|Year : 2010 | Volume
| Issue : 4 | Page : 575-577
Treatment options for renal cell carcinoma in patients with von Hippel-Lindau disease
Ilya Tsimafeyeu1, Lev Demidov2
1 Kidney Cancer Research Bureau, Bazovskaya ul. 4/1 office 15, Moscow, Russia
2 N.N. Blokhin Russian Cancer Research Center, Dept.of Biotherapy, Moscow, Russia
|Date of Web Publication||24-Feb-2011|
Bazovskaya ul. 4/1 office 15, Moscow
Source of Support: None, Conflict of Interest: None
We report on a family with von Hippel-Lindau (VHL) disease and atypically aggressive renal cell carcinoma. A woman and her brother had progressive VHL disease with multiple tumors in their kidneys. One patient developed pulmonary metastases. The patient who had localized disease received radiofrequency ablation with complete destruction of tumors. Cytoreductive nephrectomy was performed in the case of metastatic disease, following which sunitinib maleate (50 mg orally daily, 4 weeks on, 2 weeks off) was given. Examination after two treatment cycles showed complete regression of all metastases. For 19 months, the patients have been under active observation without disease progression. Also, we detected high immunohistochemical expression of vascular endothelial growth factor receptors 1 and 2 in the cytoplasm and nuclei of tumor cells.
Keywords: Renal cell carcinoma, von Hippel-Lindau disease, treatment
|How to cite this article:|
Tsimafeyeu I, Demidov L. Treatment options for renal cell carcinoma in patients with von Hippel-Lindau disease. J Can Res Ther 2010;6:575-7
| > Introduction|| |
The von Hippel-Lindau disease (VHL) is an inherited mutation of the VHL gene, which causes tumors to form in areas of the body that contain large numbers of blood vessels. One in every 32,000 children born in the US is affected by VHL.  Renal cell carcinoma (RCC) is relatively common in patients with VHL disease, yet characteristically it follows a less aggresasive course compared with sporadic RCC. Treatment for VHL varies depending on the location and size of the tumor and the associated cyst. There are no universal treatment guidelines for aggressive VHL disease and metastatic RCC.
| > Case Report|| |
Two patients (44-year-old woman and her 36-year-old brother) in good physical and mental condition had progressive VHL disease and RCC. The mother of the patients died from metastatic RCC at the age of 58 years. The woman had 10 primary tumors in the left kidney, with a maximum size of 4.6 cm. She developed a pulmonary metastatic disease. Her brother had two primary tumors in the right kidney and one tumor in the left kidney, with a maximum size of 3.1 cm. No metastases were found. Cysts in the kidneys were found in both the patients. There were no other VHL manifestations in organs and systems.
Computed tomography (CT)-guided percutaneous radiofrequency ablation (RFA) in male and open left radical nephrectomy in female were performed. Complications of RFA included minor hemorrhage and transient lumbar plexus pain.
A Fuhrman 3 grade clear cell RCC was histologically confirmed.
Material from surgically resected RCC was analyzed for immunohistochemical expression of vascular endothelial growth factor receptors 1-3 (VEGFR 1-3). Cytoplasmic immunostaining expression was quantified using a four-value intensity score (0, 1+, 2+, and 3+). Nuclear immunostaining expression was quantified using a range of 0-100 according to the percentage of positive nuclei. High VEGFR1 and VEGFR2 expression was detected in the cytoplasm (3+) and nuclei (100%) of tumor cells [Figure 1].
|Figure 1: Microphotographs (×200, 500 px) of immunohistochemical expression of VEGFR1 (a) and VEGFR2 (b) in tissue specimens of hereditary clear-cell RCC. Antibodies Santa Cruz Biotechnology, Inc. Santa Cruz, CA, USA|
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Following the surgical treatment, the sister received sunitinib malate 50 mg/day in 6-week cycles (4 weeks on, 2 weeks off). CT scan was used for response evaluation according to Response Evaluation Criteria in Solid Tumors.
Examination after two cycles of treatment showed complete regression of pulmonary metastasis. Two additive cycles of sunitinib were administered to the patient in the same dose and then the treatment was stopped. Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria, version 3.0. Grade 2 hypertension was observed and grade 1 fatigue developed during the treatment as the only side effects.
Further follow-up was identical for both the patients. Patients underwent evaluation with office visits, laboratory work-ups, and radiographic imaging (computed tomography scans of the chest, abdomen and pelvis, and bone scan) every 4 months. For 19 months, the patients have been under active observation without disease progression.
| > Discussion|| |
VHL disease is a hereditary cancer syndrome linked to a mutation of the VHL gene responsible for proteolytic degradation of the hypoxia inducible factor (HIF) transcriptional complex. During hypoxia, the HIF transcriptional complex promotes expression of growth factors such as VEGF, platelet-derived growth factor (PDGF), and erythropoietin.  Loss of VHL function results in uncontrolled HIF activity and overexpression of VEGF and PDGF, leading to RCCs, as well as the development of hemangioblastomas in the retina and the CNS, pheochromocytomas, and cystic lesions in various organs. 
Treatment for VHL varies depending on the location and size of the tumor and the associated cyst.
Previously, it was reported that no RCC metastases were found in patients with renal tumors less than 3 cm in diameter. However, several recent studies have shown the metastases development in select patients with small tumors, which cannot be ignored. Results suggest that microvascular invasion is a significant risk factor and patients with microvascular invasion should be followed more carefully. 
The authors advocate a 3-cm threshold for parenchymal sparing surgery in patients with VHL disease to decrease the risk of metastatic disease while preserving renal function, avoiding or delaying the need for dialysis and/or renal transplant and decreasing the number of operations which a patient may undergo.  Minimally invasive surgery and radiofrequency ablation could be used for treatment of small renal masses with tumor size <4 cm. 
There are no universal treatment recommendations for aggressive VHL disease and metastatic RCC. The treatment in most cases of advanced RCC with VHL usually involves surgical resection of the affected kidney before systemic therapy.
Tyrosine kinase inhibitors have gained a significant role in the treatment of sporadic metastatic RCC.  Sunitinib is one of the several agents that target the activity of angiogenic growth factors and show favorable results in clinical trials involving patients with metastatic clear-cell RCC. The data indicate that inhibition of angiogenesis is a promising strategy for the treatment of clear-cell RCC. ,
Our experience illustrates the potential of two approaches for the treatment of localized and metastatic RCC in patients with VHL disease. Radiofrequency ablation could be a safe and effective method for selected patients with small renal tumors. Sunitinib malate was associated with improved clinical status in patient with advanced VHL disease. Our findings confirm that VEGFR proteins are highly expressed in hereditary renal tumors. Further evaluation of VEGF/VEGFR inhibitors such as sunitinib, sorafenib, pazopanib or bevacizumab is needed.
| > References|| |
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