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REVIEW

Von Hippel-Lindau Disease: Current Challenges

and Future Prospects
This article was published in the following Dove Press journal:
OncoTargets and Therapy

Sven Gläsker 1,2 Abstract: Understanding of molecular mechanisms of tumor growth has an increasing
Evelynn Vergauwen 2,3 impact on the development of diagnostics and targeted therapy of human neoplasia. In this
Christian A Koch 4 review, we summarize the current knowledge on molecular mechanisms and their clinical
Alexander Kutikov 4 implications in von Hippel-Lindau (VHL) disease. This autosomal dominant tumor syn-
drome usually manifests in young adulthood and predisposes affected patients to the devel-
Alexander O Vortmeyer 5
opment of benign and malignant tumors of different organ systems mainly including the
1
Neurosurgical Practise Lake Constance, nervous system and internal organs. A consequent screening and timely preventive treatment
Singen (Hohentwiel), Germany;
2
Department of Neurosurgery, VUB of lesions are crucial for patients affected by VHL disease. Surgical indications and treatment
University Medical Center Brussels, have been evaluated and optimized over many years. In the last decade, pharmacological
Brussels, Belgium; 3Department of
therapies have been evolving, but are largely still at an experimental stage. Effective
Neurology, University Hospital Antwerp,
Antwerp, Belgium; 4Fox Chase Cancer pharmacological therapy as well as detection of biomarkers is based on the understanding
Center, Philadelphia, PA, USA; of the molecular basis of disease. The molecular basis of von Hippel-Lindau disease is the
5
Department of Pathology, Indiana
University-Purdue University, loss of function of the VHL protein and subsequent accumulation of hypoxia-inducible factor
Indianapolis, IN, USA with downstream effects on cellular metabolism and differentiation. Organs affected by VHL
disease may develop frank tumors. More characteristically, however, they reveal multiple
separate microscopic foci of neoplastic cell proliferation. The exact mechanisms of tumor-
igenesis in VHL disease are, however, still not entirely understood and knowledge on
biomarkers and targeted therapy is scarce.
Keywords: Von Hippel-Lindau, VHL, tumor suppressor gene, neuroendocrine tumor,
pancreatic tumor, pheochromocytoma, tumor formation, second hit, hemangioblastoma,
renal cancer

Overview of VHL Disease

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor
syndrome. The disease usually manifests in young adulthood and predisposes
affected patients to the development of benign and malignant tumors of different
organ systems, mainly including nervous system and internal organs. The incidence
of VHL disease has been assessed as one in 36,0001,2 and the penetrance is higher
than 90%.3
VHL disease is named after German ophthalmologist Eugen von Hippel, who
identified and described retinal hemangioblastomas,4 and Arvid Lindau, a Swedish
Pathologist, who discovered the coincidental occurrence of retinal and cerebellar
hemangioblastoma with tumors and cysts in internal organs. He published the
Correspondence: Sven Gläsker
Department of Neurosurgery, VUB clinical spectrum of VHL disease.5,6
University Medical Center Brussels,
Laarbeeklaan 101, Brussels 1090, Belgium
Clinically, the patients are divided into different groups: Patients with VHL type
Email [email protected] 1 predominantly without pheochromocytoma, and VHL type 2 predominantly with

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Box 1 Example of a Routine Surveillance Protocol for Von Hippel– not appear to be fully redundant in function. Although germ-
Lindau Disease line knock-out of HIF1α and HIF2α results in embryonic
Annual ophthalmic examinations (direct and indirect lethality the timing and cause of death appear to differ.17
ophthalmoscopy), beginning at age 1 to screen for retinal Moreover, post-natal inactivation of HIF1α and HIF2α leads
hemangioblastoma. to differing phenotypes as well. The two proteins are also
Contrast-enhanced MRI brain and full spine to screen for CNS
differentially expressed in VHL lesions, where immature
hemangioblastomas, beginning at age 12. Annual or biennial depending
cells show exclusive activation of HIF2α in contrast to frank
on manifestations
MRI examinations of the abdomen every 12 months to screen for tumors that show activation of both HIF2α and HIF1α.18,19
renal cell carcinoma and pancreatic tumors, beginning from the age of Many of the HIF-dependent proteins are involved in oxy-
12 years. gen sensation and regulation and include genes involved in the
Annual blood pressure monitoring and 24-h urine studies for uptake and metabolism of glucose (GLUT-1, 6-PFK, PDK),
catecholamine metabolites starting at age 4 y to screen for
angiogenesis (VEGF, PDGF, CTGF), control of extracellular
pheochromocytoma. Alternatively measuring plasma free
pH (CA9), mitogenesis (TGFα), and erythropoiesis
metanephrines.
Biennial audiogram starting at age 16 to screen for ELST (erythropoietin).20–23 EGFR and TGFα promote cell prolifera-
Note: Data from Maher.204
tion and survival. CXCR4 and its ligand SDF1 stimulate
chemotaxis and may also contribute to tumor cell invasion
pheochromocytoma.7 VHL type 2 is further subdivided and metastases. MMP1 and lysyl oxidase (encoded by LOX)
into type 2A (with renal cancer) and type 2B (without are implicated in ECM breakdown and tumor cell invasion/
renal cancer). In type 2C, affected patients develop solely migration. Finally, dysregulation of TWIST and activation of
pheochromocytomas.8 HGFR (encoded by c-MET) are involved in epithelial-to-
mesenchymal transition (EMT).
Deciphering of the molecular mechanisms of VHL func-
Molecular and Histomorphological tioning has had a large impact on the understanding of oxygen
Basis of VHL Disease sensation in mammalian cells and the development of neopla-
VHL inactivation has a variety of different effects on human sia in general.24 The Nobel Prize in Physiology or Medicine
tissue on molecular as well as on histomorphological levels. 2019 was awarded jointly to William G. Kaelin, Peter
Since there is no animal model available to date, which has the J. Ratcliffe and Gregg L. Semenza “for their discoveries of
full VHL phenotype, most knowledge is based on restricted how cells sense and adapt to oxygen availability.”
knockout models or on observations in human tissues.
HIF-Independent Effects
Molecular Basis of VHL Disease In addition to HIF degradation, the VHL protein is
Patients affected by VHL disease carry a germline muta- involved in HIF-independent cellular processes, which
tion of the VHL tumor suppressor gene.9 Five-hundred may be connected with tumorigenesis. It regulates the
different pathogenic germline mutations have been identi- proper deposition of fibronectin and collagen IV within
fied in families with VHL disease.10 The VHL protein the extracellular matrix.25 It furthermore stabilizes micro-
(pVHL) interacts with elongins B, C and Cullin-2 to tubules and maintains the primary cilium. The VHL pro-
form the VBC complex, an E3 ubiquitin ligase.11 This tein also activates and stabilizes p53 and, in neuronal cells,
complex mediates ubiquitin-mediated degradation.12–14 induces apoptosis by downregulation of Jun-B.25 Acute
Biallelic inactivation of VHL is thought to be the basis loss of VHL protein causes a senescent-like phenotype. It
of tumorigenesis in VHL disease. Reintroduction of the appears that it increases p400 activity, which results in
VHL function can reverse some effects of inactivation.15 inactivation (hypophosphorylation) of the retinoblastoma
The consequences of VHL inactivation can be divided into protein (pRb) and prevents senescence.26 The VHL protein
HIF-dependent and HIF-independent effects (Figure 1). can also act as an adaptor to bind CK2, which inactivates
the NF-kB agonist CARD9, leads to inhibition of NF-kB
HIF-Dependent Effects signaling and overall inhibits cell survival. It is further-
HIF is a heterodimeric transcription factor consisting of an more needed for primary cilium function by microtubule
unstable α and a stable β subunit. Different HIFα genes have stabilization and binding with aPKC and the polarity pro-
been identified in the human genome.16 HIF1α and HIF2α do teins Par3 and Par6.

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Figure 1 VHL protein functions: HIF independent and HIF dependent. Abbreviations: aPKC, atypical protein kinase C; CA9/12, carbonic anhydrase 9/12; CARD9, caspase
recruitment domain-containing protein 9; CDKN1B, cyclin-dependent kinase inhibitor 1B; CK2, protein kinase CK2; CoV, type V collagen; CTGF, connective tissue growth
factor; Cul2, Cullin 2; CXCR4, CX chemokine receptor type 4; ECM, extracellular matrix; EGFR, epidermal growth factor; FLK1, fetal liver kinase 1; GLUT1, glucose
transporter 1; GSK3B, glycogen synthase kinase 3 beta; HIF, hypoxia-inducible factor; HGFR, hepatocyte growth factor; LOX, lysol oxidase; MDM2, mouse double minute 2
homolog; MMP, matrix metalloproteinases; NFKB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS, nitric oxide synthase; PDGF, platelet-derived growth
factor; RBX1, ring box protein 1; SDF1, stromal cell-derived factor 1; TCEB1/2, transcription elongation factor B1/2; TGF, transforming growth factor; TWIST, twist related
protein; VEGF, vascular endothelial growth factor; 6PFK, 6 phosphofructokinase.

The different HIF dependent and HIF-independent mole- Histomorphological Basis of VHL Disease
cular functions imply several possible ways of how VHL Organs affected by VHL disease may develop frank tumors.
related tumorigenesis may occur and which molecular targets More characteristically, however, they reveal multiple separate
could possibly be used for therapy. Despite the broad under- microscopic foci of neoplastic cell proliferation. Detailed his-
standing of VHL functioning, it remains largely unclear, how tologic studies – combined with molecular analysis – were
a “normal” cell of a VHL patient which carries one mutated performed on autopsy material after processing the entire
VHL allele is transformed into a tumor cell. Simple inactiva- anatomic structure (eg studies on entire spinal cord
tion of the second VHL allele seems insufficient for tumor (Figures 2 and 3), cerebellum, epididymis (Figures 4 and 5),
growth27–29 and does also not explain the peculiar organ dis- or vestibular aqueduct) allowing for variably precise quantita-
tribution of the disease with mainly CNS and internal organs tion of these neoplastic foci. Studies on both the entire VHL
involved. Some keys to these unsolved questions are discussed spinal cord and surgically resected spinal cord tumors revealed
in the next section on histomorphological tumorigenesis. these microscopic neoplastic foci to represent early, VHL-

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Figure 2 Early VHL pathogenesis in the nervous system: Hemangioblastoma precursors. Histologic examination of grossly normal-appearing nerve root tissue of VHL
patients reveals numerous microscopic hemangioblastoma precursor structures within nerve roots. Reprinted with permission from Vortmeyer AO, Tran MG, Zeng W, et al
Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006;210(3):374–382.18

inactivated precursor lesions. This chapter describes histologic shows a high degree of variability. Cytologically, hemangio-
changes occurring organs affected by VHL disease with spe- blastomas are predominantly composed of two types of cells.
cial consideration of early tumorigenesis. The first cytologic component is characterized by conspicuous

Tumors Involving CNS neoplastic and VHL-inactivated clear cells that are convention-
Hemangioblastoma ally called “stromal” cells. “Stromal” cells do not exist in
The histology of neurosurgically resected hemangioblastomas normal nervous system tissue, and their origin has been

Figure 3 Hemangioblastoma progression. Proposed structural progression of hemangioblastoma from mesenchymal (A) to epitheloid (B and C) and vasculogenetic
architecture/extramedullary erythropoiesis (D–G); (A–D), immunohistochemical stain for CD31; (E–G), (H and E) stain. Immunohistochemistry for CD31 was performed
to better differentiate reactive vascular cells (positively staining cells) from neoplastic cells (negatively staining cells). (H and E) stain was performed to demonstrate
erythropoiesis within epitheloid and vasculogenetic structures. Reprinted from Exp Mol Pathol, 96(2), Glasker S, Smith J, Raffeld M, Li J, Oldfield EH, Vortmeyer AO, VHL-
deficient vasculogenesis in hemangioblastoma 162-167, Copyright (2014), with permission from Elsevier.205

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Figure 4 Early VHL pathogenesis in the epididymis: cystadenoma precursors. (A–C) Multifocality of cystadenoma precursor structures: “Tumor-free” VHL epididymis contains
multifocal microscopic precursors in the efferent ductule compartment of the caput (marked by arrows); e= normal efferent ductules. Republished with permission of John Wiley &
Sons-Books, from Epididymal cystadenomas and epithelial tumorlets: Effects of VHL deficiency on human epididymis, Glasker S, Tran MG, Shively SB, et al. J Pathol. 210(1):32–41.
permission conveyed through Copyright Clearance Center, Inc. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.48

controversial. While “stromal” cells are lipid- and glycogen- and explained by the expression of HIF, VEGF and other
rich cells with abundant clear or bubbly cytoplasm in larger angiogenic factors in stromal cells.32,33
tumors, they are smaller and less conspicuous in small tumors Hemangioblastomas show not only cytological but also
or precursor structures. The other cytologic component of marked architectural variation. Tumor cells may be scattered
hemangioblastomas is represented by abundant blood vessels. within a matrix of abundant capillaries, referred to as
The blood vessels do not show VHL inactivation 30,31
and “reticular”34 or “mesenchymal”35 architecture. Tumors may
therefore represent reactive angiogenesis. Intense reactive also reveal epitheloid tumor cell clustering, referred to as
angiogenesis is a characteristic feature of hemangioblastoma “cellular”34 or “epitheloid”35 architecture. A transition from

Figure 5 Papillary cystadenoma of the epididymis. (A), Gross examination of VHL epididymis shows enlargement of the caput epididymis (white arrows). (B),
Cystadenomas reveal papillary (pap), tubular (tu) and cystic (cy) architecture. (C), Immunohistochemical staining with anti-CD31 reveals extensive vascularization of the
tumor stroma. Numerous reactive vascular cells are in direct contact with overlying neoplastic epithelial cells. Republished with permission of John Wiley & Sons-
Books, from Epididymal cystadenomas and epithelial tumorlets: Effects of VHL deficiency on human epididymis, Glasker S, Tran MG, Shively SB, et al J Pathol. 210(1):32–41.
permission conveyed through Copyright Clearance Center, Inc. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.48

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mesenchymal to epitheloid architecture occurs gradually with Significant changes occur during the progression of
3
tumor growth. Hemangioblastomas smaller than 8 mm in size a precursor structure to tumor.39 Cytologically, the VHL-
show exclusively mesenchymal architecture, while epitheloid deficient cells markedly increase in size and develop abun-
features may be developed in tumors larger than 6 mm3; dant clear, vacuolated or eosinophilic cytoplasm. While in
epitheloid features have been consistently observed in tumors the earliest stages of tumorigenesis VHL-deficient tumor
cells show – similar to the VHL-deficient cells in the
larger than 737 mm3.35 A markedly elevated Ki67 prolifera-
precursor lesions – a diffuse distribution pattern
tion index in epitheloid areas suggests that epitheloid features
(“mesenchymal architecture”), further tumor growth con-
are associated with accelerated tumor growth.35
sistently reveals tumor cells to form small clusters
Biologically, the profound cytologic and architectural
(“epitheloid architecture”) in parts of the tumor.35
transformation from mesenchymal to epitheloid tumor clo-
The retina develops from extensions of the neural tube,
sely resembles stages of embryonic hemangioblastic
providing justification to include retinal hemangioblastomas
transformation.36 The capacity of “stromal” cells to differ-
among the craniospinal hemangioblastomas. Furthermore,
entiate into red blood cells has been subsequently
histologic features of small and larger retinal tumors are
demonstrated37,38 and a shared protein expression profile
identical to those of nerve root and cerebellar hemangioblas-
with hemangioblast precursor cells has been identified.28
tomas. Analogous to CNS tumors, retinal hemangioblasto-
Therefore, multiple lines of evidence have confirmed the
mas are composed of VHL-inactivated tumor cells with
“stromal” cells to represent hemangioblastic precursor cells. intense reactive vascularization40,41 and unrelated to capil-
The histologic evolution of hemangioblastomas is not lary hemangiomas occurring elsewhere in the body.
completely understood. The earliest stages of VHL tumor-
igenesis are represented by microscopic foci, undetectable
Endolymphatic Sac Tumors
radiologically or by the naked eye. Because of their minute
Endolymphatic sac tumors were originally described by
size, these foci can only be detected by detailed histologi-
Heffner as adenocarcinomas of probable endolymphatic
cal analysis of normal-appearing tissues of VHL patients.
sac origin.42 Endolymphatic sac tumors in VHL disease
Moreover, to obtain information on the number and dis-
are extensively vascularized tumors forming prominent
tribution of microscopic lesions, tissue blocks need to be
papillary structures, the papillae being lined by a single
step-sectioned at 50-micron intervals. Such studies have
row of cuboidal epithelial cells. Cysts lined by single rows
been performed on tissues of VHL patients that had been
of cuboidal cells are frequently present, and epitheloid clear
obtained at autopsy. Analysis of a series of cases revealed
cell proliferation is occasionally detected.27 Tumors larger
that precursor lesions of spinal cord hemangioblastomas
than 10 mm in size usually present with bony erosion, while
were exclusively located in nerve root tissue, dorsal roots the exact border between endolymphatic duct and sac is not
being far more frequently involved than anterior roots. clearly defined, it is of clinical relevance that tumors appear
Tumors preferentially developed from dorsal root precur- to originate most frequently from intraosseous portions of
sors in close proximity to the spinal cord.29,39 In general, endolymphatic sac/duct epithelium.27
precursor structures are detected in far greater abundance Studies on clinically uninvolved endolymphatic sac
than frank tumors;29,39 therefore, precursor structures have and duct of VHL patients showed evidence for VHL-
extremely low proliferative potential, and only a small inactivated cells lining cysts or papillary projections; in
subset of precursor structures will develop into tumors. analogy to studies in other tissues these microscopically
In the cerebellum, precursors originate in the molecular small cystic or papillary structures may represent early
layer.19 Numerically, precursor structures are far more stages of endolymphatic sac tumors.27
frequent in dorsal root tissue compared to cerebellar tissue.
It, therefore, appears that precursors in the cerebellum Visceral Tumors
have a higher probability to develop into clinically rele- Renal Cell Carcinoma
vant tumor than nerve root precursors.19 The diseased VHL kidney is characterized by renal cysts
Histologically, precursor CNS lesions reveal a sharply and clear cell carcinoma. These pathologic changes show
demarcated zone containing abundant capillaries and scat- wide differences in growth.43 Histologically, solid tumors
tered small VHL-deficient cells;29 by immunohistochem- and cysts are composed of clear cells and associated with
istry, VHL-deficient cells have revealed HIF2 activation.39 intense vascularization.44 There is a histopathologic

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continuum ranging from benign cysts and atypical cysts to suggesting a continuum of development from the pancrea-
carcinoma.44 Numerically, by far the most pathogenic tic cyst(s) to microcystic adenoma.54
events in the kidney are represented by microscopic cystic
and solid neoplasms.45 VHL gene function is inactivated Pancreatic Neuroendocrine Tumor
in the smallest foci of microscopic neoplasia.46,47 All clear Pancreatic neuroendocrine tumors were established as
cell tumors in the kidney are designated renal cell carci- VHL component tumors in 1998.55 Compared to sporadic
noma, although they need to reach at least 3 cm size to
neuroendocrine tumors, VHL-associated neuroendocrine
acquire the capacity to metastasize. Histologically, larger
tumors more frequently exhibit clear cell morphology
renal clear cell tumors may develop frankly malignant
which may be challenging to differentiate from metastatic
features including tumor necrosis and cytologic anaplasia
renal cell carcinoma or pancreatic microcystic adenoma
with mitotic activity.
which may occur in the same pancreas.55

Epididymis Cystadenoma
Epididymal cystadenomas are component tumors of VHL Adrenal Pheochromocytoma and Extra-Adrenal
disease composed of cuboidal epithelial cells, with papil- Paraganglioma
lary, tubular and cystic architecture, and prominent angio- Pheochromocytomas and paragangliomas are associated
genicity. Numerous tumor precursor elements were with multiple hereditary disorders. The histologic features
detected by a thorough analysis of nontumorous epididy- are distinguished from other VHL disease-associated clear
mides obtained at autopsy (Figure 4). Topographically, cell neoplasms by more variable, frequently polyhedral
precursor structures were confined to the efferent ductules cytology, basophilic and finely granulated cytoplasm and
of the caput epididymis. Precursor structures were charac- cytoplasmic bodies in both familial and nonfamilial
terized by the formation of epithelial cysts and prominent cases.56 In contrast, analysis of VHL disease-associated
epithelial proliferation into the lumina of cysts and efferent pheochromocytomas revealed tumor cells with clear or
ductules.48 A 3dimensional reconstruction of intraductular amphophilic, inclusion-free cytoplasm that were more
papillary neoplastic growth revealed the complex inter- intensely intermixed with vascular cells.57
mingling of pre-existent anatomic structure and slow neo- In conclusion, the characterization of precursor structures
plastic growth creating a hamartomatous appearance.49 has provided more precise insight on the anatomic and cytolo-
Since epididymal cystadenomas are rare neoplasms, the gic origin of neoplastic processes associated with VHL disease.
occurrence of bilateral tumors is highly associated with In all anatomic structures investigated so far, precursor struc-
VHL disease.50 tures were far more numerous than frank tumors. Therefore,
VHL inactivation (“second hit”) is necessary, but insufficient
Papillary Cystadenoma of the Broad Ligament for the development of a frank tumor. In the future, compara-
Papillary cystadenoma of the broad ligament occurs less tive molecular analysis of frank tumor and precursor structures
frequently than epididymal cystadenoma. Morphological may be helpful to identify a “third hit” promoting tumorigen-
and immunohistochemical features strongly overlap. esis from precursor material.
Morphologic and genetic studies have established this
tumor as a VHL component tumor, and it is considered
as female counterpart tumor of epididymal cystadenoma.51
VHL Disease Manifestations and
Treatment
Pancreatic Microcystic Adenoma Patients affected by VHL disease develop specific types of
Microcystic adenomas of the pancreas (serous cystadeno- heavily vascularized tumors in a highly selective subset of
mas) are tumors composed of small cysts lined by flat- organs. Multiple and bilateral tumors occur frequently.
tened or cuboidal glycogen-rich cells.52 After the initial Affected organs and lesions include retinal hemangioblas-
demonstration of VHL gene deletion and mutation in tomas, cerebellar, brainstem and spinal cord hemangio-
microcystic adenomas,53 a more detailed analysis of the blastomas, endolymphatic sac tumors, renal cell
VHL pancreas revealed the presence of numerous small carcinomas, pheochromocytomas, pancreatic cysts, micro-
microcystic adenomas as well as VHL gene-inactivated cystic serous adenomas, neuroendocrine tumors, as well as
pancreatic cysts; most cysts were of microscopic size epididymal cystadenomas.58–61

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Retinal Hemangioblastomas bone. Patients will typically present with hypoakusis or

Retinal hemangioblastomas are benign tumors that fre- hearing loss (100%), tinnitus (77%), dysequilibrium
quently occur in multiplicity and bilaterally in VHL (62%), and facial paresis (8%).75 Tumor-associated intra-
patients. Expression of high levels of VEGF in these labyrinthine hemorrhage may lead to acute hearing loss
tumors causes hypervascularization, vascular leakage and and vestibulopathy due to endolymphatic hydrops.76 All
eventually retinal detachment. patients with endolymphatic sac tumors (ELSTs) should
Annual screening by fundoscopy and if necessary fluores- undergo diagnostic testing for VHL mutations since endo-
cence angiography is recommended for VHL patients starting lymphatic sac tumors can be the first manifestation of
at 1 year of age. Early treatment of asymptomatic lesions is VHL disease.
recommended. Laser coagulation or cryotherapy can control In general, early surgical resection is recommended to
the majority of peripheral retinal hemangioblastomas.62,63 enhance the possibility of complete resection and avoid
Larger tumors can be treated by vitrectomy.64 Optic disc hearing loss or vestibular symptoms, which may be
hemangioblastomas should be monitored without treatment. irreversible.77 The timing of surgery depends on the severity
With regular screening and early treatment of detected lesions, of symptoms, the slow but variable growth of the tumors, the
visual prognosis for VHL patients is in general good: In one possibility of injury to the 7th and 8th cranial nerves and
major study approximately 8% of the eyes of VHL patients possible bilateral occurrence. The role of radiation in the
had poor visual acuity of 20/200 or worse with approx. 8% of treatment of these tumors remains controversial.78
these eyes requiring enucleation.65 Description of pharmacological therapies is scarce and is
Pharmacological treatments are in experimental stages discussed in the section on targeted therapy.
and are discussed in the section on targeted therapies.
Renal Manifestations
Patients with VHL disease may develop renal cysts and
Craniospinal Hemangioblastomas renal cell carcinomas (RCCs).46,79–83 VHL-disease-
Hemangioblastomas are benign slow-growing highly vas-
associated RCCs tend to be low grade and minimally
cularized tumors. They are frequently the first manifesta-
invasive,84 their rate of growth varies widely.85,86 VHL
tion of VHL disease. These patients frequently develop
alterations are also observed in 60–70% of sporadic
multiple hemangioblastomas.66 The hemangioblastoma
RCCs.87
tumor burden in VHL disease is associated with germline
The goal of therapy is the prevention of metastasis and
deletions and male sex.67 Depending on their size and
maintenance of kidney function. Most authors recommend
location hemangioblastomas cause different neurologic
nephron-sparing surgery for carcinomas that exceed 3 cm
symptoms.66,67 It is usually an associated pseudocyst or
in size.79,88 Other authors suggest that a diameter of 4 cm
syrinx and not the tumor itself which causes the
is also acceptable.89 The “3 cm rule” takes into account the
symptoms.68 The syrinx is caused by vascular leakage
overall survival and quality of life (considering potential
and is frequently larger than the tumor itself.66
premature renal failure and need for dialysis).
Polyglobulia occurs in 10% of patients69 and may cause
Although the gold standard for treating renal tumors is
thrombosis. Removal of the largest hemangioblastoma
open and minimally invasive partial nephrectomy, alterna-
usually resolves polyglobulia.69
tive therapies including cryotherapy and radiofrequency
Treatment is primarily surgical and is recommended
ablation are also presently utilized.90 Pharmacological
for all symptomatic tumors and for all tumors causing CSF
therapy is used for metastatic disease and is discussed in
obstruction.66,70,71 If surgery is not possible, radiation
the section on targeted therapy.
therapy may be an alternative, however, its effectiveness
remains controversial.72–74 Pharmacotherapy of CNS
Pheochromocytoma
hemangioblastoma is at an experimental stage and is dis-
In more than 33% of patients, pheochromocytomas can
cussed in the section on targeted therapy.
occur in a familial syndrome such as the VHL
syndrome.91,92 The presence of pheochromocytomas
Endolymphatic Sac Tumors defines VHL disease type 2 (A,B,C). More than 26% of
These histologically benign tumors originate in the vestib- VHL patients developed pheochromocytomas in major
ular aqueduct and grow locally invasive into the petrous series.93–96

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Few tumors are hormonally inactive with plasma-free pheochromocytoma occurred in 3 patients of a VHL
metanephrine levels within the normal reference range. The cohort consisting of 273 patients94 and recurrences
tumors occur bilaterally in up to 39% of patients.93 The occurred in 8 of the 273 patients. Bausch and colleagues
tumors can also be found in the sympathetic chain and are found a 38% risk of developing a second paraganglioma in
then mostly unable to produce and secrete pediatric patients diagnosed with pheochromocytoma.121
catecholamines.92,97–100 In general, extra-adrenal pheochro- There is no consensus on whether hormonally inactive
mocytomas have a higher frequency and potential of malig- pheochromocytomas require treatment. The decision will
nancy than pheochromocytomas located in the adrenal depend on tumor growth, symptoms, and possible
gland.101 No biomarkers are available that can reliably dis- metastasis.106,122 Mutation-adjusted surveillance aims to
tinguish a benign from a metastatic pheochromocytoma. increase life expectancy.123
Screening for pheochromocytoma includes measure-
ments of urinary catecholamine metabolites and fractio- Epididymal Cystadenoma
nated metanephrines, as well as of plasma-free About 50% of male VHL patients develop these non-
metanephrines.94,102,103 The diagnosis can further be malignant tumors.124 Epididymal cystadenomas typically
established by abdominal computed tomography and/or arise in the head of the epididymis and contain cystic as
magnetic resonance imaging.58,105 Given the low fre- well as adenomatous areas and. These lesions are usually
quency of extra-adrenal pheochromocytomas (15%) or asymptomatic. Malignant transformation has not been
metastatic (<5%) pheochromocytomas in patients with reported. Obstruction of efferent ductules and spermatic
VHL disease, selected patients should undergo 123I- cords may result in fertility problems in rare cases. If
MIBG scanning to screen for extra-adrenal or metastatic necessary, these tumors can be seen on ultrasound.
disease18,101,105 F-FDG, and more recently,67 Ga The female counterparts are cystadenomas of the broad
DOTATATE PET have been shown to offer better test ligaments. They play no major clinical role. “Adnexal
characteristics for assessment and staging of pheochromo- papillary cystadenoma” are rare, but may require surgery.
cytoma/paraganglioma than 106 MIBG scintigraphy107–110 They are of probable mesonephric origin.
The detection of a pheochromocytoma in patients with
VHL syndrome is important to prevent life-threatening Pancreatic Manifestations
hypertensive attacks. Hormonally active pheochromocy- Pancreatic manifestations in VHL disease include cystade-
tomas should generally be treated before surgical treat- nomas, cysts and pancreatic neuroendocrine tumors.125
ment of other VHL lesions to prevent intraoperative A recent series of 48 patients with VHL disease at the
hypertensive complications and require perioperative Mayo Clinic also revealed 5 patients with branch duct
blockade.111 intraductal papillary neoplasm.126
It is recommended that pheochromocytoma screening Pancreatic manifestations are observed in 35–70% of
should be started already in childhood at the age of 4 VHL patients.55,127,128 It may be difficult to differentiate
years,58,92,94,96,112 acknowledging that metastatic pheo- between benign microcystic adenoma and a pancreatic
chromocytoma occurs in asymptomatic VHL patients.113 neuroendocrine tumor. Pancreatic neuroendocrine tumors
In patients with apparently familial pheochromocytoma also reveal a staggering growth pattern similar to
there is a 50% chance of VHL disease, whereas the disease hemangioblastoma.129
is detected in only 10% of patients with sporadic Besides rare cases of bile duct obstruction or pancreatic
pheochromocytoma.92,114,115 More than 70% of pediatric insufficiency these tumors are usually asymptomatic.
pheochromocytomas are VHL related. Screening is performed by contrast-enhanced MRI with.
Treatment of nonmetastatic adrenal pheochromocy- Image acquisition has to be performed in the early arterial
toma consists of adrenal cortical sparing (partial) tumor phase. Pancreatic neuroendocrine tumors are usually solid
removal, whenever possible.116–119 Minimally invasive lesions, whereas microcystic adenomas reveal
adrenal sparing removal of the pheochromocytoma should a multicystic appearance. Microcystic adenomas usually
be performed in most if not all patients.120 need no treatment, whereas pancreatic neuroendocrine
This potentially impacts survival as the risk of death tumors need to be considered for surgery. Mutations in
from primary adrenal insufficiency may be higher than exon 3, especially of codons 161/167 are at enhanced risk
dying of a recurrent pheochromocytoma. Metastatic for metastatic pancreatic neuroendocrine tumors.130 Most

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of these lesions are small and slow-growing. In general, expectancy.140 Modern management of VHL disease-
VHL-associated pancreatic neuroendocrine tumors have associated lesions has achieved a life expectancy of addi-
a favorable prognosis compared to sporadic tumors.131 tional 10 years.141
Tumors with a diameter over 2.8 cm should be treated
surgically to avoid metastasis according to a recent multi- Biomarkers in VHL Disease
center study.130 68Ga-DOTATOC PET/CT has better sen- Timely screening for and preventive treatment of lesions is
sitivity in detecting pancreatic NET (size range 4–38 mm) key to the successful management of VHL patients.
in patients with VHL than 111In-octreoscan.132 Recent developments in oncology are biomarkers includ-
Resection of pancreatic tumors may be combined with ing tumor markers, disease activity markers, liquid biopsy
laparotomy for other VHL associated lesions.133,134 and others. We here review the knowledge of systemic
Biliary obstruction with pancreatic insufficiency can be biomarkers. Tumor-specific markers, which are detected
treated by placing biliary stents or replacing pancreatic within the tumor tissue, are not reviewed here. To date,
enzymes. A new option is organ-sparing minimally inva- systemic biomarkers do not play a role in the clinical
sive resection which can be applied to tumors in the tail practice of VHL disease, except for plasma and urinary
and the body of the pancreas.135 Chemotherapy is cur- catecholamine metabolites and fractionated metanephrines
rently under investigation and discussed in the section on for pheochromocytoma. However, there are interesting
targeted therapy. new developments. Certain markers or combinations of
markers may be further developed for clinical use in the
VHL Screening and Prognosis future and may supplement or even replace other time-
A careful family history and screening for other lesions consuming screening examinations.
associated with VHL should be performed in all patients Measuring plasma levels of HIF-dependent molecules
with hemangioblastoma, the index tumor of VHL disease. appears to be an obvious attempt to monitor disease activity
Genetic testing for VHL disease is recommended for all in VHL patients. One group has suggested using plasma
patients with hemangioblastoma.136,137 VEGF and miRNA210, a hypoxia-inducible micro-RNA,
If a diagnosis of VHL disease is established, patients to monitor disease activity in VHL patients with retinal
should undergo an annual screening program (Box 1) for hemangioblastomas. They report that levels of both mole-
the timely identification of manifestations before irrever- cules decreased in all patients under therapy with
sible deficits or metastasis occurs. Screening includes per- propranolol.142 Other groups have observed a decrease of
iodic contrast-enhanced MRI scans. While CNS serum levels of the HIF-dependent proteins VEGF and also
gadolinium accumulation will eventually occur in virtually the receptors VEGFR-2 and VEGFR-3 as well as CA9
all VHL patients, no pathological effect of this accumula- during therapy with sunitinib and sorafenib in patients with
tion is known so far.138 VHL-associated and sporadic RCC.143 Reduction of serum
The screening programs vary slightly between different VEGF levels was also detected in mice with xenografted
centers. A typical program is presented in Box 1. The VHL RCCs under propranolol treatment.144
screening includes several contrast MRI scans. Most cen- Also, monitoring tumor secretion products may be of
ters perform three different scans. Brain, spine and abdo- interest in VHL disease. VHL patients with pancreatic
men. Since the discovery of Gadolinium (Gd) depositions neuroendocrine tumors had a correlation with plasma
in the CNS it is being considered to minimize the use of vasoactive intestinal peptide and pancreatic polypeptide
Gadolinium. These depositions are particularly frequent in levels in one study.145
VHL patients.138 A shortened 35-mins whole-body MRI The significance of VHL mutations as a predictive
protocol with only one Gd injection has been recently marker in sporadic RCCs is well described. VHL muta-
suggested139 making VHL screening also quicker and tions in circulating tumor DNA have been detected by
more convenient for patients. liquid biopsy using a Taqman assay.146
The overall life expectancy of VHL patients used to be Another study describes the identification of VHL
limited with a median survival of around 50 years.2,60 mutations in circulating cancer cells with single-cell
However, the introduction of clinical screening enabled genetic analysis.147
timely diagnosis and prophylactic treatment of VHL Polyglobulia has been described as a paraneoplastic phe-
lesions leading to significantly improved life nomenon in VHL disease. It was reported to occur in CNS

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hemangioblastomas as a consequence of the secretion of targeted VHL therapy mainly focuses on inhibiting pri-
erythropoietin. More recent studies show that this phenom- mary tumor growth and angiogenesis.
enon is rare, but if present, polyglobulia subsides with the Up to date, the incomplete understanding of VHL
removal of the hemangioblastoma.69 This is consistent with tumorigenesis has thwarted the development of a targeted
reports of erythropoietic activity in a subset of therapy against the disease. Furthermore, VHL tumors are
hemangioblastomas.37 Interestingly, the level of serum ery- known for their saltatory growth pattern with quiescent
thropoietin and the extent of polyglobulia do not correlate.148 phases, which complicates the distinction between
However, the size of the solid tumor component correlates response to treatment and natural behavior. Considerable
with polyglobulia. Therefore, polyglobulia is a biomarker for effort has been spent on pharmacological trials, harvesting
tumor growth in a subset of hemangioblastomas. mixed results. There are no systematic reviews on phar-
Polycythemia has also been reported in patients with VHL macological trials in VHL disease. We have reviewed
disease and renal cancer149 and pheochromocytoma.150 more than 50 studies or case reports and summarized the
In general, the knowledge on biomarkers in VHL dis- findings here. The studies are categorized by the main
ease is scarce and this should be addressed in future action of their respective drug (Figure 6).
clinical studies on VHL disease.
Monoclonal Antibodies
Because VHL tumor vascularization (and consequently also
Targeted Therapy in VHL Disease tumor growth) is largely dependent on VEGF, many VHL
Targeted cancer therapy aims to block specific molecular treatment trials have focused on blocking the VEGF-pathway.
pathways of cancer cells. Targeted drugs can be subdi- Intravitreal injection of anti-VEGF monoclonal antibo-
vided into compounds that inhibit the growth of the pri- dies has been widely used as therapy for neovascular age-
mary tumor, prevent invasion in nearby tissue; or drugs related macular degeneration. It is now being repurposed
that block angiogenesis, metastasis and consequent devel- for retinal hemangioblastomas in VHL disease.151
opment of secondary tumors. Because most VHL related Bevacizumab is a monoclonal antibody that prevents
tumors are benign, or only carry a low rate of metastasis, interaction between VEGF-A (isoforms 206, 189, 165, 121

Figure 6 Molecular targeting in VHL disease: action mechanisms. Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FGF, fibroblast
growth factor; FGFR, fibroblast growth factor receptor; HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor
receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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and 110) and its receptors (VEGFR1/2). Research groups Pegaptanib is a monoclonal antibody that selectively binds
have reported moderate effects of intravitreal bevacizumab the VEGF-A 165 isoform (which is most predominant in
on retinal hemangioblastomas. hemangioblastomas) and thereby prevents interaction with its
Ach et al reported a VHL patient who experienced receptors (VEGFR1/2). Dahr et al published a pilot case series
growth stabilization of retinal hemangioblastomas after including 5 VHL patients with retinal hemangioblastomas that
several years of intravitreal bevacizumab injections.152 were ineligible for conventional treatment. After six intravi-
Tano et al treated two VHL patients with intravitreal bev- treal pegaptanib injections, macular exudation decreased in
acizumab in combination with vitrectomy, to stabilize two patients, and one of them experienced improved visual
a proliferative vitreoretinopathy caused by retinal hemangio- acuity. Three patients had adverse events that necessitated
blastomas. Even though exudation was suppressed, hemangio- treatment withdrawal; such as retinal detachment after laser
blastoma volumes remained stable.153 Hrisomalos et al treatment, retinal detachment caused by exudation, and pro-
reported a similar response in one VHL patient, after gressive macular edema. Pegaptanib did not reduce retinal
a regimen of 12 bevacizumab injections over 60 months.154 hemangioblastoma volumes and was therefore considered as
Tsai et al published contradictory results: photodynamic ther- a palliative treatment modality only.160
apy in combination with intravitreal bevacizumab and corti- We conclude that monoclonal antibodies directed against
costeroids reduced the volume of multiple retinal VEGF are mainly applied as adjunctive treatment to reduce
hemangioblastomas in one VHL patient, but exudation was macular exudation; in VHL patients with advanced juxtapapil-
not affected. According to Tsai et al, corticosteroids seem to be lary or peripheral retinal hemangioblastomas, which are ineli-
more effective in reducing exudation than bevacizumab.155 gible for conventional treatment. However, because of mixed
Walker et al described a VHL patient with rebound neovascu- results, larger prospective randomized trials may be needed to
larization after intravitreal bevacizumab injection, again with- evaluate their efficacy and safety.
out effect on tumor volume.156
Also, the systemic use of bevacizumab has been tested.
Wackernagel et al reported the active development of Tyrosine Kinase Inhibitors
retinal hemangioblastomas during systemic bevacizumab Tyrosine kinase inhibitors are targeted drugs that block
treatment in a VHL patient. Side effects of systemic use cellular signal transduction cascades. As for monoclonal
were paresthesias and nail petechiae.157 antibodies, pharmacologic VHL trials have mainly focused
To conclude; laser photocoagulation, cryotherapy, on the VEGF tumor pathway.
photodynamic therapy and pars plana vitrectomy seem to Semaxanib (SU5416) is a small molecule tyrosine
remain the gold standard for the treatment of retinal VHL kinase inhibitor of VEGFR2 and stem cell factor receptor
hemangioblastomas. Bevacizumab may be considered as c-kit. It has been widely used as a chemotherapeutic for
adjunctive therapy to stabilize exudation caused by multi- liver metastases of colon cancer and other malignancies.
ple treatments, and to halt neovascularization. To date semaxanib is not licensed for human use outside
Ranibizumab is another monoclonal antibody that prevents clinical trials. Its application in VHL disease has been
interaction between VEGF-A (isoforms 165, 121, 110 and tested in case reports and small series.
theoretically 206 and 189) and its receptors (VEGFR1/2). In 2002, Aiello et al reported a VHL patient with an optic
After three intravitreal ranibizumab injections, Michels et al nerve head hemangioblastoma, who was treated with 10 cycles
saw stabilization and decreased exudation of a retinal heman- of systemic semaxanib. Fundoscopic findings did not change;
gioblastoma in a VHL patient.158 Wong et al conducted however, a positive correlation was found between semaxinib
a prospective case series including 5 VHL patients with dose and visual acuity. Interestingly, Aiello et al reported no
advanced retinal hemangioblastomas, who followed a 24- change in tumor volumes of the patient’s synchronous cere-
week regimen of 7 intravitreal ranibizumab injections. Three bellar, spinal and pancreatic lesions.161
subjects noticed transient vision improvement, which was Later, other semaxanib trials have followed. Richard
however followed by progressive tumor growth and macular et al conducted a toxicity assessment study on 3 VHL
exudation. In one patient, macular exudate even increased patients. Semaxanib caused secondary polycythemia, with-
immediately. One patient experienced prolonged vision out effect on hemangioblastoma volumes.162
improvement and a decrease of macular exudate after 10 Girmens et al reported the decrease in macular exudate
injections, with stabilization of tumor volume.159 around a retinal hemangioblastoma, in a VHL patient who

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was treated with semaxanib for 7 months. However, Tsimafeyeu et al describe complete regression of
volume and vision remained stable.163 a metastatic renal cell carcinoma in a VHL patient, after
In 2004, Madhusudan et al conducted a Phase I/Phase 11 months of sunitinib treatment.178
II study with 4-week cycles of 8 semaxanib injections, Jonasch et al conducted a major pilot trial, treating 15
including 6 VHL patients. In one patient, brain/spinal VHL patients with sunitinib. After four cycles, response
hemangioblastomas and pancreatic cyst volumes remained was absent in hemangioblastomas and partial in 33% of
stable after 22.4 months of ongoing treatment and after renal cell carcinomas. Rebound growth in both tumor
41.4 months of follow-up. However, upper motor neuron groups occurred after 48 months. According to Jonasch
symptoms decreased. Another patient with retinal/brain/ et al, the higher concentrations of VEGFR2 in renal cell
spinal hemangioblastomas and renal/pancreatic/epididy- carcinomas compared to hemangioblastomas may explain
mal cysts only experienced complete regression of a sole differences in treatment sensitivity. Pancreatic NETs and
retinal lesion (which was also treated with laser coagula- cysts, retinal hemangioblastomas and renal cysts remained
tion). The patient had improved strength and sexual func- stable. Two patients with retinal hemangioblastomas
tion after 10 months of treatment. Tumor volumes experienced increased ocular discomfort, a finding also
remained stable on imaging. Clinical response in the reported by Oudard.168,173
other four patients was not described.164 In a retrospective analysis of 14 VHL patients, Roma
A similar improvement of upper motor neuron symp- et al reported partial response to sunitinib in 64% of
toms caused by semaxanib, without effect on tumor different VHL tumors (progressive renal cell carcinomas;
volume, was described by Schuch et al in a VHL patient and pancreatic, adrenal and ovarian lesions), yielding
with multiple spinal hemangioblastomas.165 a progression-free survival of 71.4% after 2 years.
To our great interest, Jennens et al reported a VHL Hemangioblastomas remained stable.171
patient with the complete metabolic and radiologic In conclusion, sunitinib response seems to be depen-
response of a metastatic renal cell carcinoma, after 11 dent on several individual patient characteristics; such as
systemic semaxanib injections.166 overall VHL disease severity, performance status, age and
Sunitinib is a first-generation tyrosine kinase inhibitor of tumor VEGFR status. Sunitinib is mainly used as
multiple receptors (including VEGFR1/2/3, and PDGFR αand a palliative treatment modality for temporary symptom
β). It is by far the most investigated targeted therapy in VHL control of renal cell carcinomas and pancreatic neuroendo-
disease. However, side effects often lead to disruption of treat- crine tumors. Complete remission of renal cell carcinomas
ment: fatigue, nausea, vomiting, diarrhea, mucositis, hemato- has been described. Sunitinib does not seem to affect
logic disturbances, nausea, hypertension and hand-foot cerebellar and retinal hemangioblastomas. Transient
neuropathy.167–179 shrinking of medullary hemangioblastomas, with neurolo-
Jimenez et al used oral sunitinib to treat a VHL patient with gic symptom improvement, was described by Oudard.173
a metastatic pelvic pheochromocytoma (positively staining for Similar to sunitinib, pazopanib is a first-generation
VEGF and PDGF beta on immunohistochemistry). The pheo- inhibitor of multiple tyrosine kinases (including VEGFR
chromocytoma started shrinking after 6 months. Interestingly, 1/2/3; FGFR3 and PDGFR αand β). It has been approved
also the patient’s renal (staining positive for VEGF) and pan- for the treatment of advanced renal cell cancer and
creatic tumor volumes decreased.167 advanced soft tissue sarcoma.
Other researchers published similar results in VHL patients In 2012, Kim et al reported a VHL patient with multi-
undergoing several years of sunitinib treatment: Ali et al (1 focal renal cell carcinoma and multiple cerebellar heman-
patient),169 Wang et al (1 patient),170 Kobayashi et al (1 gioblastomas that were all progressive under sunitinib
patient),172 Oudard et al (6 patients),173 Kim et al (4 treatment. Subsequent pazopanib treatment improved bul-
patients),174 Yuan et al (3 patients),176 Tsimafeyeu et al (1 bar symptoms and ambulation. On imaging, cerebellar
patient),178 Babinska et al (1 patient)179 and Nuñez et al (3 hemangioblastoma volume decreased, and renal cell carci-
patients).177 Results range from disease stability to partial noma growth rate slowed.180
response in (metastatic) renal cell carcinomas, in some (meta- Also remarkable is the report of Migliorini et al in
static) pancreatic neuroendocrine tumors and in one 2015, about a tetraplegic VHL patient with a non-
pheochromocytoma. resectable spinal hemangioblastoma, who regained

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ambulation after pazopanib treatment. The tumor seemed best response was a stable disease of central nervous
to be reshaped on MRI.181 system hemangioblastomas.186
Taylor et al described a VHL patient with the radiolo- Sorafenib is a multiple tyrosine kinase inhibitor of
gic shrinking of two spinal hemangioblastomas, after VEGFR2/3 and PDGFR β, among other receptors. In
pazopanib treatment. Neurologic symptoms did not 2017, Choi et al report partial response to sorafenib of
change, nor did the tumor volume of other hemangioblas- multiple small renal cell carcinomas and pancreatic cysts
tomas and one renal cell carcinoma.182 in 2 VHL patients. Retinal and spinal hemangioblastomas
In 2018, Jonasch et al conducted a single-arm nonran- did not respond. Manageable diarrhea was reported as
domized phase II study with pazopanib on 30 VHL a side effect.187
patients. After a median follow-up of 12 months, the
radiologic objective response rate was 52% in renal cell Biological Response Modifiers
carcinomas (59 tumors; 2 complete responses, 29 partial Biological response modifiers are drugs that boost or mod-
responses, 28 stable diseases), 53% in pancreatic serous ulate the host’s autologous immune response to neoplasia.
cystadenomas (17 tumors; no complete responses, 9 partial Some of these modifiers have been tested in vitro and in
responses, 8 stable diseases), and 4% in central nervous small VHL patient groups: roquinimex, thalidomide, IFN-
system hemangioblastomas (49 tumors; no complete α-2a, HIF2α inhibitors, octreotide, clarithromycin and
immunotherapy.
responses, 2 partial responses, 47 stable diseases, 2
Roquinimex is a derivative quinoline that exerts its
patients with intratumoral hemorrhage). None of the 30
anti-neoplastic potential by blocking angiogenesis and
patients developed new VHL related lesions or progressive
decreasing TNF-alpha synthesis. Second, by stimulating
disease during pazopanib treatment. Interestingly, the type
NK cell and macrophage activity, it also has immunosti-
of VHL mutation did not correlate with disease
mulant properties. In 1999, roquinimex caused a shrinking
response.183
of von-Hippel-Lindau paraganglioma xenografts in
Finally, Salim described the 9-month stability of
mice.188 No further studies have followed.
a VHL patient with retinal hemangioblastomas treated
Thalidomide acts as an immunosuppressive and anti-
with pazopanib184.
angiogenic agent, by modulating the actions of several
Reported side effects of pazopanib are fatigue, diar-
cytokines. It was withdrawn from the market due to its
rhea, increase of transaminases, oral mucositis, neutrope-
teratogenic side effects. However, in 2004, Tan et al used
nia, alopecia/hair depigmentation, hypertension, gastritis
thalidomide together with rofecoxib to control post-
and appendicitis.180,181,183
radiation inflammatory reaction in a VHL patient with
In conclusion, pazopanib seems to have a larger ther-
a cerebral hemangioblastoma.189 In 2009, Sardi et al
apeutic effect on renal cell carcinomas, compared to suni-
describe the growth stabilization of two progressive spinal
tinib. However, study results are inconsistent and side hemangioblastomas, in a VHL patient treated with thali-
effects are not to be neglected. domide during a follow-up period of 37 months.190
Erlotinib is a tyrosine kinase inhibitor of EGFR, indi- IFN-α-2a binds to type 1 interferon receptors. It has
cated for the treatment of metastatic non-small cell lung been previously applied as an antiviral agent in chronic
carcinoma and metastatic pancreatic cancer. In 2001, hepatitis C and as an antineoplastic agent in several types
Rogers et al reported progressive disease under oral erlo- of leukemia. In 2011, Niemela et al treated 3 VHL patients
tinib in a young VHL patient with multiple cerebellar and with recombinant IFN-α-2a. They reported no significant
spinal hemangioblastomas.185 shrinking of retinal, cerebellar nor spinal hemangioblasto-
Dovitinib is a tyrosine kinase inhibitor of multiple mas. Also, pancreatic and renal cysts remained stable.
receptors (including VEGFR1/2/3, PDGFRβ and FGFR1/ A mild diminishment of blood flow was noticed in retinal
3). It is currently under investigation for refractory multi- hemangioblastomas, potentially by inhibiting VEGF
ple myeloma and metastatic renal cell carcinoma. In 2018, secretion.191
Pilié et al conducted a pilot study of dovitinib in 6 VHL Following VHL inactivation, HIF2α is constitutively
patients. All patients discontinued treatment due to non- upregulated in sporadic and VHL-associated renal cell
compliance or side effects (fatigue, vomiting, severe rash, carcinomas, stimulating tumor growth by activating multi-
transaminitis, neutropenia, mucositis and dyspnea). The ple downstream targets such as VEGF, PDGF, EGFR,

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TGFα, FGF, GLUT1, Epo, NO-synthase and cyclin propranolol caused apoptosis and inhibition of down-
D. Therefore, a strong rationale exists for directly inhibit- stream HIF targets in hemangioblastoma cell cultures
ing HIF2α, instead of VEGF alone. (such as VEGF and FGF). However, its exact mechanism
In 2015, Metelo et al reported that pharmacological of action was unknown.199 Two years later, the same
HIF2α mRNA inhibition in zebrafish improved VHL phe- research group used propranolol to treat 7 VHL patients
notype (decreasing erythrocytosis and blood vessel forma- with retinal hemangioblastomas. There was no effect on
tion in the retina, brain, liver and kidney). Further preclinical tumor volume. Resorption of tumor exudate was seen in
pharmacologic moderations are needed before its implemen- two patients.142 Another two years later, Albiñana et al
tation in clinical studies.192 A remaining question is whether applied a highly specific β2-adrenergic receptor blocker
HIF2α inhibitors also influence VHL-associated hemangio- (ICI-118,551), which exhibited similar effects on heman-
blastomas, or (extra-adrenal) paragangliomas, which can be gioblastoma cells in vitro.200
either HIF-driven or non-HIF driven.193 In 2018, Shepard et al conducted a similar experiment
In 2017, Sizdahkhani et al demonstrated the presence with propranolol on in vitro VHL hemangioblastoma and
of somatostatin receptors (1, 2a, 4 and 5) in VHL related renal cell carcinoma cells. Both tumor cell types
hemangioblastomas. They discovered apoptosis of cul- responded with signs of apoptosis. Propranolol also
tured VHL hemangioblastoma cells that were treated reduced tumor volume of renal cell carcinoma xenografts
with the somatostatin analogue octreotide. Octreotide in mice. Afterwards, Shepard et al retrospectively ana-
also caused volume and symptom reduction of an inoper- lyzed the effect of propranolol on 66 hemangioblastomas
able suprasellar hemangioblastoma in one VHL patient.194 in 3 VHL patients who used to receive propranolol for
Also in 2017, O’toole et al used octreotide in a VHL other clinical reasons. Median growth rate of hemangio-
patient with multiple pancreatic neuroendocrine tumors, blastomas was reduced, but did not stop, during a 2.1-year
yielding partial response in all tumors.195 median follow-up.144
Yaghobi Joybari et al reported that octreotide/everoli- Up to date, there are no reports on alkylating agents
mus caused symptom improvement in a VHL patient with nor antimetabolites used in VHL patients. However, VHL
a metastatic pancreatic neuroendocrine carcinoma. mutation status is an important predictor for response to
Radiological follow-up data were not available.196 alkylating agents in sporadic renal cell carcinomas.201
Clarithromycin, an antibiotic, has been repurposed as Halofuginone, a plant derivate, decreases gene expres-
an anti-cancer agent. By modulating cytokine biology and sion of collagen type 1 and matrix metalloproteinases;
VEGF expression, it has inhibitory effects on inflamma- thereby thwarting VEGF-regulated angiogenesis. In 2003,
tion and angiogenesis. In 2019, Ma et al used clarithromy- Gross et al discovered that halofuginone led to angiogenic
cin to treat a VHL patient with a progressive ELST tumor. inhibition of a VHL pheochromocytoma xenograft in
After 3 months, the ELST tumor remained stable on CT mice. There was no tumor regression. The authors sug-
imaging. Pancreatic and renal lesions shrunk or remained gested the future investigation of its applicability as
stable. Some renal lesions showed progressive growth. No a chemotherapeutic in the early stages of highly vascular
side-effects were observed.197 VHL tumors.202
Only little data are available on immunotherapy in VHL Little is known about radiopharmacological treatment.
disease. In 1993, Weidmann et al established in vitro sensi- In 1995, Pujol et al report near-complete regression of
tization of lymphocytes to autologous renal cell carcinoma a metastatic pheochromocytoma in a VHL patient treated
tumor cells in two VHL patients. Combined with the injec- with Iodine-131 metaiodobenzylguanidine ([131I]
tion of interleukin-2, the sensitized lymphocytes caused MIBG).203
volume reduction of pulmonary metastasis, without affect-
ing renal cell carcinoma volume.198 Conclusion
Even though randomized prospective trials are needed,
Miscellaneous intravitreal bevacizumab injections may be considered
Based on its previous success rates with infantile heman- for refractory and exudative retinal hemangioblastomas.
giomas, in 2015 Albiñana et al investigated the effect of The effects and safety profile of ranibizumab and pegap-
propranolol on hemangioblastomas in VHL disease. tanib are less well studied, neither are the effects of bev-
Acting as a nonselective β1 and β2-adrenergic antagonist, acizumab on other VHL-related tumors.

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Regarding monoclonal antibodies, larger randomized

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