|Year : 2015 | Volume
| Issue : 4 | Page : 920-922
Sunitinib treatment of metastatic renal cell carcinoma in von Hippel-Lindau disease
Kidney Cancer Research Bureau, Moscow, Russian Federation, Russia
|Date of Web Publication||15-Feb-2016|
Kidney Cancer Research Bureau, Bazovskaya ul. 4/1 15, Moscow 125635
Source of Support: None, Conflict of Interest: None
Von Hippel-Lindau disease (VHL) is a major heritable renal cell cancer (RCC) syndrome. 24-45% of VHL patients have a cumulative risk to develop RCC. The management of VHL has changed significantly as clinicians have learned how to best balance the risk of cancer dissemination while minimizing renal morbidity. Despite the improving management of this disease, there are no evidence-based guidelines of the treatment of localized and advanced RCC in VHL. Here, we describe a 39-year-old patient with VHL disease who developed metastatic RCC and received sunitinib with complete remission.
Keywords: Metastases, renal cell carcinoma, sunitinib, surgery, von Hippel-Lindau disease
|How to cite this article:|
Tsimafeyeu I. Sunitinib treatment of metastatic renal cell carcinoma in von Hippel-Lindau disease. J Can Res Ther 2015;11:920-2
| > Introduction|| |
Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disease occurring in approximately 1 in 36,000 births. VHL is characterized by the development of hemangioblastomas, cysts, and renal cell carcinomas (RCCs). Due to the fact that VHL is a rare disease, there are no evidence-based guidelines of the treatment of patients with localized and advanced RCC. Here, we report on a patient with RCC complicating VHL disease treated with sunitinib.
| > Case report|| |
In February 2013, a previously healthy 39-year-old Caucasian male presented with an asymptomatic lesions (1.7 cm, 5.2 cm) within the inferior and upper poles of the left kidney. The patient had no family history of kidney cancer or VHL disease, and there were no significant findings on examination.
The lesions had been diagnosed on an abdominal ultrasound. A follow-up contrast enhanced computed tomography (CT) confirmed two hyper vascular tumors in the left kidney and showed two small tumors (0.4 cm, 0.7 cm) in the right kidney, large heterogeneous mass with areas of necrosis, cystic change in the left adrenal gland, and multiple cysts in the pancreas. There were no metastases in lungs, lymph nodes, and other tissues. A contrast-enhanced magnetic resonance imaging (MRI) showed multiple hemangioblastomas in the brain and spinal cord. Asymptomatic retinal angiomas were seen through direct ophthalmoscopic evaluation. Measurement of plasma catecholamines and urinary catecholamine metabolites revealed increased hormone levels. Blood was sent for DNA analysis and a known VHL gene mutation was identified.
Recommendation was made to the patient for left nephrectomy with adrenal gland removal. A surgery after premedication with adrenergic blockers was done. Patient had no any complications. Histopathologically, the left kidney mass was diagnosed as a clear cell RCC, a Fuhrman nuclear grade of 3, and pT3a. Largest tumor contained tumor tissue and cysts. Histological features of pheochromocytoma were identified.
Material from surgically resected RCC was analyzed for immunohistochemical expression of fibroblast growth factor receptor-1 (FGFR1), FGFR2, and vascular endothelial growth factor (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 expression of VEGFR2 and FGFR1 was detected in the cytoplasm (3+) and nuclei (100%) of cancer cells in both tumors. VEGFR1, VEGFR3, and FGFR2 positive expression was found in the tumor vessels.
Despite of recommended 3 months follow-up, the patient went to a clinic in January 2014 and complained of severe headache. A contrast enhanced MRI demonstrated a 31 mm, enhancing, hemangioblastoma in the brain. The size of RCC tumors and hemangioblastomas remained the same from the time of diagnosis, but the patient developed a pulmonary metastatic disease.
Four weeks after the surgical removal of the brain hemangioblastoma, sunitinib therapy was initiated at a standard regimen of 50 mg once daily for 4 weeks, followed by 2 weeks without treatment. Patient had intermediate prognosis according to MSKCC criteria. 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 as well as both tumors in the right kidney. There was no significant impact of sunitinib on other VHL-related lesions. Four 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 1 hand-foot syndrome was observed, and Grade 1 fatigue developed during the treatment as the only side effect.
Patients underwent follow-up with office visits, laboratory work-ups, and radiographic imaging (CT scan of the chest, abdomen, and pelvis) every 3 months. For 11 months, the patient has been under active observation without features of RCC progression.
| > Discussion|| |
In the Russian Federation, kidney cancer is diagnosed in about 20,000 people a year, resulting in 8500 deaths.  VHL disease is a hereditary cancer syndrome linked to a mutation of the VHL gene responsible for the 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, and erythropoietin.  Moreover, several researches showed a novel HIF-independent function of VHL in cell motility control via regulation of FGFR1 endocytosis. In VHL null tumor cells or VHL knock-down cells, FGFR1 internalization is defective, leading to surface accumulation and abnormal activation of FGFR1. Also, VHL is recruited to FGFR1-containing, but not EGFR-containing, endosomal vesicles.  FGF/FGFR axis plays a significant role in RCC pathogenesis. , Expression and mutations of FGFR in patients with VHL disease are unknown.
Clinical hallmarks of VHL disease are the development of retinal and central nervous system hemangioblastomas (blood vessel tumors), pheochromocytomas, multiple cysts in the pancreas, and kidneys. RCC is relatively common in patients with VHL disease, yet characteristically it follows a less aggressive course compared with sporadic RCC.
Treatment for VHL varies depending on the location and size of the tumor and the associated cyst. 
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 the treatment of small renal masses with tumor size <4 cm including metastatic RCC. 
There are no evidence-based guidelines for the management of aggressive VHL disease and metastatic RCC. Sunitinib has gained a significant role in the treatment of sporadic metastatic RCC. Several studies and clinical cases suggest that sunitinib could be effective in patients with metastatic RCC and VHL disease [Table 1].
|Table 1: Efficacy of sunitinib treatment of metastatic RCC in VHL disease |
Click here to view
Our experience illustrates the potential of two approaches for the treatment of localized and metastatic RCC in a patient with VHL disease. Surgery could be a safe and effective method for patients with small renal tumors and brain hemangioblastomas. Sunitinib malate was associated with improved clinical status in patient with advanced RCC and VHL disease. Our findings confirmed that VEGFR proteins are highly expressed in hereditary renal tumors. Previously Jonasch et al.  showed that mean phosphorylated FGFR substrate-2 levels were higher in hemangioblastomas (P = 0.003). For the 1 st time, we revealed high expression of FGFR1 in the renal tumor. Further evaluation of the efficacy of the targeted therapy and biomarkers is needed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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