Progression of hemangioblastomas in pregnancy in von Hippel-Lindau syndrome

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Dear Editor,

Hemangioblastomas of the cerebellum, brainstem and spinal cord are among the most common tumors associated with von Hippel-Lindau syndrome (VHL). Despite their benign nature, these highly vascularized cystic tumors in the elokvent regions can significantly increase morbidity and mortality [1]. The possible influence of pregnancy on the growth of these lesions remains unclear to date. In this case report, we present a rare case of a pregnant patient with clinical manifestation of multiple CNS hemangioblastomas.

A pregnant 28-year-old female patient with VHL collapsed in the emergency waiting room. She presented for 3 weeks of progressive headache, vomiting and photophobia. During clinical examination, the patient was conscious (GCS 15), oriented, afebrile, without fatal disturbance, with isocortical pupils, no pathological findings on the cranial nerves, no lateralization on the extremities, no muscle weakness at the bedside, and standing or walking could not be examined because of torpid headache. Urgent CT scan of the brain showed obstructive hydrocephalus and swelling of the left cerebellar hemisphere with probable tumor. The patient had previously undergone resection of a hemangioblastoma in the thoracic spinal cord at another neurosurgical center, treatment for vitreoretinal traction, spontaneous abortion in the first trimester, and an induced abortion for a congenital fetal developmental defect in the second trimester. At her last MRI scan 10 years ago, the patient was free of pathological CNS lesions. She was regularly monitored for pancreatic cysts. A current MRI with contrast agent revealed 10 new infratentorially located hemangioblastomas, some with significant collateral edema, and one lesion in the spinal cord at the C1 level (Figure 1). Furthermore, a complete preoperative examination, including ophthalmologic and gynecologic examinations, was completed without finding any additional new pathology. Considering the patient's pregnancy and the risks of general anesthesia, the shortest and most effective procedure was planned -⁠ image-guided, navigated microsurgical resection of the three dominant lesions using an ultrasound aspirator. Because the patient was at 13 weeks gestation (12 + 3), when the uterus is fully covered by the pelvis, there was no limitation in the perioperative positioning of the patient. In the right lateral position, a massive lesion in the cervical spinal cord was resected from an extended suboccipital retrosigmoid craniotomy with debridement of the proximal half of the C1 vertebral arch, as well as two other reachable lesions with significant perifocal edema from the left cerebellar hemisphere. Postoperatively, clinical complaints resolved and the patient was readmitted to home care after one week. The pregnancy continued to progress physiologically. The patient was advised to deliver by caesarean section to prevent potential complications caused by increased intracranial pressure during per vaginal delivery [2]. The patient delivered a healthy baby at 38 weeks of gestation. One year after the procedure, the patient was still free of clinical complaints, but there was progression of the cystic component of the hemangioblastoma located in the right cerebellar hemisphere. However, the patient preferred conservative management due to the care of her infant. After 2 months, there was further progression in the size of the lesion, so resection of the lesion and resection of another small hemangioblastoma from the right retrosigmoid approach was performed. After the procedure, the patient was discharged to home care without clinical complaints and was regularly dispensed. Six months later, the patient became pregnant again and during pregnancy the previously observed lesion in the cervical spinal cord at the C4/5 level progressed. During pregnancy, there was also progression of the cystic component of one lesion located in the right cerebellar hemisphere; the other cerebellar lesions studied remained stationary during pregnancy. The patient was free of clinical complaints throughout the pregnancy and delivered a healthy baby by elective caesarean section at 38 weeks. One month after delivery, further progression of the cervical spinal cord lesion occurred, and the patient remained asymptomatic; therefore, conservative management was again preferred (Figure 2).

VHL syndrome is an autosomal dominant inherited disease with an incidence of 1 : 36,000. The disease is caused by a mutation in the VHL tumor suppressor gene on the short arm of chromosome 3 (3p25), which produces the VHL protein involved in hypoxia-inducible factor (HIF) proteolysis. Deficiency of VHL protein leads to overproduction of vascular endothelial growth factor (VEGF) and dysregulation of other neoplastic processes in hemangioblasts [3]. The VHL syndrome is characterized by retinal and CNS hemangioblastomas, clear cell renal cell carcinoma, pheochromocytoma, pancreatic neuroendocrine tumors, cysts and cystadenomas of parenchymatous organs with clinical manifestation in the third decade of life.

There are several hypotheses for the progression of hemangioblastomas during pregnancy. One of them is direct hormonal influences on estrogen and progesterone receptors of hemangioblastomas [4]. Furthermore, the influence of proangiogenic factors such as placental growth factor (PIGF) [5]. Increased venous pressure due to uterine enlargement during vena cava inferior compression and increased circulating blood volume with decreased osmolality may result in the progression of peritumoral edema leading to worsening of the clinical condition [4]. A retrospective analysis by Gimbert et al. documenting 56 pregnancies in 30 women with VHL showed a 5% maternal morbidity and 96% fetal survival with a mean gestational age of 38.2 weeks and a mean birth weight of 3.1 kg [6]. However, the results of several studies disagree clearly on the relationship of pregnancy to hemangioblastoma progression. In a prospective study by Ye et al. 36 women of childbearing age with regular craniospinal axis MR examinations were followed for a mean of 7.5 years. Nine pregnant women were found to have no significant difference in tumor progression compared to the others [7]. Similar findings were reported in a study by Binderup et al [8]. Only a retrospective study by Frantzen et al. revealed a significant progression of cerebellar hemangioblastomas within 48 pregnancies in 29 women with VHL. The authors also recommended follow-up brain MRI in the fourth month of pregnancy and before delivery [9].

The literature suggests that surgical resection is the preferred treatment for symptomatic craniospinal axis hemangioblastomas as it is usually accompanied by low morbidity. There is no clear consensus on the management of asymptomatic lesions. Most authors recommend resection of only symptomatic lesions or lesions that can be safely removed in the vicinity of a symptomatic lesion, as resection will not be a curative procedure in patients with VHL anyway. According to some studies, resection of the lesions, especially from the spinal cord region, is recommended before the development of sensorimotor symptomatology because even after complete resection of the lesion, the neurodevelopment may not be corrected [10].

Pregnancy in women with VHL syndrome is not associated with increased perinatal mortality and is not contraindicated. Patients should be dispensed by a multidisciplinary team and attend regular clinical and radiological follow-ups with regard to fetal safety. The management of labour and the type of analgesia or anaesthesia, if any, should also be planned in advance according to the patient's individual clinical condition.