Keywords
hemangioblastoma - von Hippel-Lindau - microsurgery - radiotherapy - syringomyelia
- holocord syrinx
Introduction
von Hippel-Lindau disease (vHLD) constitutes an autosomal dominantly inherited multisystem
neoplasia syndrome due to a mutation on the short arm of chromosome 3 (3p25). Typical
manifestations are angiomas of the retina (central serous retinitis) and hemangioblastomas
(HABs) of the infratentorial and spinal central nervous system (CNS) region (predominantly
posterior fossa). Further neoplasias are renal cell carcinomas, pancreatic neuroendocrine
tumors, pheochromocytomas, and endolymphatic sac tumors.[1]
[2]
[3]
Though rarely encountered sporadically, spinal HABs are common in vHLD as multifocal
lesions that often require multiple surgical interventions. We present a case of vHLD
with complicated multiple spinal HABs and holocord syrinx formation undergoing both
microsurgery and radiotherapy in a short follow-up period. In current literature,
radiotherapy for spinal HABs is reviewed and outcomes are discussed with regard to
the presented case.
Clinical Presentation
Our 37-year-old male patient had ophthalmologic examination due to progressive visual
disturbance. Fundoscopy revealed central serous retinitis. Due to positive family
history for renal cell carcinoma in the patient's mother, more extensive diagnostics
were performed. Cranial and whole spine magnetic resonance imaging (MRI) showed holocord
syrinx formation with multiple contrast enhancing nodular lesions, predominantly in
the right cerebellar tonsil and at spinal cord levels T1, T2, and at T11/12 junction
that were consistent with HABs ([Figs. 1] and [2]). On neurological examination, he presented with increased lower limb reflex levels,
mild gait ataxia, and a tendency to fall to the right. All of these signs were not
previously noticed by the patient. vHLD was genetically proven in the patient and
his mother.
Fig. 1 Magnetic resonance imaging scans of the cervical spine on first clinical onset of
symptoms, T2-weighted (A), and contrast-enhanced T1-weighted (B) images showing an
extended syrinx formation due to a large contrast enhancing formation at the cervicothoracic
junction.
Fig. 2 Magnetic resonance imaging scans of the thoracic spine on first clinical onset of
symptoms. T2-weighted (A) and contrast enhanced T1-weighted (B) images further demonstrate the extent of the syrinx down to the conus medullaris
among multiple contrast enhancing lesions.
He first underwent laminectomies C7 and T1 to approach the upper lesions and decompress
the syrinx. Intraoperatively, only one lesion at T1 could safely be removed and the
syrinx was fenestrated.
Histology showed a tumor of moderate cell density. The tumor was composed of large
stromal cells with either vacuolated or homogeneously eosinophilic cytoplasm. These
were embedded in a dense capillary network. Stroma cells stained positive for S100;
the capillary network was highlighted by Tibor Pap silver impregnation and factor
VIII immunohistochemistry. Proliferation index was below 2%. Histomorphology and immunohistochemical
staining pattern were consistent with the diagnosis of HAB WHO I°. vHLD-associated
HABs are histomorphologically indistinguishable from sporadic HABs.
The lesion at T2 was left untouched due to total adherence to the corresponding nerve
root. Histological diagnosis was HAB. The postoperative course was uneventful except
of temporary left hemi hypoesthesia sub-Th5. Postoperative MRI showed a collapse of
the cervical portion of the syrinx and total resection of the lesion at T1. Early
MRI controls revealed progression of the cervical portion of the syrinx. Hence, another
surgical procedure via laminectomy T12 was performed to resect the lesion at T11/12
junction, but the resection was not possible for a too anterior position of the vascular
lesion. Additionally, a syringo-subdural shunt was implanted. Postoperatively the
patient presented with isolated ataxia of the right leg.
After scooping out the options for surgical treatment, radiotherapy of the spinal
cord was planned, but before initiating the latter, control MRI showed progression
of the accompanying cyst of the right cerebellar tonsil lesion. The clinical presentation
did not change, while the right leg ataxia was still present. So, the patient first
underwent suboccipital craniotomy. The lesion could be totally removed.
Hence, irradiation of the posterior fossa and the spinal axis was performed using
conventional computed tomography-planned isocentric multifield external beam radiotherapy
with 5 × 1.8 Gy weekly until 36 Gy. Sequentially, a boost of 9 Gy to the tumor bed
in the posterior fossa and to the multiple spinal hemangiomas from C7 to Th12 was
performed up to a total dose of 45 Gy.
The patient afterward developed lower limb weakness and progressive gait ataxia requiring
the use of corticosteroids. The control MRI 2 months after radiotherapy showed a progression
of one remaining lesion at T2 accompanied by an extension of the cervicothoracic portion
of the syrinx. Thus, a second approach to the lesion was undergone via laminectomy
T2 and the lesion could be totally resected.
Throughout the further clinical course after the last surgery, a mild improvement
in the gait ataxia was noticeable. Follow-up MRIs demonstrated a remarkable collapse
of the cervical portion of the syrinx and a stable size of the remaining multiple
nodular intramedullary lesions ([Figs. 3] and [4]). The whole follow-up period after radiotherapy covered 60 months.
Fig. 3 Magnetic resonance imaging scans of the cervical spine 60 months after radiotherapy.
T2-weighted (A) and contrast-enhanced T1-weighted (B) images demonstrate a considerable collapse of the cervical portion of the syrinx
after resection of the cervicothoracic hemangioblastoma.
Fig. 4 Magnetic resonance imaging scans of the thoracic spine 60 months after radiotherapy.
T2-weighted (A) and contrast-enhanced T1-weighted (B) images show partial collapse of the thoracic portion of the syrinx and stable-sized
contrast enhancing lesions after radiotherapy.
During this period, the patient underwent multiple ophthalmologic surgeries and intravitreal
local radiotherapy for a HAB of the left retina. He also underwent partial left sided
nephrectomy due to renal cell carcinoma.
Overall, the patient's neurologic status was fluctuating deterioration linked to the
surgical procedures but stabilized to a moderate gait ataxia and hyperreflexia of
the lower limbs.
Discussion
Spinal cord HABs account for a relatively small amount of primary spinal cord tumors.[4] Although they are often accompanied by local syringomyelia, only a few cases with
an extensive, holocord syrinx have been published to date.[5]
[6]
[7] Since the signs and symptoms in patients with HABs mostly arise from peritumoral
cysts and syrinx formation, treatment strategies should focus not only on curative
but also on good functional outcome. Hence, the resolution of local and more extensive
mass effects, such as syringomyelia, is a definitive target of treatment.[2]
[3] The judicious treatment of symptom producing lesions while avoiding unnecessary
treatment of asymptomatic tumors, which might not grow, could, according to Lonser
et al, provide clinical stability.[8]
Although surgical resection constitutes the therapy of choice for spinal HABs, radiotherapy
has become increasingly important for the treatment of surgically not amenable lesions
in both cranial and spinal locations.[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
As published by various authors before, high-dose focal radiotherapy for HABs can
achieve stabilization of tumor growth ([Table 1]) in the per se not particularly radiosensitive tumors.
Table 1
Previous studies on radiotherapy for spinal hemangioblastomas
|
Author
|
Method
|
Patients with spinal HAB
|
Spinal HABs
|
Mean follow-up (months)
|
Outcome
|
|
Chang et al., 1998[16]
|
SRS
|
2
|
2
|
13.5
|
Tumor decreased
|
|
Koh et al., 2007[24]
|
EBRT
|
18
|
8
|
61
|
5-year disease free survival, 57%
|
|
Ryu et al., 2003[17]
|
SRS
|
7
|
7
|
12
|
Local control rate, 100%
|
|
Moss et al., 2009[25]
|
SRS
|
31
|
16
|
33.5
|
Local control rate, 92%
|
|
Chang et al., 2011[15]
|
SRS
|
5
|
8
|
50
|
Local control rate, 87.5%
|
|
Simone et al., 2011[20]
|
ICSRT
|
7
|
84 (spinal and infratentorial)
|
73.8
|
Local control rate, 24%
|
|
Selch et al., 2012[21]
|
LINAC
|
9
|
20
|
51
|
Local control rate, 95%
|
|
Pan et al., 2017[22]
|
SRS
|
28
|
46
|
54
|
Local control rate, 94%
|
Abbreviations: EBRT, external beam radiotherapy; ICSRT, infratentorial craniospinal
radiation therapy; LINAC, linear accelerator; SRS, stereotactic radiosurgery.
However, results of studies with radiotherapy for HAB have to be interpreted with
caution as the known multiphasic growth pattern of these tumors makes interpretation
of tumor size during follow-up difficult; therapeutic effects and intrinsic changes
of tumor size can possibly not be distinguished; and long-term follow-up is needed
to better evaluate efficacy of treatment. As shown by Asthagiri et al for intracranial
HABs, excellent local control rates (> 80%) 2 years after SRS are diminishing during
long-term analysis (68%, control rate after 8.5 years).[23]
For interpretation of clinical data, it is relevant that HABs in patients with vHLD
might have better overall survival and longer disease-free intervals compared with
sporadic tumors.[24]
Radiotherapy of multifocal spinal HAB of our case report remains a particular therapeutic
challenge: (1) identification of “first to treat” symptomatic lesions might be difficult,
(2) the decision for or against treatment of asymptomatic lesions is controversial
due to unpredictable growth, (3) dose constraints of the spinal cord restrict use
of conventional radiotherapy, (4) nearly half of the vHLD-associated HABs is not visible
on the first imaging series.[3]
To improve prognosis in this complicated setting, infratentorial craniospinal irradiation
has been used as a treatment approach. Simone et al first described a case series
of this technique using conventional multifield infratentorial craniospinal irradiation
(24 × 1.8 Gy, 43.2 Gy) to the entire craniospinal region without the hemispheres in
seven patients with diffuse and multilocal CNS HABs with vHLD. Although local control
was limited (23.9%) and the development of new lesions could not be limited, clinical
stabilization or even improvement in five of seven patients during a mean follow-up
period of ∼74 months could point toward some efficacy of this approach.[20]
Conclusion
In conclusion, treatment of multiple HABs requires a multidisciplinary approach, optimization
of treatment is made difficult by growth pattern of tumors and long-term follow-up
on radiological control, and functional outcome is needed to evaluate and improve
quality of treatment.
