Metastatic hemangioblastoma (disseminated hemangioblastomatosis).
Hemangioblastomas constitute 1-2% of all brain tumors and 5-15% of posterior fossa tumors in adults (10). Hemangioblastomas occur in association with the autosomal-dominantly inherited von Hippel-Lindau (VHL) syndrome, but the sporadic solitary cerebellar hemangioblastoma is the most common presentation. The patients in this sporadic category develop symptoms in middle age and are more commonly men. Hemangioblastomas are benign and surgical removal of the angiomatous mural nodule is generally curative. We present a patient with a completely excised solitary cerebellar hemangioblastoma that recurred 15 years later as multiple metastatic lesions throughout the neuraxis.
Malignant spread years after the removal of a solitary hemangioblastoma is an uncommon event; few cases have been reported in the literature over the past 35 years. In 1976, Mohan et al reported two adult men in whom multiple metastatic hemangioblastomas were found 8 and 14 years after the original resection (6). In 2002, Weil et al reported two adult men ages 34 and 41 and two adult women ages 43 and 47 who developed disseminated hemangioblastomatosis 1 to 8 years after complete resection of solitary cerebellar hemangioblastomas (10). In 2005, Kato et al described a 50 year old woman who was diagnosed with metastatic hemangioblastoma 21 years following resection of a solitary cerebellar lesion (4). In 2009, Kim et al reported a 41 year old male in whom disseminated hemangioblastomatosis developed 10 years following primary surgical excision. (5). None of the patients had the stigmata of von Hippel-Lindau disease and all were felt to have sporadic tumors. Histology in these cases revealed the typical microscopic features of hemangioblastomas without mitotic figures or other features of anaplasia. No histological differences were noted between the original biopsies and the recurrent tumors years later.
Two other case studies have been published describing the development of disseminated hemangioblastomatosis less than a year following surgery for the primary solitary lesion. Hande and Nagpal published a case of a 4-year-old child who developed multiple symptomatic CNS lesions over a six-month interval after originally presenting with a fourth ventricular hemangioblastoma. Clinical and familial evidence of VHL was absent (2). In 2008, Ramachandran et al described extramedullary leptomeningeal hemangioblastomatosis in a 75 year old man with no previous health problems. He originally presented with a 3 cm mass involving the cervical spine that was subsequently resected. Five months following surgery, symptoms including delusions, hallucinations, cognitive decline, and weight loss were experienced with progressive worsening of neurologic status over the subsequent 10 months ultimately resulting in death. Autopsy findings confirmed disseminated extramedullary hemangioblastomatosis involving all levels of the spinal cord. The neoplasm was morphologically characteristic of hemangioblastoma, however, unlike the previous cases cited, rare enlarged hyperchromatic nuclei were documented and a higher Ki-67 labeling index of 5% was reported (8).
This manuscript reports the 10th case of an adult with presumed sporadic disease and metastatic hemangioblastoma occurring after original resection. Unfortunately, genetic analysis for VHL was not performed in this patient. His tumors displayed no histological difference between the original tumor and the diffuse leptomeningeal deposits found at autopsy. Mitotic figures were not seen and MIB-1 (Ki67) immunohistochemistry, which labels proliferative cells, showed only a few positive nuclei (<1%). There was some invasion into brain parenchyma by the tumor in the subarachnoid space but most of the larger nodules were well circumscribed with compression of the surrounding brain parenchyma.
Patients with VHL disease, with gene localization on chromosome 3p (9), frequently have multiple hemangioblastomas throughout the neuraxis including the spinal cord, but multiple lesions are not typically found in patients without VHL. In gene carriers of VHL, these hemangioblastomas may recur, or new lesions may develop, but the patients tend to have a slowly evolving course. Although germline mutation evidence suggests that 10 to 20% of sporadic hemangioblastomas contain abnormalities in the VHL gene (1,3,7), the vast majority of patients with sporadic tumors have no recognized genetic link with VHL.
Since metastatic hemangioblastoma/disseminated hemangioblastomatosis is a rare entity -particularly in cases of spontaneous hemangioblastomas- metastases other than those due to secondary CNS infiltration by contiguous malignancy should be considered. In the case of our patient, multiple lesions were discovered along the neuraxis involving the superficial parenchyma, leptomeninges, and dura, approximately fifteen years following his diagnosis of hemangioblastoma. Given his age (63 years old), the time from his initial diagnosis, and smoking history (50 pack years), metastatic lung carcinoma is high on a list of differential diagnoses. Adenocarcinomas of the lung, in particular, may display diffuse leptomeningeal carcinomatosis , with vertebral and paravertebral metastases. Additional metastases to consider include malignant melanoma, renal cell carcinoma, and colorectal carcinoma; each of these are capable of blood-borne neuraxial metastases. Histologically, metastases are typically well-demarcated from adjacent parenchyma, displaying a pushing border. Radiologic findings typically reveal multiple contrast-enhancing lesions located at the junction of gray and white matter and are often associated with significant edema.
Contributed by Emily F. Gorman, MD; Asim K. Bag, MD; Cheryl Ann Palmer, MD