Management Strategies

and Outcomes for

VHL-related Craniospinal
Hemangioblastomas
Journal Reading

- Clarissa Tan - Frischa Rositawati

- Yonathan Stanly Marcellino - Gabriel Justin Darmajaya
- Farisa Nurizky Pakki - Gabriella Beatrice
- Firda Zahravy Nabilla - Gustira Aditya Pratama
JOURNAL
Author

Christ Ordookhanian1, Paul E. Kaloostian1, Samer S.

Ghostine, Philippe E. Spiess2, Arnold B. Etame3

Affiliation
1
Department of Neurological Surgery, University of
California at Riverside School of Medicine, Riverside,
CA, USA;
2
Department of Urologic Oncology, Lee Moffitt
Cancer Center and Research Institute, Tampa, FL, USA;
3
Department of Neuro-Oncology, H. Lee Moffitt
Cancer Center and Research Institute, Tampa, FL, USA

Published

2017
 INTRODUCTION
● Hemangioblastoma → CNS

● 1-2% of CNS tumor

● Hemangioblastoma → packed capillaries within proliferative stromal cells → Source of

neoplastic components and genetic defect

● Type hemangioblastoma

○ Solitary sporadic tumors

○ Multiple familial tumor → Von Hippel-Lindau (VHL) → autosomal dominan

Epidemiology
Incidence 1 in 36,000

Prevalence 1 in 38,000

Age range Infant to 70 tahun

Average age of diagnosis VHL 26-29

Male:Female 1:1

De novo mutation 20%

Familial mutation 80%

Common Clinical Manifestation
CNS HB 30-80%

Renal cell carcinoma 30-70%

Renal cyst 60%

Retinal angiomas 15-70%

Endolymphatic sac tumors 3-16%

Pancreatic cyst 20-70%

Pancreatic neuroendocrine tumor 15-56%

Pheochromocytoma 16%
 Von Hippel-Lindau
● Usually occur sporadically

● VHL-related HB arise from defects associated with loss of tumor suppression function
of the VHL gene

● VHL → 60% of the patients had multiple hemangioblastoma

● The most common place for VHL-HB → posterior fossa and spinal cord

● By knowing the location of VHL can significantly increase the safety of the patient

● The most common cause of demise in VHL patients appears to be from posterior
fossa hemorrhages associated with HB and also renal cell carcinoma (RCC)
 PATHOGENESIS
● VHL: autosomal dominant syndrome with age-related penetrance, characterized
with over 300 germ-line mutations of the VHL gene on the short arm of
chromosome 3p25.
● Deletion of a single copy of the VHL gene (loss of heterozygosity) can predispose
patients to the syndrome. Approx 1/3 of VHL → deletion mutations.
● Loss of the tumor suppressive function of VHL secondary to inactivation of both
alleles → the basis for the development of neoplasms in patients with VHL.
● Despite familial genetic pattern, can also manifest de novo without a prior family
history.
● VHL gene product (pVHL) → regulation through ubiquitination of hypoxia-inducible
factor alpha (HIF-α).
○ Hypoxic conditions → VHL protein complex doesn’t recognize and bind to HIF-α.
○ Defects in VHL protein complex → prevent its regulation and degradation of
HIF- α -> stabilization of HIF-α → downstream up-regulation of hypoxia response
genes (VEGF and PDGF that have a role in neoplastic transformation).
 PATHOGENESIS
● Genetic defects in VHL can predispose to HB in the craniospinal axis, the genetic
mechanisms not explained.
● Besides VHL mutations, germline allelic variations of several genes including CCND1,
MMP1, and MMP3 have been implicated in pathogenesis of HB.
● Several studies → examined tissue expression of EGFR in HB demonstrated universally
that there was an over-expression of EGFR in HB (EGFR plays a role in cell
proliferation and angiogenesis).
● A more recent large study → 44 HB samples using droplet digital polymerase chain
reaction and high-resolution single nucleotide polymorphism (SNR) arrays implicated
23 candidate in the pathogenesis of HB. The candidate genes included the following:
EGFR, PRDM16, PTPN11.
 CLINICAL PRESENTATION
Patients with HB —> symptomatic / asymptomatic

● Lesions in the posterior fossa: bleeding —> obstructive hydrocephalus

● Associated symptoms: nausea, headache, weakness
● Compression of the brain stem —> herniation
● Small hemorrhages in the brainstem —> neurological symptoms
● Symptomatic lesions —> large cyst and brain edem

Spinal HB —> asymptomatic

● Clinical presentation: symptoms of myelopathy —> gait disturbance, paralysis, sensory

deficits, bowel and bladder dysfunction
● Pain often resembles myelopathy
● Symptoms of myelopathy are usually associated with spinal cord compression —>
tumor bleeding
● Patients may present with spinal subarachnoid hemorrhage
 RADIOGRAPHIC DIAGNOSIS of HEMANGIOBLASTOMA

● Hemangioblastoma → one of the earliest manifestations of VHl syndrome

● The best diagnostic modalities of hemangioblastoma → gadolinium-enhanced MRI
● Appearance → homogenous lesion with cystic component & hemorrhage
● Spinal cord lesion→ small nodules on the pial surface or intramedullary syrinx
● Patient at risk for VHL syndrome → should be screened with neuro-axis MRI
● If there are lesions on the MRI results of the brain → continue with MRI of the spine
● Alternative imaging in cases of contraindications to MRI → Contrast CT-Scan &
angiography
● Ct-scan → homogeneously enlarged nodule → can also assess the extent of
compression, bleeding & hydrocephalus
● Angiography → demonstrate the classic tumor vascular blush
RADIOGRAPHIC DIAGNOSIS of HEMANGIOBLASTOMA

Pictures 1 : multiple enhancing

hemangioblastoma involving
cerebellum, brainstem, and spinal
cord on MRI
RADIOGRAPHIC DIAGNOSIS of HEMANGIOBLASTOMA

Pictures 2 : multiple
intramedullary cystic lesions
consistent with VHL
hemangioblastoma
 NATURAL HISTORY of HEMANGIOBLASTOMA
● Several studies have examined the natural history of HB as it relates to the
development of symptom and optimal timing of interventions

○ Wanebo et al → 160 patients with VHL, cysts expanded faster than tumor and
were the basis for neurological symptoms → cystic lesion should be observed
and considered for treatments when there is expansion

○ Ammerman et al → 158 patient with VHL over 10 year, concluded that clinical
symptom approach spared patient from four additional unnecessary procedure

○ Lonser et al → 225 patients with VHL, assessment of increased tumor burden

for male sex, younger age, and partial deletion in VHL gene. Male patient were
found with rapidly growing tumor, symptoms and cyst → consideration when
managing patient with VHL
 SURGICAL RESECTION of CRANIOSPINAL RESECTION

Surgery is the preferred treatment modality of HB → low morbidity of surgery, relieve

compressive neurological symptoms and can be curative.
↳ Clear for symptomatic or large lesions, and it’s debatable for asymptomatic lesions.

Some have advocated for treating intramedullary lesions at the onset of diagnosis →
opposed to the development of neurological symptoms → least likely to improve after
surgery following neurological deterioration.

Prospective study (1921 CNS HB in 225 patients) → found that most of asymptomatic lesions
develop gradually, whereas neither tumor size nor growth rate were universal determinants
of neurologic symptoms.
↳ Concluded that surgery for HB should only be recommended at the onset of
neurological symptoms.
 SURGICAL RESECTION of CRANIOSPINAL RESECTION

Also similar to resection of any vascular malformation.

The Goals:
↳ Entails circumferential dissection along the interface between tumor and brain
without prematurely violating the tumor.
↳ Intrinsic arterial are circumferentially coagulated and disconnected resulting in an
enblock resection (with risks for intraoperative as well as postoperative hemorrhage).

A midline myelotomy → safest approach → minimizing damage to the posterior columns.

Preoperative embolization could be considered in order to minimize postoperative blood loss

(Due spinal lesions are generally intramedullary, neurophysiologic monitoring (sensory &
motor))
 SURGICAL RESECTION of CRANIOSPINAL RESECTION

As surgical resection of HB can be curative with less morbidity, there are tumor-related
characteristics that can significantly impact outcomes:
- Solid tumor configuration (not tumor size) due highly vascularized → had a propensity
postoperative hematomas requiring surgical intervention.

Favorable outcomes have been reported for tumors in the medulla and spinal cord when the
onset of symptoms was the main indication for surgical intervention:
↳ Study reported → experience in 34 patients with HB, attained gross total tumor
resection in approximately 85% of cases → There were no mortalities from surgery,
and <18% of patients experienced worsening of symptoms following surgery.
↳ Another study → experience in 14 patients with 15 brainstem HB lesions → 9 out of 14
patients experienced higher performance levels to their preoperative performance.

→ The pathological outcome strong correlated to adverse outcome

 RADIOTHERAPY FOR HEMANGIOBLASTOMA
● Radiation can also be used to address multiple lesions as well as in the setting of tumor recurrence.
Although not a curative strategy, it can provide reasonable and sustained local tumor control
● If patients are not good surgical resection candidates or where lesions are not amenable to safe
resection, stereotactic radiation is a favorable option.
○ Kano et al (2015) → Long-term outcomes of stereotactic radiosurgery (SRS) in the
management of HB consisting of 186 patients with 517 lesions:

3 years 5 years 10 years

Overall survival rates 94 90 74

Associated tumor control rates 92 89 79

Hence, excellent local control rates are feasible with SRS.

 RADIOTHERAPY FOR HEMANGIOBLASTOMA
● There appears to be differential response to intracranial SRS for sporadic versus VHL-related HB.
○ Hanakita et al (2014) → long-term outcomes in 57 intracranial HB treated with SRS

Tumor control rate 5 years 10 years

Sporadic HB 67% 44%

VHL-related HB 97% 83%

Besides VHL pathology, SRS was much effective for small and solid tumors compared to
large and cystic tumors.
● SRS is equally effective for spinal HB in terms of halting tumor progression and improving
neurological symptoms associated with HB.
○ Pan et al (2017) → assessed radiographic and clinical outcomes in 34 spinal HB tumors.
Following SRS treatment, 94% of the tumors were either stable or regressed with local control
rates at 1, 3, and 5 years being 96, 92, and 92%, respectively. Symptom improvement was
associated with 81% of treated lesions.
Hence, SRS was deemed as a safe approach for spinal HB.
 RADIOTHERAPY FOR HEMANGIOBLASTOMA
● Bridges et al (2017) → Comparison of retrospective data of surgical resection versus SRS for spinal
HB showed that only 2% of tumors treated with SRS actually progressed.
○ SRS was associated with minimal side effects.
○ Surgical resection resulted in successful removal of tumor with a recurrence rate of
approximately 5%.
○ At least 96% of patients were either clinically stable or improved on long-term follow-up from
surgery.
● Overall, SRS for HB appears to be an effective alternative strategy whenever safe surgical resection
is not practical. It appears to be more effective for VHL patients with HB, small tumors, and solid
lesions.
 CONCLUSION

● HB is a benign tumor —> significant neurological impairment or even death following

intratumoral hemorrhage or cystic expansion of the tumor.
● most lesions are asymptomatic with very minimal growth
● Factors associated with tumor progression and treatment outcomes should be
considered in the timing of intervention.
● Symptomatic lesions—> surgery
● Radiosurgery is an alternative