Von Hippel-Lindau Clinical Vignette

Question 1

*1) Recognize the clinical manifestations of VHL disease.

Answer 1

Characterized by formation of cystic and highly vascularized tumors in many organs:

• Cerebellar and spinal cord hemangioblastomas (Occur in 60-80% patients, mean age at diagnosis 30 years)
• Retinal hemangioblastomas (Occur in 50% patients; mean age at diagnosis 25 years)
• Bilateral kidney cysts
• clear cell renal cell carcinomas (RCC) (Occur in 75% of VHL patients by age 60yr (mean 39yr)Accounts for 50% VHL deaths)
• Pheochromocytomas (Occur in 25% of patients; mean age at diagnosis 27 years)
• Pancreatic cysts and pancreatic neuroendocrine tumors (Cysts occur in 75% patients.Pancreatic NETs occur in 11-17% patients; mean age at diagnosis 38 years)
• Endolymphatic sac (inner ear) tumors (ELST) (Occur in 10-15% of patients, mean age at diagnosis 22 years)
• Cystadenomas of the genitourinary tract (epididymal, broad ligament)

*take me to BRRECC to ski Pretty Please? (im trying here..) 
or Itzams UMSLE STEP 1 approved way to remember it:
(H) Hemangioblastomas
(I) increased renal cancer
(P) Pheochromocytoma
(P) Port-wine stains
(E) Eye dysfunction
(L) Liver, pancreas, kidney cysts

Major causes of death in patients with VHL are metastatic RCC and CNS hemangioblastomas.

Question 2

*2) Learn the molecular basis of VHL disease and the pathogenesis of clear cell renal cell carcinoma.

Answer 2

Molecular Genetics of VHL:
-VHL is located on short arm of chromosome 3
3p25-26
-VHL is a tumor suppressor gene.
-VHL protein is part of a complex that targets unwanted proteins for proteosomal degradation by ubiquitination.

Actions of VHL protein:

• Regulation of hypoxia inducible transcription factor (HIF)
• Suppression of aneuploidy
• Microtubule stabilization/primary cilia maintenance

So! VHL loss or inactivation leads to:
HIF accumulation
High rate of aberrant chromosome numbers (aneuploidy)
Disruption of primary cilia maintenance leading to formation of renal cysts and RCC

Pathogenesis of ccRCC:

-Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of RCC.
1. The majority of ccRCC cases are sporadic(96%). Only 4% are inherited. However, VHL
loss or mutation is responsible for almost 2/3 of the sporadic cases of ccRCC.
2. Knudson’s TWO HIT theory is that the development of VHL-related tumors requires inactivation of the 2 copies of the VHL gene.
a. In sporadic ccRCC, two hits (mutations or silencing of the VHL gene) are
needed for development of renal tumors.
b. In VHL disease, patient already has inherited one hit (VHL gene mutation)
and it only take one more hit to develop renal tumors.

Question 3

*3) Understand the molecular rationale for therapies used to treat clear cell renal cell carcinoma and how these targets were identified through understanding diseases such as VHL.

Answer 3

Traditional cytotoxic chemotherapy does not work for ccRCC.
Current therapies in 3 main categories:
-Immunotherapy
-VEGF-targeted agents:
(Sunitinib and sorafenib); but they are dirty AF multikinase inhbitors
-MTOR inhibitors

In clinical trials:
-HIF-2a inhibitors.

Understanding the pathogenesis of a rare disease like VHL helps us understand ccRCC biology and treatment.

Question 4

Classifications of von Hippel-Lindau disease & Diagnostic Criteria

Answer 4

Classifications:
-Type 1: HB + ccRCC
(Due to total or partial loss of VHL)

• Type 2A: HB + PHEO
• Type 2B: HB + PHEO + ccRCC

-Type 2C: PHEO only
(Due to VHL missense mutation)

Diagnostic criteria for VHL disease:
-One VHL-associated lesion AND a positive family history of VHL-associated lesion

-Two VHL-associated lesions

Question 5

Control of HIF-α by VHL is oxygen- dependent

Answer 5

Under normoxic conditions, HIF-alpha is hydroxylated by proline and asparagine hydroxylase. In the presence of normal wild type VHL, this HIF-alpha is ubiquated by VHL protein and undergoes proteosomal degradation.

In the presence of mutated VHL gene, cells behave as if they are under hypoxic conditions and result in the accumulation of HIF, which in turn activates the transcription of multiple downstream proteins including VEGF, PDGF and TGF alpha and beta which then stimulates angiogenesis, endothelial proliferation and autocrine growth and survival of cancer cells.

Question 6

Incidence, Clinical Manifestations, and Genetics of VHL disease

Answer 6

Von Hippel-Lindau syndrome has an autosomal dominant pattern of inheritance:

1. Incidence 1:36,000 live births.
2. The VHL gene is a tumor suppressor.
3. Penetrance of VHL disease is >95% by age 65.
4. High variability in disease severity and age of onset.
5. De novo VHL mutations occur in ~20% of cases.