Brain Pathology Case of the Month - November 2009

DIAGNOSIS  Clear cell renal cell carcinoma metastatic to capillary hemangioblastoma in the setting of von Hippel-Lindau disease


Von Hippel-Lindau disease (VHL), an autosomal dominant disorder with incomplete penetrance, is found in approximately 1 in 36,000 newborns (1). VHL is characterized by a variety of benign and malignant tumors and cysts. The most common tumors associated with VHL are CNS and retinal hemangioblastomas, clear cell renal cell carcinoma, and pheochromocytoma. Renal cell carcinoma is found at autopsy in two-thirds of VHL patients and accounts for one-third of the deaths in VHL patients. Forty percent of patients develop metastatic renal cell carcinoma (1, 7), and a small number of these metastatic renal cell carcinomas metastasize to another tumor.

Tumor-to-tumor metastasis is a relatively rare phenomenon, but studying such occurrences may help us learn mechanisms of tumor invasion and metastasis (1). The first reported tumor-to-tumor metastasis was that of a lung carcinoma to a meningioma by Fried (3) in 1930. Since then, cases reported in the literature reveal that meningioma is the most common recipient tumor, with breast and lung carcinomas being the most common donors (5). Renal cell carcinoma to CNS hemangioblastoma is the second most common donor-recipient tumor association (1).

The precise mechanism of tumor-to-tumor metastasis in general is unknown but many theories have been postulated. The high collagen and lipid content found in meningiomas is thought to provide a "fertile soil" in which the recipient tumor can grow (8). Also, abundant vascularization in the recipient tumor, focal disruption of the blood brain barrier, and an immunocompromised patient may increase the likelihood of secondary metastases (2). Hemangioblastomas are thought to be favorable recipient tumors because of their slow growth, rich vascularity, high glycogen content, and often stagnant and slow blood flow in aberrant vessels (1). In addition, hemangioblastomas are often asymptomatic and may not require immediate resection so they have more time to host a metastasis (9). Also, the impaired VHL protein function disrupts fibronectin matrix assembly, which may make these tumors more susceptible to metastasis (5).

The first documented case of renal cell carcinoma metastatic to a CNS hemangioblastoma in a patient with VHL was described in 1992 by Jamjoom (4). Since then, thirteen other cases of renal cell carcinoma to hemangioblastoma have been described in the literature (1, 2, 5, 7). It is postulated that the practice of observing renal cell carcinomas measuring less than three centimeters in VHL patients, so as to preserve renal function, may contribute to this phenomenon. In contrast, most other visceral tumors in VHL patients, including pheochromocytoma and pancreatic neuroendocrine tumors, are resected immediately upon discovery. Because it is often not resected right away, the renal cell carcinoma has more time to metastasize (5). It has also been reported that similar paracrine factors may be secreted by the cellular components of hemangioblastoma and renal cell carcinoma, which may increase the tropism of metastasizing renal cell carcinoma for hemangioblastoma (1). Since the clinical course and management of hemangioblastoma and metastatic renal cell carcinoma are clearly different, it is important to be able to distinguish them.

Hemangioblastoma usually has a benign course following surgery, whereas metastatic renal cell carcinoma to the brain is often treated much more aggressively and has a worse prognosis (6). Neither in this case nor in the previously reported cases was there radiographic evidence of a metastatic focus within the hemangioblastoma, and in only one case was the metastasis seen grossly when the tumor was sectioned (5). We therefore rely heavily on the microscopic examination to make the diagnosis, which itself can be difficult because both tumors have similar cytological features. Hemangioblastoma consists of cells with vacuolated cytoplasm and abundant vascular stroma. The clear lipidized cells in clear cell renal cell carcinoma can have a similar appearance and can be easily confused with hemangioblastoma using hematoxylin and eosin staining only (2, 10). Several immunostains have been shown to be useful in distinguishing the two tumor types (6) (Table 1). In this case we applied a selective panel of stains that included cytokeratin AE1/AE3, CD10, EMA, and inhibin-alpha, which unequivocally confirmed the finding of metastatic renal cell carcinoma within a hemangioblastoma. Recently, aquaporin 1 has been shown to be a reliable marker for the distinction between renal cell carcinoma and hemangioblastoma (10).

We emphasize that such cases of metastatic renal cell carcinoma to a hemangioblastoma can be easily missed if not for careful microscopic examination and liberal use of immunostains whenever suspicion arises. In one reported case by Mottolese (7), the small focus of metastatic renal cell carcinoma was not even seen on the hematoxylin and eosin stained section, and was only suspected because of the patient's history of renal cell carcinoma and discovered after immunostains were applied. The size of the metastatic focus was not reported in the previous cases, but was very small (3 mm) in the present case. This raises the question: are such small metastases clinically significant and do these patients behave any worse than those with a hemangioblastoma alone? Currently, there is not enough data in the literature to address this issue, but one may speculate that these patients would be more likely to have other foci of metastatic renal cell carcinoma and that the small focus would have the propensity to grow quickly. It is therefore important that the entire resection material be submitted for pathologic examination so that a potential metastasis is not missed.


  1. Altinoz MA, Santaguida C, Guiot M-C, Del Maestro RF (2005) Spinal hemangioblastoma containing metastatic renal cell carcinoma in von Hippel-Lindau disease. Case report and review of the literature. Journal of Neurosurgery Spine.3(6):495-500.
  2. Bret P, Streichenberger N, Guyotat J (1999) Metastasis of renal carcinoma to a cerebellar hemangioblastoma in a patient with von Hippel Lindau disease: a case report. British Journal of Neurosurgery.13(4):413-6.
  3. Fried B (1930) Metastatic inoculation of a meningioma by cancer cells from a bronchogenic carcinoma. American Journal of Pathology.6:47-52.
  4. Jamjoom A, Kane N, Nicoll J (1992) Metastasis of a renal carcinoma to a cerebellar haemangioblastoma in a case of von Hippel-Lindau disease. Neurosurgical Review.15(3):231-4.
  5. Jarrell ST, Vortmeyer AO, Linehan WM, Oldfield EH, Lonser RR (2006) Metastases to hemangioblastomas in von Hippel-Lindau disease. J Neurosurg.105(2):256-63.
  6. Jung S-M, Kuo T-t (2005) Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear cell renal cell carcinoma. Modern Pathology.18(6):788-94.
  7. Mottolese C, Stan H, Giordano F, Frappaz D, Alexei D, Streichenberger N (2001) Metastasis of clear-cell renal carcinoma to cerebellar hemangioblastoma in von Hippel Lindau disease: rare or not investigated? Acta Neurochirurgica.143(10):1059-63.
  8. Sonet A, Hustin J, De Coene B, Gilliard C, Gustin T, Doyen C, Vandenbossche L, Jost E, Robin V, Chatelain B, Bosly A (2001) Unusual growth within a meningioma (leukemic infiltrate). Am J Surg Pathol.25(1):127-30.
  9. Sorscher SM (2008) Metastasis in von hippel-lindau disease.[comment]. J Neurosurg.109(3):568; author reply -9.
  10. Weinbreck N, Marie B, Bressenot A, Montagne K, Joud A, Baumann C, Klein O, Vignaud J-M (2008) Immunohistochemical markers to distinguish between hemangioblastoma and metastatic clear-cell renal cell carcinoma in the brain: utility of aquaporin1 combined with cytokeratin AE1/AE3 immunostaining. Am J Surg Pathol.32(7):1051-9.

Contributed by Sarah E. Martin, Sohaib M. Al-Khatib, Michael S. Turner, Annette C. Douglas-Akinwande, and Eyas M. Hattab

International Society of Neuropathology