Introduction
Von Hippel-Lindau (VHL) disease (Online Mendelian
Inheritance in Man identifier, #193300) is a rare autosomal
dominant tumor-predisposition syndrome that is caused by pathogenic
germline variants of the VHL tumor suppressor gene, which is
located on chromosome 3p25-26. VHL exhibits an estimated prevalence
of 1 in 39,000-91,000 individuals and a birth incidence of 1 in
36,000-45,500 live births (1).
Clinical conditions associated with VHL disease include retinal and
central nervous system (CNS) hemangioblastomas, clear cell renal
cell carcinoma, pheochromocytoma, pancreatic neuroendocrine and
endolymphatic sac tumors, and epididymal and broad ligament
cystadenomas (2). CNS
hemangioblastomas most commonly arise in the cerebellum and spinal
cord (3). In particular,
suprasellar hemangioblastomas are CNS hemangioblastomas that remain
notably rare and may represent an uncommon manifestation of VHL
disease (4).
For example, a study by Filizoglu and Ozguven
(5) reported a histologically
confirmed suprasellar hemangioblastoma in a 52-year-old male
patient with established VHL disease. The lesion demonstrated
notable gallium-68 DOTA-Tyr3-octreotate uptake,
highlighting the potential role of somatostatin receptor PET/CT in
the management of VHL disease. The present case differed from the
aforementioned report by demonstrating concurrent involvement of
the suprasellar region, cerebellum and spinal cord in a patient
with hemangioblastoma who did not have a known family history or
molecular confirmation of VHL disease. The cerebellar lesion
observed in the present patient was histopathologically confirmed
to be a hemangioblastoma, but the suprasellar lesion was
radiologically presumed as a hemangioblastoma; direct sampling of
the suprasellar lesion was not pursued due to its marked
vascularity, encasement of the left internal carotid artery and
displacement of the optic chiasm. The present case illustrated how
integrated MRI findings across multiple CNS compartments, together
with pathological confirmation of the tumor type from a surgically
accessible lesion, can support a clinical diagnosis of VHL disease
and guide clinical management strategies in cases where biopsy or
resection of a highly vascular suprasellar lesion carries notable
vascular and visual risks.
Case report
A 39-year-old male patient was admitted to the
Department of Neurosurgery of Jiangyou People's Hospital (Jiangyou,
China) in November 2024, with a 1-month history of positional
dizziness that was aggravated by standing and relieved by rest,
which was also accompanied by progressive painless visual blurring
in the left eye. The patient denied experiencing headaches, nausea,
vomiting, gait imbalance, limb weakness, sensory disturbance or
seizures. The patient had undergone resection of a cerebellar
lesion at another institution 14 years earlier, but detailed
clinical records and histopathological findings for this prior
lesion were unavailable. The patient had no history of
hypertension, diabetes mellitus, cardiovascular disease, chronic
infection or drug allergy. However, the patient did have a
15-pack-year smoking history and reported occasional alcohol
consumption. The family history of the patient was negative for
hereditary disorders, including VHL disease, across three
generations.
On admission, the patient exhibited tachycardia (111
bpm) and a blood pressure of 114/90 mmHg. The results of general
physical examinations, including assessment of the patient's
general condition and cardiovascular, respiratory and abdominal
systems, as well as other routine systemic examinations, were
otherwise unremarkable. The results of neurological examinations,
including assessment of consciousness, pupillary responses, visual
function, motor and sensory function, deep tendon reflexes and
coordination and balance, showed that the patient was alert and
oriented, and the patient scored a Glasgow Coma Scale score of
15(6). The patient exhibited
equally sized pupils at 2.5 mm bilaterally and normal pupillary
reflexes were observed. The patient also exhibited a corrected
visual acuity of 20/40 in the left eye, and confrontation visual
fields showed no visual field defects. The results of motor
examinations, including assessment of muscle strength, muscle tone
and muscle bulk, showed that the patient exhibited full strength in
all muscle groups, exhibiting grade 5 on the Medical Research
Council Muscle Scale (7), with
normal muscle tone and bulk. Sensory examination included
assessment of superficial sensation (light touch, pinprick and
temperature) and deep sensation (vibration and joint position
sense), with no abnormalities identified bilaterally. Deep tendon
reflexes were symmetrical and graded as 2+ (normal) (8), and no pathological reflexes were
elicited. Cerebellar examinations revealed a positive Romberg test
result and mild bilateral dysmetria during finger-to-nose testing.
Notably, meningeal signs were absent and ophthalmologic
examinations after pupillary dilatation revealed no evidence of
retinal hemangioblastomas. Abdominal CT and ultrasonography
revealed a polypoid lesion in the gallbladder, with no renal,
adrenal or pancreatic abnormalities suggestive of VHL disease.
Scrotal and epididymal ultrasonography revealed no abnormalities
suggestive of VHL disease. Routine laboratory examinations
including liver and renal function tests, specifically alanine
aminotransferase, aspartate aminotransferase, total bilirubin,
serum creatinine and blood urea nitrogen, showed no clinically
relevant abnormalities.
MRI was performed before resection of the cerebellar
lesion using a 1.5-T scanner, with contrast-enhanced images
obtained after intravenous administration of 0.1 mmol/kg
gadopentetate dimeglumine. MRI scans revealed multiple lesions in
the suprasellar region, left cerebellar hemisphere and spinal cord.
In the left cerebellar hemisphere, a large cystic lesion with
smooth walls measuring 5.9x4.6x3.5 cm was observed, showing
hypointensity in T1-weighted images and hyperintensity in
T2-weighted scans (Fig. 1A and
B). The lesion contained a
posterolateral mural nodule that exhibited mild hypointensity in
T1-weighted images and hyperintensity in T2-weighted images
(Fig. 1A and B), with no diffusion restriction observed
on diffusion-weighted imaging (Fig.
1D). Sagittal T2-weighted imaging further demonstrated the
cystic lesion with its mural nodule (Fig. 1F). Following contrast
administration, the mural nodule showed a marked increase in signal
intensity on post-contrast T1-weighted images, indicating marked
contrast enhancement consistent with the hypervascular nature of
the lesion (Fig. 1E), with notable
perilesional edema on T2-weighted fluid-attenuated inversion
recovery (FLAIR) images (Fig. 1C)
causing compression of the dorsolateral brainstem and effacement of
the fourth ventricle. In the suprasellar region, a solid nodule
measuring 2.3x2.0x2.3 cm was identified, which showed heterogeneous
hypointensity in T1-weighted images (Fig. 2A) and hyperintensity in T2-weighted
and T2-weighted FLAIR images (Fig.
2B and C). No diffusion
restriction was observed on diffusion-weighted imaging. After
contrast administration, the suprasellar lesion showed notable
homogeneous signal enhancement (Fig.
2D-F). This lesion was also shown to contain multiple
serpentine flow voids (Fig. 2B and
C), which were more conspicuous on
contrast-enhanced images compared with initial MRI scans (Fig. 2D-F). The suprasellar lesion encased
the left internal carotid artery and displaced the optic chiasm.
Spinal cord imaging revealed intramedullary signal abnormalities
extending from the T3 to T9 vertebral levels, which appeared
hypointense in T1-weighted images (Fig. 3A) and hyperintense in T2-weighted
and short TI inversion recovery images (Fig. 3B and C). The background spinal cord-signal
abnormalities did not show marked enhancement following contrast
administration (Fig. 3D); however,
within these abnormalities, discrete nodules showing marked
contrast enhancement were identified at the T5 and T7 vertebral
levels (Fig. 3E and F), but these lesions were not subjected
to biopsy or histopathological examination. Despite the
aforementioned spinal MRI findings, no clinical symptoms or
neurological signs specifically attributable to the T5 and T7
lesions were identified in the patient; lower-extremity strength
and sensation were preserved, deep tendon reflexes were
symmetrical, and no pathological reflexes were observed. The
overall imaging pattern was suggestive of VHL disease, given the
multifocal CNS lesions involving the cerebellum, suprasellar region
and spinal cord with imaging features suggestive of
hemangioblastomas.
Given the observations of notable brainstem
compression, microsurgical resection of the left cerebellar lesion
was prioritized and performed 4 days after the patient's admission.
By contrast, the characteristics of the suprasellar lesion, which
displayed notable encasement of the left internal carotid artery,
marked vascularity and a close relationship with the displaced
optic chiasm, markedly increased the risks of vascular injury,
intraoperative hemorrhage and visual pathway damage occurring
during biopsy. Accordingly, biopsy or resection of this lesion was
not pursued, and MRI surveillance was recommended.
Intraoperatively, cerebellar tissue herniation was observed ~1.5 cm
above the bone edge and was resolved following aspiration of 20 ml
light yellow cystic fluid. The decompression achieved by aspiration
restored parenchymal pulsation and exposed the mural nodule of the
aforementioned left cerebellar lesion, which was a well-demarcated
hypervascular tumor measuring 1.6 cm in diameter. The tumor was
located adjacent to the transverse and sigmoid sinuses and caused
marked compression of the surrounding neural structures. Gross
total resection was achieved under microscopic visualization using
a light microscope, followed by hemostasis and placement of a
synthetic dural graft. As shown in Fig. 4, the resected specimen was a
well-circumscribed reddish solid tumor nodule.
As demonstrated in Fig.
5, histopathological examinations of the resected lesion
confirmed the diagnosis of grade 1 hemangioblastoma, in accordance
with the 2021 Classification of Central Nervous System Tumors
guidelines published by the World Health Organization (9). Following resection, the specimen was
immediately sent to the pathology department and fixed in 10%
neutral buffered formalin at room temperature for 24 h, routinely
paraffin-embedded and sectioned at a thickness of 3-4 µm. H&E
staining was performed at room temperature, with sections stained
with hematoxylin for 5 min and eosin for 1 min, following the
aforementioned fixation in 10% neutral buffered formalin and
routine paraffin processing. For immunohistochemistry, heat-induced
antigen retrieval was performed using EDTA antigen retrieval
working solution (pH 9.0) at 100˚C prior to antibody staining.
Prior to primary antibody incubation, endogenous peroxidase
activity was blocked using 3% hydrogen peroxide at room temperature
for 5 min. No separate non-specific protein blocking step was
performed prior to primary antibody incubation. The following
ready-to-use primary antibodies were used: CD34 (clone QBEnd/10;
cat. no. Kit-0004; Fuzhou Maixin Biotechnology Development Co.,
Ltd.), S-100 (clone SD16; cat. no. AR0210; Xiamen Talent Biomedical
Technology Co., Ltd.), Ki-67 (clone BP6045; cat. no. I10092E-01;
Tuling Biomedical Co., Ltd.) and vimentin (clone BP6010; cat. no.
I10032E-01; Tuling Biomedical Co., Ltd.). A ready-to-use secondary
antibody immunohistochemical detection reagent (cat. no. DD23;
Xiamen Talent Biomedical Technology Co., Ltd.) and DAB chromogen
supplied by Xiamen Talent Biomedical Technology Co., Ltd. were
used. Immunohistochemical staining was performed using a TALENT 144
fully automated immunohistochemistry stainer (Xiamen Talent
Biomedical Technology Co., Ltd.) according to the manufacturer's
preset protocol. The stained sections were examined using a Nikon
Ci-S light microscope (Nikon Corporation). H&E staining
demonstrated abundant delicate capillaries embedded in a fine
fibrillary stroma (Fig. 5A), with
intervening stromal cells showing foamy cytoplasm and vacuolated
nuclei (Fig. 5B).
Immunohistochemical analysis revealed the notable expression of
CD34 in endothelial cells (Fig.
5C) and the expression of S-100 and vimentin in stromal cells
(Fig. 5D and E). The Ki-67 labeling index was
determined by manual counting of positively stained tumor cells
under light microscopy and was ~5% (Fig. 5F). Overall, the histomorphological
and immunophenotypical findings of the present case were compatible
with a hemangioblastoma diagnosis. Immunostaining for inhibin-α was
not performed as part of the diagnostic panel, although it may
serve as an ancillary marker for hemangioblastoma (10).
Although genetic counseling and VHL gene mutation
analysis were recommended to the patient in order to confirm the
diagnosis, guide long-term surveillance strategies and facilitate
family screening for VHL, the patient declined genetic testing
despite counseling regarding its potential clinical and familial
benefits. Genetic counseling for potentially at-risk family members
remained advisable, as early detection of VHL-associated tumors has
been shown to improve clinical outcomes (11). Postoperatively, the patient
recovered satisfactorily, with notable improvements in dizziness,
and was discharged on postoperative day 7 with recommendations for
regular surveillance imaging and multidisciplinary follow-up. No
additional adjuvant treatment was administered following resection
of the cerebellar lesion, while the suprasellar and spinal lesions
were managed conservatively, with imaging surveillance recommended.
At the 3-month multidisciplinary follow-up appointment, the patient
remained clinically stable, with no new or worsening neurological
symptoms, but declined the recommended surveillance imaging and
expressed reluctance to participate in long-term surveillance.
Therefore, the subsequent radiographic status of the suprasellar
and spinal lesions could not be assessed.
Discussion
Clinical diagnosis of VHL disease are based on any
of the following three criteria: i) A positive family history plus
at least one characteristic VHL-associated tumor, such as a retinal
or CNS hemangioblastoma, clear cell renal cell carcinoma,
pancreatic neuroendocrine tumor or endolymphatic sac tumor; ii) the
presence of two or more retinal or CNS hemangioblastomas; or iii)
one retinal or CNS hemangioblastoma together with at least one
characteristic visceral VHL-associated tumor, excluding renal and
epididymal cysts (12).
In the present case, the patient exhibited no known
family history of VHL and was diagnosed with histologically
confirmed cerebellar hemangioblastoma, whereas the suprasellar
lesion observed in the present case was radiologically presumed.
The combination of lesions observed in the present case, including
a histologically confirmed cerebellar hemangioblastoma, a
radiologically presumed suprasellar hemangioblastoma and
spinal-cord lesions with imaging features characteristic of
hemangioblastoma, represented a rare manifestation of VHL disease.
The imaging findings for spinal lesions were markedly suggestive of
hemangioblastoma, including discrete contrast-enhancing
intramedullary nodules within non-enhancing T2-hyperintense spinal
cord-signal abnormalities (13).
Although the suprasellar and spinal lesions were not histologically
confirmed, their characteristic vascular imaging patterns, together
with the presence of pathology-confirmed cerebellar
hemangioblastoma, supported the clinical diagnosis of multifocal
VHL disease (14). The absence of
genetic confirmation for VHL disease remains a limitation of the
present case, as it precluded definitive molecular diagnosis and
cascade screening for at-risk family members. According to the
established clinical diagnostic criteria (15), the combination of a histologically
confirmed cerebellar hemangioblastoma and additional CNS lesions
with characteristic VHL-associated imaging features supported a
clinical diagnosis of VHL disease, even in the absence of genetic
testing.
Hemangioblastomas are vascular CNS tumors that
typically appear as well-defined masses in conventional imaging
results (16). These tumors are
generally classified into three types based on imaging features:
Simple cysts, large cysts with small mural nodules and solid or
predominantly solid nodules with minimal cystic change (17). Although hemangioblastomas may occur
throughout the CNS, they predominantly arise in the cerebellum,
brainstem and spinal cord (17).
Suprasellar involvement is rare. Given the notable surgical risk
associated with the suprasellar lesion, biopsy or resection of this
lesion was not pursued in the present case.
Notably, in the present case, the suprasellar lesion
demonstrated characteristic imaging features of hemangioblastoma,
particularly marked hypervascularity, notable homogeneous
enhancement of the lesion following contrast administration
compared with pre-contrast images and serpentine flow voids. The
predominant differential diagnoses for a hypervascular suprasellar
lesion include: i) Pituitary macroadenoma; ii) angiomatous
meningioma; and iii) papillary craniopharyngioma (18). Pituitary macroadenomas, the most
common sellar tumors, typically extend superiorly through the
sellar diaphragm, producing a characteristic ‘snowman’
configuration. In MRI scans, pituitary macroadenomas usually appear
isointense relative to gray matter in T1-weighted images and
demonstrate variable signal intensity in T2-weighted imaging
results. Following contrast administration, the solid components of
pituitary macroadenomas typically exhibit a less intense and often
heterogeneous increase in signal intensity than the normal
pituitary gland, although cystic degeneration and hemorrhage may be
present (19,20). However, pituitary macroadenomas do
not typically demonstrate the notable serpentine flow voids or
marked hypervascular features observed in hemangioblastomas.
Although rare hypervascular adenomas may exhibit flow voids, the
combination of notable serpentine flow voids, marked contrast
enhancement and the absence of typical sellar expansion or obvious
dural attachment and bone involvement favored a radiological
diagnosis of suprasellar hemangioblastoma in the present case
(21).
Angiomatous meningiomas are typically dural-based
tumors that show notable contrast enhancement and MRI scans of
these tumors may contain intratumoral or peritumoral flow voids.
However, these tumors usually exhibit broad dural attachment, which
is often accompanied by dural thickening, as evidenced by the
presence of the dural tail sign in MRI scans, hyperostosis or
adjacent bone remodeling, features that were absent in the present
case (18). Papillary
craniopharyngiomas usually develop in adults and are typically
solid lesions showing contrast enhancement without calcification,
although calcification is commonly observed in tumors of the
adamantinomatous subtype (22).
However, the marked hypervascularity and serpentine flow voids
observed in the present case are atypical features of
craniopharyngiomas, making this diagnosis improbable. As such, the
combination of marked hypervascularity, serpentine flow voids and
the absence of obvious dural attachment or bone involvement in the
suprasellar lesion in the present case favored a radiological
diagnosis of suprasellar hemangioblastoma. Together with the
presence of a histologically confirmed cerebellar hemangioblastoma
and the characteristic spinal-cord imaging findings of
hemangioblastomas observed in the present case, these features
supported the clinical diagnosis of VHL disease.
The current management of VHL-associated
hemangioblastomas primarily involves surgical resection. This aims
to achieve gross total tumor removal with minimal permanent
postoperative neurological deficits, particularly for cerebellar
and spinal lesions (23).
Concurrently, resection of VHL-associated hemangioblastomas aims to
prevent acute obstructive hydrocephalus, which is a major cause of
central nervous system mortality that occurs in ~28% of symptomatic
cases (24). Preoperative
embolization may reduce the risk of intraoperative bleeding in
highly vascular lesions, but the potential benefits of this
strategy must be weighed against procedure-related risks (25). Stereotactic radiosurgery represents
an alternative approach for inoperable multifocal or recurrent
tumors, although assessing the efficacy of this strategy remains
challenging because of natural growth-arrest patterns, which can
make it difficult to distinguish treatment-related tumor control
from spontaneous growth stabilization (26).
In the present case, comprehensive abdominal
evaluations revealed no renal, adrenal, pancreatic or genital
manifestations suggestive of VHL. However, lifelong
multidisciplinary abdominal-tumor surveillance remains important in
patients with VHL disease; this is because clear cell renal cell
carcinoma, for which the lifetime risk of ~70% in patients with VHL
disease, represents the leading cause of VHL-related mortality, and
untreated pheochromocytoma crises and metastatic pancreatic
neuroendocrine tumors also contribute notably to mortality in
patients with VHL disease (27,28).
As such, abdominal-tumor surveillance should include abdominal
regular MRI and annual catecholamine screening to reduce
non-neurological mortality (29-31).
The present patient displayed a histologically
confirmed cerebellar hemangioblastoma, spinal cord lesions with
characteristic MRI features of hemangioblastomas and a solid
suprasellar nodule exhibiting notable homogeneous enhancement
following contrast administration and serpentine flow voids. Taken
together, these findings strongly supported a clinical diagnosis of
VHL disease. Although histological verification of all lesions
would have been ideal, the convergence of pathology-proven
cerebellar hemangioblastoma and characteristic
hemangioblastoma-associated neuroimaging findings provided notable
diagnostic evidence indicative of VHL disease. Genetic testing
would have provided a definitive molecular diagnosis and enabled
the cascade screening of family members; however, the patient
declined such testing, thereby limiting the completeness of the
diagnostic workup and precluding family-level genetic counseling.
Given the high mortality risk associated with renal cell carcinoma
and pheochromocytoma, in addition to those associated with CNS
manifestations, lifelong surveillance for these conditions remains
important (32). Despite
counseling regarding the risks of recurrence, progression and the
development of additional VHL-associated tumors, the patient
remained reluctant to undergo long-term surveillance, which limited
the assessment of subsequent disease evolution.
In conclusion, the present case highlighted a rare
suprasellar lesion in clinically diagnosed VHL disease with
multifocal central nervous system involvement. Together with the
histologically confirmed cerebellar hemangioblastoma and
spinal-cord imaging findings characteristic of hemangioblastomas,
the suprasellar lesion supported a clinical diagnosis of VHL
disease and broadened the differential diagnosis of hypervascular
sellar and parasellar masses in patients with VHL disease. In
future cases where VHL disease is clinically suspected,
hemangioblastoma should be considered in the differential diagnosis
of atypical sellar or parasellar lesions.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
ZW and LaZ conceived and designed the study. ZW
analyzed the data and wrote the original draft of the manuscript.
LeZ and MT collected and organized the clinical data and images.
LaZ critically revised the manuscript and provided overall
supervision. ZW, LeZ, MT and LaZ confirm the authenticity of all
the raw data. All authors read and approved the final version of
the manuscript.
Ethics approval and consent to
participate
The present study was approved by the Ethics
Committee of Jiangyou People's Hospital (approval no. JY-2025-0031)
and was conducted in accordance with the ethical standards of the
institutional ethics committee and The Declaration of Helsinki.
Patient consent for publication
Written informed consent was obtained from the
patient for the publication of clinical details and any
accompanying images.
Competing interests
The authors declare that they have no competing
interests.
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