Hemangioblastoma and von Hippel-Lindau disease: genetic background, spectrum of disease, and neurosurgical treatment

Hemangioblastoma of the central nervous system (CNS) occurs as a sporadic tumor or as a component of the hereditary von Hippel-Lindau (VHL) disease. The classical report dates back to 1926 when the Swedish pathologist Arvid Lindau (1892-1958) presented his thesis on cystic cerebellar tumors [1]. Lindau studied these tumors at the Seraphimer Hospital in Stockholm and extended his research by a longer journey to Berlin, Leipzig, Prague, and other university institutes where he saw autopsy protocols and specimen of patients with additional visceral tumors of the kidney, pancreas, and adrenals [2]. Comparing the histology of cerebellar tumors and those of the eyes in several of such patients, he provided evidence that both are identical. Today we use the term angioma or hemangioblastoma of the retina. It was the eminent neurosurgeon Harvey Cushing who suggested naming the disorder Lindau’s disease. The modest Swede, however, underscored the impact of the German ophthalmologist Eugen von Hippel (1867-1939), and now both names are used equivocally.

Hemangioblastomas are benign tumors of the CNS and are defined by their histopathology [3]. Striking components are lipid-loaden foamy cells and abundant capillaries (Fig. 1). In addition, many hemangioblastomas of the CNS form cysts of various sizes. The cysts are filled by amber-colored fluid. The main component of this fluid is erythropoietin. VHL is a syndrome that is characterized by various tumors and cystic lesions in several organs, as presented in detail below. Clinically, two presentations are observed: (i) an individual with a family history of VHL and the presence of a CNS or retinal hemangioblastoma, a pheochromocytoma or a clear cell renal cell carcinoma; or (ii) an index case (an individual with no family history) with two or more hemangioblastomas or two or more visceral tumors or one hemangioblastoma and one visceral tumor [4]. Today the diagnosis is mostly based on molecular findings. One lesion and the presence of a pathogenic VHL germline mutation lead to diagnosis.

Biallelic inactivation of the VHL tumor suppressor gene is thought to initiate tumorigenesis. The first allele is inactivated by a germline mutation or deletion and the second allele by deletion or mutation at a later stage. Inactivation of the VHL tumor suppressor gene has several consequences on the molecular level. The most prominent is dysregulation of oxygen sensation with upregulation of hypoxia inducible factor (HIF) and its several downstream targets. The Nobel Prize for Medicine and Physiology 2019 was awarded to the researchers who discovered this mechanism. HIF induces angiogenesis, blood formation, metabolic changes, and several other effects. In addition, VHL tumor suppressor gene inactivation has also several HIF-independent effects including cell cycle regulation and apoptosis.

VHL germline mutations cause a variety of developmental changes and tumors in humans. Although the germline mutations are present in every cell of the body, the disease targets a highly selective subset of organs including the nervous system, eye, inner ear, kidney, pancreas, adrenal gland, and epididymis or broad ligament. The affected organs reveal numerous microscopic developmental changes and pre-neoplastic lesions. From these lesions, tumorigenesis may occur later on. In analogy in all affected organs, the tumors develop in a stepwise progression from precursor lesions to different stages of tumor growth [5‐7].

In the CNS, the microscopic precursor lesions occur mainly in the dorsal roots [8] and in the molecular layer of the cerebellum [9]. The cells of origin are probably developmentally arrested hemangioblast precursor cells [5, 10]. Interestingly, the microscopic precursors already reveal biallelic VHL inactivation even if they are not growing. Initiated by mechanisms, which are not yet known, these microscopic cell clusters begin to cause reactive angiogenesis. A small subset of clusters may then grow further. They grow from the dorsal roots into the spinal cord without infiltrating it. The cells start to increase their cytoplasm revealing a foamy appearance. The capillary network becomes dilated and the tumors look similar to clear cell renal carcinoma [11]. Next to the neoplastic “stromal cells,” the other cytologic component of hemangioblastomas is represented by abundant blood vessels. The blood vessels do not show VHL inactivation [12, 13] and therefore represent reactive angiogenesis. During progression, the hemangioblastoma tumor cells imitate the morphology of the hemangioblast, an embryonic precursor cell for blood, endothelium, and smooth muscle. Larger and fast-growing hemangioblastomas typically reveal features of this more differentiated stage [11]. In progressed stages, hemangioblastoma tumor cells can reveal blood island formation and extramedullary hematopoiesis. They can also differentiate into vasculogenetic structures [14].

Hemangioblastoma accounts for approximately 0.5% of all tumors of the CNS. For the spinal tumors, hemangioblastoma accounts for 2.1% of all spinal tumors in the SEER (Surveillance, Epidemiology, and End Results) database of the NIH [15].

CNS hemangioblastomas are seen in about 60–80% of VHL patients, with a remarkable difference within and among affected families [16, 17]. In some, kindred CNS hemangioblastomas are the dominant lesion and present in up to all patients, whereas in others, penetrance for these tumors is low or even zero.

The spectrum of manifestations of the VHL disease comprises developmental changes with multiple pre-neoplastic lesions as well as cysts and tumors in various organs. Of these tumors, some are highly prone to become malignant and to settle local or distant metastases, in particular, clear cell renal cell carcinomas and pancreatic neuroendocrine tumors [18, 19]. The risk for metastases of kidney and pancreas tumors is dependent on size (odds ratio 1.25 for each 1 cm increase, p < 0.001) [20]. We recommend a cut-off diameter for renal surgery of 4 cm for renal cell cancer and 2.5 cm for pancreatic neuroendocrine tumors [19‐23]. The decision for nephron sparing surgery should be done extremely carefully because recurrent or new renal tumors will occur and recurrent renal surgery is inevitable. In contrast, retinal hemangioblastomas are always histologically benign neoplasms similar to their CNS counterparts. Their impact is the risk for uni- or bilateral blindness due to detachment of the retina or if they are located at the optic disc where treatment options like proton beam radiation are limited and always associated with loss of vision. Intermedian tumor entities are pheochromocytomas and paragangliomas; in these, metastases occur in about 5% of the patients. Other components of the VHL disease are endolymphatic tumors of the inner ear (ELST) and cysts or cystadenomas of the epididymis and the broad ligament. Their clinical relevance is less prominent, but uni- or bilateral deafness can occur, and infertility has been described in men. Characteristic for the visceral VHL-associated tumors is a multifocal and bilateral, simultaneous, or metachronous occurrence.

von Hippel-Lindau disease is an autosomal dominant disorder with high, but age-dependent penetrance. Underlying are germline mutations of the VHL gene located on chromosome 3p25-26 encoding the VHL protein of 213 amino acids [24]. The mutations are randomly distributed over the entire gene. Missense or truncating mutations as well as deletions and rearrangements of the entire gene occur. Truncating mutations comprise nonsense mutations, intraexonic deletions, and insertions of one or more nucleotides and splice site mutations. Patients with truncating mutations are often more severely affected compared with those with missense mutations. Hot spots of mutations are the nucleotides 499 and 500 in codon 167.

Screening procedure for the molecular diagnosis of VHL was initially Sanger sequencing of the 3 exons of the VHL gene [25]. For the detection of large deletions, MLPA is the method of choice [26]. Recently, next-generation sequencing including the whole exon/whole genome has been introduced as a highly diagnostic procedure [27].

The detection of CNS hemangioblastomas can be distributed across the 1st to the 8th decade of life. The majority of VHL patients are diagnosed in their thirties and forties. Sporadic, single hemangioblastoma is diagnosed about 10–20 years later compared with its syndromic counterpart. Both sporadic and VHL-associated hemangioblastomas are extremely rare in childhood (incidence < 1 per 1,000,000). The youngest age of VHL-associated CNS hemangioblastoma is reported at 6 years [28]. But the most common early manifestations in VHL patients < 18 years are retinal (34%) and CNS (29%) hemangioblastoma [28]. If a CNS hemangioblastoma is first detected in childhood, an underlying VHL disease should always be suspected and further examined [29, 30].

CNS hemangioblastomas cause various symptoms depending on the tumor size and localization. Typically, most of the space-occupying process is caused by the cystic component of the tumor [31]. These tumor-associated cysts occur more frequently in younger individuals and seem to progress more rapidly [32].

Cerebellar tumors can be associated with headache, gait imbalance, ataxia, and abnormal head position. Large cerebellar tumors can cause nausea, vomiting, and papilledema. Brainstem and spinal hemangioblastomas may show radix-specific neurological deteriorations, urinary or bowel abnormalities, singultus, dysphagia, myelopathic disorders, or symptoms of syringomyelia. Some hemangioblastomas are associated with polyglobulia [33‐35]. Hemorrhage from the highly vascularized CNS hemangioblastoma is very rare, but has been reported [36]. The risk of hemorrhage is very low; it was calculated at 0.0024 per person per year and predominantly occurs with large tumors [37].

Compared with adults, pediatric VHL patients have a higher prevalence of obstructive hydrocephalus and tumor-associated cysts. This is associated with a shorter duration from onset of symptoms to surgery of 1.5 ± 2.1 months (range, 3 days–12 months) [29] compared with adult VHL patients with a duration of 8 months [38]. It is important to note that CNS hemangioblastoma in children might remain clinically occult until severe symptoms occur. The same applies for retinal hemangioblastoma.

A total of 60–80% of VHL patients are considered to have cerebellar and 40–59% spinal, often multiple hemangioblastomas. However, the prevalence may be even higher considering MRI scans that show multiple tiny nodules visible on high-resolution T1-weighted contrast-enhanced sequences (Fig. 2).

Hemangioblastomas are typically located in the posterior parts of the cerebellum, the spinal cord (Fig. 3), and the medulla oblongata. However, they also occur in the anterior parts and rarely even supratentorially. Cerebellar and spinal hemangioblastomas typically have a strongly enhancing solid and a cystic part. One-third of the larger tumors are purely solid and may have a central necrosis. The strongly enhancing part always has a pial surface, and, depending on its size, flow voids within and around the tumor are visible. Due to the higher protein (erythropoietin) content, the cystic part of a hemangioblastoma is not as hypointense as cerebrospinal fluid on T1-weighted images but strongly hyperintense on FLAIR and T2-weighted images. In contrast to the pilocytic astrocytoma, the wall of the hemangioblastoma cyst does not enhance. The solid and the cystic tumor portions of CNS hemangioblastoma may grow; however, tumor growth is often dominated by increasing cyst size (Fig. 4).Retinal hemangioblastomas (“angiomas”) are best detected by standard ophthalmological funduscopy with dilated pupils. Early detection of small tumors facilitates the treatment by laser coagulation with minimal risk for the vision. Only large tumors are characterized by strongly enhancing irregular structures in the dorsal part of the globe. They can be associated retinal detachment and a V-shaped configuration of the globe especially when they show an exophytic growth towards the subretinal space. Endolymphatic sac tumors (ELST) are usually irregular petrous bone masses, which originate from the endolymphatic epithelium and arise within the intraosseous portion of the endolymphatic duct/sac of the vestibular aqueduct (Fig. 5).

In order to detect tiny tumor nodules and to distinguish them from vessels, high-resolution images are needed (Fig. 2). The Freiburg protocol includes a sagittal T1-weighted contrast-enhanced cranial sequence with fat saturation and 1-mm³ isotropic voxels (4:53 min) followed by sagittal T1-weighted 3-mm thick slices of the upper and lower spine (4:45 min each). Axial 3-mm thick slices through suspicious lesions in the spinal canal and T2-weighted sequences may be added.

VHL patients typically develop multiple CNS hemangioblastomas. Still, it is not necessary to surgically remove all of these tumors. Usually a wait-and-scan policy with repeated MRI scans can be recommended in asymptomatic patients.

The up to now unpredictable growth behavior of hemangioblastomas makes surgical indication difficult, as these tumors do not necessarily grow continuously. They may be stable in size for an unknown time before the solid tumor part will begin to proliferate. At an uncertain point in time, hemangioblastomas can then stop growing and remain stable again, before proliferating anew later [35]. Previous studies have shown that about half of all CNS hemangioblastomas were stable in size over long-term follow-up [39, 40]. CNS hemangioblastomas may also develop peritumoral edema or, finally, a typical tumor-associated cyst that may rapidly increase in size compressing and damaging surrounding neural tissue [41, 42].

Particularly in pediatric patients with few studies available, the optimal timing of surgical intervention remains a matter of debate [29, 30]. Lifelong repeated MRI scans of the brain and spinal cord (annual) are recommended for VHL patients, irrespective of the number of previously known tumors or absence of symptomatology [4, 28, 29, 42].

There is general consensus that symptomatic tumors should be surgically removed. For asymptomatic but progressive tumors in follow-up MRI, however, treatment strategies differ in the literature. Some authors are hesitant about tumor resection in this situation because the asymptomatic patient is exposed to the surgical risk including neurological damage [31]. In contrast, most authors (including us) advocate surgical resection for growing tumors that do not (yet) cause clinical symptoms, since neurological symptoms that already have developed in the natural course of VHL disease are usually not reversible and hemangioblastoma surgery can be performed with low morbidity in experienced hands [30, 43, 44]. Still, this strategy has to be adapted in patients with repeated previous operations and multiple hemangioblastomas.

Ultimately, this means that it is currently always necessary to work out a tailored and personalized therapy strategy with respect of the location of the tumor, change of tumor size or associated cyst, and symptomatology and general condition of the VHL patient. This can only be sufficiently accomplished in a multidisciplinary team approach in specialized centers involving the patient and parents.

Fundamentally, the special aspects of pediatric surgery and anaesthesiological management have to be considered. Advanced perioperative medical care and patient blood management are of utmost importance, especially for young children with low circulating blood volume surgery for highly vascularized tumors such as hemangioblastomas [29, 45]. In this context, a precise microsurgical technique is essential, both to minimize blood loss and to maintain an appropriate anatomical overview.

The aim of microsurgical treatment is the complete resection of the solid tumor component. Under the surgical microscope/exoscope and using magnification, the typical reddish or orange tumor and tumor-associated blood vessels can be identified. The blood vessels supplying versus draining the tumor need to be identified and then carefully cauterized and transected, vessel by vessel with constant attention to swelling or bleeding of the tumor itself. Next, the junction between the tumor surface and the surrounding neural tissue is identified and incised. This is a crucial step that requires considerable experience in neurosurgical and hemangioblastoma surgery. There is no natural capsule or histologically defined border zone. However, in most instances, the dedicated surgeon is able to find a plane of dissection that facilitates rather bloodless preparation and it is key to constantly control and regain this surgically defined plane of dissection, in which development proceeds only with delicate manipulation. It is very important not to enter the highly vascularized tumor, as this can lead to extensive bleeding. While removing the solid tumor component, the adjacent cyst is usually opened and collapses after resection of the solid part. Arteries bypassing the tumor and feeding eloquent neural tissue have to be spared. In case of doubt, such blood vessels can be temporarily clipped, and only intraoperative neuromonitoring (see below) may reveal whether the vessel can be severed (Fig. 6) [42, 46, 47].

Intraoperative 3D neuronavigation (Fig. 7) and intraoperative ultrasound (Figs. 8 and 9) facilitate minimally invasive surgery [48], localization of deeply located tumors, and intraoperative verification of the extent of tumor resection [42, 49].

In recent years, progress in anesthesia and intensive care management as well as technical and surgical advances have led to small but meaningful improvements for pediatric VHL patients.

We demonstrated in a first series of spinal hemangioblastomas the feasibility and safety of minimally invasive tumor removal via an operating tube (Fig. 10) [47]. Related advantages are less tissue trauma, less blood loss, and shorter hospital stays [47, 50]. Likewise, minimally invasive tubular removal of selected cerebellar hemangioblastomas is possible [48].

Furthermore, fully microscope-integrated intraoperative videoangiography with the fluorescent dye indocyanine green (ICG) can be used to distinguish between feeding and draining vessels (Fig. 11) [51].

Intraoperative neuromonitoring is a further safety tool to monitor nerve function during surgery [42, 52]. Neuromonitoring is especially helpful for tumors with relation to the cranial nerves, the brainstem, or the fourth ventricle to enable the surgeon for adjusting the surgical strategy. In intramedullary hemangioblastoma, a stimulation probe can be used to identify the corticospinal tract and dorsal column to facilitate transmedullary access to ventrally located hemangioblastomas and to avoid substantial motor deficits [52, 53].

Large solid hemangioblastomas harbor a considerable risk of intra- and postoperative hemorrhage [37]. Most authors recommend preoperative embolization in these cases to minimize bleeding tendency (Fig. 12) [42]. Since embolization can involve severe complications in individual cases [42, 54], potential benefits and risks must be considered. In addition, endovascular treatment should be reserved for specialized centers with extensive expertise.

Stereotactic radiosurgery has been recently proposed as safe and effective treatment modality for stabilizing the tumor size of CNS hemangioblastomas in adults, particularly in cases of multiple or recurrent tumors and patients who are not surgical candidates [55‐57]. This presumed effect of radiosurgery however can also be attributed to a coincidentally simultaneous quiet phase of tumor growth. Therefore, radiosurgery should only be considered in an ultima ratio situation in which CNS hemangioblastomas cannot be controlled surgically and indeed require treatment. It should also not be applied prophylactically for multiple tumors. Moreover, there is little data on stereotactic radiosurgery and its late complications in children [29].

Medical therapy is at an experimental stage. To date, no chemotherapy has proven effective on hemangioblastoma growth.

Several studies illustrate favorable outcome after surgical removal of hemangioblastoma in the cerebellum, spinal cord, and brainstem [31]. The resection of cerebellar lesions upon presence of symptoms in VHL patients resulted in improvement or stabilization in 98% of cases [46]. Long-term imaging follow-up at 5 years did not reveal recurrence. Spinal cord hemangioblastomas can also be safely resected, and complete surgical resection is curative [58]. Ventral tumors or completely intramedullary tumors might be associated with an increased risk of postoperative worsening. Complete resection of symptomatic lesions led to neurological stability in 96% of cases. After 5 and 10 years, 86% and 78% of patients remained functionally stable indicating that the long-term deterioration of neurological function is usually associated with the progression of VHL disease [58].

Asymptomatic CNS hemangioblastoma may enter a phase of stable disease for many years and show favorable course without any treatment and define need to adapt follow-up and screening examinations [35]. On the other hand in VHL patients, CNS hemangioblastomas remain the leading cause of death next to renal cell carcinoma [59]. For VHL patients, tumor burden at diagnosis and young age seem to be the most important risk factors for new tumor development [35]. Prognosis further improved for VHL patients due to consistent use of surveillance programs with early detection of associated tumors [59]. Experts from different countries proposed recommendations for genetic counseling and molecular genetic screening for germline mutations of the VHL gene and clinical investigations. These, however, vary regarding the first age for the target organs and the intervals and the methods of clinical investigations. This is also the case of the authors here, but most of us agree with these recommendations. Molecular genetic testing should be performed:

Morbidity and mortality in VHL patients have decreased substantially due to better insight into the pathophysiology and natural history of the clinical manifestations, better imaging techniques, and improvements in therapy. Careful surveillance is critical to early detect lesions and monitor asymptomatic manifestations for progression with the aim to prevent severe sequelae such as persistent neurological deficit, blindness, and death.

The optimal frequency for various imaging and screening procedures, which attempts to balance the risks and costs versus the potential for a delayed diagnosis, is not known. Available surveillance recommendations for pediatric VHL patients are inhomogeneous and mainly based on small case series and expert opinions. Regarding CNS hemangioblastoma, the Danish recommendations include one baseline MRI of the CNS between 5 and 14 years of age and then follow-up MRI every 1–2 years from the age of 15 years. The Dutch protocol, the American VHL alliance, and the Clinical Cancer Research (CCR) pediatric oncology series recommend biennial MRI scans starting at age 15, 16, and 8 years, respectively [17, 28]. Yet other authors advocate annual MRI scans from the age of 11 years [4]. British guidelines propose every 12–36 months in adolescence [28]. The heterogeneity of these recommendations therefore does not permit clear and reliable guidelines.

The Freiburg VHL screening program covers approximately 300 MRIs of the CNS of monitored VHL patients each year, with about 15 of these being pediatric patients. Our experience from 30 years Freiburg VHL Registry with approximately 600 operations on CNS hemangioblastomas shows that pediatric VHL patients become very rarely symptomatic from CNS hemangioblastoma. The youngest symptomatic patient in our series was 10 years old. In this patient, the arising symptoms could not be anticipated despite an MRI 1 year before. The youngest VHL patient in our series who underwent surgery for an asymptomatic CNS hemangioblastoma, which had grown during the surveillance period, was 14 years old.

This substantial expertise in surveillance and neurosurgical treatment over the last 30 years has resulted in the following Freiburg screening protocol for VHL patients including relatives who share the given VHL germline mutation (Table 1):

Experiences made by many patients in Germany, but also in many other countries, show that the waiting time from asking for a clinical investigation date is a complex procedure; currently the intervals last mostly several months and coordination of investigations for personal interview by the coordinator, retinoscopy, CNS-MRI, and MRI of the abdomen for 1 day is a challenge. One must, however, take in account that these patients have already the psychological burden of knowing of a lifelong very high risk for tumors. Once patients have decided to undergo a new investigation, many of them can experience psychological alterations. Therefore, intervals between receiving the request for clinical investigations and the offered date should be as short as possible, meaning less than a month. Reporting of the investigation results and their interpretation as well as the decisions, the VHL board should be communicated to the patients and families in a coordinated and timely fashion. In our experience, every day counts for the patients, and all this should not last more than a week.

Organized VHL monitoring of patients aims to minimize the burden on families, increase surveillance compliance, and allow early detection of manifestations and thus optimized timing of surgery. Since such tumor surveillance is time-consuming and requires financial and psychosocial efforts, screening programs should be run by experienced, multidisciplinary teams coordinated by age-adequate providers.

Regarding the pediatric population, CNS hemangioblastoma in VHL disease challenges health care providers in several ways. Diagnosis of CNS hemangioblastoma or multiple retinal hemangioblastoma in childhood nearly always leads to diagnosis of VHL disease. Although VHL-associated tumors may manifest in early childhood, detection of e.g., high blood pressure and vision loss in infants or even paresthesia in teenagers remains a major problem in pediatric reality. Improved education of caregivers and providers is needed to avoid delayed diagnosis. Childhood hemangioblastomas in the posterior fossa can be dramatic events due to delayed diagnosis and peritumoral cysts with the potential of rapid size increase.

Regarding outcome of surgical therapy, the majority of symptomatic children showed improved clinical symptoms after surgical removal of CNS hemangioblastoma in experienced hands (72.2% improved, 19.4% remained stable), with postoperative complications being generally minor and temporary [29, 30].