Von Hippel-Lindau disease is characterized by a variety of multi-system benign and malignant tumors and cysts. Most common tumors associated with VHL disease are hemangioblastomas, which are commonly located in the posterior fossa. Several case reports have described cerebellar or spinal hemangioblastomas first manifesting during the late pregnancy. Studies have also demonstrated significantly greater progression of cerebellar hemangioblastomas during pregnancy (1). Postpartum progression of hemangioblastoma causing cerebellar tonsillar herniation one week after giving birth has also been reported (2).
We identified and reviewed 23 previously published cases of CNS hemangioblastomas diagnosed during pregnancy. Majority of them (17) were in the cerebellum with most common symptoms at presentation including headache, dizziness, ataxia, blurred vision and nausea. Symptoms were frequently attributed to pregnancy at initial presentation. Seven cases were associated with Von Hippel Lindau disease, with the remaining 16 determined to be sporadic hemangioblastomas. All seven women with Von Hippel Lindau disease developed symptoms during the 3rd trimester of pregnancy. One case was complicated by hemorrhage from the tumor leading to paraplegia.
Of the 16 sporadic cases reported, 11 patients developed symptoms during the 3rd trimester, 3 patients presented during the 1st trimester, and 2 patients presented during the 2nd trimester. 2 of the sporadic cases were complicated by tumor hemorrhage during the 3rd trimester, leading to quadriparesis and paraplegia respectively. One case was complicated by tumor hemorrhage during delivery.
We suggest that rapid tumor growth as well as rare but life-threatening complications, such as tumor hemorrhage, are most likely to happen during the 3rd trimester of pregnancy. This is likely because this period of time is when pregnancy-associated physiologic changes are most prominent. Unfortunately, this is also when other obstetric complications, such as gestational hypertension and preeclampsia, present and thus may obscure the clinical picture and lead to a delay or missed diagnosis of a CNS tumor. Close monitoring of women with personal or family history of Von Hippel Lindau disease during the 3rd trimester of pregnancy is especially important.
Several mechanisms have been suggested as potential explanation for hemangioblastomas becoming clinically evident during pregnancy. The increase in intravascular volume may lead to engorgement and subsequent increase in size of these highly vascular tumors. Additionally, decreased threshold for ADH secretion may result in lower serum osmolality and contribute to peritumoral edema. At the same time, increased levels of VEGF during pregnancy may promote growth of hemangioblastomas. In their prospective cohort study, Evans et al demonstrated significantly higher levels of VEGF in pregnant women compared to the non-pregnant cohort, also noting serum VEGF concentration positively correlated with gestational age (3). Furthermore, up-regulation of VEGF expression has been postulated to promote the growth of hemangioblastomas (4). This is supported by evidence for regression of retinal hemangioblastomas after intravitreal anti-VEGF therapy (5). This hypothesis is in concordance with the mechanism of action of VHL protein (pVHL), which is involved in degradation of hypoxia-inducible-factors (HIFs). The inactivation of this protein in VHL disease, results in overproduction of HIFs despite adequate tissue oxygen saturation. (6). A hormonal hypothesis for tumor growth due to increased tumoral expression of hormone receptors even if suggested, has not been demonstrated (7, 8).
As demonstrated in this case report, detection of cerebellar hemangioblastoma in pregnancy may be delayed as symptoms such as headache, vomiting, dizziness, and blurred vision are not uncommon in otherwise healthy pregnant women. Careful neurological examinations in pregnant patients presenting with new onset neurological signs and symptoms should be emphasized to avoid life threatening complications such as brain stem herniation and hydrocephalus. If a cerebellar hemangioblastoma is detected, it is crucial to screen patients for other VHL-related tumors such as pheochromocytoma; as these tumors also are associated with high risk of pregnancy-related complications. Appropriate management of these patients remains unclear. In this case, patient underwent emergent C-section due to signs of fetal compromise. A few case reports have proposed near term C-section as an appropriate approach in patients with either sporadic or VHL-associated hemangioblastomas (9, 10). Silveira Rodrigues et al reported the case of a pregnant woman who presented with rapidly progressive dysautonomia in the setting of sporadic spinal hemangioblastoma with rapid resolution of symptoms the day after delivery (10). Similar rapid resolution of symptoms was described by Ortega-Martinez et al in a pregnant woman with multiple filum terminale hemangioblastomas (11). However, in life-threatening cases such as obstructive hydrocephalus and severe neurological manifestations, delivery alone may prove insufficient and warrant further intervention such as CSF diversion, to prevent severe neurological sequelae. Surgical excision may be considered in case of significant mass effect or persistent symptoms. While surgery is the definitive treatment for clinically significant sporadic hemangioblastomas; VHL disease is characterized by multiple tumors and higher risk of recurrence. In such cases frequency of surgical interventions should be minimized and preserved for symptomatic patients, as these are highly hemorrhagic tumors.