Introduction

Hemangioblastomas (HBs) are considered one of the rarest tumors that can occur, comprising only 1–2.5% of all intracranial tumors and accounting for 3% of all central nervous system (CNS) tumors and 7–8% of posterior cranial fossa tumors [1–4]. HBs are benign, highly vascular, and are mainly found in the cerebellum, followed by the spinal cord, brain stem, and retina [1, 2, 5, 6]. Cystic HBs are found more frequently in the cerebellar hemispheres, unlike the solid tumors found mainly in the brainstem and spinal cord [4]. Cystic HBs may develop sporadically or due to von Hippel-Lindau (VHL) disease, accounting for approximately 25% of all patients [4]. Retinal HBs are clinical symptoms of VHL, with a frequency of about 25% to 60% [7, 8]. Patients suffering from these cerebellar tumors experience prominent headaches, nausea, elevated intracranial pressure or cerebellar ataxia, and, in some cases, hearing loss [9]. HBs are more frequently diagnosed in males than females and tend to occur more frequently in patients between the ages of 30–60 but can occur in younger age groups with VHL [9, 10]. Studies have also suggested an association between higher birth weight and a higher risk of brain and CNS tumors in children [11].

The most reliable treatment method for these tumors is total resection, which ensures the best long-term survival outcomes [2, 5]. Even though there has been increasing evidence of stereotactic radiosurgery (SRS) as an effective treatment option for HBs, microsurgical resection is still the standard approach for most cases [4]. More specifically, the suboccipital keyhole approach for cerebellar HBs is safer and more effective in reducing complications and tissue damage than traditional surgical methods [5]. Historically, surgical removal was associated with unfavorable clinical outcomes, resulting in high morbidity and mortality rates of up to 50% for solid HBs in the posterior fossa [5]. Despite recent advancements in micro neurosurgical techniques, cerebellar HBs pose specific surgical challenges due to factors like the posterior fossa’s deep surgical corridor, difficulty debulking the tumor mass due to substantial vasculature, difficulty gaining early access to the feeding artery behind the tumor, and interference from large, tortuous draining veins during the resection [12]. Recently, there has been some success with targeting vascular endothelial growth factor (VEGF) using an antiangiogenic agent, bevacizumab, in patients suffering from multilocular HBs [13].

Although the underlying mechanism of HBs is unknown, it is often linked to VHL disease, an inherited multisystem disorder resulting from a mutation in the VHL gene [14]. Mutations in this gene are thought to initiate tumorigenesis by upregulating hypoxia-inducible factor (HIF) [15]. Efforts for developing new treatments targeting the pathobiological mechanisms underlying HB growth and proliferation may hold promise for achieving better outcomes with less invasive patient interventions.

Pre-clinical literature concerning HBs and cerebral tumors

Single-gene inherited disorders are the main risk factors for brain and CNS tumors [11]. Autosomal dominant disorders that can lead to a higher risk of brain and CNS tumors include VHL disease, Li-Fraumeni syndrome, neurofibromatosis type 1 and type 2, and Turcot syndrome [16].

Common brain tumor symptoms include headache, altered mental status, ataxia, nausea-vomiting, and muscle weakness [17]. These symptoms can present differently depending on the tumor’s location. HBs can appear pathologically different in various patients. For HBs found in the supratentorial region, the most common symptoms in patients include headache, visual disturbances, and endocrine changes [18]. When examining VHL patients, visual disturbances and endocrine changes were the most common symptoms [18]. The most common symptoms for HBs found in the brainstem were headache and/or dizziness, paresthesia, and pyramidal signs [19].

Juxta-papillary HBs are associated with the optic disc and can present as a fullness in the inner retina. Extra-papillary HBs, located elsewhere in the retina, can appear as a red or gray dot resembling a microaneurysm in the retina [7]. If left untreated, these lesions can lead to vision loss [7]. Though most HBs occur sporadically, around 25% of diagnosed HB cases are associated with VHL [20]. Patients with VHL tend to develop HBs at a younger age compared to those who do not have the disease [20]. One study found that patients with VHL had hemangioblasts expressing brachyury, a protein expressed during early development, suggesting that they may have a predisposition for HBs from embryologic development [21]. Patients with VHL also have a higher chance of tumor recurrence than non-diseased patients [22].

Solid tumors, which can spread through the body by displacing growth and metastasis, are more common across age groups. Aggressive cerebral tumors may invade surrounding tissues through infiltrative growth. Additionally, slower growth in cerebral tumors has been thought to grow by a displacement process called capillary fingering [23]. The immune system responds to these growths in various ways. For instance, patients with HB have higher levels of circulating endothelial progenitors that help to re-establish blood flow, which decreases upon tumor removal. In response to cerebral tumors, the immune system activates the heat shock response, characterized by an overproduction of heat shock proteins and chaperones. High levels of these proteins in tumor cells have been shown to lower tumorigenicity [24].

Some of the leading imaging methods for HBs include computed tomography, magnetic resonance imaging (MRI), magnetic resonance angiography, and contrast-enhanced ultrasound. Emerging ways to treat and understand HBs include µ-Doppler-imaging. An advantage of µ-Doppler ultrasound imaging is its ability to image without bolus contrast and its high sensitivity to vasculature flow. It has additionally been used to identify vascular and physiological anatomy details with better precision [25].

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Figure 1. 

VHL-induced HB pathology. PHD: prolyl hydroxylase; OH: hydroxyl; CUL2: cullin-2; RBX1: RING-box protein 1; Ub: ubiquitin; EB: elongin B; EC: elongin C; ARNT: aryl hydrocarbon receptor nuclear transporter; GLUT1: glucose transporter 1; PDGF: platelet derived growth factor; TGFA: transforming growth factor alpha. The figure was created with BioRender.com

HBs often occur from developmentally arrested structural elements in the cerebellum’s molecular layer or in the spinal cord [16]. VHL germline mutations cause the build-up of HIF-1, subunit alpha (HIF-1α) due to the failure of the VHL complex and its inability to ubiquitinate HIF-1α where it undergoes proteasome degradation as seen in Figure 1 [26]. Following degradation, HIF-1α forms a complex with HIF-1 subunit beta (HIF-1β), triggering the activation of multiple genes such as VEGF, glucose transporter 1, platelet-derived growth factor, and transforming growth factor alpha [27]. These growth factors can increase reactive angiogenesis and form permeable HB vessels. These vessels allow the diffusion of plasma-ultrafiltrate, which primarily contains erythropoietin and forms peritumoral cysts [28]. Peritumoral cysts are associated with the neurological symptoms caused by HB [29].

Current treatments

Emerging HB treatments

While chemotherapies do not treat cerebral tumors effectively due to the impermeability of the BBB, there have been advances in designing chemotherapies. The most common chemotherapy drugs used are carmustine, nimustine, and lomustine [70, 71]. One potential advancement involved belzutifan, a promising anti-angiogenic HIF-2α inhibitor. Belzutifan works by inhibiting the interaction between HIF-1α and HIF-2β, thereby preventing the expression of HIF-1α growth factor gene targets. In a phase 2 clinical trial, researchers observed a positive response to belzutifan in approximately 30% of patients diagnosed with CNS HB [49].

Another example is temozolomide, an alkylating agent that has emerged as the most efficacious chemotherapy treatment for cerebral tumors, including HB. The efficacy of temozolomide can be attributed to its unique ability to penetrate the BBB [72]. Pazopanib, another promising chemotherapy option, exhibits mild adverse reactions such as transient diarrhea, oral mucosal ulcerations, and hypertension. Fortunately, the side effects associated with this therapy are relatively mild when compared to the significant benefits of treating HB and achieving clinical improvement [73]. Moreover, this therapy has been shown to enhance the patient’s quality of life by improving neurological function, swallowing ability, ambulation, and reducing dysarthria [73].

Somatostatin analog chemotherapy has also demonstrated efficacy in treating VHL-HBs. Octreotide, a commonly used somatostatin analog, reduces the viability of HB cells by promoting apoptosis through the B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein pathway. However, it does not downregulate growth factors, indicating the presence of an additional molecular target. In a preliminary clinical trial, patients undergoing treatment for nine months experienced a significant reduction in tumor cell volume, from 3.45 cm³ to 2.45 cm³ [74].

Immunotherapy has also emerged as a potential treatment option for HBs. One such immunotherapeutic agent is bevacizumab, a humanized monoclonal antibody vaccine that has shown promising clinical applications [75]. Theoretically, agents like bevacizumab can inhibit VEGF, disrupting the blood supply crucial for tumor growth [75]. A case study involving a man with surgically unresectable cervical cord HB, leading to quadriparesis, demonstrated significant tumor regression on follow-up MRI imaging after undergoing treatment with bevacizumab [76]. In a separate case, a female patient initially underwent an unsuccessful tumor reduction surgery and was subsequently prescribed dexamethasone and SRS. However, this treatment proved to be ineffective as the size of her HB continued to grow. As a result, bevacizumab treatment was initiated. This intervention led to significant clinical improvement, with the patient regaining her ability to ambulate and demonstrating radiographic reduction in tumor size [77].

Another group of promising therapeutic agents for treatment are β2 receptor antagonists, such as ICI-118,551 and PT2385. These antagonists interfere with HIF signaling, exhibit anti-angiogenic properties, and inhibit tumor cell migration. Notably, these agents offer an alternative to propranolol, another β-antagonist commonly used but limited to hypertensive individuals due to blood pressure-lowering effects [78, 79]. While this drug may show promising results, it is important to note that further research is necessary to determine its clinical effects. The potential benefits of treating cancer with these agents must be carefully weighed against the minimal side effects associated with the treatment, such as edema, fatigue, and anemia.

Summary of existing and novel HB treatments

HBs are highly vascularized, benign tumors most often seen in the CNS that are often associated with the formation of erythropoietin-filled cysts [15]. If left untreated, HB cells affect neurological function and, although rare, can lead to hemorrhage [15]. Current treatments for cerebral tumors include surgical resectioning, radiation treatment, and chemotherapies.

Surgical resectioning is one of the more successful treatments in treating cerebral tumors and HBs, as studies have shown it to decrease disease progression [37, 30]. The resectioning can also be assisted by intraoperative imaging like IMRI, 5-ALA, and FS has been shown to improve survival outcomes but requires more research [33]. A combination of surgical resectioning with radiotherapy demonstrates a two-fold increase in survival rates [57]. Specific radiotherapies like SRS also provide an advantage to their WBRT counterparts in improving survival rates and mitigating the risk of radiation necrosis as seen in Table 1 [50]. There is no difference in survival rates using the therapies alone or in conjunction, but using the SRS and WBRT together helps achieve better local control [80]. Brachytherapy, which is an invasive therapy that uses localized radioactive implants, has also shown effectiveness in treating HBs [64, 65]. However, it has not been adopted as the standard of care due to lack of data, inexperience in physicians, and risk of radiation necrosis [66]. A more recent and promising brachytherapy like GammaTile uses cesium-131 to mitigate the risk of necrosis and has a collagen shell around the radioactive material to allow the implant to dissolve into the body [67–69].

Chemotherapies are not widely used to treat either cerebral tumors or HBs, specifically due to the relative impermeability of the BBB to most therapeutic agents [41, 42]. However, promising results have been observed with anti-angiogenic drugs such as temozolomide, anlotinib, pazopanib, and belzutifan, which effectively inhibit VEGF and subsequently reduce the blood supply to tumors [47–49, 72, 73]. Another class of chemotherapies includes Somatostatin analogs, which promote apoptosis of HB tumor cells [74]. β-Antagonists like ICI-118,551 and PT2385, are alternative therapies that exhibit anti-angiogenic properties and disrupt tumor metastasis [78, 79]. Novel immunotherapies like bevacizumab can also treat HBs and have been shown to improve the quality of life for patients [75, 76, 81].

Conclusions

This review lays out three main treatments for cerebral tumors: surgical resectioning, radiotherapy, and chemotherapy, and enumerates their limitations. Recent research has turned to biodevices to overcome these limitations, like the impermeability of the BBB. A novel method that is being researched is to increase the efficacy of chemotherapies by using ultrasound technology to temporarily disrupt the BBB and make it more permeable to agents in the bloodstream. Researchers are currently testing a skull implant with nine ultrasound emitters to test how it may increase the efficacy of chemotherapy, influencing survival rates [82]. Another device that could be used to deliver drugs that cannot cross the BBB are microdevices that are released in the brain for a more targeted effect [83]. It could help treat specific areas of tumor growth to allow for a smoother resection or target tumors deep in the tissue. Research into HB treatments are ongoing, and scientists are still working on expanding standard care methods with novel chemotherapies, immunotherapies, targeted anti-angiogenic/somatostatin agents, and promising biodevices.