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1. Incidence 1:36,000 live births.


What type of gene is vhl?
penetrance by age 65?
how often are de novo mutations?

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.


how is VHL characterized?
hint there are seven things

VHL syndrome is characterized by formation of cystic and highly vascularized tumors in
many organs. The major causes of death in patients with VHL are metastatic RCC and
CNS hemangioblastomas.*
1. Cerebellar and spinal cord hemangioblastomas*
2. Retinal hemangioblastomas
3. Bilateral kidney cysts and clear cell renal cell carcinomas (RCC)*
4. Pheochromocytomas
5. Pancreatic cysts and pancreatic neuroendocrine tumors
6. Endolymphatic sac (inner ear) tumors (ELST)
7. Cystadenomas of the genitourinary tract (epididymal, broad ligament)


how would you diagnose this in someone w/o family history of the disease?

. An individual without family history of VHL presenting with two or more
characteristic lesions:
1. Two or more hemangioblastomas of the retina, spine, or brain or
a single hemangioblastoma in association with a visceral
manifestation (e.g., multiple kidney or pancreatic cysts)
2. Renal cell carcinoma
3. Adrenal or extra-adrenal pheochromocytomas
4. Less commonly, endolymphatic sac tumors, papillary
cystadenomas of the epididymis or broad ligament, or
neuroendocrine tumors of the pancreas


How would you diagnose this in someone with a family history of the disease

ii. An individual with a positive family history of VHL syndrome in whom one
or more of the following syndrome manifestations is present:
1. Retinal angioma
2. Spinal or cerebellar hemangioblastoma
3. Adrenal or extra-adrenal pheochromocytoma
4. Renal cell carcinoma
5. Multiple renal and pancreatic cysts


Genetic testing

1. Sequence analysis
2. Gene targeted deletion/duplication analysis
ii. Presymptomatic genetic testing may be offered to first-degree family
members of patients with germline mutation detected.


what are the two types of VHL?

1. Type 1: Hemangioblastoma + Clear cell renal cell carcinoma
i. Due to total or partial loss of VHL
2. Type 2: Pheochromocytoma +/- Hemangioblastoma +/- Clear cell renal cell
i. Type 2A: Hemangioblastoma + Pheochromocytoma
ii. Type 2B: Hemangioblastoma + Pheochromocytoma + Clear cell renal cell
iii. Type 2C: Pheochromocytoma only
iv. Due to VHL missense mutation


what is the vhl gene responsible for?

A. VHL is located on short arm of chromosome 3 (3p25-26)
1. VHL is a tumor suppressor gene.
2. The VHL protein is part of a complex that targets unwanted proteins for
proteosomal degradation by ubiquitination.
i. Actions of VHL protein include regulation of hypoxia inducible
transcription factor (HIF), suppression of aneuploidy, and maintenance of
primary cilia and stabilization of microtubules.
ii. Therefore, VHL loss or inactivation leads to HIF accumulation, a high rate of
aberrant chromosome numbers (aneuploidy), and a disruption of primary
cilia maintenance leading to formation of renal cysts and renal cell


tell me about vhl abd oxygen

1. Under normoxic conditions, HIF is hydroxylated by proline and asparagine
hydroxylase. In the presence of normal wild type VHL, HIF is ubiquitinated by
VHL protein and undergoes proteosomal degradation.
2. Under hypoxic conditions, HIF does not get hydroxylated and HIF is not
degraded. HIF protein accumulates and activates the transcription of
downstream genes that are involved in angiogenesis, metabolism, apoptosis, and
other processes that promote cancer growth and survival under low O2 conditions.
3. Cells with mutated VHL gene behave as if they are under hypoxic conditions.


what is the most common histologic subtype of RCC?

C. Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of RCC.
1. The majority of ccRCC cases are sporadic. 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 g


Therapies used to treat clear cell renal cell carcinoma

Management of local renal cell carcinoma typically involves surgical resection with
either partial or radical nephrectomy.
B. Management for metastatic renal cell carcinoma involves systemic therapy including
vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, MTOR
inhibitors, and immunotherapies.


type 1

Total or partial VHL loss
Improper folding
Up‐regulation of HIF Hemangioblastoma
Renal cell carcinoma
Low risk of pheochromocytoma


type 2a

VHL missense mutation Up‐regulation of HIF
Inability to stabilize microtubules
Low risk of renal cell carcinoma
High risk of pheochromocytoma


typa 2b

VHL missense mutation Up‐regulation of HIF Hemangioblastoma
High risk of renal cell carcinoma
High risk of pheochromocytoma


Type 2C

VHL missense mutation pVHL maintains ability to down‐regulate HIF.
Decreased binding to fibronectin.
Defective fibronectin matrix assembly.
Pheochromocytoma only


Management of localized RCC

• Role of neoadjuvant or adjuvant therapy
• Currently NOT standard of care.
• Adjuvant IL2 and IFN‐ negative trials
• Adjuvant TKI (ASSURE) negative
• Adjuvant mTOR (EVEREST) inhibitor trials are ongoing
• Ongoing surveillance is critical, 20‐30% will relapse
• H&P, CMP Q6months x 2 years, then annually x 5 years
• Chest and A/P Imaging at 2‐6 months, then as indicated
• Lung is most common site of relapse (50‐60%)