Journal of Kidney Cancer and VHL 2015; 2(3): 114-129. Doi: http://dx.doi.org/10.15586/jkcvhl.2015.35
Review Article
Pathology of the Nervous System in Von Hippel-Lindau Disease
Alexander O. Vortmeyer, Ahmed K. Alomari
Yale School of Medicine, Department of Pathology, Division of Neuropathology, Connecticut, USA.
Abstract
Von
Hippel-Lindau (VHL) disease is a tumor syndrome that frequently
involves the central nervous system (CNS). It is caused by germline
mutation of the VHL gene. Subsequent VHL inactivation in selected cells
is followed by numerous well-characterized molecular consequences, in
particular, activation and stabilization of hypoxia-inducible factors
HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis
remains poorly understood. Hemangioblastomas are the most common
manifestation in the CNS; however, CNS invasion by VHL
disease-associated endolymphatic sac tumors or metastatic renal cancer
also occur, and their differentiation from primary hemangioblastoma may
be challenging. Finally, in this review, we present recent morphologic
insights on the developmental concept of VHL tumorigenesis which is
best explained by pathologic persistence of temporary embryonic progenitor
cells.
Received: 14 May 2015; Accepted after revision: 06 June 2015; Published: 11 June 2015.
Author
for correspondence: Alexander
O. Vortmeyer MD, PhD, Yale School of Medicine, Department of Pathology,
Division of Neuropathology, Connecticut, USA. E-mail: [email protected]
How
to cite: Vortmeyer AO, Alomari AK . Pathology of the Nervous System in Von Hippel-Lindau Disease.
Journal of Kidney Cancer and VHL 2015;2(3):114-129. Doi: http://dx.doi.org/10.15586/jkcvhl.2015.35
Introduction
Von Hippel–Lindau (VHL) disease is an
autosomal dominant disorder that is caused by germline mutations in the tumor
suppressor gene VHL on chromosome 3p25 (1, 2). It is characterized by frequent
development of selective tumor types in specific topographic locations. Among
others, central nervous system (CNS) hemangioblastoma and clear cell renal cell
carcinoma (RCC) are the most consistently encountered tumors (3).
Tumorigenesis in VHL syndrome is linked
to the loss of VHL tumor suppressor protein function in cell differentiation
(4-7).The loss of protein function is the result of a second genetic “hit”
which inactivates the wild type VHL allele (8). Subsequent to VHL gene
inactivation and loss of VHL protein function, hypoxia-inducible factors (HIF1
and HIF2) are activated (9-11). HIF1 is a heterodimer transcription factor
composed of HIF1α and HIF1β subunits (12). Through conditional transcriptional
activation of effectors controlling vascularization, glucose metabolism and
cell differentiation, HIF1 plays an important role in cellular response to
oxygen changes (12). HIF2α (also known as endothelial PAS domain-containing
protein -1 (EPAS1)) is another hypoxia-inducible factor that functions as an
integral component of transcription factors involved in the body response to
low oxygen level (13). In comparison to HIF1α which is expressed ubiquitously,
HIF2α has a restricted tissue distribution and is expressed primarily in the
vasculature of early developing embryo and subsequently in the lung, kidney
interstitial cells, liver parenchyma, and neural crest cells (14).
VHL protein is part of a multiprotein
complex that targets HIFα subunits for ubiquitin-mediated degradation in
proteasomes (11, 15-19). In hypoxic conditions or with VHL biallelic
inactivation, both HIF1α and HIF2α subunits will evade degradation, accumulate
in the cell and complex with other subunits to form functional proteins (9, 10,
20). The consequences of HIF1α and HIF2α up-regulation are multifaceted. One
major change includes the transcriptional activation of genes containing
hypoxia responsive elements. VEGF is among the target genes that will be
overexpressed leading to enhanced angiogenesis and oxygen delivery (12, 21).
Additionally, HIF2α up-regulation is linked to enhanced dysregulated
erythropoiesis while HIF2α deletion has been shown to result in anemia
associated with decreased expression of erythropoietin (22, 23).
Despite the significant alterations at
the cellular and molecular levels in association with VHL silencing, it has remained
unclear, however, why loss of VHL function and subsequent HIF activation lead
to tumorigenesis. Molecular and structural analogies of tumor cells with
developmental tissues (6, 14, 24, 25) have led to revisitation of the
hypothesis of a developmental origin of VHL disease-associated tumors (26, 27).
There is increasing evidence that the “second hit” causes loss of pivotal VHL
function during organ development leading to maldeveloped structures that
represent prerequisites for tumor formation (28).
In VHL disease, the CNS is
predominantly affected by hemangioblastic tumorigenesis, but may also be
involved by endolymphatic sac tumors (ELST) or metastatic disease.
Hemangioblastomas
Hemangioblastomas of the nervous system
are present in 80% of VHL patients and represent a defining feature of VHL
syndrome (3, 29). Topographic distribution of these tumors show a consistent
pattern with the retina, cerebellum, brainstem and dorsal spinal cord being the
most frequently involved locations (3). With recent advancements in sensitive
imaging techniques, there has been a shift in the distribution of these tumors
with increasing proportion of spinal tumors in comparison to the pre MRI era
(30). Supratentorial tumors represent less than 3% of all tumors in most series
(30, 31). In contrast to sporadic hemangioblastomas, VHL patients frequently
have multiple hemangioblastomas, as is the case in 127 out of 160 patients in
one report (30).
Clinical and radiological presentation
Hemangioblastomas are benign tumors
with no metastatic potential. However, as with other space occupying lesions of
the brain, they may cause neurological deficit and carry a significant
mortality rate if left untreated due to hydrocephalus, tonsillar herniation and
brainstem compression (29, 32). Not infrequently, these tumors have an
associated pseudocyst or syrinx evident by magnetic resonance imaging (MRI)
(33) (Figure 1). In addition to this
cystic component, which may be much larger than the tumor itself, these tumors
have a typical MRI appearance of densely contrast-enhancing solid mass with
smooth margins (30, 34, 35).
Figure 1. Radiological and histologic presentation of hemangioblastomas. A,
T1-weighted postcontrast MR image shows right cerebellar hemangioblastoma
(arrow) with an associated cyst (arrowheads); B, corresponding precontrast, fluid-attenuated inversion recovery,
MR image demonstrating cyst hyperintensity (from Lonser et al., Ann Neurol
2005;58:392-399). C,
Hemangioblastoma may present with mesenchymal (upper) and epitheloid structures
(lower); Immunohistochemistry for vascular antigen CD34 reveals reactive vascularization
(upper and lower right), neoplastic cells are negative for anti-CD34 (from
Shively et al., J Pathol 2008;216:514-20).
Pathological features
The gross appearance of these tumors
commonly shows a solid nodule with an associated pseudocyst. Pseudocysts result
from secretory tumoral activity (33) and disappear after successful surgical
removal of the tumoral nodule (33). The tumoral nodule is usually soft with
bright or dark red color, and occasional yellow areas seen upon sectioning (28).
Histological findings vary greatly and are dependent on tumor size (25). There
are two main cellular constituents of hemangioblastomas, “stromal” cells and
vascular cells. By selective genetic analysis, “stromal” cells have been shown
to be neoplastic cells (36, 37). The origin of the “stromal” cell has been
controversial(38); however, most consistently proposed has been a
hemangioblastic or hemangioblastic progenitor origin (27, 39-42). Since
hemangioblasts were originally discovered in embryonal tissues almost 100 years
ago (43-45) and are not known to exist in adult CNS tissue, the concept of a
developmental origin of hemangioblastoma developed early (26, 27) and will be
further discussed below.
The second cellular constituent of
hemangioblastoma is represented by abundant vascular cells that show no evidence
of biallelic VHL inactivation and are therefore mostly – if not entirely –
reactive (36, 46). The most plausible explanation for the abundance of reactive
vascular structures in hemangioblastoma is the tumoral “stromal” cell
expression of angiogenic factors (47). However, whether a subset of vascular
structures may represent differentiation products of neoplastic hemangioblastic
“stromal” cells (vasculogenesis) has been investigated with controversial
results.
Most immunohistochemical studies
identify “stromal” cells and vascular cells as separate cytological
constituents with no evidence of transition between the two cell types: they
either report distinct immunoreactivity with different markers of interest
(48-52) or find vascular markers factor VIII and/or factor XIIIa exclusively
expressed in the vascular component of tumors (48, 53). In contrast, other
studies reported expression of vascular markers in “stromal” cells (54-56).
Cell culture studies either revealed no evidence of interconvertibility between
endothelial cells and “stromal” cells (57) or evidence for vascular
differentiation capacity of “stromal cells”(58). Microdissection studies
revealed evidence for vasculogenesis in precursor structures of
hemangioblastomas (59), but not in frank tumors (46).
Within hemangioblastomas, the
proportion of “stromal” and vascular cells can vary greatly and has been used
as the basis of the traditional morphologic sub-classification of
hemangioblastoma into a vascular-rich reticular (also called “mesenchymal”)
cell phenotype and a “stromal” cell-rich cellular (also called “epitheloid”)
variant (60) (Figure 1). A study of
156 variably-sized hemangioblastomas revealed strong correlation between
histologic subtype and tumor size (25). In the aforementioned study, all tumors
smaller than 8 mm3 showed exclusive reticular structure, also known
as “angiomatotic”, or “mesenchymal”, that is characterized by small loosely
scattered tumor cells separated by extensive vascularization (25). Larger
tumors reveal additional phenotypic change, neoplastic stromal cells that are
enlarged in size with abundant cytoplasm and large nuclei, and frequently
clustered in groups (25). Cytologically,
the stromal cells in these latter neoplasms may have an abundant glycogen or
lipid-rich cytoplasm imparting a clear appearance of the cell on routine
H&E sections. Foci of extramedullary erythropoiesis can be detected in
cellular (epitheloid) areas, but are not detected in reticular (mesenchymal)
tumor portions. It has therefore been postulated that reticular lesions
represent an earlier stage of tumorigenesis from which epitheloid tumor with
extramedullary erythropoiesis may develop (25). Interestingly, these
morphologic changes within individual hemangioblastomas have previously been
interpreted as different stages of embryonic hemangioblastic maturation (40).
Endolymphatic Sac Tumors
The endolymphatic duct/sac system is
composed of single-lumen thin long endolymphatic duct ending in a short
pouch-like endolymphatic sac (61). The interior of this system is lined by
single-layered cuboidal endolymphatic duct/sac epithelium (62). The
intraossesous part of the endolymphatic duct/sac system is also referred to as
the vestibular aqueduct (63) and represents the site of origin of ELST (64).
The endolymphatic duct/sac system is part of the nonsensory membranous
labyrinth of the inner ear with a potential functional role in maintenance of
homeostasis and pressure of the inner ear, phagocytosis of debris and
immunologic functions (65-68).
Epidemiology
ELST was first established as a
distinct pathologic entity by Heffner in 1989 (69). However, ELST had not been
recognized as a component tumor of VHL disease until 1997, after the
identification of 15 inner ear tumors in 13 out of 121 patients with VHL disease,
while none of 253 patients without evidence of VHL disease had inner ear tumors
(70). Additional studies documenting VHL inactivation by microdissection and
PCR-based loss of heterozygosity analysis provided genetic and molecular
confirmation of this association (64, 71, 72). Moreover, neoplastic cells were
found to show activation of both HIF1and HIF2 as well as expression of CAIX and
GLUT-1 which are downstream targets of HIF, and co-expression of EPO and EPOR,
which has been implicated in promotion of tumor growth (64, 73). The prevalence
of ELST in VHL patients has been reported to be approximately 10% to 15% based
on imaging studies, with 30% of these patients having bilateral tumors (74).
Clinical presentation
ELST can cause hearing loss, tinnitus, vertigo
and facial nerve paresis (75). Hearing loss can occur in larger tumors with
invasion of the otic capsule, but also in smaller tumors. The proposed
mechanisms of hearing loss in these tumors include hemorrhage and/or endolymphatic
hydrops (76, 77).
Morphology
ELSTs present grossly as bright or dark
red soft tissue masses (76). The histological appearances of these tumors are
variable and are usually composed of a mixture of three main architectural
patterns; papillary, cystic and epithelioid clear cell (64, 69). One
consistently observed feature is the presence of extensively vascularized
papillary structures. These papillary structures are lined by a single row of
cuboidal epithelial cells. Focal cystic growth can be observed in a subset of
tumors as is focal clusters of epitheloid clear cell. The cysts have a single
epithelial lining and frequently contain proteinaceous material. Mitotic
figures are rare. Extensive hemosiderin deposits are common and associated with
degenerative features including fibrosis, inflammation and cholesterol cleft
formation (Figure 2).
Immunohistochemical analysis of VHL disease-associated ELSTs reveals positive
immunoreactivity with anti-NSE, anti-MAK6, and anti-AE1/AE3 (64, 78).
Immunohistochemistry for EMA and S100 is positive in subsets of cases (79).
Some sporadic tumors have also been reported to be positive for GFAP and
vimentin (78).
Figure 2.
Radiologic, morphologic and immunohistochemical features of ELSTs. Serial
magnetic resonance (MR) and computed tomography (CT)-imaging of the temporal
region from a VHL patient with hearing loss demonstrating the development of a
left endolymphatic sac tumor. (A)
Axial, T1-weighted enhanced MR-imaging reveals enhancement in the region of the
left endolymphatic duct (arrows). (B) Corresponding, axial, non-enhanced,
CT of the left temporal bone shows bony erosion confined to the left
endolymphatic duct (arrowhead).
Morphologic spectrum of ELSTs: Papillary structures were observed in all
tumors (C), whereas cystic areas (D) were seen in half of the
cases. One tumor had areas of epitheloid
clear cell clusters (E), reminiscent
of clear cell renal carcinoma. Extensive hemosiderin deposits were evident in
half of the tumors (F). A feature of
all tumors was intensive vascularization (G,
immunohistochemistry with anti-CD 34). Note the abundant vessels in papillary
stroma (arrows) and the immediate contact of numerous small vessels with the
cystic epithelium (arrowheads), which appears to be induced by expression of
HIF and VEGF by the epithelial tumor cells. Immunohistochemistry for NSE (H), MAK6 (I) and AE1/AE3 (J) was
consistently positive (from Glasker et al., Cancer Res 2005;65:10847-53).
In addition to frank tumors, multifocal
microscopic cystic and papillary structures were identified in the intra- and
extra-osseous endolymphatic duct/sac system in VHL patients (64). These
structure were different in their molecular profile from similar cystic
proliferations identified in non VHL patients; in VHL patients, the cystic and
papillary structures showed loss of the wild-type VHL allele in addition to
positive nuclear staining for HIF1 and HIF2 and expression of target proteins
CAIX and GLUT-1 (64, 80). It has been proposed that these structures represent
tumor precursors (64).
Metastasis
Metastasis into the nervous system can
occur from three different types of VHL disease-associated tumors. Most
frequently, metastasis is caused by RCC which often may show striking
resemblance to primary hemangioblastoma or ELST. Far less frequently observed
are metastatic pheochromocytoma/paraganglioma or metastatic neuroendocrine
tumors.
Metastatic renal clear cell carcinoma
Metastasis of RCC can occur anywhere
within the nervous system. However, if metastasis occurs into cerebellum,
brainstem, or spinal cord, differentiation from primary hemangioblastoma may
constitute a diagnostic challenge. Both tumors share histologic features
including cells with clear or vacuolated cytoplasm, extensive vascularization
and occasional clustering of epitheloid cells. Additionally, both tumors share
VHL gene deficiency as well as expression of VEGF, HIF, CAIX and other VHL
target proteins. Several subtle morphological features have been proposed to
help differentiate these tumors. Most importantly, cytoplasmic membranes are
more distinct in renal cell carcinoma, while less well defined in
hemangioblastoma cells. Also, identification of mitotic figures strongly favors
metastatic renal cell carcinoma. Necrosis is virtually never seen in
hemangioblastoma, unless tumors had been pretreated with radiation or embolization
(28).
Immunohistochemistry is a valuable tool
to distinguish hemangioblastoma from metastatic RCC. Epithelial membrane
antigen (EMA) was originally described to selectively identify RCC (81, 82).
However, focal expression of EMA may rarely occur in hemangioblastoma (83) (Figure 3). Anti-inhibin A showed a high sensitivity and
specificity for hemangioblastoma in one study (84). Other potentially useful
markers include anti-CD10 for the identification of RCC and D2-40 and
aquaporin-1 for the selective identification of hemangioblastoma (85-88). More
recently, a combination of PAX-2 and PAX8 (positive in RCC) and inhibin A
(positive in hemangioblastoma) has been proposed as the most useful panel of
markers to resolve this differential diagnosis (89). Another important role of
immunohistochemistry is the identification tumor heterogeneity that is caused
by tumor metastasis into hemangioblastoma which is being reported in up to 8%
of hemangioblastomas (90, 91).
Figure 3.
Metastatic RCC. Left, Metastatic
renal cell carcinoma to brain resembling hemangioblastoma, H&E stain;
right, immunohistochemistry for EMA shows characteristic membranous staining.
VHL tumorigenesis
Development of tumors in VHL disease– Arvid
Lindau’s hypothesis
Decades ago, the hypothesis of a
hemangioblastic nature of CNS tumors in VHL disease fueled an even older debate
on the origin of cancer which notably has not been settled until today. In the
early and mid-1800s, Joseph Recamier and Robert Remak both noted that cancer
tissue resembled embryonic tissue (92). In 1874-1875 Francesco Durante and
Julius Cohnheim proposed cancer to originate from small collections of
embryonal cells that persist and do not differentiate into mature adult tissue
(92-94). In the early 1900s, this theory was rejected (92, 95, 96). When,
however, Arvid Lindau discovered and described in detail the gross and
histologic changes of VHL disease, he came to the conclusion that “…all types
of neoplasia might be explained by a disturbed balance during mesodermal
development during the third month of embryonal life” (26). While Arvid Lindau
was therefore a strong supporter of the “embryonic rest”-hypothesis to explain
CNS tumorigenesis in VHL disease, he subsequently noted that “an underlying
early maldevelopment” may give rise to two different pathologic processes:
“Hemangioblastoma” and “capillary angiomatosis” (27). He was, however, unable
to explain how “early maldevelopment” can produce such extreme neoplastic diversity:
a tumor composed of hemangioblastic cells on one hand, and a tumor composed of
mature vascular cells on the other.
Lindau’s hypothesis – analytical and experimental
evidence
More recently, we worked on a
resolution of this seemingly contradictory nature of VHL disease-associated CNS
tumors. Key strategy for this effort was to change the primary target of
histologic analysis. Instead of analyzing tumor tissues, we analyzed
normal-appearing tissues of VHL patients in which tumors are known to frequently
occur, spinal cord and cerebellum.
The study of tumor-free central and
peripheral nervous system tissue of VHL patients revealed numerous microscopic
structures that are not encountered in similar tissues of non-VHL control
patients (24, 64, 97, 98) (Figure 4). In essence, these structures represent
the “early embryonal maldevelopment” postulated by Lindau and have hence been
designated “developmentally arrested structural elements” (DASEs) (97). DASEs
represent precursors of CNS tumors in VHL disease; however, only a small number
of DASEs progress to frank tumor during the lifetime of a VHL patient (24, 25,
97).
The key constituent of DASEs are small
primitive VHL-deficient cells that apparently represent immature hemangioblast
progenitor cells, accompanied by reactive vasculature (24, 97, 98) (Figure 4). Early tumor arising from
DASEs is highly vascularized and resembles “angiomatosis”. Upon further tumor
growth, tumor cells increase in size, develop epitheloid architecture and may
differentiate in blood (25, 42, 58). The morphologic sequence of tumorigenesis
from DASEs to frank tumor reveals transition of mesenchymal cells into
epitheloid structures and thus explains the diverse and complex histologic
presentation of CNS tumor in VHL disease.
Figure 4.
Developmentally arrested structural elements (DASEs), incidentally discovered
in grossly normal-appearing nerve root tissue of VHL patients by histologic
analysis of random spinal cord sections obtained at autopsy (from Vortmeyer et
al., Ann. Neurol. 2004; 55:721-728). All depicted DASEs were present
intradurally in different nerve roots. All lesions reveal circumscribed
accumulations of persistent embryonal VHL-deficient hemangioblast progenitor
cells (see references 24 and 98). A,
cross-section of a nerve root, filled with embryonal cells; B, The central portion of the root
shows an accumulation of embryonal cells which is sharply demarcated from
surrounding normal root tissue; C, A
longitudinal nerve root section reveals frequently observed longitudinal
extension of DASE’s along fiber tracts; D,
intraradicular DASE with embryonal cells, diffusely scattered around neurites; E, DASE, selectively involving a
central nerve root fascicle; F,
circumscribed DASE in nerve root; focal clear cell phenotype and early
multifocal vascular perfusion may indicate early progression into
hemangioblastoma.
According to Knudson’s two hit
hypothesis, tumorigenesis in VHL disease is initiated by the “second hit”,
inactivation of the wild type copy of the VHL allele in patients that carry the
VHL mutation (8). The recent identification of numerous VHL-deficient DASEs in
tumor-free CNS tissues of VHL patients led to the conclusion that the “second
hit” is necessary, but insufficient for tumorigenesis (98, 99). Instead,
“second hits” appear to be capable of producing DASEs from which frank tumors
may or may not develop. The nature of the third hit allowing DASEs to develop
into frank tumor remains unknown.
Persistence of temporary embryonal progenitor cells
In VHL disease, the embryonal rest
hypothesis does not necessarily imply the generation of neoplastic tissue during
organ development. Instead, it implies the causative genetic hit to occur
during organ development with the effect of developmental arrest of variable
numbers of embryonal/fetal cells that have the capacity of eventual neoplastic
proliferation. Key arguments are:
a) Organ selectivity: Precursor and
tumor formation occurs abundantly in selective tissue structures, and not at
all in others; In VHL disease, there is dramatically increased risk of
development of hemangioblastoma, renal clear cell carcinoma, cystadenoma of
pancreas and endolymphatic sac, and neuroendocrine tumors, but no increased risk
for any other type of cancer.
b) Tumor specificity: While large
varieties of different tumors are known to exist in CNS and kidney, only tumors
with specific histology occur in affected organs.
c) Consistent topographic distribution
of precursor structures/tumors: Tissue development is strongly associated with
pattern formation. VHL disease not only targets the nervous system, it does so
in a near-predictable pattern of distribution. Neoplastic structures are
frequently observed in spinal cord and cerebellum, only rarely in cerebrum.
Within the cerebellum, the molecular layer is primarily affected. In spinal
cord tissue, precursors/tumors are detected far more frequently in dorsal than
in ventral roots. The most frequently affected specific topographic CNS site is
the obex of the brainstem (E. Oldfield, personal communication).
d) Stem/progenitor cell properties of
VHL deficient neoplastic cells: Multiple different analytic and/or experimental
approaches have identified the VHL-deficient neoplastic cell as primitive
hemangioblastic progenitor cell with capacity of differentiation into red blood
cells and/or primitive vascular structures. Although not definitively
demonstrated, there is strong supportive evidence for hemangioblastic
differentiation to occur during brain (and even stronger evidence for kidney)
development. Hemangioblastic cells are not part of the mature nervous system;
instead, hemangioblastic cells persist in the nervous system due to pathologic
events during tissue development and represent a condicio sine qua non for
tumor development.
Alternative hypotheses
Alternative hypotheses for tumor
development include a) tumorigenesis from a pre-existent glial, neuronal, or
mesenchymal cell (100); b) tumorigenesis from circulating cells (101); c)
tumorigenesis from a stem cell (96, 102, 103).
a) Tumorigenesis from a pre-existent
cell in the nervous system would imply dedifferentiation of mature cells into
hemangioblastic progenitor cells which not only has never been demonstrated,
but should be expected to be an extraordinarily complex molecular and
structural process. Activation of HIF occurs in tissues under hypoxic stress,
but is not known to be related to tumorigenesis. Structural analysis of
precursor/tumor structures in the nervous system reveal the pathology to evolve
from minute poorly differentiated foci into larger lesions with increased
maturation (24), with erythropoiesis occurring only in largest-sized frank
tumors (25). Simply, the abundance of minute structural changes in VHL tissues
is explained more easily by an origin from VHL-deficient aberrant cells;
furthermore, the most frequent occurrence of precursor structures in nerve root
tissue provides a very limited set of candidate cells for tumor development.
b) Circulating bone marrow cells have
been implicated in the generation of or contribution to brain tumors (101).
This hypothesis would explain tumor specificity, but require bone marrow
hematopoietic cells to be primarily targeted by the second hit. The VHL
deficient hemangioblastic progenitor/stem cell is the most primitive form of
hemangioblast, originally discovered in the yolk sac (45). To support this
hypothesis, it would be necessary to demonstrate presence of these primitive
hemangioblastic precursor cells in fetal or adult bone marrow. More difficult
to explain, however, would be the principles of organ selectivity and
topographic distribution of VHL tumors. In addition, bone marrow pathology is
not known to exist in VHL disease.
c) Since VHL deficient tumor cells in
nervous system have been identified as hemangioblastic progenitor cells, an
origin from VHL-deficient stem cells with hemangioblastic differentiation
potential certainly deserves consideration. While the role of stem cells in the
brain remains controversial, a stem cell origin of brain (and many other)
tumors is being increasingly accepted (103). By definition, stem cells are
totipotent cells with differentiation potential along multiple (in the brain
along astrocytic, oligodendroglial and neuronal) cell lineages which is not the
case in VHL disease (tumor specificity). Nevertheless, while the pathogenic
cell in VHL nervous system remains best-characterized as VHL-deficient
hemangioblastic progenitor cell, the second hit could occur in a totipotent
stem cell, with VHL inactivation being exclusively permissive for
hemangioblastic differentiation. However, the stem cell hypothesis fails to
explain organ selectivity and consistent topographical lesion distribution
within organs. Also, experimental knock-out of the VHL gene in cell systems has
so far not revealed evidence for hemangioblastic differentiation.
In essence, stem cell hypothesis and
embryonal rest hypothesis are not entirely exclusive. Like hematopoietic progenitor cells, stem
cells are derived from embryonal cells. The key difference is the time of the
second hit, VHL inactivation. The stem cell theory would allow for the second
hit to occur any time, while the embryonic rest hypothesis postulates the
second hit to occur early during tissue development, producing an early and
pathologic set of VHL deficient hemangioblastic progenitor cells. It is the
embryonic rest hypothesis which most comfortably explains the key arguments
presented above.
This modified embryonal rest hypothesis
has not been proven, but it most effortlessly explains clinical, pathologic and
experimental evidence available so far. Similarly effortlessly it can be
applied to any other classic tumor suppressor gene syndrome (e.g. MEN1,
neurofibromatosis), with confirmatory literature on record. Thus, VHL disease
is a naturally occurring human tumor suppressor gene “model” the unique
features of which give insight into the biology of neoplastic disease and
cancer.
Conclusion
VHL disease is a classic tumor
suppressor gene syndrome caused by VHL gene germline mutation. In the nervous
system, the “second hit” - VHL wild-type gene inactivation – induces DASEs
which have the potential to develop into benign hemangioblastic tumors. In the
kidney, VHL-deficient cells give rise to renal clear cell carcinoma which can
metastasize into brain and spinal cord. Endolymphatic sac tumors may develop in
the vestibular aqueduct with the potential of brain invasion. While the
molecular consequences of VHL inactivation have been worked out in detail,
fundamental questions have remained unexplained by these studies. The
fundamental questions include organ selectivity, tumor specificity, the
consistent lesional distribution pattern, and the embryonal/stem cell nature of
the tumor cells. These intriguing features are best explained by the “second
hit” occurring during nervous system development. Application of this concept
may generate new research approaches to VHL-deficient tumors, their sporadic
counterparts as well as tumors in the context of other tumor suppressor gene
syndromes.
Acknowledgements
Many thanks to Dr. Douglas Brash for
numerous fruitful scientific discussions.
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