Spinal leptomeningeal hemangioblastomatosis occurring without craniospinal surgery in von Hippel-Lindau disease

Abstract

Hemangioblastomatosis represents an unusual and malignant leptomeningeal dissemination of hemangioblastoma (HB). It has been reported in patients with sporadic HB or von Hippel-Lindau (VHL) disease. Hemangioblastomatosis had been reported following resection of a primary HB lesion in all cases except one patient with a sporadic HB. We present a patient with VHL with several HBs at the brainstem, cerebellum, pituitary stalk and retina who developed spinal hemangioblastomatosis without previous craniospinal surgery. A whole spine MRI showed the spinal dissemination from the primary lesions. The patient received craniospinal radiotherapy due to the extensive spinal leptomeningeal dissemination and multiple HBs. MRI performed 12 months after the radiotherapy showed stability of the lesions.

Background

Hemangioblastoma (HB) is a rare central nervous system tumour that affects the cerebellum, brainstem, spinal cord and retina. These tumours account for 1%–2% of all primary central nervous system tumours.^{1 2} Sporadic HB is usually solitary and accounts for 70%–75% of cases, whereas in 25%–30% of patients, it is a manifestation of von Hippel-Lindau (VHL) disease with multifocal HBs.^{3 4} The mutated gene in VHL disease is a tumour suppressor gene located on the short arm of chromosome 3.^{3 5 6} In addition to HBs, multiple visceral neoplasms are characteristic of VHL disease, including renal clear cell carcinoma, pheochromocytoma and pancreatic neuroendocrine tumour.^{1 7–11} Although HBs are usually treated with total resection, local recurrence is not uncommon, having a greater frequency of repeat surgery in patients with VHL than in sporadic cases.¹⁰

Hemangioblastomatosis represents a very rare manifestation of HB, causing leptomeningeal dissemination of the tumour and producing significant neurological impairments. In 1976, Mohan et al first described this malignant spread of HB to the spinal cord occurring several years after surgical removal of a cerebellar HB.¹² Hemangioblastomatosis has been documented in patients with VHL disease following surgical removal of a cerebellar HB.9 11 13–16 It has also been reported in patients without VHL disease after surgical removal of a cerebellar HB.3 4 8 17–24 The literature contains only one case of hemangioblastomatosis occurring without surgical resection of the primary lesion in a patient without VHL disease.²⁵ To the best of our knowledge, hemangioblastomatosis in a patient with VHL disease without surgical resection of the primary lesion has never been reported. We describe a patient with VHL disease having several HBs at the brainstem, cerebellum, pituitary stalk and retina who developed spinal hemangioblastomatosis without prior cranial or spinal surgery.

Case presentation

A man in his late 40s with VHL disease with known solid HBs at the dorsal cervicomedullary area, cerebellum, pituitary stalk and right eye retina started noticing occasional bilateral leg numbness for the last 6 weeks. None of his HBs had previously demonstrated a cystic component. All previous spinal MRIs had shown only the solid cervicomedullary HB without any additional spinal lesions. He presented to the neurosurgical clinic for re-evaluation with a new brain MRI, which demonstrated that the cervicomedullary HB had developed a large cyst (figure 1). The neurological examination only showed mild light touch hypoesthesia in both legs. Temperature sensation, vibration and proprioception were intact at the upper and lower extremities. He had no weakness or unsteady gait. Deep tendon reflexes had a normal response. Although the development of the new cyst at the cervicomedullary area could explain the leg numbness, a whole spine MRI was requested to evaluate for new spinal lesions.

Figure 1.

Sagittal brain MRI T1-weighted image with contrast shows the enhancing cervicomedullary hemangioblastoma (black arrow), which developed a new large cyst (yellow arrow) under the tumour. Note the enhancing pituitary stalk mass measuring 4 mm in the largest diameter (red arrow).

Thirty-two years ago, the patient’s diagnosis of VHL disease was established when a left suprarenal mass was found on an abdominal CT scan during a hypertension workup. Surgical removal of the adrenal gland was compatible with a pheochromocytoma. His systemic blood pressure continued uncontrolled the following month; thus, a new abdominal CT scan was performed. A smaller right suprarenal mass was identified and immediately removed, which was also positive for pheochromocytoma. Twelve years ago, a follow-up abdominal CT scan revealed a mass on the left kidney, which was removed and was compatible with a clear-cell renal carcinoma. His first brain MRI was performed at this time as a screening imaging, which showed three enhancing nodules consistent with HBs at the dorsal cervicomedullary area measuring 4 mm in the largest diameter, left cerebellar cerebellopontine area measuring 3 mm in the largest diameter and pituitary stalk measuring 4 mm in the largest diameter. A screening MRI of the whole spine did not show additional spinal lesions. Yearly brain MRI studies showed stable lesions. Spine MRI studies were ordered every 3 years, showing no new spinal lesions. The patient’s mother died of VHL disease at 35 years of age. Three siblings have the disease, and two have died from multiple HBs in the brain and metastatic renal carcinoma.

Investigations

The recent whole spine MRI showed enhancing leptomeningeal seeding at the mid-cervical, lower thoracic and lumbosacral areas (figure 2). On the T2-weighted images, the cervical spinal cord was edematous and swollen, extending from the cervicomedullary area to the C6 area (figure 3).

Figure 2.

Sagittal spine MRI sagittal T1-weighted image with contrast demonstrates enhancing leptomeningeal seeding (yellow arrows). (A) Cervical, (B) thoracic, (C) lumbar.

Figure 3.

Sagittal cervical spine MRI T2-weighted image shows the edematous and swollen cervical spinal cord (yellow arrow) below the cystic area, extending from the cervicomedullary junction to the C6 area.

Differential diagnosis

The primary differential diagnosis based on the MRI findings was spinal leptomeningeal seeding (hemangioblastomatosis) from the cervicomedullary HB. Spinal carcinomatosis from the renal cell carcinoma or other visceral tumours could also be a possibility; however, the patient’s nephrectomy was performed 12 years prior, and a recent abdominal ultrasound and CT scan showed no renal or pancreatic lesions.

Treatment

The case was consulted with the radio oncologist, who recommended whole spinal cord radiotherapy because of the extensive spine leptomeningeal seeding. Whole-brain radiotherapy was also recommended, given the three small cerebellar HBs and the possibility of cranial leptomeningeal seeding. A total dose of 54 Gy in 30 fractions to the brain and 41.4 Gy in 23 fractions to the spinal cord were given to the patient without complications.

Outcome and follow-up

One month after completing the radiotherapy, his leg numbness disappeared. Twelve months postradiotherapy, a repeat MRI of the brain and spine showed similar enhancing lesions without any new mass. The swelling of the cervical cord was mildly reduced. As there were no symptoms related to the cyst, close radiological follow-up observation was recommended.

Discussion

Hemangioblastomatosis is a rare but malignant leptomeningeal dissemination of HB. Dissemination to the spinal cord typically occurs several years after resection of a cerebellar or brainstem HB. The aetiology of this unusual biological behaviour has been debated over the years. Mechanical dissemination of tumour cells into the subarachnoid space after surgery had been implicated.^{18 26 27} Dissemination of tumour cells through the physiological cerebrospinal fluid pathway is thought to occur due to gravity.^{15 23} Bakshi et al proposed that hemangioblastomatosis may occur because of the release of tumour cell factors promoting aggressive angiogenesis and vascular permeability.¹³ Wanebo et al suggested that overexpression of vascular endothelial growth factors can produce uncontrolled angiogenesis leading to leptomeningeal dissemination.⁷

Until recently, the spillage and dissemination of tumour cells during surgery have been thought to be the principal aetiology for developing hemangioblastomatosis, as no cases without previous surgery have been reported.4 8 18 24 27 However, in 2020, Oya et al reported for the first time a patient without VHL disease who developed disseminated HB without resection of the mass.²⁵ The patient had a tentative diagnosis of a supracerebellar HB, which was not operated on because she did not want surgery and opted for radiotherapy. Before the radiotherapy was initiated, she developed hydrocephalus and was managed only with decompressive craniectomy of the occipital bone followed by radiotherapy to the tumour. Two years later, the patient developed leptomeningeal dissemination, which proved to be HB after a biopsy of the Sylvian fissure leptomeninges. Based on the clinical course and outcome, the authors proposed that radiotherapy might have caused chromosomal instability throughout the whole genome, with genome copy number aberration causing the dissemination. In our patient with VHL disease, hemangioblastomatosis occurred without any previous cranial surgery or radiotherapy. However, the patient presented a significant radiological transformation of the lower cervicomedullary HB, developing a large cystic area before the leptomeningeal dissemination was identified. Our case shows that a patient with VHL disease can develop spinal leptomeningeal hemangioblastomatosis even without craniospinal surgery to remove the primary tumour.

Spinal leptomeningeal hemangioblastomatosis has an average 8–10 years interval from primary HB disease presentation to the diagnosis of disseminated disease.^{3 20 24} The average time to present disseminated disease is similar in sporadic and VHL disease cases.²⁴ The condition has poor overall survival, with patients rarely surviving beyond 2 years.3 8 9 20 22 24 25 The mean survival time for patients with early discovery of dissemination is substantially longer than the mean survival time for patients with late detection of dissemination.²⁴ Disseminated disease to the brainstem remains the most prevalent cause of mortality, which results in compression of critical pontomedullary regions and ultimately respiratory failure.^{4 20 24}

For the treatment of hemangioblastomatosis, Zhang et al recommend surgical biopsy and decompression if symptomatic lesions are present.¹⁵ However, repeat surgery is usually ineffective.³ The use of vascular endothelial growth factor and epidermal growth factor receptor inhibitors, interferon and oral temozolomide has not proven beneficial.^{15 16} Reyes-Botero et al reported a patient for whom partial clinical recovery and radiological response were observed after treatment by sunitinib malate, a receptor tyrosine kinase inhibitor.²¹ Despite adjuvant craniospinal radiotherapy, patients developed recurrence, suggesting that HB with leptomeningeal dissemination is a radio-resistant neoplasm.^{3 11 19} However, the radiotherapy doses applied in some cases might be suboptimal, which may explain the lack of efficacy in controlling further tumour growth.^{3 17} For all patients with HBs, long-term follow-up is recommended to monitor the progression of the disease.1 8 10 15 19 24 Newer, effective systemic therapies for hemangioblastomatosis are needed.

Patient’s perspective.

Since my early adulthood, I have undergone many surgeries and treatments for my von Hippel-Lindau disease. However, this time, I was scared. As soon as my neurosurgeon told me that the tumour had spread to the spinal canal, I was frightened and my wife was terrified. My first thought was that I might lose the ability to walk. I was offered radiotherapy to my brain and spinal cord as a possible measure to stop the growth. Understanding it was one of the few options, I immediately consented. The numbness rapidly improved after the radiotherapy. Although the lesions still are present after 6 months of the treatment, I feel relieved that no new symptoms or lesions have appeared.

Learning Points.

• Leptomeningeal hemangioblastomatosis is a rare late manifestation of hemangioblastoma.

• Spinal leptomeningeal hemangioblastomatosis can occur in patients without prior surgery.

• Radiotherapy may offer clinical stability for spinal leptomeningeal hemangioblastomatosis.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).