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John E. Wanebo, Russell R. Lonser, Gladys M. Glenn and Edward H. Oldfield

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.

Conclusions. 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.

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Daniel Choo, Lawrence Shotland, Maryann Mastroianni, Gladys Glenn, Carter van Waes, W. Marston Linehan and Edward H. Oldfield

Object. Von Hippel—Lindau (VHL) disease is a hereditary multiple-neoplasia syndrome mapping to chromosome 3p25–26. Endolymphatic sac (ELS) tumors have been identified as a neoplastic manifestation of VHL disease. The purpose of this study was to evaluate comprehensively the natural history of inner ear disease in a large population of patients with confirmed or suspected VHL disease and to correlate the clinical features with the VHL genotype.

Methods. The authors collated and analyzed clinical and genotypic data obtained in patients enrolled in an Institutional Review Board—approved protocol in which families and individuals affected by VHL disease were studied. These data included results from multidisciplinary history workups and physical examinations, imaging studies, and a battery of audiological tests.

One hundred seventy-five patients were enrolled in the study, 129 with confirmed VHL disease and 46 of their family members in whom test results for VHL disease were negative and who served as controls. Twenty-one patients had ELS tumors that were evident on magnetic resonance images; three of them had bilateral ELS lesions. Hearing loss, often sudden in onset and severe to profound in nature, vestibulopathy, aural fullness, and tinnitus represented the primary symptoms of ELS tumor. Distinct patterns of auditory and vestibular dysfunction occurred at different stages of the disease. Phenotypic data showed that 17 of 21 patients with ELS tumors did not have pheochromocytomas, whereas all had VHL disease affecting the kidney, all but two had VHL disease affecting the central nervous system, and all but one had disease affecting the pancreas. Genotyping revealed 10 rearrangements (partial deletions), eight single bp substitutions, and one 3-bp insertion. Although there was no difference in the incidence of hearing loss between populations, symptoms of imbalance and aural fullness were more common in patients with VHL disease but without imaging evidence of ELS tumor than they were in family members who did not have VHL disease (p < 0.01).

Conclusions. Endolymphatic sac tumors are frequently associated with VHL disease. Symptoms of disequilibrium or aural fullness in patients with VHL disease may be an early indication of endolymphatic dysfunction. Patients with VHL disease provide a unique opportunity to examine the effects of specific gene mutations and a discrete neoplastic process on the human inner ear. The study of ELS tumors in this group also provides a pathological model of ELS function and supplies evidence for a role of the ELS in clinical Ménière-like disease(s).

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H. Jeffrey Kim, John A. Butman, Carmen Brewer, Christopher Zalewski, Alexander O. Vortmeyer, Gladys Glenn, Edward H. Oldfield and Russell R. Lonser

Object. Endolymphatic sac tumors (ELSTs), which often are associated with von Hippel—Lindau (VHL) disease, cause irreversible hearing loss and vestibulopathy. Clinical and imaging surveillance protocols provide new insights into the natural history, mechanisms of symptom formation, and indications for the treatment of ELSTs. To clarify the uncertainties associated with the pathophysiology and treatment of ELSTs, the authors describe a series of patients with VHL disease in whom serial examinations recorded the development of ELSTs.

Methods. Patients with VHL disease were included if serial clinical and imaging studies captured the development of ELSTs, and the patients underwent tumor resection. The patients' clinical, audiological, and imaging characteristics as well as their operative results were analyzed.

Five consecutive patients (three men and two women) with a mean age at surgery of 34.8 years and a follow-up period of 6 to 18 months were included in this study. Audiovestibular symptoms were present in three patients before a tumor was evident on neuroimaging. Imaging evidence of an intralabyrinthine hemorrhage coincided with a loss of hearing in three patients. Successful resection of the ELSTs was accomplished by performing a retrolabyrinthine posterior petrosectomy (RLPP). Hearing stabilized and vestibular symptoms resolved after surgery in all patients. No patient has experienced a recurrence.

Conclusions. Audiovestibular symptoms, including hearing loss, in patients with VHL disease can be the result of microscopic ELSTs. Once an ELST has been detected, it can be completely resected via an RLPP with preservation of hearing and amelioration of vestibular symptoms. Early detection and surgical treatment of small ELSTs, when hearing is still present, should reduce the incidence and severity of hearing loss, tinnitus, vertigo, and cranial nerve dysfunction, which are associated with these tumors.

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H. Jeffrey Kim, John A. Butman, Brewer Carmen, Christopher Zalewski, Alexander O. Vortmeyer, Gladys Glenn, Edward H. Oldfield and Russell R. Lonser

Object

Endolymphatic sac tumors (ELSTs), which often are associated with von Hippel–Lindau (VHL) disease, cause irreversible hearing loss and vestibulopathy. Clinical and imaging surveillance protocols provide new insights into the natural history, mechanisms of symptom formation, and indications for the treatment of ELSTs. To clarify the uncertainties associated with the pathophysiology and treatment of ELSTs, the authors describe a series of patients with VHL disease in whom serial examinations recorded the development of ELSTs.

Methods

Patients with VHL disease were included if serial clinical and imaging studies captured the development of ELSTs, and the patients underwent tumor resection. The patients' clinical, audiological, and imaging characteristics as well as their operative results were analyzed.

Five consecutive patients (three men and two women) with a mean age at surgery of 34.8 years and a follow-up period of 6 to 18 months were included in this study. Audiovestibular symptoms were present in three patients before a tumor was evident on neuroimaging. Imaging evidence of an intralabyrinthine hemorrhage coincided with a loss of hearing in three patients. Successful resection of the ELSTs was accomplished by performing a retrolabyrinthine posterior petrosectomy (RLPP). Hearing stabilized and vestibular symptoms resolved after surgery in all patients. No patient has experienced a recurrence.

Conclusions

Audiovestibular symptoms, including hearing loss, in patients with VHL disease can be the result of microscopic ELSTs. Once an ELST has been detected, it can be completely resected via an RLPP with preservation of hearing and amelioration of vestibular symptoms. Early detection and surgical treatment of small ELSTs, when hearing is still present, should reduce the incidence and severity of hearing loss, tinnitus, vertigo, and cranial nerve dysfunction, which are associated with these tumors.