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http://dx.doi.org/10.1016/j.jocn.2014.04.024

Renal cell carcinoma to haemangioblastoma metastasis: A rare manifestation of Von Hippel–Lindau syndrome Benjamin F. Dessauvagie a,⇑, G. Wong b, P.D. Robbins a a b

Department of Tissue Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Hospital Avenue, Nedlands, Perth, WA 6009, Australia The State Neurosurgery Service, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA, Australia

a r t i c l e

i n f o

Article history: Received 21 March 2014 Accepted 21 April 2014

Keywords: Haemangioblastoma Metastasis Renal cell carcinoma Tumour-to-tumour metastasis Von Hippel–Lindau syndrome

a b s t r a c t Brain metastases are the most common intracranial malignancy in adults and may occasionally deposit within a pre-existing primary brain neoplasm. We describe, in two directly related family members, the rare occurrence of renal cell carcinoma (RCC) metastasis to haemangioblastoma (HB) in the context of Von Hippel–Lindau syndrome. Detection of this phenomenon can be marred by histological overlap between RCC and HB and therefore careful histological examination, and consideration of supportive immunohistochemistry, is required when examining all HB resections. Metastatic RCC to HB upstages a primary RCC and is clinically diagnostic of Von Hippel–Lindau syndrome. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Brain metastases are the most common intracranial malignancy in adults [1,2] and may occasionally deposit within a pre-existing primary brain neoplasm. Correct diagnosis, in this scenario, can be difficult due to the small size of the metastatic deposit and the potential overlap of histological features between the host and metastatic tumour [3]. Metastatic renal cell carcinoma (RCC) to haemangioblastoma (HB), usually in the context of Von Hippel–Lindau (VHL) syndrome, is an example of this phenomenon and its accurate detection has important clinical ramifications. 2. Case reports 2.1. Patient 1 A 54-year-old woman with VHL syndrome and a history of high grade, bilateral clear cell RCC presented with pain, spasm and weakness in her right arm. Serial neuroimaging investigations revealed an enlarging right sided, solitary, contrast enhancing, intramedullary mass at C6/C7. No synchronous intracranial lesions were identified. A C4–T1 laminectomy was performed revealing a vascular lesion which was excised and submitted to pathology. ⇑ Corresponding author. Tel.: +61 8 9346 1862; fax: +61 8 9346 4122. E-mail address: [email protected] (B.F. Dessauvagie).

Pathological examination revealed a compound tumour (Fig. 1A). The predominant component consisted of nests of polygonal cells with pleomorphic nuclei, prominent nucleoli and moderate amount of eosinophilic to clear cytoplasm in a background delicate vascular stroma. Mitoses were readily identified and there were areas of necrosis (Fig. 1B). Sparse reticulin fibres were evident (Fig. 1C). The tumour cells were strongly immunopositive for epithelial membrane antigen (EMA), vimentin, CAM5.2, CD10 and AE1/AE3 (Fig. 1D). RCC antigen, inhibin, CK7 and CK20 were negative. The surrounding minor component featured lipidised, amitotic stromal cells enmeshed in a reticulin-rich capillary network (Fig. 1E). These stromal cells exhibited immunopositivity for inhibin (Fig. 1F) and vimentin and were negative for EMA, CAM5.2, AE1/AE3, CD10, RCC, CK7 and CK20. A diagnosis of metastatic clear cell RCC to HB was made. She was followed for 2 years, during which time she developed multiple bony and pulmonary RCC metastases, before succumbing to disseminated disease. 2.2. Patient 2 A 28-year-old man, the son of Patient 1 and also suffering from VHL syndrome, presented with multiple radiologically identified renal masses, a thoracic intramedullary mass and a solid-cystic contrast enhancing fourth ventricular mass. Excision of the renal tumours showed multiple low grade clear cell RCC. A craniotomy

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Fig. 1. Pathological findings in Patient 1. (A) Scanning magnification of the compound tumour. The host haemangioblastoma (HB) is seen partially surrounding the metastatic renal cell carcinoma (RCC) (haematoxylin and eosin [H&E], original magnification  0.6). (B) The RCC component showing nuclear pleomorphism, prominent nucleoli, mitoses and areas of necrosis (H&E, original magnification  200). (C) Nest of cells are surrounded by reticulin fibres in the RCC component (reticulin stain, original magnification  200). (D) Scanning magnification demonstrating cytokeratin positivity in the RCC component (lower left) and negativity in the host HB (AE1/AE3, original magnification  0.6). (E) Amitotic, bland spindle cells separated by capillary lumens comprise the HB component (H&E, original magnification  200). (F) A pericellular reticulin pattern characterises the HB component (reticulin stain, original magnification  200).

was performed with the tumour excised and submitted to pathology. Pathological examination demonstrated a compound tumour (Fig 2A). In this case the predominant component was HB with occasional small aggregates of haematopoiesis (Fig. 2B, C). The HB cells were inhibin positive (Fig. 2D) and negative for AE1/AE3, CAM5.2, PAX-8 and EMA (Fig. 2E, F). A single 1.2 mm metastatic RCC focus was identified (Fig. 2B). Reticulin staining in the RCC was sparse (Fig. 2C) and immunohistochemical stains revealed positivity for AE1/AE3, CAM5.2, PAX8, and EMA and negativity for inhibin (Fig. 2D–F).

He is currently well with less than a year of follow-up. 3. Discussion Metastatic tumours are the most common neoplasms to affect the central nervous system (CNS) [1]. They are encountered in approximately one-quarter of advanced-stage cancer patients in autopsy series [2]. While most metastatic lesions involve normal brain parenchyma and the leptomeninges, occasionally pre-existing CNS tumours are the recipients of metastatic tumours. Such tumours are typically low grade and slow growing and include

Case Reports / Journal of Clinical Neuroscience 22 (2015) 215–218

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Fig. 2. Pathological findings in Patient 2. (A) Scanning magnification of the compound tumour composed predominantly of haemangioblastoma (HB). A small renal cell carcinoma (RCC) deposit is present (haematoxylin and eosin [H&E], original magnification  0.6). (B) The intersection between RCC (lower left) and HB (upper right) (H&E, original magnification  20). (C) Contrasting patterns of reticulin fibre deposition at the intersection between RCC and HB (reticulin stain, original magnification  200). (D) Absent inhibin staining in the RCC with strong positivity in the HB (original magnification  200). (E) Strong cytokeratin positivity in the RCC with negative staining in the HB (AE1/AE3, original magnification  200). (F) PAX-8 positivity in the RCC and negativity in the HB (original magnification  200).

meningiomas, schwannomas, pituitary adenomas and low grade glial neoplasms. The biological mechanisms of tumour-to-tumour metastasis are poorly understood. Typically the recipient tumour is indolent and slow growing and is therefore present as a potential metastatic site over a long period of time. At the cellular level, the host tumour stromal microenvironment, a rich and slow flowing blood supply, and focal disruption of the blood–brain barrier also play a part [4]. Diagnostic criteria for tumour-to-tumour metastases have been defined previously as: (a) the metastatic focus must be at least partially enclosed by a rim of histologically distinct host tumour tissue; (b) the existence of metastatic carcinoma must be proven by morphologic and immunohistochemical methods; and (c) the fea-

tures of the latter must be comparable to those of a demonstrated primary tumour [5]. These criteria were met in our two patients. Metastases to HB were first reported in 1988 and since then, including the two patients herein, eighteen additional cases have been published (Table 1). The most frequent metastatic tumour is RCC (in 16 patients) with solitary examples of metastatic prostate carcinoma, testicular mixed germ cell tumour and pancreatic neuroendocrine tumour. The recipient HB have been located in the cerebellum, the cervical spinal cord, the thoracic cord and the sacral cord. All but two patients had VHL syndrome. To our knowledge, an RCC to HB metastasis has not been documented in directly related family members. It is well established that clear cell RCC metastasises to the posterior fossa, or indeed RCC metastasises to HB, may pose a

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Table 1 Collated data of all metastases to haemangioblastomas reported in the literature Documented cases [reference] Crockard et al. 1988 [8] Jamjoom et al. 1992 [9] Bret et al. 1999 [10] Mottolese et al. 2001 [11] Hamazaki et al. 2001 [12] Fakih et al. 2001 [13] Abou-Hamden et al. 2003 [14] Altinoz et al. 2005 [4] Jarrell et al. 2006 [15]

Polydorides et al. 2007 [3] Ichikawa et al. 2011 [16] Present Patient 1 Present Patient 2

Age, sex

Haemangioblastoma location

Primary tumour

VHL syndrome

53 M 49 F 42 M 36 M 46 F 47 F 37 F 39 M 43 M 36 F 60 F 46 F 28 F 44 F 41 M 57 F 22 M 54 F 28 M

Cerebellum Cerebellum Cerebellum Cerebellum Cerebellum Thoracic spinal cord Cervical spinal cord Cervical spinal cord Thoracic spinal cord Sacral spinal cord Cerebellum Cerebellum Cerebellum Thoracic spinal cord Thoracic spinal cord Cervical spinal cord Cerebellum Cervical spinal cord Cerebellum

Prostatic CA RCC RCC RCC RCC RCC RCC RCC RCC RCC RCC RCC Pancreatic neuroendocrine tumour RCC RCC RCC Mixed germ cell tumour RCC RCC

No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes

CA = carcinoma, F = female, M = male, RCC = renal cell carcinoma VHL = Von Hippel–Lindau.

diagnostic challenge due to overlapping histological characteristics. The presence of nuclear atypia, nucleoli, mitotic figures and haemorrhagic areas lined by neoplastic cells, as opposed to flat endothelial cells, favour RCC over HB [3,6]. Immunohistochemical stains can be used to support this histological distinction. HB are typically diffusely positive for inhibin with a Ki67 proliferative index 5% and a reticulin poor stroma [3,6]. VHL syndrome, affecting 1 in 40,000 people, is an autosomal dominant disorder with almost complete penetrance that is due to germline mutations in the VHL gene on chromosome 3q25-26 [7]. It is characterised by cerebellar, retinal, spinal, and rarely peripheral nerve HB, RCC, pheochromocytomas, paragangliomas, and various other malignant and benign tumours [7]. Clinical diagnosis requires a family history of the disease and one of the aforementioned tumours or the presence of a CNS/retinal HB plus one other tumour and therefore, as mentioned, the diagnosis of metastatic RCC to a HB meets clinical criteria for diagnosis [3]. RCC is the most common metastatic tumour amongst those documented to metastasise to HB and it usually occurs in the context of VHL syndrome. We propose that careful histological examination and immunohistochemical stains, when appropriate, should be applied in all cases of HB, as the diagnosis of a RCC to HB metastasis can be microscopic, upstages the primary tumour (with prognostic ramifications) and is clinically diagnostic of VHL syndrome. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements The authors would like to acknowledge the contributions of pathologists Drs J. Ma Wyatt, I. Low and J. Cernelc and surgeon http://dx.doi.org/10.1016/j.jocn.2014.04.024

Mr N. Knuckey who were involved in the workup and management of these cases. References [1] Wen PY, Loeffler JS. Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases. In: Basow DS, editor. UpToDate. Waltham: Wolters Kluwer Health; 2013. Available at: http:// www.uptodate.com. Accessed October 8, 2013. [2] Posner JB, Chernik NL. Intracranial metastases from systemic cancer. Adv Neurol 1978;19:579–92. [3] Polydorides AD, Rosenblum MK, Edgar MA. Metastatic renal cell carcinoma to hemangioblastoma in von Hippel–Lindau disease. Arch Pathol Lab Med 2007;131:641–5. [4] Altinoz MA, Santaguida C, Guiot MC, et al. Spinal hemangioblastoma containing metastatic renal cell carcinoma in von Hippel–Lindau disease. Case report and review of the literature. J Neurosurg Spine 2005;3:495–500. [5] Pamphlett R. Carcinoma metastasis to meningioma. J Neurol Neurosurg Psychiatry 1984;47:561–3. [6] Scheithauer BW, Vogel FS. Surgical pathology of the nervous system and its coverings. 4th ed. Philadelphia: Churchill Livingstone; 2002. [7] Frosch MP, Anthony DC, De Girolami U. The central nervous system. In: Kumar V, Abbas AK, Fausto N, editors. Robbins and Cotran pathologic basis of disease. Philadelphia: Elsevier; 2005. p. 1347–419. [8] Crockard HA, Barnard RO, Isaacson PG. Metastasis of carcinoma to hemangioblastoma cerebelli: case report. Neurosurgery 1988;23:382–4. [9] Jamjoom A, Kane N, Nicoll J. Metastasis of a renal carcinoma to a cerebellar haemangioblastoma in a case of von Hippel–Lindau disease. Neurosurg Rev 1992;15:231–4. [10] Bret P, Streichenberger N, Guyotat J. Metastasis of renal carcinoma to a cerebellar hemangioblastoma in a patient with von Hippel Lindau disease: a case report. Br J Neurosurg 1999;13:413–6. [11] Mottolese C, Stan H, Giordano F, et al. Metastasis of clear-cell renal carcinoma to cerebellar hemangioblastoma in von Hippel Lindau disease: rare or not investigated? Acta Neurochir (Wien) 2001;143:1059–63. [12] Hamazaki S, Nakashima H, Matsumoto K, et al. Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel–Lindau disease. Pathol Int 2001;51:948–53. [13] Fakih M, Schiff D, Erlich R, et al. Intramedullary spinal cord metastasis (ISCM) in renal cell carcinoma: a series of six cases. Ann Oncol 2001;12:1173–7. [14] Abou-Hamden A, Koszyca B, Carney PG, et al. Metastasis of renal cell carcinoma to haemangioblastoma of the spinal cord in von Hippel–Lindau disease: case report and review of the literature. Pathology 2003;35:224–7. [15] Jarrell ST, Vortmeyer AO, Linehan WM, et al. Metastases to hemangioblastomas in von Hippel–Lindau disease. J Neurosurg 2006;105: 256–63. [16] Ichikawa T, Hamazaki S, Sakai N, et al. Mixed germ cell tumor and hemangioblastoma in the cerebellum: report of a rare coexistence. Brain Tumor Pathol 2011;28:279–84.

Renal cell carcinoma to haemangioblastoma metastasis: a rare manifestation of Von Hippel-Lindau syndrome.

Brain metastases are the most common intracranial malignancy in adults and may occasionally deposit within a pre-existing primary brain neoplasm. We d...
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