Journal of Clinical Neuroscience 18 (2011) 939–944

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Journal of Clinical Neuroscience

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Clinical Study

A 10-year retrospective study of hemangioblastomas of the central nervoussystem with reference to von Hippel–Lindau (VHL) disease

Somanath Padhi a,⇑, RajLaxmi Sarangi b, Sundaram Challa c, Priyatamjee Bussary d, Manas K. Panigrahi e,Anirudh K. Purohit f

a Department of Pathology, Pondicherry Institute of Medical Sciences, Ganapathichettykulam, Kalapet, Puducherry 605 014, Indiab Department of Biochemistry, Pondicherry Institute of Medical Sciences, Puducherry, Indiac Department of Pathology, Nizam’s Institute of Medical Sciences, Hyderabad, Indiad Department of Imageology, Nizam’s Institute of Medical Sciences, Hyderabad, Indiae Department of Neurosurgery, Krishna Institute of Medical Sciences, Hyderabad, Indiaf Department of Neurosurgery, Nizam’s Institute of Medical Sciences, Hyderabad, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 24 November 2010Accepted 23 December 2010

Keywords:CNS hemangioblastomasPhaeochromocytomaRCCRetinal angiomasVHL disease

0967-5868/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.jocn.2010.12.050

⇑ Corresponding author. Tel.: +91 0413 3051111.E-mail address: somanath.padhi@gmail.com (S. Pa

We aimed to analyze the clinical, radiological, surgicopathological and clinical outcome data of patientswho underwent surgery for central nervous system (CNS) hemangioblastoma (HBL) with or without vonHippel–Lindau (VHL) disease. The clinico pathological and radiological findings, management and clinicaloutcome of patients with CNS HBL (operated between 2000 and 2009) were analyzed retrospectively. Thedifferences between sporadic and VHL-associated HBL were analyzed. Forty-nine patients (28 male, 21female) underwent surgery for CNS hemangioblastoma. Thirty-nine patients (80%) harbored sporadicHBL whereas 10 (20%) had VHL disease. The mean age at diagnosis for VHL-associated HBL was 32 yearswhen compared to 40 years in sporadic HBL. The lesions were solitary in 41 patients and multiple ineight. The cerebellum was the most common site of HBL (35/49, 71%). Six patients with sporadic andtwo with VHL disease had spinal lesions. On imaging (available in 43/49 patients), a cyst with a muralnodule was the most common finding, seen in 16 patients (37.2%) whereas nine patients (21%) had solidand cystic lesions. Clinical presentation, radiological features, and histomorphology of HBL with or with-out VHL disease were similar. Multiple cysts in the pancreas, kidney, broad ligament, epididymis, clearcell renal cell carcinoma, phaeochromocytoma and retinal angiomas were the visceral manifestationsseen in patients with VHL disease. Of all patients with VHL disease, three required multiple surgeriesfor new lesions and one died of renal failure and sepsis. Among the patients with sporadic disease (31/39), two died of surgical complications, one died of postoperative sepsis, three were lost to follow-upand the remainder had resolution of symptoms at 1 year following surgery. We concluded that the diag-nosis of VHL disease is important as management is more difficult and lifelong follow-up and counselingare required in these patients and for their at-risk relatives.

� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Hemangioblastomas (HBL) are benign, grade 1, capillary-richneoplasms of the central nervous system (CNS) that contain vari-ably lipidized neoplastic stromal cells of unknown histogenesis.1,2

These constitute 1% to 2.5% of all intracranial and 2% to 3% of allintramedullary spinal cord tumors.3 HBL arise either in the settingof von Hippel–Lindau (VHL) disease or more commonly as a soli-tary sporadic lesion without additional stigmata or a family his-tory.1–6 Approximately 10% to 40% of primary symptomatic HBL

ll rights reserved.

dhi).

are associated with VHL disease, but it seems to be underreportedas some patients with HBL do not undergo appropriate screeningfor VHL disease.7

VHL disease is an autosomal dominant inherited disordercaused by a germ line mutation of the VHL gene located on theshort arm of chromosome 3 (3p25-26). The presence of this mu-tated gene is characterized by intracranial or intraspinal HBL (oftenmultiple); retinal angiomas; cystic lesions of the kidney, pancreas,liver, and epididymis; benign and malignant renal tumors; adrenalphaeochromocytoma; extra adrenal paragangliomas; and papillaryendolymphatic sac tumors of the inner ear.1–7 Sporadic HBL mostcommonly present in adults from 30 years to 65 years of age, morecommonly in males. In contrast, VHL-associated tumors tend to oc-cur at a younger age (mean age, 29 years). The cerebellum is the

Table 1Presenting characteristics of patients with hemangioblastoma (HBL) in sporadiccompared to von Hippel–Lindau (VHL) disease treated between 2000 and 2009 at theNizam’s Institute of Medical Sciences, Hyderabad, India

Sporadicdisease

VHLassociation

No. of patients (%) 39 (80) 10 (20)No. of males (%) 22 (56.5) 6 (60)No. of females (%) 17 (44) 4 (40)Mean age at presentation of neurological

symptoms (years)40 32

940 S. Padhi et al. / Journal of Clinical Neuroscience 18 (2011) 939–944

most common site of involvement in patients with sporadic andVHL disease, whereas involvement of the brainstem, spinal cord,and spinal nerve roots are common in the latter.1,2 Polycythemia,a result of tumoral production of erythropoietin, occurs in approx-imately 10% of patients.1,8,9

We aimed to retrospectively analyze the presentation, radiolog-ical findings, surgical management, pathology, and clinical out-come of patients with HBL with and without VHL disease whounderwent surgery between 2000 and 2009 at Nizam’s Instituteof Medical Sciences.

Fig. 1. Location of central nervous system hemangioblastomas in patients treatedbetween 2000 and 2009 at the Nizam’s Institute of Medical Sciences, Hyderabad,India. VHL = Von Hippel Lindau disease.

Table 2Clinical presentation in 49 patients with hemangioblastoma treated between 2000and 2009 at the Nizam’s Institute of Medical Sciences, Hyderabad, India

Symptoms/signs Percentage of patients(%)

Headache 100Cerebellar signs (dizziness, disequilibrium,

vertigo)70

Papilloedema 65Cranial nerve palsy 20Weakness of the extremities 16Visual blurring/blindness 4Headache, episodic palpitation 2Headache, cerebellar signs, abdominal mass,

oliguria2

2. Methods

This retrospective study was conducted in the Department ofPathology. The neuropathology records were reviewed to identifyall patients who underwent surgery for HBL between 2000 and2009. The medical, radiological, surgical, pathological, and clinicaloutcome data from these patients were reviewed. Additional man-ifestations of VHL disease were recorded and any associated familyhistory was obtained by consulting the treating surgeon as well astelephone contact with the patients’ relatives. The diagnosis of VHLdisease was made purely on a clinical basis as per the updated cri-teria described by Conway et al.4 According to these criteria, in theabsence of a family history of CNS or retinal HBL, the diagnosis ofVHL disease requires the presence of multiple (at least two) HBL orone HBL and any one of the described visceral manifestations. In apatient with a family history of CNS or retinal HBL, a diagnosis ofVHL disease requires only the presence of one HBL or other mani-festation of VHL disease.2,4,10 Genetic testing can confirm a diagno-sis of VHL disease in a person with clinical symptoms, who may ormay not meet the above diagnostic criteria. The enhanced MRIand/or CT scans were analyzed regarding the location and numberof lesions (solitary/multiple) and their nature (pure cyst, cyst withmural nodule, cyst with irregular rim enhancement, solid andcystic, pure solid, and syrinx formation).11–14 Packed cell volume(PCV)/haematocrit (Hct), both at the time of diagnosis and follow-ing surgery, was recorded whenever available, by using bothautoanalyser and Wintrobe’s hematocrit tube. The histologicaldiagnosis was made by the presence of a fine meshwork ofcapillaries with varying proportions of lipidized (vacuolated) and/or eosinophilic neoplastic stromal cells on hematoxylin andeosin (H&E)-stained tissue sections supplemented with reticulinstaining.12,13

The follow-up clinical data of patients after surgery was col-lected whenever available. Follow-up duration from the first sur-gery ranged from 16 days to 132 months for patients with VHLdisease-associated HBL, and for a minimum period of 10 monthsto 12 months for those with sporadic disease.

3. Results

Forty-nine patients underwent surgeries for CNS HBL at ourhospital. These included 28 males and 21 females (M:F ra-tio = 1.3:1) with ages ranging from 5 years to 65 years (meanage = 45 years). The mean age at diagnosis for sporadic HBL andfor HBL associated with VHL disease was 40 years and 32 yearsrespectively. A slight male predilection was noted for both sporadicand VHL disease associated HBL (Table 1). In all patients, histopa-thological evaluation of tumor tissue confirmed the diagnosis. Sev-enty percent of the tumors were located in the cerebellum, and16% (8/49) were within the spinal canal (six sporadic and two inVHL disease) (Fig. 1). The clinical presentations in all patients arelisted in Table 2. On imaging analyses (MRI and/or CT scan), 16 pa-tients had a cyst with an enhancing mural nodule (see Fig. 4A),nine tumors were mixed solid and cystic (Figs. 2A, B; 3A), and

two were purely solid (Table 3). Of the 31 patients who underwentsurgery for sporadic HBL, two died due to surgical complications,one died because of postoperative sepsis, three were lost to fol-low-up, and the remaining patients were in good neurological con-dition at 12 months of follow-up. Among the 10 patients whofulfilled the criteria for VHL disease, HBL was solitary in two andmultiple in eight; two had multifocal lesions involving the cerebel-lum and the spinal cord. Cysts involving the pancreas, pelvic region(broad ligament, epididymis) and kidney were seen in five, four,and two patients respectively, whereas clear cell renal cell carci-noma (RCC), phaeochromocytoma, and retinal angiomas occurredin one, one, and two patients respectively (Figs. 2C, F; 3B; 4B).One patient had a sister with retinal angiomas who died followingsurgery due to surgical complications for cerebellar HBL. Three pa-tients with VHL disease underwent multiple surgeries for new HBL,one died on postoperative day 16 because of renal failure and sep-sis while an inpatient, whereas the other patients had residual

Fig. 2. Imaging and histopathology studies of patient 6 (Table 5) with von Hippel-Lindau disease: axial (A) T1-weighted and (B) T2-weighted brain MRI showing a mixedintensity lesion with solid and cystic components in the vermis of the cerebellum with flow voids, suggestive of hemangioblastoma; (C) contrast enhanced CT scan of theabdomen showing multiple cysts with septal calcification in the pancreas, an exophytic heterogeneously enhancing mass lesion involving the upper pole of right kidney, andsmall cortical tiny cysts in the left kidney; (D) stained section of the hemangioblastoma showing polygonal cells with eosinophilic to vacuolated cytoplasm and thincapillaries (hematoxylin and eosin [H&E], �400); (E) stained section of a hemangioblastoma showing groups of cells encircled by reticulin fibres (silver reticulin stain, �400);and (F) stained section of a clear cell renal cell carcinoma showing polygonal cells in sheets with an intervening delicate capillary network (H&E, �100). (This figure isavailable in colour at www.sciencedirect.com.)

Fig. 3. (A) Sagittal T1-weighted brain MRI showing an intensely enhancing lesionwith a cystic component in the cerebellum, suggestive of hemangioblastoma; and(B) pelvic ultrasound showing a cyst in the pelvic region in a patient with vonHippel–Lindau disease.

Table 3Characteristics on imaging in 43 of 49 patients with hemangioblastomas treatedbetween 2000 and 2009 at the Nizam’s Institute of Medical Sciences, Hyderabad, India

Characteristics VHL associated Sporadic disease

Cyst with MN 4 12Pure cyst – 6Cyst with irregular RE 2 3Solid and cystic 4 5Pure solid – 2Syrinx formation – 5

Total 10 33

MN = mural nodule, RE = rim enhancement, VHL = von Hippel–Lindau disease.

S. Padhi et al. / Journal of Clinical Neuroscience 18 (2011) 939–944 941

neurological deficit on follow up (Table 4). The mean packed cellvolume/hematocrit (available in 22 patients) measured prior toand following surgery was 40% and 37.3%, respectively.

4. Discussion

HBL appeals to surgeons because of its curability, to patholo-gists because of distinctive histomorphology, to geneticists be-cause of its association with the phakomatoses, and to aninternist because of the increase in erythropoietin.15 Althoughhistologically benign and slow growing, HBL tends to cause

life-threatening complications due to the expansion of peritumoralcysts. The morbidity and mortality associated with them can be re-duced significantly if these lesions are appropriately diagnosed andtreated.3,4

A comparative analysis between our series of patients withthree other series is presented in Table 5. Patients with VHL diseaseare an important subset of patients who present with CNS HBL. Inour series, 10 (20%) patients who required surgical resection for aCNS HBL had VHL disease. This percentage is similar to the studiesby Neumann et al.3 (23%) whereas a higher percentage (38%) wasnoted in a study by Conway et al.4 As previously described in theliterature,1–4,16 the mean age at diagnosis of VHL-associated HBLwas 32 years, a decade earlier than those with sporadic disease(mean age, 40 years). A greater percentage (50–60%) of patientsin both groups were male (Table 1).

Fig. 4. (A) Coronal T1-weighted brain MRI showing a cyst and mural nodule in thecerebellum suggestive of hemangioblastoma; and (B) stained tissue section of anadrenal mass in the same patient with nests of cells surrounded by thin capillariessuggestive of phaeochromocytoma (hematoxylin and eosin, �400). (This figure isavailable in colour at www.sciencedirect.com.)

942 S. Padhi et al. / Journal of Clinical Neuroscience 18 (2011) 939–944

Retinal hemangiomas are typically the first manifestation ofVHL disease.4,10,14,17 In our study, CNS hemangioblastomas werethe inclusion criteria, and stigmata of VHL disease were lookedfor in those patients. HBL were the initial manifestations in sevenof 10 (70%) patients, whereas retinal angiomas were seen in twopatients as the presenting feature (patients 8 and 9, Table 4). Thishigh prevalence of CNS HBL as the presenting manifestation of VHLdisease was probably because of neurosurgical bias of our institute.However, this prevalence emphasized the need to screen all pa-tients presenting with CNS HBL for VHL disease. Similar to Neu-mann et al.,3 a greater proportion of patients had sporadic spinallesions (six patients) in our study compared to lesions caused byVHL disease (two patients). This was in contrast to the results ofConway et al.,4 where a greater proportion of patients with spinalHBL were associated with VHL disease. The lesions were multiple

Table 4Age at presentation, imaging studies, extracranial manifestations, family history, and surgic2009 at the Nizam’s Institute of Medical Sciences, Hyderabad, India

Age/sex Location ofHBL

Solitary/multiple

Radiology Extra CNS le

1 27/Male Right CH M Solid and cystic None

2 42/Female Right CH M Cyst with MN Right parova

3 32/Male Right CH S Cyst with RE Pancreatic c

4 40/Male Right CH andcervical cord

M incerebellum, S incord

Cyst and MN Adrenal Ph.urinary VMA

5 40/Female Right CH andcervical cord

M Cyst and MN Right parape

6 25/Female Vermis S Complex cyst and MNand flow void

Pancreatic ccyst, right cy

7 16/Female Bilateral CH andvermis

M Solid and cystic Pancreatic ccyst

8 19/Male Cerebellum M Solid and cystic Pancreatic cangiomas

9 30/Male Left CH andmedulla

M Solid and cystic Retinal angi

10 50/Male Right CH M Cyst with RE Pancreatic ccyst, epididy

CH = cerebellar hemisphere, CNS = central nervous system, HBL = hemangioblastoma, M(unilateral), RCC = clear cell renal cell carcinoma, RE = rim enhancement, RND = residual

in eight patients and multifocal in two (patients 4 and 5, Table 4).Hence, a high degree of suspicion for VHL disease should be raisedin a young patient with HBL and in patients with spinal lesions. Inaddition, multiple and multifocal lesions are diagnostic of thecondition.1,2

Significant differences between sporadic and VHL disease-associated HBL were not noted in relation to the clinical presenta-tion, imaging results, and histomorphology. The predominantradiological pattern of a cyst with a mural nodule or a mixed solidand cystic pattern in our patients was in accordance with thehistomorphology (more vacuolated and less eosinophilic stromalcells, thin capillaries, Fig. 2D, E) described by Sundaram et al.,13

and de la Monte and Horowitz.18

The management of patients with HBL in VHL disease is difficultcompared to that of patients with sporadic lesions. Patients withhereditary HBL tend to develop new lesions with time, thus requir-ing frequent surgery.3,4 The most common cause of morbidity andmortality is associated with frequent tumor recurrence and surgi-cal intervention. The cause of death in 30% to 50% of patients isRCC.19 In the present series, the increased morbidity associatedwith patients with VHL disease occurred because of incompleteresection of CNS lesions at first surgery as a result of their deeperlocation as well as unavailability of advanced microneurosurgicalfacilities in our institute before 2005. Appearance of new CNS le-sions, detected by 6-monthly follow-up imaging studies, also ledto frequent surgical intervention. Besides these, additional mani-festation of VHL disease such as clear cell RCC (Fig. 2F), phaeo-chromocytoma (Fig. 4B), retinal angiomas, and cysts involvingthe pancreas, kidney (Fig. 2C) and pelvic region (Fig. 3B) occurredin our patients, which led to increased morbidity.

In comparison to the report by Conway et al. (5%),4 death oc-curred in 4/49 (8.0%) of patients of HBL (three sporadic, one VHLassociated). Only one patient with VHL disease (patient 6, Table 4)died of sepsis and multiorgan failure following successful excisionof HBL and RCC (Fig. 2A–F). There was no histomorphological orimmunohistochemical evidence of metastasis of the RCC to the

al outcomes of 10 patients with von Hippel–Lindau disease treated between 2000 and

sions Family history Follow-up

NA Three surgeries for new HBL, RND, no newlesions at 132 months of follow-up

rian cyst NA Operated twice for new HBL, RND, no newlesions at 65 months of follow-up

yst Sister withblindness anddied ofintracranialbleeddue to HBL

Complete excision of HBL, minimal RND, nonew lesions at 60 months of follow-up

(UL), raised NA Three surgeries for new HBL, operated outsidefor phaeochromocytoma, RND at 72 months offollow-up

lvic cyst NA 48 months of follow-up with RND

yst, left renalstic RCC

NA Complete excision of HBL, right nephrectomy,died on postoperative day 16 due to sepsis

yst, par ovarian NA Under periodic follow-up every 6 months, RNDpresent

yst, retinal NA Blindness in both eyes at presentation

omas NA Blindness in right eye at presentation, RNDfollowing surgery

yst, right renalmal cyst

NA Under periodic follow-up with RND

= multiple, MN = mural nodule, NA = not available, Ph (UL) = phaeochromocytomaneurological deficit, S = solitary, VMA = vanillylmandelic acid.

Table 5Comparison of patients with hemangioblastoma between the present series and three previously published series

Yearref No. ofpatients withHBL

Male/female

VHL(%)

Age at diagnosis(years) (VHL/sporadic)

Commonest manifestation Family history

19893 44 21/23 14/44(23%)

29/47 Cerebellar HBL, retinal angiomas, phaeochromocytoma, pancreaticand renal cyst, RCC

Positive in 8,counseling

20014 40 21/19 15/40(38%)

36/45 Cerebellar and spinal (13%) HBL, multiple HBL (53%), retinal HBL (7/40), RCC, phaeochromocytoma, islet cell tumor

No family counselingor genetic testing

200126 82 50/32 14/82(17%)

34.5 Cerebellar HBL, (multiple in 7), pancreatic cyst, RCC, renal cyst, retinalangiomas, phaeochromocytoma

Positive in 5, genetictesting for 1

Presentseries,2010

49 28/21 10/49(20%)

32/40 Cerebellar HBL (multiple in 8), cysts in pancreas, broad ligament,kidney, epididymis, retinal angiomas, RCC, phaeochromocytoma

Positive in 1,counseling

HBL = hemangioblastoma, RCC = clear cell renal cell carcinoma, VHL = von Hippel–Lindau disease.

S. Padhi et al. / Journal of Clinical Neuroscience 18 (2011) 939–944 943

HBL.20 The other patients, who showed evidence of a residual neu-rological deficit, were under periodic follow-up (Table 4). Elucida-tion of family history revealed the occurrence of retinal angiomasand cerebellar HBL in the sister of patient 3 (Table 4) who diedof massive intracranial bleed in another hospital, the details ofwhich were not available. Except for patient 3, none of the familymembers of the other patients were aware of the hereditary natureof VHL disease. Although counseling was offered to the at-risk rel-atives of our patients, no genetic testing could be performed be-cause of lack of facilities and financial constraints. The surgicaloutcomes were more favorable in 31 of 39 sporadic HBL, of whichdeath due to surgical complication (bleeding and CSF leak) oc-curred in two patients, whereas one patient died of postoperativesepsis (bronchopneumonia and multiorgan failure).

The Cambridge protocol was devised by Maher et al.21 forscreening patients with VHL disease or at-risk relatives. As perthe protocol, all asymptomatic patients should undergo annualphysical and urinary examinations – 24-hour estimation of vanil-lylmandelic acid, annual ophthalmoscopic and renal ultrasoundevaluation, enhanced MRI evaluation of CNS and CT evaluation ofthe abdomen every 3 years. Screening for at-risk relatives shouldbegin at five years of age with an annual ophthalmoscopy, ultra-sound, MRI and/or CT scan of the abdomen, as well as an MRIand CT evaluation of the CNS every 3 years.21,22

The exact pathophysiologic mechanism of VHL disease remainsenigmatic. Inactivation of the VHL tumor suppressor gene and sub-sequent loss of function in VHL, and VHL Elongin BC, result in dys-function in the ubiquitination of hypoxia inducible factor (HIF),which leads to the overexpression of several hypoxia-induciblegenes such as vascular endothelial growth factors, erythropoietin,and platelet-derived growth factor, which could explain the devel-opment of angiogenic tumors.7,23,24 The expression of various pro-teins such as Scl, brachyury, Csf-1R, Gata-1, Flk-1, and Tie-2 on thestromal cells suggests an embryonic progenitor cell origin with ahemangioblastic differentiation. Besides these, the interaction ofTie-2 proteins with HIF could be an initiating event in the patho-genesis of the lesions.25

In our series the exact prevalence of VHL disease, may be falselylow because not all patients diagnosed with HBL and/or their fam-ily members were subjected to the full screening protocols sug-gested by Neumann.10

To conclude, our experience reinforces the concept thatalthough surgical outcomes for CNS hemangioblastoma are gener-ally favorable, the management of VHL-associated lesions is amuch more difficult and prolonged endeavor. Neuroradiologicalscreening of patients with VHL disease is useful for identifyingHBL before they become symptomatic. Lifelong follow-up is re-

quired, and family screening and counseling are of paramountimportance.

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