Von Hippel Lindau syndrome (VHL)
Epidemiology and
Etiology:
- Autosomal
dominant inheritance
- germline mutations in VHL tumour
suppressor gene
- 80%
inherited
- 20% de novo
- marked
phenotypic variability
- age-dependent
penetrance
- Pheochromocytoma:
- younger
age at (5-64y) than other hereditary syndromes
- RCC:
- Younger
age than sporadic RCC (35-45y mean)
Common sites:
- marked
phenotypic variability
- CNS
(subtentorial – cerebellum) & retina:
- Hemangioblastomas
(70% by 60y)
- Also
intraspinal
- Supratentorial
meninges
- Endolymphatic
sac tumours (11%)
- Kidney:
- Renal
cell carcinoma (35%)
- Adrenal:
- Pheochromocytoma
(type 2 mutations – missense)
- Pancreas:
- Pancreatic
endocrine tumours (5-10%)
- Microcystic
adenomas, benign serous cysts (35-75%)
- Epididymis
(males) and broad ligament / mesosalpinx (females):
- Papillary
cystadenomas (50% of males)
Gross features:
- Pheo:
- Multifocal,
both adrenal and extra-adrenal commonly
- RCC:
- Often
multifocal
- Marked
pseudocapsule in most
- Renal
cysts typically also
- Hemangioblastoma:
- Pancreas:
Histologic features:
- Pheo:
- thick
vascular capsule
- myxoid
and hyalinized stroma
- round,
small to medium tumour cells
- amphophilic
and clear cytoplasm
- absence
of cytoplasmic hyaline globules
- lack
of nuclear atypia or mitoses
- intermixed
small vessels
- no
extratumoural adrenomedullary hyperplasia (contrast to MEN 2)
- RCC:
- Always
clear cell CA
- No
distinguishable features from sporadic usually
- Most
grade 1 or 2
- May
be hard to distinguish mets from hemangioblastomas (in CNS and spine
sites)
Immunophenotype:
Marker:
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Sensitivity:
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Specificity:
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Molecular features:
- VHL mutations (3p25)
- Loss
of function
- Over 300 mutations have been identified
- All 3 exons
- Codon 167 is a
mutation hotspot
- Partial and complete deletions, frameshift,
nonsense, missense, and splice
site mutations
- VHL
function :
- Regulating
proteolytic degradation of subunits of HIF-1 and HIF-2
- Most
VHL tumours are very vascular and express hypoxia-inducible genes such
as VEGF and VEGFR
- Likely
SCF-like function
- Targeting
specific proteins for ubiquitination
- Type 1
mutations:
- No
(or rare) pheochromocytomas
- Mostly
truncating or null mutations, or missense
mutations that grossly disrupt the folding of the VHL protein
- Type 2
mutations:
- Pheochromocytomas
often
- missense mutations (almost
invariably
- Type
2A:
- Low risk
of renal cell carcinoma
- Type
2B:
- High
risk of renal cell carcinoma
- Type 2C:
- Risk
for pheochromocytoma only
- No eye
and CNS tumours
- Complete
deletion:
- Low risk
of both Pheo and RCC
Other features:
- Pheo:
- only
normetanephines and not metanephrines in plasma and urine
- frequently
asymptomatic (16-30% symptomatic)
- less
frequent rate of malignancy (<5%)
- Pancreatic
endocrine tumours:
References:
- Von
Hippel-Lindau Syndrome -- GeneReviews
-- NCBI Bookshelf. Available at:
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vhl
[Accessed June 13, 2009].