblastoma is one of the earliest manifestations of VHL disease. The lifetime risk of permanent visual loss defined as a visual acuity of 0.5 or less is about 35% in gene carriers. It increases to 60% if there is already retinal capillary hemangioblastoma. If VHL disease is suspected, a careful ophthalmological examination should be included in the clinical screening program. Having confirmed the diagnosis, regular ophthalmoscopic monitoring is essential in order to detect developing tumors at an early stage. Therapeutic options for small to medium sized peripheral tumors are laser or cryocoagulation; larger- hemangioblastomas can be treated by brachytherapy using ruthenium plaques, while asymptomatic juxtapapillary tumors can be observed at regular intervals.

Treatment of recurrent cerebellar hemangioblastoma with external radiotherapy in a patient with von Hippel-Lindau disease: a case report and review of the literature.

Von Hippel-Lindau Disease, a multisystem familial cancer syndrome, is inherited as an autosomal-dominant trait. Common manifestations of the disease are retinal, cerebellar and medullary hemangioblastomas; renal cysts and carcinomas; pancreatic cysts; pheochromocytoma; and papilllary cystadenoma of the epididym. We report the case of a 40-year-old man with type I von Hippel-Lindau disease treated with external radiotherapy for recurrent cerebellar hemangioblastoma.

Cranial irradiation--an unusual cause for diabetes insipidus.

Central diabetes insipidus frequently occurs due to tumours in the region of pituitary or hypothalamus or following surgical trauma to these regions. Rarely it has been reported following cranial irradiation. We report the case of a middle aged woman who underwent surgical removal of a frontal capillary hemangioblastoma and received cranial irradiation. She presented ten months later with features of diabetes insipidus which was confirmed to be of central origin. She responded well to desmopressin nasal spray. Radiation induced damage to the hypothalmo-pituitary axis presents usually with anterior pituitary hormone deficiencies, most commonly that of growth hormone. Presentation as central diabetes insipidus is very uncommon.

Hemangioblastoma of the third ventricle.

A third ventricle tumor, in addition to a recurrent cerebellar hemangioblastoma, was found in a 47-year-old woman on follow-up magnetic resonance imaging (MRI) 5 years after operation of the cerebellar tumor. On MRI, the tumor was hypo- to isointense on T1-weighted images and hyperintense on T2-weighted images compared with the normal gray matter, and was strongly enhanced with gadolinium. The tumor was first treated with fractionated conventional external-beam radiation (5120 cGy in 16 fractions over a 4-week period), resulting in a slight decrease in size of the tumor. For a definite diagnosis and mass reduction, surgery was performed using an interhemispheric translamina terminalis approach, resulting in a partial removal of the tumor due to profuse bleeding. Histological diagnosis was hemangioblastoma. Hemangioblastomas of the third ventricle are extremely rare and have not been specifically discussed. We describe the detailed clinicopathological features of the present case together with the possible explanation for the development of this tumor in this rare location.

Hemangioblastoma of the posterior fossa. The role of multimodality treatment.

The authors made a review of a series of patients with hemangioblastomas of the posterior fossa treated between 1973 and 1993. A total of 32 patients were analyzed with 24 patients receiving resection, 8 patients receiving radiosurgery and 2 patients receiving conventional radiotherapy. The mortality in the patients with a resection was considered acceptable with 2 deaths (8%) and with a morbidity of 3 patients (12.5%). A review of the literature suggests that conventional radiotherapy with high doses (45-60 Gy) may have a role in the post-operative control of hemangioblastomas and in some cases could be employed even before the resection in order to facilitate the surgery. The radiosurgical treatment is regarded like adjuvant. Poor results were obtained with radiosurgery in large tumors where low doses (less than 20 Gy) were used. Because of the rarity and complexity of these tumors, mainly when associated with von Hippel-Lindau disease, a multicenter study could be useful with the assessment of the optimal utilization and combination of these treatment modalities.