Surgical management of brainstem hemangioblastomas in patients with von Hippel Lindau disease

J Neurosurg 98:95 105, 2003 Surgical management of brainstem hemangioblastomas in patients with von Hippel Lindau disease ROBERT J. WEIL, M.D., RUSSELL R. LONSER, M.D., HETTY L. DEVROOM, R.N., JOHN E. WANEBO, M.D., AND EDWARD H. OLDFIELD, M.D. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland C Object. Hemangioblastomas of the brainstem constitute 5 to 10% of central nervous system (CNS) tumors in patients with von Hippel Lindau (VHL) disease. At present, optimal management of brainstem hemangioblastomas associated with VHL disease is incompletely defined. In an attempt to clarify some of the uncertainty about the operative treatment of these lesions and its outcome, the authors reviewed all cases of VHL disease in which resection of brainstem hemangioblastomas was performed at the National Institutes of Health during a 10-year period. Methods. Twelve consecutive patients with VHL disease (six male and six female patients [mean age 31.7 9 years; range 15 46 years]) who underwent 13 operations to remove 17 brainstem hemangioblastomas were included in this study (mean follow-up period, 88.4 37.4 months; range 37 144 months). Serial examinations, hospital charts, magnetic resonance images, and operative records were reviewed. To evaluate clinical course, clinical grades were assigned to each patient before and after surgery. Preoperative neurological function was the best predictor of long-term outcome. In addition, patients who underwent CNS surgeries for hemangioblastomas were more likely to improve or to remain neurologically stable. Tumor or cyst size, the presence of a cyst, or the location of the tumor (intramedullary, extramedullary, or mixed; posterior medullary, obex, or lateral) did not affect outcome. No patient was neurologically worse after brainstem surgery. At longterm follow-up review (mean 88.4 months), only one patient had declined neurologically and this was due to the cumulative neurological effects caused by eight additional hemangioblastomas of the spinal cord and their surgical treatment. Conclusions. Brainstem hemangioblastomas in patients with VHL disease can be removed safely; they generally should be resected when they become symptomatic or when the tumor has reached a size such that further growth will increase the risks associated with surgery, or in the presence of an enlarging cyst. Magnetic resonance imaging is usually sufficient for preoperative evaluation and presurgical embolization is unnecessary. The goal of surgery is complete resection of the lesion before the patient experiences a disabling neurological deficit. KEY WORDS tumor suppressor gene magnetic resonance imaging microsurgery stereotactic radiosurgery ENTRAL nervous system hemangioblastomas are benign tumors that arise predominantly in the spinal cord and the infratentorial portion of the brain. 2,30,34,36, 40,41 In patients with sporadic or VHL disease associated hemangioblastomas, the cerebellum is the most common site of the lesion, followed by the spinal cord and brainstem. The average age of the patient at onset of hemangioblastomas associated with VHL disease is generally within the third or fourth decades, 10 to 15 years younger than in patients who present with sporadic lesions. 17,35,40,41 Usually male and female patients are equally affected, regardless of whether their lesions are sporadic or the familial type. Although sporadic cases are characterized by solitary tumors, 40 in patients with VHL disease, multiple CNS tumors are the rule and may develop continually throughout the patient s life, which complicates their management. 30 32,34,36,41 In addition to the multiplicity of CNS lesions, renal, adren- Abbreviations used in this paper: CNS = central nervous system; MR = magnetic resonance; NIH = National Institutes of Health; VHL = von Hippel Lindau. al, and pancreatic lesions demonstrate similar multiplicity and heterochronicity. 30,31,34 Brainstem tumors comprise 2 to 10% of hemangioblastomas. 2,16,30,36,41 Like their counterparts in the cerebellum and spinal cord, they may be solid, solid cystic, or nearly completely cystic with a small mural nodule. Brainstem lesions may be intramedullary, extramedullary, or mixed. The most common single location of brainstem hemangioblastomas is at the obex; 16 other locations include the posterior or posterolateral medulla oblongata. 1,2,36 Pathologically, brainstem hemangioblastomas are identical to hemangioblastomas that originate elsewhere in the CNS. 2,21,36,50 Although stereotactic radiosurgery has recently been advocated as a mode of treatment for certain cerebellar hemangioblastomas, 4,37 the principal treatment of brainstem hemangioblastomas has been surgical. There has been no comprehensive review of the surgical management of brainstem hemangioblastomas in patients with VHL disease. We reviewed 12 consecutive patients who underwent surgical resection of brainstem hemangioblastomas at the NIH between 1987 and 1998 to evaluate the effect of vari- 95

R. J. Weil, et al. Grade I II III TABLE 1 Clinical/functional classification scheme* Definition neurologically normal; mild focal deficit not significantly affecting function of involved limb: mild spasticity or reflex abnormality; normal gait presence of sensorimotor deficit affecting function of involved limb: mild to moderate gait difficulty: severe pain or dysesthetic syndrome impairing patient s quality of life: still functions & ambulates independently more severe neurological deficit: requires cane/brace for ambulation or significant bilateral upper extremity impairment: may or may not function independently IV severe deficit: requires wheelchair or cane/brace with bilateral upper extremity impairment: usually not independent * Reprinted from McCormick, et al. ous clinical factors on short-term (3 6 months) and final neurological outcome. Clinical Material and Methods Patient Population Between 1987 and 1998, 12 consecutive patients (six male and six female patients) with VHL disease underwent surgery for symptomatic (11 cases) or asymptomatic, but enlarging (one case) brainstem hemangioblastomas by the senior author (E.H.O.) at the NIH. The 12 surgically treated patients were selected from 48 patients with hemangioblastomas of the brainstem, as demonstrated by MR imaging during the same period. All lesions were located in the medulla oblongata and most possessed some component that presented at or close to an accessible pial surface. Patients selected for operation harbored a solid component of tumor larger than 125 mm 3 and a cyst larger than 1000 mm 3 or both; in addition, all patients were either experiencing symptoms (11 of 12) or harbored a rapidly enlarging tumor and cyst (see Case 12 later in this paper as well as the paper by Wanebo, et al. 51 ). The 36 patients who were not surgically treated harbored tumors that were small ( 125 mm 3 ) with small ( 500 mm 3 ) or no cysts; none of these patients was experiencing symptoms. After surgery, all were followed up a minimum of 3 years. Patients and their families were screened at the NIH for the presence of mutations and deletions of the VHL gene under an institutional review board approved protocol. All patients fit the diagnostic criteria for VHL disease. 17,41,52 Patient Evaluation Patients were evaluated with serial neurological examinations and MR imaging (0.5- or 1.5-tesla magnet; General Electric Medical Systems, Milwaukee, WI) before and after surgery. Tumor and cyst volumes were calculated by measuring the largest diameter in all three coordinate planes and applying the following formula: volume = (width height length) 0.5. 29 Cysts were evaluated postoperatively by MR imaging and categorized as collapsed or absent (inactive), or unchanged or growing (active). Detailed neurological examinations were conducted at the initial screening and immediately before and after an operation. Follow-up examinations were performed at TABLE 2 Patient characteristics* CNS Lesions Extra-CNS Lesions Age Case (yrs), Brain- Cere- Spinal Retinal Pan- No. Sex stem bellum Cord Angioma ELST Renal creatic Other 1 27, M ECs 2 32, F HCs 3 33, M ECs 4 32, F 5 32, F 6 45, M 7 24, F 8 31, M 9 40, F 10 46, M 11 23, M 12 15, F *See Clinical Material and Methods for definitions of mutations. Abbreviations: EC = epididymal cyst; ELST = endolymphatic sac tumor; HC = hepatic cyst; pancreatic = pancreatic cysts or tumors; renal = renal cysts or carcinoma; = present; = absent. At time of brainstem surgery. 6-month intervals for 1 year and yearly thereafter, unless new symptoms or signs developed. Inpatient charts, clinic notes, and operative reports were examined. Patients were also contacted by telephone at the conclusion of the study period to confirm and supplement the data. The neurological function of the patients was graded according to the scale described by McCormick, et al. (Table 1). 33 Mutation Analysis The VHL germline analysis was performed in 11 of the 12 patients with the familial form of the disease by analyzing peripheral blood samples, as described in Chen, et al. 6 The VHL gene consists of 852 nucleotides in three exons, with exon 1 containing nucleotides 1 through 553, exon 2 nucleotides 554 through 676, and exon 3 nucleotides 677 through 852, according to the nomenclature of Latif, et al. 25 Surgical Technique Patients are placed prone and a suboccipital craniectomy is performed, combined, as necessary, with C1 2 laminectomies, to expose the inferior portion of the cerebellum, cervicomedullary junction, and rostral portion of the cervical segment of the spinal cord. Preoperative embolization, ventricular drainage, intraoperative monitoring, or intraoperative hypotension are not used. Intraoperative ultrasonography is performed to help localize intramedullary tumors precisely and to examine the relationship between the tumor and its cyst and other tumors, if present. A Y-shaped dural incision is made and the dural edges are reflected laterally to expose the lesion. Using the operating microscope, the arachnoid in the region of the hemangioblastoma is opened and the hemangioblastoma and its associated vessels are identified. In cases in which the tumor reaches the pial surface, the pia mater is sharply incised with a diamond knife at the margin of the tumor, for dissection of the capsule of the superficial portion of the tumor and for access to the deeper portions of the tumor. In cases of midline tumors that do not reach the posterior pia mater, after a midline pial in- 96

Surgery of brainstem hemangioblastomas TABLE 3 Clinical and operative characteristics* Tumor Cyst Early Total No. Final Follow Case Preop Volume Volume EBL Postop of CNS Postop Final Up No. Signs & Symptoms Location Position Grade (mm 3 ) (mm 3 ) (ml) Grade Surgeries Grade Outcome (mos) 1 coughing, singultus obex EM I 550 45000 300 I 1 I stable 140 2 swallowing & gait difficulties; medulla EM IM II 840; 360 1980 100 I 1 I improved 59 limb paresthesias 3 swallowing & gait difficulties medulla IM EM II 1350 1690 700 II 3 II stable 107 4 speech difficulties, N, V obex IM II 320 1690 150 II 3 II stable 107 5 decreased LE sensation; gait difficulties obex IM I 550; 350 NP 200 I 3 I stable 98 6 swallowing disturbances, V, vertigo, medulla IM II 1960; 20 4200 600 II 10 II stable 43 & ataxia 7 decreased LE sensation medulla IM I 1800 1200 100 I 1 I stable 66 8 decreased LE sensation medulla EM II 130 NP 150 II 4 III worse 106 9 gait disturbances medulla IM = EM II 1100 5650 500 I 2 I improved 144 10 coughing, ataxia medulla EM IM I 720 N/P 100 I 2 I stable 44 11 bilat LE weakness; ataxia medulla IM EM IV 860; 520 1030 200 III 2 III improved 110 12 asymptomatic obex IM I 600; 320 2250 150 I 1 I stable 37 * Preoperative and postoperative grading are based on the McCormick grading system (Table 1). Early postoperative grading took place 3 to 6 months after surgery. Outcome refers to improving one or more grades, declining one or more grades, or remaining the same grade at final evaluation, compared with preoperative neurological status. Abbreviations: EBL = estimated blood loss during surgery; EM = extramedullary component; IM = intramedullary component; LE = lower-extremity; location = location within region of brainstem; N = nausea; NP = cyst not present; position = region of the medulla or obex (all tumors originated in the midline or paramedian areas; V = vomiting; = the EM or IM component was greater than 50% of the tumor volume. Five patients harbored two tumors. cision the posterior median raphe is separated to reach the most accessible portion of the tumor capsule. Hemangioblastomas typically have a thin rim of soft gliotic neural tissue at the junction of the tumor capsule and the surrounding brainstem. After defining the interface between the surface of the tumor and adjacent neural tissue, the hemangioblastoma is resected by microsurgical dissection at the tumor neural tissue interface by working circumferentially and proceeding to the deeper regions by creating progressively deeper layers of dissection. Care is taken to coagulate and interrupt vessels individually as they enter or leave the tumor capsule. Irrigation concurrent with each use of the bipolar forceps prevents adherence of small vessels or the tumor capsule to the bipolar tips and prevents unnecessary bleeding. For very large tumors, the central portion of the tumor is coagulated using the bipolar forceps and removed in a piecemeal manner to permit manipulation of the tumor margin and to gain access to the ventral edge of the tumor. Tumor removal can thus be achieved with visualization of the interface between the tumor and the brainstem. No attempt is made to address the cysts associated with these tumors because the cysts disappear with tumor removal. The dura mater is closed and the fascial, subcutaneous, and cutaneous layers are closed in the standard fashion. Results All mean data presented in this paper represent means standard deviations. Twelve patients underwent 13 operations to remove 17 brainstem hemangioblastomas larger than 125 mm 3 in volume. There were six male and six female patients and the mean age at surgery in this group was 31.7 9 years (range 15 46 years) (Table 1). The age at first presentation from any CNS lesion (excluding retinal angioma) was 25 7.2 years in this group and the average number of CNS hemangioblastomas per patient, excluding the brainstem lesions, was 5.2 4.5 (range 0 15 tumors). In addition to brainstem tumors, nine patients harbored cerebellar and spinal hemangioblastomas, 10 had retinal angiomas, and two had endolymphatic sac tumors (Table 2). 32,41,52 The VHL germline mutation analysis was performed in 11 of 12 families of which these patients were members. An abnormality of the VHL gene was detected in all 11 families screened. In four of the families, a missense mutation was detected, one each at nucleotides 475, 545, 605, and 712; the first two mutations were located at the 3 end of exon 1 and the last two mutations at the 5 end of exon 3, the traditional location for most VHL missense mutations; the missense mutation at nucleotide 605 was located within exon 2. In one family, the germline change involved substitution of two nucleotides in exon 1 at positions 543 and 544. The remaining six families were found to have deletions of larger segments of the VHL gene. The most common symptoms and signs before surgery were related to posterior column disturbances (gait difficulties or ataxia), which affected seven patients, lower (ninth 12th) cranial nerve dysfunction (six patients), impaired upper- or lower-extremity sensory function (four patients), and bilateral lower-extremity weakness (one patient); one patient experienced no symptoms (Table 3). In all but the last patient (Case 12), the presenting signs and symptoms were progressive. At the time of surgery, there were five Grade I (42%), six Grade II (50%), and one Grade IV (8%) patients; the mean McCormick grade was 1.75 0.87 (Arabic numerals substituted in mean grades to allow fractions). At surgery, all lesions were found to lie posteriorly in the midline or the paramedian area posteriorly: six lesions were located posteriorly in, or immediately adjacent to, the midline of the medulla oblongata; four were at the obex; one was in the posterolateral aspect of the medulla near the inferior cerebellar peduncle; and one was in the ventrolateral 97

R. J. Weil, et al. FIG. 1. Case 12. A and B: Contrast-enhanced sagittal (A) and axial (B) MR images of the brain obtained 6 months before surgery, revealing a small hemangioblastoma and no cyst. C and D: Sagittal (C) and axial (D) MR images obtained immediately before surgery, demonstrating enlargement of the tumor and rapid development of a cyst with brainstem compression. E and F: Intraoperative photographs showing a bulging medulla oblongata, without evident tumor (E); an enlarged draining vein is present in the midline (superior aspect of the medulla at top of panel). After incising the pia mater and gently opening the midline raphe, the tumor capsule is exposed, which permits complete resection by dissection of the interface between the tumor capsule and surrounding neural tissue (F). G: Postoperative axial MR image confirming complete resection of the tumor and disappearance of the brainstem cyst 2 weeks after surgery. aspect of the medulla in front of a posteriorly projecting cyst. Five tumors were entirely intramedullary and were not visible on the posterior surface of the brainstem, and one tumor was extramedullary, arising from the pia mater at the obex or the posterior midline of the medulla oblongata. Six tumors were partially intramedullary and partially extramedullary. In three cases, the extramedullary portion of the tumor was larger than the intramedullary portion, whereas the converse was true in two cases; in one case, the intra- and extramedullary components were equal in size. The mean tumor volume was 726 548.6 mm 3 (range 20 1960 mm 3 ). In nine of the 12 patients there were associated brainstem cysts, which were often large in relation to the tumor volume (the cysts were larger than the tumor in eight of nine patients). The mean volume of the cyst was 7187.8 14,260 mm 3 (range 1030 45,000 mm 3 ); the mean cyst volume tumor volume ratio was 11.1 24.9 (range 0.7 81.8). The mean operative blood loss was 270.8 60.6 ml (range 100 700 ml) and the mean operative time was 5.3 3.2 hours (range 3 11 hours). No patient had undergone previous surgery for the lesion that was resected; however, most patients had undergone at least one prior surgery for a CNS hemangioblastoma and in the group the mean number of total CNS surgeries for hemangioblastomas was 2.75 2.5 (range 0 10; Table 3). The neurological condition was unchanged as a result of surgery in nine patients who were stable at 3 and 6 months after surgery, and in three patients there was neurological improvement (advanced one grade; Table 3). One asymptomatic patient (Case 12) experienced transient heaviness and tingling of the distal right lower extremity, which resolved by the 4th postoperative week and a second patient (Case 7) had mild aggravation of preoperative paresthesias, which resolved within 1 month. At long-term follow up, one patient had declined one neurological grade in comparison with his preoperative condition. In this patient (Case 8), the cumulative neurological effects of multiple spinal 98

Surgery of brainstem hemangioblastomas hemangioblastomas (eight separate tumors) and the surgery necessary to treat them were the source of the lower extremity deficits. At the time of final evaluation there were seven Grade I (58%), three Grade II (25%), and one Grade III (8%) patients. The mean early ( 3 months) postoperative functional grade was 1.5 0.7 and the mean final functional grade as of the last follow-up examination ( 36 months) was 1.59 0.8. The mean follow-up interval was 88.4 37.4 months (range 37 144 months). Preoperative and Operative Characteristics and Outcome All five patients who were neurologically normal or nearly normal (Grade I) before surgery remained in that condition at the early follow-up visit after surgery. Among six Grade II patients two (33%) improved (33%) and four (67%) remained stable. The Grade IV patient improved one grade. Sex, tumor size, number of tumors, presence or size of an enlarging cyst, or total volume occupied by the tumor(s) and cyst combined did not predict the preoperative or postoperative grade of a patient, or whether the neurological grade would change as a result of surgery. After surgery for removal of the tumor, eight of nine cysts collapsed and became inactive. One patient (Case 6) required a repeated operation 6 months after the first surgery for a persistent cyst associated with a separate, small, 20-mm 3 brainstem tumor that had not been appreciated at the first surgery (see Case 6 in the following section); postoperatively, the cyst resolved. The total number of previous CNS surgeries for hemangioblastomas did not predict the postoperative outcome, although all patients who had undergone three or fewer surgeries were stable or improved and no patient who had undergone more than two CNS surgeries improved. Complications were rare. There were two cases of cerebrospinal fluid leakage that resolved with permanent diversion of the cerebrospinal fluid, and one instance of superficial wound infection that resolved with a regimen of oral antibiotics. There were no instances of postoperative hemorrhage, no gastrointestinal hemorrhages, no episodes of intra- or postoperative hemodynamic instability, and no recurrent tumors. No patient required mechanical ventilation longer than 16 hours postoperatively and the average stay in the intensive care unit was 1.8 0.8 days (range 1 3 days). Two patients, who at their last follow-up examination ( 36 months postoperatively) were functioning at their preoperative grade, experienced transient ( 1 month) worsening of their preoperative symptoms. Illustrative Cases Case 12 This 15-year-old girl was noted in January 1997 to have bilateral retinal angiomas, which prompted a screening examination for VHL disease (Fig. 1). There was no family history of VHL syndrome. Magnetic resonance imaging demonstrated a 6 6 5 mm (90 mm 3 total volume) hemangioblastoma located at the obex; there was no cyst. Biochemical screening, physical examination, and abdominal MR imaging did not demonstrate other stigmata of VHL disease. Magnetic resonance imaging of the neuraxis 6 months later was unchanged. The patient remained asymptomatic. In January 1998, however, repeated MR imaging demonstrated rapid growth of the medullary hemangioblastoma (600 mm 3 ), development of a moderately large cyst (2250 mm 3 ), and brainstem distortion. Although the patient experienced no symptoms, it was believed that the rapid growth of the tumor and the new, sudden appearance of a large cyst with distortion of the medulla oblongata warranted surgical intervention. She underwent suboccipital craniectomy and C-1 laminectomy. Although the lesion appeared on MR imaging to have a posterior surface presentation, intraoperative exploration revealed only an enlarged draining vein on the bulging, posterior surface of the medulla oblongata at the site of the tumor. Intraoperative ultrasonography was performed to confirm the precise location of the tumor underlying the midline raphe. To obtain access to the intramedullary tumor, the midline raphe was used to separate the posterior columns, permitting the tumor to be resected completely. After surgery, the patient remained asymptomatic and repeated MR imaging demonstrated resolution of the cyst. Case 2 This 32-year-old woman presented in October 1995 with a 3-month history of progressive right lower-extremity paresthesias (Fig. 2). During the next several months transient swallowing difficulties, recurrent yawning, and singultus attacks developed with moderate gait ataxia. Magnetic resonance imaging demonstrated a cystic hemangioblastoma in the posterior medulla oblongata. Suboccipital craniectomy and C-1 laminectomy revealed a midline tumor in which the extramedullary component was larger than the intramedullary portion. After this relatively large tumor was resected by dissection at the tumor margin, the cyst collapsed, revealing an additional, small mural nodule (not evident as a separate tumor on the MR image), which was also resected. Postoperatively, this patient s gait and swallowing abnormalities resolved and serial postoperative MR imaging demonstrated complete removal of the tumor and resolution of the cyst. Case 6 This 45-year-old man first experienced CNS symptoms in 1979 with onset of headaches and persistent nausea and vomiting; a left-sided cerebellar tumor with an associated cyst was removed. During the next 17 years, he underwent seven subsequent operations for removal of additional cerebellar and spinal hemangioblastomas. At presentation to the NIH, he exhibited stable neurological deficits, including moderate gait difficulty, right-lateral gaze nystagmus, leftarm spasticity, and bilateral lower-extremity weakness (4 / 5), with associated hyperreflexia. For several weeks before surgery in August 1997, he expressed new complaints of increased ataxia, vertigo, vomiting, and swallowing difficulties. Magnetic resonance imaging showed a posterior medullary hemangioblastoma associated with a large cyst and a small focus of enhancement along the inferior pole of the cyst. Suboccipital craniectomy was performed and one large (1960-mm 3 ) irregular hemangioblastoma, which appeared to be the product of two separate hemangioblastomas that had merged with progressive growth (Fig. 3A and B), and three small (all 20 mm 3 ) hemangioblastomas were removed. During dissection of the deep margin of the large hemangioblastoma, the cyst was entered and decompressed. Because there was little likelihood that the small 99

R. J. Weil, et al. FIG. 2. Case 2. A C: Axial (A), sagittal (B), and coronal (C) contrast-enhanced MR images of the brain obtained preoperatively. D and E: Intraoperative photographs showing a principally extramedullary tumor (superior at top of panel). The tonsils have been elevated to expose the tumor (D). Subpial dissection of the inferior margin of the tumor after incision of the pia mater at its junction with the tumor margin (E). Removing the large extramedullary tumor revealed a second, smaller tumor that was also removed. F and G: Postoperative axial (F) and sagittal (G) MR images obtained 6 (F) and 12 (G) months after surgery, demonstrating complete tumor removal and disappearance of the cyst. tumor lying at the caudal pole of the cyst caused the syringobulbia, in the presence of the large tumor, and because a myelotomy at the spinal cord brainstem junction would be required to reach the smaller lesion, no attempt was made to remove it. Although this patient initially improved, he returned to the NIH in March 1998 with recrudescent brainstem dysfunction. Magnetic resonance imaging demonstrated a large brainstem cyst and a focal, 2-mm-diameter area of enhancement at the inferior margin of the cyst, distant from the site 100

Surgery of brainstem hemangioblastomas FIG. 3. Case 6. A and B: Coronal MR images obtained before (A) and after (B) addition of contrast material, revealing a large hemangioblastoma and cyst. C and D: Preoperative sagittal MR views of the tumor obtained before (C) and after (D) addition of contrast material, demonstrating a large tumor along the posterior margin of the cyst and a small focus of enhancement (arrow) in D along the most caudal pole of the cyst at the midpoint of the odontoid. E G: Contrastenhanced MR images obtained 6 months after the first surgery, in which the large hemangioblastoma was removed, revealing a persistent cyst. H: Intraoperative photograph obtained at repeated surgery, showing a small orange-red mural nodule within the operative mirror (arrowhead; superior is at the top of the panel and the patient s left side is situated to the left of the panel). The mirror reflects the small tumor at the most inferior extent of the intramedullary cyst. I: Intraoperative photograph of the 2-mm-diameter tumor before resection and after entry into the cyst. J and K: Contrastenhanced MR images obtained 1 month after surgery, confirming removal of the tumor and decompression of the cyst. of the previous brainstem hemangioblastoma. At surgery, a small hemangioblastoma was identified at that site and removed (Fig. 3). Postoperatively, the ataxia and swallowing difficulties abated, and the patient s vertigo and vomiting resolved. His previous neurological deficits have remained stable. Magnetic resonance imaging performed 3 months after surgery demonstrated a collapsed, inactive cyst and no evidence of residual tumor. Discussion Historical and Genetic Review of VHL Disease In 1928, Cushing and Bailey coined the term hemangio- blastoma to describe a set of vascular tumors of the CNS previously known as vascular gliomas and to differentiate them from vascular malformations such as telangiectasia, cavernous angiomas, and venous angiomas. 12 In their review, they noted that the first description of a CNS hemangioblastoma had been made by Hughlings Jackson 20 in 1872. Recognition of the angiomatous nature of the retinal lesions awaited a report by Threacher Collins 8 in 1894 containing the pathological description of retinal angiomas in a brother and sister. Eugen von Hippel 49 presented his first case of angiomatosis retinae in 1895 and added two familial cases in 1904. 40 Although Pye-Smith had reported a patient with cerebellar, pancreatic, and renal cysts in 1885, it was not until 1926 that Arvid Lindau, 26 a Swedish neu- 101

R. J. Weil, et al. TABLE 4 Classification of VHL disease* Clinical Manifestation Type I Type IIA Type IIB Type IIC CNS hemangioblastoma retinal angioma endolymphatic sac tumor renal cell carcinoma pancreatic tumors pheochromocytoma VHL mutation type(s) mutations are frequent (up amino acid substitutions in missense mutations isolated familial pheochromocytomas as a to 95% of patients) & of up to 100% of patients, in exon 1, altering form of VHL, w/ a specific amino acid several types, including outside core VHL binding contact between substitution outside the elongin & CUL2 small deletions or inser- domain w/ elongin pvhl & elongin C, binding domains, leading to a dominant tions, nonsense & splice- in 70 90% of cases negative effect on the wild-type site mutations copy of pvhl *Table adapted from data shown in references 3 6, 11, 17, 32, 41, 45, and 55. rologist, combined retinal angiomas with cerebellar hemangioblastomas as a possible, coherent clinical syndrome. 40 For several years, however, he did not believe that the visceral manifestations of what has come to be known as von Hippel Lindau disease were related to the CNS expression of the VHL syndrome that he had described. 26,27 Over the course of the next 50 years, the nosology of VHL disease was refined and a complex, autosomal-dominant familial syndrome was defined. 17,30,31,41,52 Greater insight into the nature of hemangioblastomas, at least those associated with VHL disease, awaited the development of two important features: Knudson s tumor suppressor hypothesis and simplified techniques for rapid DNA mutational analysis. In 1971, Knudson, using a detailed statistical analysis of sporadic and inherited retinoblastoma, first proposed the idea of a tumor suppressor gene. 24 The tumor suppressor protein acts as a brake on cell proliferation or division. For uncontrolled cell growth to occur, both copies of the gene must be altered, the so-called two hits. Using gene mapping in 1988, Seizinger, et al., 43 mapped the VHL gene to the short arm of chromosome 3. During the next 5 years, the targeted region on 3p was progressively narrowed by performing genetic linkage studies in more than 100 families with VHL disease. 17,18,48,52 Overlapping germline deletions in unrelated patients with VHL disease were identified and the VHL gene was isolated by positional cloning in 1993. 25 Additional studies have shown that the VHL gene possesses three exons and encodes a 4.7-kb transcript widely expressed in fetal and adult tissues. 14,19,22,25 It is noteworthy that expression of the VHL gene is not restricted to organs affected by VHL disease. The human VHL gene encodes a protein (pvhl) containing 213 amino acids, which regulates transcript elongation by RNA polymerase II through its interaction with proteins called elongins. 15,19,25,52 The VHL protein, elongins B and C, and the Cul2 complex appear to act within the ubiquitination cascade, leading to proteosomal degradation of a number of proteins, including a prime target of pvhl, hypoxia-inducible factor 1. 52 Dysregulation of the interactions between pvhl and hypoxia-inducible factor, which is highly dependent on oxygen levels, is thought to play a role not only in the formation of tumors found in VHL disease, but in a broader spectrum of tumorigenesis and tumor angiogenesis. Despite the emerging details known about pvhl, clinical heterogeneity is nonetheless a hallmark of VHL disease. 17,31 This is reflected in the multiplicity of VHL gene mutations that have been identified in VHL kindreds. Approximately 15 to 20% of patients have large germline deletions, 27% have missense mutations, and 27% have frameshift or nonsense mutations. 5,6,10,55 One area of mutation clustering has been noted in exon 3 (amino acids 157 189), an area of the protein that is critical for binding members of the elongin family, which interact with RNA polymerase II. 5,15 Similarly, a small number of recurrent mutations have been seen, usually in association with hypermutable regions such as CpG dinucleotides. 52,55 Unlike several other familial tumor syndromes, such as multiple endocrine neoplasia Type 2, neurofibromatosis Type 1, and retinoblastoma, however, de novo mutations are not more likely to have a paternal origin. 3,17,52,55 In a detailed examination of genotype phenotype associations, Chen, et al., 5,6 investigated 114 families with VHL disease. Mutations, detected in 75% of families, were clustered at the 3 end of exon 1 and the 5 end of exon 3; mutations in exon 2 of the VHL gene were uncommon. Fifty-six percent of the alterations in families without pheochromocytoma were deletions, nonsense mutations or microdeletions/insertions. In contrast, 96% of mutations in patients with pheochromocytoma were missense mutations. This has led to the recognition of at least two subgroups of VHL disease: Type I (VHL disease without pheochromocytoma) and Type II in which patients with pheochromocytoma may or may not have renal or pancreatic involvement (Table 4). 3,5,6,52 In several large kindreds there appears to be a founder effect (one individual from whom all other familial cases derive) to account for the specific missense mutations associated with various subgroups of Type 2 VHL disease. 3,6,52 To date, however, it does not appear that there is a specific genotype to correlate with brainstem involvement. Although seven (65%) of 11 tested patients in our study had germline deletions of the VHL gene, which is more than twice the rate seen in large series of mixed populations of patients with VHL disease, the numbers involved are too small to draw a distinct conclusion. Further investigation is required to determine whether phenotypic genotypic correlations exist for brainstem or other CNS hemangioblastomas associated with VHL disease. 3,5,21,41,50,52 102

Surgery of brainstem hemangioblastomas Literature Review of Surgery for Brainstem Hemangioblastomas Until the late 1960s and the introduction of the clinical use of the operating microscope, the surgical and early postoperative morbidity and mortality rate associated with resection of brainstem hemangioblastomas was considerable ( 50%) and was believed to influence the exclusion of only the most superficial lesions from operative treatment. With reports by Chou, et al., 7 and Yasargil, et al., 54 on microsurgical resection of brainstem and intramedullary spinal cord tumors, respectively, surgery of brainstem hemangioblastomas became increasingly accepted as a mode of treatment in specialized neurosurgical centers. In the series of Chou, et al., three tumors were removed; one was extramedullary and the other two were combined extra- and intramedullary. One patient died, one was left impaired but stable, and a third was neurologically normal. Over the course of the next decade, nearly 20 more patients were reported from several centers. 9,10,38,39,42,44,47 In all described cases, the tumor component was predominantly, if not entirely, extramedullary. Among the 15 well-documented cases, seven patients were neurologically improved or stable after surgery, three were worse, and five patients (33%) died. In one case surgery was successfully performed while the patient was in circulatory arrest. 44 In 1986, Djindjian 13 described the microsurgical removal of a wholly intramedullary brainstem hemangioblastoma. His patient improved postoperatively. Additional reports of single cases and small series involving the surgical removal of brainstem hemangioblastomas have since been reported. 2,10,23,45,46,53 In 1992, Baumgartner and Wilson 2 described six patients; postoperatively three had a persistent mild, one a moderate, and one a severe neurological deficit, and one patient (17%) died as a result of surgery. Kohno, et al., 23 reported the complete resection of an intramedullary hemangioblastoma, which was performed using an incision in the posterior median sulcus; an excellent result was achieved in this patient. In 1994, Hopkins and colleagues described five patients with brainstem tumors who underwent surgery, without noting the exact location; four improved, one was unchanged neurologically, and there were no deaths. 46 Finally, Yasargil 53 reported on the surgical treatment of midbrain, pontine, and medullary hemangioblastomas in 18 patients; complete removal was possible in 16. One patient (6%) died, two were left with significant neurological deficits, and 15 were either neurologically normal or possessed only minimal neurological deficits. There were no recurrences, although the specific interval of follow up was not stated. Operative Management of Brainstem Hemangioblastomas in Patients With VHL Disease In previous reports of surgical treatment of patients with brainstem hemangioblastomas, those with VHL disease formed only a small minority (0 25%) of the patients described. Because of the fragmented nature of the reports of surgical treatment of brainstem hemangioblastomas, as well as the paucity of information about the management of one of more brainstem hemangioblastomas in the setting of VHL disease, we reviewed our series of 12 consecutive patients with brainstem hemangioblastomas, in whom longterm follow up ( 36 months) was available. Several features were identified that were useful in the management and operative treatment of these patients. First, as occurs with hemangioblastomas of the spinal cord that are associated with VHL disease, 28 the preoperative neurological status of the patient was the best predictor of the postoperative functional outcome. Patients with little or no neurological dysfunction before surgery were likely to remain neurologically intact; all Grade I patients remained neurologically normal after surgery. Furthermore, although the numbers are small, the patients who had undergone fewer CNS surgeries were more likely to be neurologically intact or improved after resection of their brainstem hemangioblastomas than were those who had undergone numerous other neurosurgical procedures for hemangioblastomas in the cerebellum or spinal cord. Tumor and cyst size did not affect the outcome. The location of the tumor, whether it was at the obex or elsewhere in the medulla oblongata, or at a position principally within or external to the brainstem, also did not affect the outcome of surgery. Contrary to most previous reports, tumors with intramedullary components were not significantly more difficult to remove, and were not associated with greater operative blood loss, more frequent complications such as gastrointestinal bleeding, or with poorer long-term outcomes than mixed or wholly extramedullary tumors. In our series, gastrointestinal hemorrhage and other serious complications were not observed. Unlike other investigators, we did not routinely perform preoperative angiography or find that preliminary embolization was necessary in any patient. In most tumors, the blood supply was from branches of one or both posterior inferior cerebellar arteries; less common feeders were derived from the anterior inferior cerebellar and superior cerebellar arteries and muscular branches of the vertebral artery. Finally, whereas at some centers the use of somatosensory or motor evoked potential monitoring is sometimes selected, we have not found it necessary in our experience. Although some surgeons have suggested the use of stereotactic radiosurgery to treat brainstem hemangioblastomas, there is only one report that has described the application of the technique in more than one patient. 4 In a group of five patients with VHL disease, Chang, et al., 4 reported that four of six tumors (size 500 mm 3 ) decreased in size and two were stable over an 11 to 63 month follow-up period. Unfortunately, radiation necrosis of the brainstem developed in two of the five patients and another required periodic percutaneous aspirations of a brainstem cyst associated with the tumor. Furthermore, in a study of patients with cerebellar hemangioblastomas treated with stereotactic radiosurgery with longer follow-up durations, Niemela, et al., 37 noted that seven of 10 patients required surgery after irradiation during a follow-up period extending to 91 months. Three of four cysts present at the time of irradiation required surgical decompression; one de novo cyst was also treated surgically 51 months after irradiation. Based on our results, we suggest that surgical resection should be the first option for treating patients with symptomatic brainstem lesions, whether the principle component of the enlarging mass is the tumor or the cyst. All 12 patients described here were neurologically stable or improved following surgery. Over the long term ( 36 months), 11 of the 12 patients remained stable or improved. The one patient whose neurological state worsened suffered 103

R. J. Weil, et al. a progressive decline caused by the appearance of eight additional spinal hemangioblastomas and their subsequent treatment. Thus, the preoperative status of the patient is the best predictor of immediate and long-term neurological outcome. In general, we recommend operating on those patients who present with signs and symptoms directly referable to the brainstem tumor. Patients with enlarging asymptomatic tumors and cysts deserve close observation and examination and more frequent neuroimaging. Rapid enlargement of a tumor or cyst with an interval of a few months justifies consideration of surgical resection, especially for large lesions, as does the onset of new signs and symptoms attributable to the brainstem tumor. Lesions that produce symptoms referable to the brainstem or those larger than 1 cm 3, particularly those associated with progressive syringobulbia, are amenable to surgical resection. Important features of surgical resection include utilization of intraoperative ultrasonography to identify intramedullary tumor components; sharp incision of the pia mater at the tumor margin, starting at the pial surface; development of a pial plane between the tumor, the cerebellar tonsil(s), and the vascular supply; and meticulous preservation of the interface between the tumor capsule and surrounding neural tissue. The tumor should be removed in its entirety, utilizing the devacularization provided by careful bipolar cauterization of each vessel as it enters or leaves the tumor capsule; early or unanticipated entry into the tumor or use of the ultrasonic aspirator is likely to lead to copious hemorrhage, which may be difficult to control or may lead to incomplete resection. Intraoperative monitoring of sensory or motor evoked potentials has been utilized by other surgeons, but was not used in this series. The cyst itself does not require attention and its collapse early during the tumor removal can make resection of this lesion more difficult. Although the cyst may create additional space within the region of the fourth ventricle, it is not the focal point of operative resection. In the three patients without a cyst presented here, there was no difference in surgical outcome, compared with those patients with a cyst. In all cases in this series, the cyst resolved with removal of the solid tumor component. Conclusions Surgical resection of most hemangioblastomas of the dorsal brainstem in patients with VHL disease is a safe and effective primary treatment of these tumors. In general, these lesions exhibit an indolent growth pattern and, given the likelihood of other CNS lesions demanding treatment, surgery for the brainstem hemangioblastoma may wait until symptoms and signs can be attributed to it. 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Weil, M.D., Surgical Neurology Branch, NINDS, NIH, Building 10, Room 5D 37, Bethesda, Maryland 20892-1414. email: weilr@ninds.nih.gov. 105