Neurosurg. Rev. 15 (1992) 231-234
Metastasis o f a renal carcinoma to a cerebellar haemangioblastoma in a case o f von Hippel-Lindau disease Abdulhakim Jamjoom ~, Nicholas Kane2, and James NicoU3 1Division of Neurosurgery, Department of Surgery, King Khalid University Hospital, Riyadh, Saudi Arabia, 2Department of Neurosurgery and 5Neuropathology, Frenchay Hospital, Bristol, England
Abstract A patient with Von Hippel-Lindau disease had a longstanding cerebeltar cyst which recurred for the fifth time. At operation there was evidence of a renal carcinoma metastasis in the wall of the cyst which was probably a haemangioblastoma. Keywords: Haemangioblastoma, metastasis, renal carcinoma, Von Hippel-Lindau syndrome.
1 Introduction Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder with variable penetrance, characterized by cerebellar haemangioblastoma, retinal angiomatosis, renal abnormalities and cysts of the spinal cord, pancreas, kidneys and liver [1]. Renal carcinoma is the cause of death in approximately one third and is present at autopsy in two thirds of patients affected with VHL disease [3]. Although LINDAUoriginally believed that the renal tumours were always benign, the metastatic potential of these tumours is well documented. A review of the literature reveals that 40% of 53 cases of VHL with renal carcinoma had metastases [1]. We report an unusual case of VHL disease, in which a renal carcinoma metastasized to the wall of a longstanding recurrent cerebellar cyst, which was probably a haemangioblastoma.
2 Case report A 49-year-old woman originally presented 17 years ago, with an 18-month history of occipital headaches and vomiting. Clinical examination revealed mild truncal ataxia, horizontal optokinetic 9 1992by Walter de Gruyter& Co. Berlin. New York
nystagmus and marked bilateral papilloedema. Myodil ventriculography confirmed the presence of raised cerebrospinal fluid pressure and the suspicion of a space occupying lesion near the fourth ventricle. At subsequent posterior fossa craniectomy an intrinsic cerebellar cyst and nodule were removed. Histological examination showed gliotic cerebellum with no evidence of tumour. Over the next 14 years, the patient underwent three further operations to remove recurrence of the right cerebellar cyst. On the last occasion a drainage tube was inserted between the cyst and the cisterna magna. On each occasion, biopsy of the cyst wall showed gliotic tissue with no evidence of tumour and no definite diagnosis was made. One year ago, the patient presented with signs and symptoms of raised intracranial pressure again and a CT scan showed reaccumulation of the cerebellar cyst for the fifth time, and a tumour nodule was noted on the medial aspect of the cyst (Figure 1). At exploration a tumour nodule within the cyst wall was found to be obstructing the drainage tube. The position of the cerebellar cyst was identical to that in previous operations, however, the nodule on the medial aspects of the cyst was in a previously unexplored area. Histological examination showed the majority of this tissue to consist of extensively necrotic unequivocal "clear cell" carcinoma, confirmed by immunostaining for cytokeratin, most likely of a renal origin (Figure 2a, b). However, a small area of the specimen had the appearance of a haemangioblastoma with a fine meshwork of capillaries, intervening cells with foamy cytoplasm (Figure 3a), the characteristic reticular pattern (Figure 3b) and absent immunostaining for cytokeratin. Subsequent CT scan of the abdomen dem-
232
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma
Figure 1. CT scan (with contrast) showing the recurrent cerebellar cyst with a tumour nodule at its medial aspect (arrowed).
Figure 2a. Renal carcinoma biopsy (haematoxylin & eosin x 600). The tumour cells have features typical of a clear cell carcinoma with large nuclei, prominent nucleoli and vacuolated cytoplasm. Mitoses were numerous and there was extensive turnout necrosis. Reticulin fibres were not present between the tumour cells.
Figure 2b. Renal carcinoma biopsy (CAM 5.2 Dako Ltd. x 375). The tumour cell cytoplasm is immunostained for cytokeratin, confirming the diagnosis of carcinoma. There was no immunostaining for Epithelial Membrane Antigen or S100 protein.
onstrated the presence o f a solid lesion at the u p p e r pole of the left kidney, consistent radiologically with a renal cell carcinoma. Lytic lesions o f two vertebral bodies were thought to represent metastases. Cysts were also present in the right kidney a n d pancreas. A diagnosis o f V H L disease was made. This was based u p o n the presence o f longstanding cerebellar cyst which is p r o b a b l y a haem a n g i o b l a s t o m a , renal carcinoma, the findings o f multiple visceral cysts and the pertinent family history (the patient's father died o f renal carcin o m a at 50 years o f age). The patient was discharged home a n d succumbed to carcinomatosis within three months. A n a u t o p s y was not performed.
Figure 3a. Area resembling haemangioblastoma (haematoxylin & eosin x 600). This area contains the fine meshwork of intersecting capillaries characteristic of haemangioblastoma. The tumour cells have small nuclei and indistinct nucleoli in contrast to Figure 2a, and mitoses were absent from this area. The tumour cells have foamy rather than vacuolated cytoplasm, and were not immuno-stained for cytokeratin, Epithelial Membrane Antigen or $100 protein.
Figure 3b. The haemangioblastoma-like area (Gordon and Sweets' reticulin x 600) has the characteristic fine meshwork of reticulin fibres. Neurosurg. Rev. 15 (1992)
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma 3 Discussion The histological distinctioz~ between primary haemangioblastoma and a clear cell carcinoma metastasis in the cerebellum is often difficult, because both tumours may have cells with abundant vacuolated cytoplasm containing intracytoplasmic glycogen and a vascular stroma with associated reticulin fibres [6]. Immunohistochemically, epithelial cell antibodies are most useful in making the distinction by positively identifying a carcinoma [2, 6]. The majority of renal carcinomas are immunostained with antibody to Epithelial Membrane Antigen (EMA) and many, but not all, are immunostained with anticytokeratin antibodies. Haemangioblastomas are not immunostained with epithelial cell antibodies. Antibody to S 100 protein immunostains a proportion of haemangioblastomas while carcinomas are not immunostained with this antibody. In our case, the area of the biopsy which morphologically resembled carcinoma was immunostained with a cytokeratin antibody (CAM 5.2), but not with EMA or $100 antibodies. The immunohistochemistry therefore confirmed the diagnosis of metastatic clear cell carcinoma. The area of the biopsy which morphologically resembled a haemangioblastoma was not immunostained for cytokeratin, EMA or S100 protein. Although we cannot totally exclude the possibility that the longstanding cerebellar cyst may have been a simple glial cyst, we feel the most likely cause in a patient with VHL disease is haemangioblastoma and this is confirmed by histological findings. Haemangioblastomas are rare tumours of the central nervous system, predominately located in the cerebellum. They account for 1% to 2.5% of all intracranial neoplasms [7], occurring sporadically or as a manifestation in 23% [7] to 36% [4] of cases of Von Hippel-Lindau syndrome. Haemangioblastomas typically form cysts lined by gliotic tissue with turnout consisting of a mural nodule, which is often very small in size [8]. Previous CT
233
scans (with and without intravenous contrast), and microsurgical explorations of the recurrent cyst, had failed to demonstrate a turnout nodule. Angiography was not performed and may have been useful as it has been reported to reveal the tumour in up to 95% of haemangioblastoma cases [7]. Recurrence of these tumours may occur in up to 25% of cases [5]. DE LA MONTE et al [5] reported an increased risk of recurrence of haemangioblastoma in patients aged less than 30 years, cases with VHL, and in cases with multicentric tumours of the CNS at initial diagnosis. The phenomenon of haematogenous spread of carcinoma to benign intracranial tumours has been described in meningiomas, acoustic schwannomas and pituitary adenomas [4]. CROCKaRD et al [4] reported a case of metastasis of a prostatic carcinoma to a recurrent cerebellar haemangioblastoma. To our knowledge, renal carcinoma metastasizing to a haemangioblastoma cerebelli, both turnouts being part of the constellation of VHL, has not been reported previously. We conclude that it is important to be highly suspicious of haemangioblastoma in cerebellar cysts. As shown by our case, CT scanning and surgical exploration cannot always be relied upon to the demonstrate a tumour. Angiography and magnetic resonance imaging should be considered because they are particularly valuable in demonstrating the site of highly vascular tumours in the posterior fossa, such as haemangioblastoma. Patients with cerebellar haemangioblastoma should be screened for the visceral manifestations of VHL disease. When the latter diagnosis is made, patients will require regular follow-up to diagnose renal malignancy early. At risk family members should also be screened. Acknowledgements: The authors are grateful to the Mr. H. B. GRIFFn'H, FRCP, FRCS for his permission to report this case.
References []] CHRISTENSONP, J CRAIG, M BIBRO, K O'CONNELL: Cysts Containing Renal Cell Carcinoma in Von Hippel-Lindau Disease. J Urol 128 (1982) 798-799 [2] CLELLANDC, C TREIP: Histological Differentiation of Metastatic Renal Carcinoma in the Cerebellum from Cerebellar Haemangioblastoma in Von HippelLindau's Disease. J Neurol Neurosurg & Psych 52 (1989) 162- I66
Neurosurg. Rev. 15 (1992)
[3] COOVER J, A ARIEFF: Lindau Disease Treated by Bilateral Nephrectomy and Haemodialysis. West J Med 130 (1979) 456-458 [4] CROCKaRDH, R BARNaRD, D ISSACSON:Metastasis of Carcinoma to Haemangioblastoma Cerebelli: Case Report. Neurosurg 23 (1988) 382-384 [51 DE LA MONTESM, SA HOROWITZ:Haemangioblastomas: C~inicat and HistopathoIogicai Factors Correlated with Recurrence. Neurosurg 25 (1989) 695698
234
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma
[6] GOULDESBROUGHD, J BELL, A GORDON: Use of Immunohistochemical Methods in the Differential Diagnosis Between Primary Cerebellar Haemangioblastoma and Metastatic Renal Carcinoma. J Clin Path 41 (1988) 861-865 [7] NEUMANNH, H EGGERT,K WEIGEL,H FRIEDBURG, O WIESTLER,P SCHOLLMEYER:Haemangioblastomas of the Central Nervous System. J Neurosurg 70 (1989) 2 4 - 3 0
[8] RUSSELLD, L RUBINSTEIN:Pathology of the Nervous System. 5th Ed. Edward Arnold, London 1989 Submitted October 9, 1990. Accepted April 17, 1991. Dr. A. Jamjoom Division of Neurosurgery Department of Surgery King Khalid University Hospital P.O. Box 2925 Riyadh 11461 Saudi Arabia
Neurosurg. Rev. 15 (1992)
Metastasis o f a renal carcinoma to a cerebellar haemangioblastoma in a case o f von Hippel-Lindau disease Abdulhakim Jamjoom ~, Nicholas Kane2, and James NicoU3 1Division of Neurosurgery, Department of Surgery, King Khalid University Hospital, Riyadh, Saudi Arabia, 2Department of Neurosurgery and 5Neuropathology, Frenchay Hospital, Bristol, England
Abstract A patient with Von Hippel-Lindau disease had a longstanding cerebeltar cyst which recurred for the fifth time. At operation there was evidence of a renal carcinoma metastasis in the wall of the cyst which was probably a haemangioblastoma. Keywords: Haemangioblastoma, metastasis, renal carcinoma, Von Hippel-Lindau syndrome.
1 Introduction Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder with variable penetrance, characterized by cerebellar haemangioblastoma, retinal angiomatosis, renal abnormalities and cysts of the spinal cord, pancreas, kidneys and liver [1]. Renal carcinoma is the cause of death in approximately one third and is present at autopsy in two thirds of patients affected with VHL disease [3]. Although LINDAUoriginally believed that the renal tumours were always benign, the metastatic potential of these tumours is well documented. A review of the literature reveals that 40% of 53 cases of VHL with renal carcinoma had metastases [1]. We report an unusual case of VHL disease, in which a renal carcinoma metastasized to the wall of a longstanding recurrent cerebellar cyst, which was probably a haemangioblastoma.
2 Case report A 49-year-old woman originally presented 17 years ago, with an 18-month history of occipital headaches and vomiting. Clinical examination revealed mild truncal ataxia, horizontal optokinetic 9 1992by Walter de Gruyter& Co. Berlin. New York
nystagmus and marked bilateral papilloedema. Myodil ventriculography confirmed the presence of raised cerebrospinal fluid pressure and the suspicion of a space occupying lesion near the fourth ventricle. At subsequent posterior fossa craniectomy an intrinsic cerebellar cyst and nodule were removed. Histological examination showed gliotic cerebellum with no evidence of tumour. Over the next 14 years, the patient underwent three further operations to remove recurrence of the right cerebellar cyst. On the last occasion a drainage tube was inserted between the cyst and the cisterna magna. On each occasion, biopsy of the cyst wall showed gliotic tissue with no evidence of tumour and no definite diagnosis was made. One year ago, the patient presented with signs and symptoms of raised intracranial pressure again and a CT scan showed reaccumulation of the cerebellar cyst for the fifth time, and a tumour nodule was noted on the medial aspect of the cyst (Figure 1). At exploration a tumour nodule within the cyst wall was found to be obstructing the drainage tube. The position of the cerebellar cyst was identical to that in previous operations, however, the nodule on the medial aspects of the cyst was in a previously unexplored area. Histological examination showed the majority of this tissue to consist of extensively necrotic unequivocal "clear cell" carcinoma, confirmed by immunostaining for cytokeratin, most likely of a renal origin (Figure 2a, b). However, a small area of the specimen had the appearance of a haemangioblastoma with a fine meshwork of capillaries, intervening cells with foamy cytoplasm (Figure 3a), the characteristic reticular pattern (Figure 3b) and absent immunostaining for cytokeratin. Subsequent CT scan of the abdomen dem-
232
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma
Figure 1. CT scan (with contrast) showing the recurrent cerebellar cyst with a tumour nodule at its medial aspect (arrowed).
Figure 2a. Renal carcinoma biopsy (haematoxylin & eosin x 600). The tumour cells have features typical of a clear cell carcinoma with large nuclei, prominent nucleoli and vacuolated cytoplasm. Mitoses were numerous and there was extensive turnout necrosis. Reticulin fibres were not present between the tumour cells.
Figure 2b. Renal carcinoma biopsy (CAM 5.2 Dako Ltd. x 375). The tumour cell cytoplasm is immunostained for cytokeratin, confirming the diagnosis of carcinoma. There was no immunostaining for Epithelial Membrane Antigen or S100 protein.
onstrated the presence o f a solid lesion at the u p p e r pole of the left kidney, consistent radiologically with a renal cell carcinoma. Lytic lesions o f two vertebral bodies were thought to represent metastases. Cysts were also present in the right kidney a n d pancreas. A diagnosis o f V H L disease was made. This was based u p o n the presence o f longstanding cerebellar cyst which is p r o b a b l y a haem a n g i o b l a s t o m a , renal carcinoma, the findings o f multiple visceral cysts and the pertinent family history (the patient's father died o f renal carcin o m a at 50 years o f age). The patient was discharged home a n d succumbed to carcinomatosis within three months. A n a u t o p s y was not performed.
Figure 3a. Area resembling haemangioblastoma (haematoxylin & eosin x 600). This area contains the fine meshwork of intersecting capillaries characteristic of haemangioblastoma. The tumour cells have small nuclei and indistinct nucleoli in contrast to Figure 2a, and mitoses were absent from this area. The tumour cells have foamy rather than vacuolated cytoplasm, and were not immuno-stained for cytokeratin, Epithelial Membrane Antigen or $100 protein.
Figure 3b. The haemangioblastoma-like area (Gordon and Sweets' reticulin x 600) has the characteristic fine meshwork of reticulin fibres. Neurosurg. Rev. 15 (1992)
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma 3 Discussion The histological distinctioz~ between primary haemangioblastoma and a clear cell carcinoma metastasis in the cerebellum is often difficult, because both tumours may have cells with abundant vacuolated cytoplasm containing intracytoplasmic glycogen and a vascular stroma with associated reticulin fibres [6]. Immunohistochemically, epithelial cell antibodies are most useful in making the distinction by positively identifying a carcinoma [2, 6]. The majority of renal carcinomas are immunostained with antibody to Epithelial Membrane Antigen (EMA) and many, but not all, are immunostained with anticytokeratin antibodies. Haemangioblastomas are not immunostained with epithelial cell antibodies. Antibody to S 100 protein immunostains a proportion of haemangioblastomas while carcinomas are not immunostained with this antibody. In our case, the area of the biopsy which morphologically resembled carcinoma was immunostained with a cytokeratin antibody (CAM 5.2), but not with EMA or $100 antibodies. The immunohistochemistry therefore confirmed the diagnosis of metastatic clear cell carcinoma. The area of the biopsy which morphologically resembled a haemangioblastoma was not immunostained for cytokeratin, EMA or S100 protein. Although we cannot totally exclude the possibility that the longstanding cerebellar cyst may have been a simple glial cyst, we feel the most likely cause in a patient with VHL disease is haemangioblastoma and this is confirmed by histological findings. Haemangioblastomas are rare tumours of the central nervous system, predominately located in the cerebellum. They account for 1% to 2.5% of all intracranial neoplasms [7], occurring sporadically or as a manifestation in 23% [7] to 36% [4] of cases of Von Hippel-Lindau syndrome. Haemangioblastomas typically form cysts lined by gliotic tissue with turnout consisting of a mural nodule, which is often very small in size [8]. Previous CT
233
scans (with and without intravenous contrast), and microsurgical explorations of the recurrent cyst, had failed to demonstrate a turnout nodule. Angiography was not performed and may have been useful as it has been reported to reveal the tumour in up to 95% of haemangioblastoma cases [7]. Recurrence of these tumours may occur in up to 25% of cases [5]. DE LA MONTE et al [5] reported an increased risk of recurrence of haemangioblastoma in patients aged less than 30 years, cases with VHL, and in cases with multicentric tumours of the CNS at initial diagnosis. The phenomenon of haematogenous spread of carcinoma to benign intracranial tumours has been described in meningiomas, acoustic schwannomas and pituitary adenomas [4]. CROCKaRD et al [4] reported a case of metastasis of a prostatic carcinoma to a recurrent cerebellar haemangioblastoma. To our knowledge, renal carcinoma metastasizing to a haemangioblastoma cerebelli, both turnouts being part of the constellation of VHL, has not been reported previously. We conclude that it is important to be highly suspicious of haemangioblastoma in cerebellar cysts. As shown by our case, CT scanning and surgical exploration cannot always be relied upon to the demonstrate a tumour. Angiography and magnetic resonance imaging should be considered because they are particularly valuable in demonstrating the site of highly vascular tumours in the posterior fossa, such as haemangioblastoma. Patients with cerebellar haemangioblastoma should be screened for the visceral manifestations of VHL disease. When the latter diagnosis is made, patients will require regular follow-up to diagnose renal malignancy early. At risk family members should also be screened. Acknowledgements: The authors are grateful to the Mr. H. B. GRIFFn'H, FRCP, FRCS for his permission to report this case.
References []] CHRISTENSONP, J CRAIG, M BIBRO, K O'CONNELL: Cysts Containing Renal Cell Carcinoma in Von Hippel-Lindau Disease. J Urol 128 (1982) 798-799 [2] CLELLANDC, C TREIP: Histological Differentiation of Metastatic Renal Carcinoma in the Cerebellum from Cerebellar Haemangioblastoma in Von HippelLindau's Disease. J Neurol Neurosurg & Psych 52 (1989) 162- I66
Neurosurg. Rev. 15 (1992)
[3] COOVER J, A ARIEFF: Lindau Disease Treated by Bilateral Nephrectomy and Haemodialysis. West J Med 130 (1979) 456-458 [4] CROCKaRDH, R BARNaRD, D ISSACSON:Metastasis of Carcinoma to Haemangioblastoma Cerebelli: Case Report. Neurosurg 23 (1988) 382-384 [51 DE LA MONTESM, SA HOROWITZ:Haemangioblastomas: C~inicat and HistopathoIogicai Factors Correlated with Recurrence. Neurosurg 25 (1989) 695698
234
Jamjoom et al., Metastasis of carcinoma to haemangioblastoma
[6] GOULDESBROUGHD, J BELL, A GORDON: Use of Immunohistochemical Methods in the Differential Diagnosis Between Primary Cerebellar Haemangioblastoma and Metastatic Renal Carcinoma. J Clin Path 41 (1988) 861-865 [7] NEUMANNH, H EGGERT,K WEIGEL,H FRIEDBURG, O WIESTLER,P SCHOLLMEYER:Haemangioblastomas of the Central Nervous System. J Neurosurg 70 (1989) 2 4 - 3 0
[8] RUSSELLD, L RUBINSTEIN:Pathology of the Nervous System. 5th Ed. Edward Arnold, London 1989 Submitted October 9, 1990. Accepted April 17, 1991. Dr. A. Jamjoom Division of Neurosurgery Department of Surgery King Khalid University Hospital P.O. Box 2925 Riyadh 11461 Saudi Arabia
Neurosurg. Rev. 15 (1992)
