General
- Haemangioblastoma is a highly vascular tumour containing neoplastic stromal cells that have clear to vacuolated cytoplasm and characteristic immunohistochemical features (e.g., inhibin positivity) and molecular findings (e.g., VHL alterations).
Definition
- A tumour histologically characterised by neoplastic stromal cells and abundant small vessels.
- Essential:
- A tumour composed of large, multivacuolated, and lipidized stromal cells with occasional hyperchromatic nuclei, as well as a rich capillary network AND
- Stromal cells with immunohistochemical positivity for markers such as inhibm (at least focally) OR
- Loss or inactivation of the VHL gene OR
- In a patient with von Hippel-Lindau syndrome
- Desirable:
- In patients with von Hippel-Lindau syndrome, absence of immunohistochemical staining for markers of renal cell carcinoma
Aetiology
Haemangioblastoma type | Sporadic | VHL-associated |
Genetic mech | Loss or inactivation of the VHL gene (78%) | Biallelic inactivation of VHL gene |
Age of presentation | 20 yrs younger | |
Localisation | Cerebellar hemisphere | Cerebellar hemisphere, brain stem, spinal cord, and nerve roots |
Number of lesions | Single | Multiple (65% of pts) |
- Association of sporadic vs VHL associated haemangioblastoma
ㅤ | Sporadic HBMs | VHL-associated |
Type Ce | 48 (60.8%) | 33 (67.3%) |
Type Ci | 8 (10.1%) | 7 (14.3%) |
Type Cm | 4 (5.1%) | 1 (2.0%) |
Type S | 19 (24.1%) | 8 (16.3%) |
Numbers
- Adults mainly
- VHL associated haemangioblastoma:
- Average age at presentation of VHL-associated tumours is approximately 20 years younger than that of sporadic tumours
- Symptomatic presentation is usually in people aged 18–30 years, and the disease has 95% penetrance by 60 years, although there is considerable variability.
- M:F ratio of 1:1.
- Hemangioblastomas represent
- 2% of all intracranial neoplasms, they account for 7% to 12% of posterior fossa tumors.
- An annual incidence rate of 0.15 cases per 100 000 population.
- 2% to 10% of all primary spinal cord tumors are hemangioblastomas
- Most common posterior fossa primary brain tumour in adults
Grading
- WHO grade 1
Localisation
- Can occur in any part of the nervous system
- Mainly cerebellar hemisphere
- Posterior, medial, or both portions (70% to 80% of all cerebellar hemangioblastomas) of the cerebellum.
- But see table for sporadic and VHL associated comparison
- Supratentorial and peripheral nervous system lesions are rare.
- 1-5% supratentorial
- Mainly pituitary stalk and tuber cinereum
- Spinal cord hemangioblastomas usually (96%) arise posterior to the dentate ligament at the dorsal root entry zone (66% of posterior spinal cord hemangioblastomas).
- 25%-40% percentage of VHL will have spinal haemangioblastoma
- Brainstem hemangioblastomas frequently occur in the posterior medulla at the obex.
Classification
Tumor nature | Location of cyst | Refined cyst-location–based classification | Traditional morphology-based classification |
Cystic | Extra-tumoral cyst | Type Ce (tumor with non-enhanced cystic wall) | Type 2 (macrocystic) fq:65% |
ㅤ | Intra-tumoral cyst | Type Ci (tumor with enhanced cystic wall) | Type 1 (pure cystic) fq:6% Type 3 (microcystic): fq:25% |
ㅤ | Extra- and intra-tumoral cysts | Type Cm (mixed) | No category assigned |
Solid | Type S (solid) | Type 4 (solid): fq:4% |
- Gadolinium-enhanced T1W images of magnetic resonance imaging of hemangioblastomas (HBMs).
- Type Ce refers (A,B) HBMs of classical radiological features with a main cyst and a mural nodule.
- Purely cystic HBMs (C) used to be an independent subtype, however, they were classified as Type Ci together with HBMs with multiple intratumoral cysts (D).
- Tumors with mixed intratumoral and extratumoral cysts (E) were also identified (Type Cm).
- Solid tumor (F) was the second most common subtype of HBMs.
Origin
- Stromal component
- Stromal cells might originate from a developmentally arrested haemangioblast precursor.
- Haemangioblastoma stromal tumour cells, upon inactivation of the Von Hippel-Lindau (VHL) protein, exhibit accumulation of HIF 1 alpha (Hypoxia-Inducible Factor 1 alpha). This accumulation triggers altered gene expression, which results in increased vascularisation (angiogenesis/vasculogenesis) and metabolic adaptation, such as lipid deposition (the clear cell phenotype).
- Haemangioblasts or haemangioblast progenitor cells all form the following
- Choroid plexus cells
- Neuroendocrine cells
- Fibrohistiocytic cells
- Cells of neuroectodermal derivation
- Heterogeneous cell populations
- The neoplastic stromal cells lack typical endothelium-associated markers like von Willebrand factor, CD34, ERG, and CD31.
- Instead, they express markers like alpha-inhibin, D2-40, brachyury (cytoplasmic expression), NSE, NCAM1, S100, ezrin, CXCR4, aquaporin-1, and several carbonic anhydrase isozymes.
- Vascular component
- is reactive so from many sites around the body
Pathophysiology
Peritumoral Cyst Formation
- 80% of CNS hemangioblastomas are associated with a peritumoral cyst (a cyst that forms at the margin of the tumor).
- 70% of symptomatic cerebellar and brainstem hemangioblastomas have peritumoral cyst
- > 90% of symptomatic spinal cord hemangioblastomas have peritumoral cyst (syringomyelia)
- Development of a peritumoral cyst follows a defined sequence:
- Increased vascular permeability of the hemangioblastoma
- Extravasation of a plasma ultrafiltrate into the tumor interstitial spaces
- High interstitial tumor pressure then drives plasma ultrafiltrate into the surrounding CNS parenchyma.
- Peritumoral edema forms when the Production of plasma ultrafiltrate exceeds resorptive capacity of the peritumoral tissue.
- Further increases in peritumour oedema leads to solid stresses (stretching) that favor cyst formation.
- When a cyst forms, it will have the lowest resistance for the plasma ultrafiltrate to flow towards to then the peritumoral cyst expands
- Finally, the peritumoral cyst stops expanding once the cyst wall surface area is large enough to absorb the excess fluid, and becomes quiescent.
- Because the hemangioblastoma is the source of extravasated plasma ultrafiltrate, peritumoral edema and cysts resolve after tumor removal, and treatment does not require cyst wall resection or fenestration.
- Studies have shown that irradiation transiently increases vascular permeability, possibly leading to peritumoral edema and cyst formation.
- Subsequently, judicious use of irradiation of hemangioblastomas associated with peritumoral edema and cysts is warranted
- A reduction in hemangioblastoma vascular permeability may be beneficial. Anti–vascular endothelial growth factor (VEGF) tumor treatments have been associated with edema reduction and symptom improvement, despite having no effect on tumor size
- In both sporadic haemangioblastoma and VHL, allelic losses or mutations of the VHL gene are found in stromal cells.
- Haemangioblastoma often occurs sporadically or in association with von Hippel-Lindau syndrome (VHL).
- Loss of VHL function is a central event in haemangioblastoma formation.
- The loss of function of VHL protein → pseudohypoxic state (Consist of increased expression of genes that drive vascularization, cyst formation, lipid storage, metabolic adaptation, and extramedullary erythropoiesis) → The variously lipid-filled stromal cells release angiogenic factors, including vascular endothelial growth factor (VEGF) → production of the rich vascular network present in the tumour.
- Constitutive overexpression of VEGF-A explains the extraordinary vascularization of VHL-associated neoplasms due to increased angiogenesis/vasculogenesis, as well as the formation of cysts due to increased vascular permeability.
Histopathology
Macroscopic
- Occasionally, the tumour is yellow due to rich lipid content.
- Classic appearance is that of a cyst with a solid vascular nodule that abuts a pial surface
- Haemangioblastomas are typically well-circumscribed pseudoencapsulated masses that may be cystic with a mural solid nodule or (less commonly) entirely solid.
- Tumours are up to 125 mm in diameter in extraneuraxial locations and generally < 30 mm in the cerebellum.
Microscopic
- 2 components:
- Characteristically large and vacuolated but can show considerable cytological variation
- Stromal cells account for only 10-20% of the cells
- In many tumours, vascular cells are more abundant than stromal cells; in others, stromal cells are more abundant and may reveal solid epithelioid aggregates that may be associated with extramedullary haematopoiesis.
- The most characteristic and distinguishing morphological feature of the stromal cell is numerous lipid-containing vacuoles.
- It is the neoplastic component of the tumour whereas the vascular component is just reactive to the stromal component
- VHL tumour suppressor gene inactivation or loss in stromal cells → VCB complex (VHL tumour suppressor protein + TCEB1 + TCEB2) is not functioning → VCB complex cannot regulate cell cycle and cannot degrade HIF1A and HIF2A →
- Result of cannot regulate cell cycle → inc stromal cell formation
- Result of cannot degrade HIF1A and HIF2A → upregulation of hypoxia-responsive gene (VEGF & EPO) despite cells not in hypoxic state (This condition is called pseudohypoxia) → secretion of VEGF (&EPO) from stromal cells → paracrine angiogenesis of surrounding vascular component
- Can resemble metastatic renal cell carcinoma
- Due to haemangioblastoma’s has its typical numerous lipid-containing vacuoles, (clear-cell morphology of haemangioblastoma) → this resembles RCC
- Complicated by the fact that VHL pts are also prone to RCC
- Cases of tumour to-tumour metastasis (RCC metastatic to haemangioblastoma) have also been reported
- Non-neoplastic component, just reacting to the neoplastic component
- Abundant non-neoplastic cells, including endothelial cells, pericytes, and lymphocytes.
- Vascular intratumoural haemorrhage may occur
Stromal component cells
A) Intradural, extramedullary localization is typical for spinal haemangioblastomas. Most tumours are well circumscribed, but they may also encroach on the spinal cord parenchyma.
B) Abundant vascularity of haemangioblastoma is often in the form of thin-walled vessels.Some vessels appear as highly branching staghorn vessels.
C) Neoplastic stromal cells have clear to vacuolated cytoplasm admixed with abundant capillary vessels.
D) The stromal cells show mild nuclear pleomorphism. There is a rich capillary network.
Vascular cell component
- Tumour edge is generally well demarcated
- Infiltration into surrounding neural tissues rarely occurs
- In adjacent reactive tissues, particularly in cystic and syrinx walls, astrocytic gliosis and Rosenthal fibres are frequently observed.
- Mitotic figures are rare
Immunophenotype
Stromal cells
- Positive
- Neuron-specific enolase,
- NCAM1
- S100, and
- Ezrin
- Vimentin
- CXCR4
- Aquaporin-1
- Brachyury
- + in chordomas also
- Several carbonic anhydrase isozymes
- EGFR
- HIF1A and HIF2A
- VEGF
- Angiogenic growth factor
- PDGF
- Negative
- Endothelial cell marker
- von Willebrand factor
- CD34
- Endothelium-associated adhesion molecules
- CD31
- GFAP
- VEGFR1 and VEGFR2
Vascular endothelial cells
- Positive
- Endothelial cell marker
- von Willebrand factor
- CD34
- Endothelium-associated adhesion molecules
- CD31
- Negative
Clinical features
- Compression causing
- Impaired CSF flow due to a cyst or solid tumour mass → Increase of ICP and hydrocephalus
- Neurological deficit
- Cerebellar deficits such as dysmetria and ataxia can also occur
- Headache (70% to 80% of patients)
- Gait ataxia (55% to 65%)
- Dysmetria (30% to 65%)
- Hydrocephalus (20% to 30%)
- Nausea and vomiting (5% to 30%)
- Brainstem hemangioblastomas
- Hypesthesia (40% to 55%)
- Gait ataxia (20% to 30%)
- Dysphagia (20% to 30%)
- Hyperreflexia (20% to 25%)
- Headache (10% to 20%)
- Disorders of appetite and feeding (2% to 5%)
- Spinal tumours → local compression → pain, hypaesthesia, and incontinence
- Hypesthesia (80% to 90%)
- Weakness (60% to 70%)
- Gait ataxia (50% to 65%)
- Hyperreflexia (40% to 60%)
- Pain (10% to 30%)
- Hemangioblastomas produce erythropoietin → polycythemia (5% of patients)
- Hemorrhage is a rare complication of CNS hemangioblastoma
Radiological
General
- Neuroimaging typically demonstrates contrast-enhancing nodules that are frequently associated with cystic structures.
- The solid component is usually peripheral in location within the cerebellar hemisphere.
- Flow voids may be seen within the nodule due to enlarged feeding/draining vessels.
- Spinal tumours may be associated with a syrinx.
CT
- The mural nodule is isodense to the brain on non-contrast scans with fluid density surrounding cyst
- Postcontrast intense homogeneous enhancement of the mural nodule
- The cyst walls do not usually enhance
- Calcification is not a feature
MRI
- T1
- Hypointense to isointense mural nodule
- CSF signal cyst content
- T1+C
- Mural nodule vividly enhances
- Cyst wall does not enhance
- Pilocystic astrocytoma's cyst wall enhances
- T2
- Hyperintense mural nodule
- Flow voids due to enlarged vessels may be evident especially at the periphery of the cyst, seen in 60-70% of cases
- Fluid-filled cyst, similar to CSF
Image
MR perfusion imaging
- High rCBV ratios
Angiography (DSA)
- Enlarged feeding arteries and often dilated draining veins are demonstrated, with a dense tumour blush centrally
Image
Differential diagnosis
- Renal cell carcinoma (RCC)
RCC | Haemangioblastoma | |
+ | Epithelial markers (EMA) CD10 | D2-40 Inhibin alpha Angiogenic growth factors (PDGF) |
- | Epithelial markers (EMA) CD10 |
- Pilocystic astrocytoma's cyst wall enhances, haemangioblastoma's cyst wall does not enhance
Management
Observation
- Indication
- Deep-seated lesions in patients with minimal symptoms
- For multiple hemangioblastomas in VHL patients
- Non-symptomatic or small (~1 cm or smaller) lesions
Surgery
- Attention should be paid to the tumour's relation to the brainstem, fourth ventricle, and the posterior inferior cerebellar artery (PICA), because the PICA usually provides the dominant feeding arteries to these tumours.
- Indication
- Single, symptomatic, and superficial lesions
- Large and solid posterior fossa hemangioblastomas
- High risk
- Behave like high-flow AVMs
- Should be approached earlier in their symptomatic course because their natural history is often consistent with rapid growth.
- For multiple hemangioblastomas in VHL patients
- Only the symptomatic or large and easily accessible tumours are removed.
- VHL: As a rule of thumb, removing a malignant renal tumour or pheochromocytoma, which can cause a life-threatening catecholamine surge during surgery, should take priority over removing a benign cerebellar lesion.
- An exception to this rule is a situation when obstructive hydrocephalus is present, and if so, the compressive posterior fossa tumor should be removed first.
- Pre op embolization
- Not done in a single small tumour
- Because embolization cannot target the multiple small feeders
- Used in the case of a large, solid tumour
- Large feeders are targetable by embolization
- Large feeders are not readily accessible intraoperatively and the risk of substantial intraoperative blood loss is significant.
- Prep
- Haemostatic
- Isocool broad tips
- Surgicel
- Flowseal
- U/S and navigation
- 2x sucker
- Approach
- Suboccipital
- Retro mastoid
- Midline supracerebellar
- Paramedian supracerebellar
- Telovelar approach
- Intradural
- Do not open cyst until it is exposed and the nodule is identified.
- Exposing the cyst
- Often portions of the hemangioblastoma reach the exposed pial surface.
- A cortical incision parallel to the folia is used to access tumors that do not have surface presentation.
- The cortical incision is extended to the most accessible portion of the hemangioblastoma capsule.
- Pia at the tumor-pia junction is circumferentially incised, providing clear exposure of the tumor capsule–cerebellum interface.
- Only after the feeders are coagulated then the deeper circumferential dissection precisely at the tumor capsule–cerebellum interface is performed to remove the tumor from the surrounding tissue.
- If the dura is found tense after completion of the craniotomy, the cyst may be punctured and drained under navigation or ultrasound guidance using a dandy cannula to relax the brain.
- Allows the cerebellum to fall away from the dura and decreases the risk of cerebellar herniation through the dural opening.
- Needle should not disturb the targeted vascular lesion.
- Keep the cyst wall open by
- Placing a cotton wool ball into the cyst.
- Using retractors to keep cyst open
- Try to use tisseal glue to stick the cerebellar cortex to the tentorial surface.
- Open cyst in a controlled manner
- Feeders
- Vessels crossing the tumor margin (where the edge of the tumor meets the cerebellum) are coagulated with bipolar coagulation and sharply divided.
- Work within the cyst to identify and coagulate vessels draining the nodule
- Concurrent irrigation with bipolar cautery of vessels prevents adherence of the vessels to the bipolar tips and avoids unnecessary bleeding.
- The tumor softens and darkens as its vascular supply is interrupted during circumferential dissection.
- At this point, suction can be gently placed on a cotton patty to retract the tumor and provide increased exposure of the deeper hemangioblastoma capsule–cerebellum interface.
- Clear visualization of this interface is critical and is maintained by placement of cotton patties at its margins.
- Dealing with the nodule
- Do not go for the nodule directly as it will bleed.
- Buzz the base of the nodule in the cyst wall then remove it.
- Cyst wall should be left intact since it is not made up of tumor tissue but compressed gliotic cerebellum
- For large hemangioblastomas, two operative maneuvers can be employed to reduce the tumor mass → to reduce manipulation/retraction of the cerebellum.
- First, the central component of the tumor can be coagulated with broad bipolar cautery tips and concurrent irrigation and then removed with microscissors or ultrasonic aspiration in piecemeal fashion.
- Typically, this maneuver is used in later stages of the dissection, when the blood supply has been reduced, to minimize bleeding.
- Second, with the broad bipolar cautery tips and concurrent irrigation, the tumor can be shrunk by circumferential capsular coagulation.
- Because cauterization of the tumor surface can turn the hemangioblastoma tan-white, it is avoided at the deepest capsule–cerebellum interface, permitting the red-orange color of the tumor to remain distinct from the adjacent neural tissue during deeper circumferential dissection.
- Peritumoral cyst walls (when present) are inspected after tumor removal to assess for additional tumors
- Additional cyst-associated tumors are removed to minimize the chance of cyst recurrence.
- For solid tumor
- Avoid violating the tumor itself since this will lead to brisk hemorrhage.
- Dissection should be carried out between the external surface of the tumor and adjacent compressed gliotic cerebellum.
- Even after the major arterial supply has been controlled, there will frequently be many small perforating arteries or arterioles feeding the tumor that require coagulation.
- As soon as the dissection planes meet behind the tumor, it can be rolled out of the cerebellar bed and bleeding controlled.
- If the tumor tissue is violated prior to separation from the adjacent cerebellum, the tumor should be rapidly dissected from the cerebellar bed and hemorrhage controlled afterwards;
- Attempting hemostasis within the center of tumor is futile and only leads to continued hemorrhage and delayed swelling.
- Outcome
- A cerebellar hemispheric cystic tumor with a mural nodule is the simplest to remove and carries the lowest risk (mortality <2%),
- A large solid tumor in or near the brainstem is the most difficult and carries up to 50% mortality risk.
Radiosurgery for hemangioblastomas
- Indication
- Patients with multiple hemangioblastomas or surgically inaccessible lesions.
- Options
- Stereotactic radiosurgery (SRS)
- External beam radiotherapy
- Proton beam radiotherapy
- SRS is generally given in a single dose of 1800 to 2000 cGy.
- SRS controls the majority of primary and recurrent hemangioblastomas less than 3 cm in size.
- Outcomes
- Response to SRS is enhanced in noncystic hemangioblastomas.
- Local control is estimated at 82 to 94% at 5 years following treatment.
- Cons
- Radiosurgery does not reduce the cyst size,
- additional surgical removal or repeated evacuations of the cyst may be necessary.
Antiangiogenic therapy
- FGR inhibitors may constitute an option for hemangioblastomas that are not amenable to surgery or radiosurgery.
Long term follow up
- Hemangioblastomas are slow-growing tumors, but a risk of rapidly enlarging cysts is still present and a striking tendency for multiple occurrence (cranial and spinal) is habitual in VHL disease.
- Pregnancy can be accompanied by the enlargement of a cyst within a few months, sometimes leading to dramatic complications for both mother and fetus.
- Regular surveillance includes periodic
- Craniospinal gadolinium-enhanced MRI
- Abdominal CT scan or ultrasonography
- Urinary catecholamines,
- Ophthalmologic
- Audiologic evaluations
- Bloods
- Rising hematocrit may suggest progression or recurrence.
- Repeat craniospinal MRI every 6 months in the presence of lesions and later yearly if stable
Prognosis
- Haemangioblastoma is a frequent manifestation of VHL (60% of pts have VHL disease)
- Genetic counselling and molecular genetic screening for germline mutations in the VHL gene are therefore essential for patients with haemangioblastoma
- Good if surgical resection can be performed successfully
- Permanent neurological deficits are rare and can be avoided when CNS haemangioblastomas are diagnosed and treated early
- Patients with sporadic tumours have a better outcome than those with tumours associated with VHL (due to multiple lesions)
Spinal haemangioblastoma management
- Indication
- Symptomatic or growing lesions
- Minimally invasive techniques have recently been performed with the advantage of minimizing pain and progressive deformity.
- Preoperative embolization may be considered.
- Intraoperative adjunct
- Indocyanine green videoangiography can be helpful in identifying feeding vessels intraoperatively.
- Neurophysiology
- Because of its well-defined margins, careful surgical removal of this benign lesion often provides a cure.
- Recurrence is rare following total resection, and mild transient neurological deficits are not unusual.
- The observed deficits often improve within weeks following surgical excision.
- Overall, symptomatic improvement occurs in two-thirds of patients with sporadic hemangioblastomas.
Made with Bullet