Haemangioblastoma of the posterior cranial fossa: clinico-neuropathological study

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1 ORIGINAL ARTICLE Folia Neuropathol. Vol. 41, No. 4, pp Copyright 2003 Via Medica ISSN Haemangioblastoma of the posterior cranial fossa: clinico-neuropathological study Teresa Wierzba-Bobrowicz 1, Bogna Schmidt-Sidor 1, Grażyna Maria Szpak 1, Waldemar Lechowicz 1, Rafał Górski 2, Janusz Jagielski 2, Henryk Koziara 2 1 Department of Neuropathology, Institute of Psychiatry and Neurology, Warszawa, Poland 2 Department of Neurosurgery, District Hospital of Bródno, Warszawa, Poland Haemangioblastoma (HBs) may occur sporadically in the central nervous system, or in association with von Hippel-Lindau (VHL) disease. Haemangioblastoma of the central nervous system is often seen in the posterior cranial fossa. VHL is an autosomaly dominant disorder. In sporadic HBs tumours, VHL alleles are reported to be inactive in up to 50% of tumours. Five patients with tumours of the posterior cranial fossa were examined by scyntygrapghy, computed tomography or magnetic resonance imaging (MRI). Metastases were initially diagnosed by neuroimaging examinations in two patients, and HBs in the remaining cases. In four patients, tumours were removed neurosurgically. Two patients had evidence of VHL disease. All resected tumours and autopsy materials were studied histologically and immunohistologically. Most antibodies that were used showed positive immunoreactions with stromal, endothelial, and pericyte or macrophage cells in tumours diagnosed as haemangioblastoma. Preoperative diagnosis of haemangioblastoma is mostly precise with MRI or magnetic resonance angiograghy. The surgical treatment of HBs is only a part of the complex therapeutical process. Diagnosis based on the gene analysis can be very useful in early detection or protection against potential recurrence of this disease in patients and their families. key words: haemangioblastoma, von Hippel-Lindau (VHL) disease, posterior fossa, diagnosis, immunohistochemistry INTRODUCTION Haemangioblastoma (HBs) may occur sporadically in the central nervous system, or in association with von Hippel-Lindau (VHL) disease. Intracranial HBs are mostly found in the cerebellar hemispheres, followed by the vermis, cerebellopontine angle and brainstem [3, 12]. HBs occur in the posterior cranial fossa in 80% of cases [5, 9, 14]. VHL is an autosomaly dominant disorder characterised by HB of CNS and retina, renal cell carcinoma (RCC), Address for correspondence: doc. dr hab. Teresa Wierzba-Bobrowicz Department of Neuropathology, Institute of Psychiatry and Neurology ul. Sobieskiego 9, Warszawa, Poland tel: (+48 22) , fax: (+48 22) bobrow@ipin.edu.pl pheochromocytoma (PHEO), islet tumours as well as cysts in the kidney, pancreas and epididymis. In the VHL patients, a large spectrum of germline mutations in the VHL gene has been detected [8, 13]. In sporadic HBs tumours, VHL alleles are reported to be inactive in up to 50% of the tumours. This disease has been rarely diagnosed in Poland, although its prevalence is much higher than expected, and it is estimated at 1: MATERIAL AND METHODS Five patients with tumours of the posterior cranial fossa were examined by scyntygraphy (SC), computed tomography (CT) or magnetic resonance imaging (MRI). In two cases, VHL disease was diagnosed (co-existed with retinal angioma, renal cyst and syringomyelia)

2 Folia Neuropathol., 2003, Vol. 41, No. 4 Table 1. Clinical characteristics of patients Sex Onset of disease Methods Clinical Accompanying Survival (years) of examination diagnosis pathological changes time F 13 Scyntygraphy Cystic tumour Syringomyelia, 3 years in the cerebellum retinal angioma radiotherapy M 31 CT, MRI (3 ) Tumour in the Cyst at the bottom 9 months cerebellum and pole of the medullo-cervical region right kidney ( 2 cm, susp. meta) F 66 CT Tumour in 2 years the cerebellum ( 2 cm, susp. meta) M 23 CT Tumour in the Alive cerebellum ( 4 cm) M 38 MRI Cystic/solid type of Neurosurgical Alive tumour in the cerebellum, operation was done medullo-cervical region 17 years earlier. ( 5 cm) Final diagnosis: HBs These examinations revealed cystic tumours (3 cases) or metastatic tumours (2 cases). In four patients, the tumours were removed neurosurgically (Table 1). All resected tumours and autopsy materials were studied histologically (H&E, Gomori, PTAH) and immunohistologically. Paraffin-embedded fragments from tumours were examined with antibodies against S-100 (Novocastra, 1:400), GFAP (Daco 1:2000), vimentin (Daco 1:50), actin (Daco 1:100) VCAM (Daco 1:50), CD68 (Daco 1:100), CD34 and CD31 (Daco 1:30), Ki67 and HLA II (Daco 1:50). After counterstaining, the preparations were embedded and examined under a light microscope. RESULTS In four clinically examined patients, neurological cerebellar symptom was initially detected. Neuroimaging examinations often showed pathological hypotensive masses in cerebellum (Fig. 1). In two patients, they were interpreted as metastatic tumours. In patients aged 31 years, quadriparesis and sphincteral disorder were observed; CT showed pathological nodular masses in medulla and small focus in the left cerebellar hemisphere. Pathological masses at the medullar level Th 1, Th 2, C 7, and the left cerebellar hemisphere were observed using MRI (Fig. 2A). In the right kidney, an area with slightly decreased density and a small cyst at the bottom pole of the kidney were visible (Fig. 2B). In four patients, the tumours were removed neurosurgically. Two patients (13 years F and 31 years M) died and two patients (men aged 23 and 38 years) are still alive. A woman aged 66 years, whose operation was abandoned, died because of haemorrhagic cerebral stroke. A neuropathological examination showed cystic tumours in the cerebellum (Fig. 3). The tumour pattern made of capillary vessels of different sizes, sometimes extensively dilated, and stromal cells with light cytoplasm and elongated nuclei were seen under the light microscope (Fig. 4A). Argentophilic fibres (Fig. 4B) surrounded the vessels and stromal cells. Vessels were immunoreactive with both endothelial cell markers (CD31, C34) and vimentin (Fig. 5A, B). Stromal cells sometimes showed foamy structures of cytoplasm and oval or elongated Figure 1. CT: pathologic hypotensive masses in central part of cerebellum (M, 23 years)

3 Teresa Wierzba-Bobrowicz et al., Haemangioblastoma of the posterior cranial fossa 2A 2B Figure 2A. MRI: pathological masses in the cerebral left hemisphere, medulla and C7 of spinal cord (M, 31 years); B. CT: a small cyst at the bottom pole of the right kidney (M, 31 years). large nuclei. These cells were also immunoreactive with protein S-100, GFAP and sometimes with vimentin (Fig. 6A, B, C). Some cells dispersed among capillary vessels and stromal cells (Fig. 7) represented the histocompatibility locus antigens (HLA II). The neoplastic cells showed proliferation index of a slight degree and glial fibres often surrounded the cells. HBs were diagnosed in all the cases studied. DISCUSSION Histological examination demonstrated a highly vascularised tumour with intercapillary stromal cells. The most antibodies that were used showed positive immunoreactions with stromal, endothelial, and pericyte or macrophage cells in tumours diagnosed as haemangioblastoma (cystic type). Many neuroimaging examinations (SC, CT, MRI) were performed in all patients. However, MRI scanning of pathological changes was the most precise method. Xu et al. [14], who described HBs in the cervical segment of the spinal cord, made an attempt to distinguish three types of HBs based on MRI scanning: syringeal type, cystic type, and solid type. Other investigators [2] described angiographic and resonance diagnostic of HBs in correlation with the tumour size, clinical symptoms and VHL co-existince or not. An early and precise radiological diagnosis of haemangioblastoma often plays an essential role in successful neurosurgical management of this disease [11, 12]. The World Health Organisation (WHO) classified haemangioblastoma [4] as a tumour of unknown histogenesis (code 9161). Figure 3. Cystic tumour in cerebellum (F, 66 years). It is mainly classified like this because of its stromal cells whose aetiology is still the subject of debate. The origin of these cells is attributed to the line of endothelial cells, glial cells, and epithelioid or primitive blood cells [1, 6, 7, 10]. According to criteria set by Neumann [9], in two of the 5 HB cases, VHL was diagnosed (co-existed with retinal angioma, renal cyst and syringomyelia). Analysis of the family linkage or detection of possible mutations can be used to investigate the VHL gene, which is located near the tip of the short arm of chromosome 3 (3p25 26) can be investigated by analysing the family linkage or detecting possible mutations. Available DNA testing enables to identify carriers of the pathological VHL gene, which makes it possible to implement a program of periodical control examinations and to proceed with intensive treatment before the manifestation of symptoms, and thus to reduce mortality among VHL patients. CONCLUSION Preoperative diagnosis of haemangioblastoma is more precise when MRI or magnetic resonance angiograghy (MRA) is used. A better understanding of the tumour vascular pattern together with an advanced microsurgical technique can improve surgical efficacy. Surgical treatment of HBs is only a part of the complex therapeutical process. Diagnosis based on gene analysis can be very useful in early detection of this disease in patients and their families. Patients should be under constant observation to protect them against potential recurrence, or de novo growth of haemangioblastoma as well as to reveal other symptoms of VHL disease

4 Folia Neuropathol., 2003, Vol. 41, No. 4 4A 5A 4B Figure 4A. The tumour pattern composed of blood vessels of different size and stromal cells (M, 38 years). H & E. Bar represents 30 mm; B. Reticular fibres around vessels and stromal cells (M, 21 years). Gomori. Bar represents 60 mm. 5B Figure 5. Epithelial cells of tumour vessels (F, 66 years). Positive reaction with: A. Vimentin (bar represents 30 mm); B. antibody CD 34 (bar represents 60 mm). 6A 6B 6C Figure 6. Stromal cells showing positive reactions with: A. Protein S-100 (M, 38 years); bar represents 30 mm; B. GFAP (M, 23 years) bar represents 30 mm; C. GFAP; (M, 31 years); bar represents 30 mm. Figure 7. Cells expressing major histocompatibility complex class II (MHC II) among the neoplastic cells (F, 66 years). Bar represents 30 mm

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