The autosomal dominant hereditary disorder von Hippel-Lindau (VHL) disease is caused by a germline mutation in the VHL gene. VHL is characterized by abundantly vascularized tumors in multiple organs; such VHL tumors may include hemangioblastoma of the retina and central nervous system (CNS), renal cell carcinoma (RCC), pancreatic tumors, pheochromocytoma, endolymphatic sac tumors, epididymal cystadenoma as well as cysts and cystadenoma in the kidney, pancreas, epididymis and broad ligament (1). The incidence of VHL disease has been estimated to be 1 in 36,000 live births in the Caucasian population, with gradually more apparent clinical manifestations occurring between ~18 and 30 years of age (2). Clinical diagnostic criteria include a positive family history and at least one typical VHL tumor. For isolated cases, at least two typical manifestations, including one hemangioblastoma, are required for diagnosis (3). Cases of sporadic VHL disease are rare. Approximately 20% of VHL patients demonstrate negative family history, with disease resulting from a de novo mutation (4). The VHL gene has been mapped to chromosome 3 (3p25–26) (5). Identification of pathogenic germline VHL mutations has been reported to provide a reliable method for the confirmation of diagnosis (6). The current study reports a case of de novo VHL disease in a male patient with advanced bilateral multifocal RCC involvement. Written informed consent was obtained from the patient. The relevant literature is also reviewed.

In adults, RCC accounts for ~3% of all cancers and ~85% of all primary malignant kidney tumors (8). In addition, ~5% of RCCs have a hereditary basis, of which VHL is the most common cause. Furthermore, ~75% of RCCs have clear cell histology, which is hereditarily caused by VHL (9). RCC and cysts in VHL disease are characterized by multicentricity and bilateral location in >75% of patients (10,11). The mean age at presentation is 10–20 years earlier than the age reported for sporadic renal disease (12). Transition from a cyst to a solid lesion is rare; however, the lining epithelium may be dysplastic or may have characteristics of carcinoma-in-situ, resulting in RCC (11). The case reported in the current study presented with a typical triad of symptoms, including hematuria, flank pain and flank mass. However, cases with this ‘triad syndrome’ are more advanced and rare; RCC and cysts often remain asymptomatic for long intervals (13,14). Thus, serial imaging of the kidneys for monitoring and early diagnosis has the potential to enhance overall patient outcome. The standard method for the detection of renal involvement in patients with VHL is contrast-enhanced abdominal CT imaging (15).

At present, no definitive guidelines are available with regard to the timing and surgical approach for these multicentric bilateral tumors. However, the primary aim of treatment should be cancer control, rather than cure, as well as the preservation of functional parenchyma in order to avoid the morbidity associated with renal or adrenal loss. A number of studies have reported that the majority of RCCs in VHL exhibit a low pathological grade (16), gradual growth (17) and do not metastasize at diameters of <3 cm (18). Therefore, an individual renal lesion may be maintained under regular surveillance until it reaches 3 cm in diameter, at which point NSS is performed to balance the prevention of metastatic progression against the reduction of the number of interventions (19). However, studies have revealed that the majority of patients with VHL-associated RCC eventually develop local recurrence with the concomitant requirement for repeated renal surgery (16). Certain clinicians recommend open NSS as the standard of care for treating RCC in the setting of VHL disease due to the inability of laparoscopy to achieve reliable hypothermia, in addition to the prolonged ischemia and increased complication rates associated with this approach. However, based on our experiences, the large incision of the abdominal wall may be problematic, resulting in muscle injury, the development of hernias and cosmetic damage. Laparoscopic NSS, performed by experienced surgeons on selected patients, is an alternative to open surgery (20); the oncological outcome, based on available series with limited follow-up data, appears to be similar to the outcome achieved with open NSS (21). Furthermore, an increasing trend towards the use of percutaneous radiofrequency ablation or cryoablation for small RCCs has been observed as this method is less invasive compared with other therapies (22,23). However, in rare cases with an advanced clinical stage of RCC in which the kidney cannot be preserved, such as that of the present study, or probable end-stage renal disease from the reiterated surgical treatments of localized tumors, total nephrectomy may be the only option due to a lack of alternative therapies. For patients who have undergone bilateral nephrectomy, renal replacement therapy may not be avoided (24,25).

VHL disease occurs due to the inheritance of a mutated germline copy of the VHL gene from an affected parent. The wild type copy of the gene is then inactivated by a somatic event. However, ~20% of patients with VHL develop the disease due to a de novo mutation. Inactivation of the wild type allele observed in tumors from VHL patients is consistent with the classic ‘two hit’ hypothesis of tumorigenesis (26,27). Currently, >400 different mutations have been identified, including deletion, missense, nonsense, frameshift and insertion mutations (http://www.umd.be/VHL/W_VHL). In the present study, the germline mutation c.194C>G of the VHL gene was detected in the patient; it was predicted that this mutation may induce a serine-to-tryptophan substitution at amino acid position 65 (p.Ser65Trp) within the VHL protein (pVHL). Serine at amino acid position 65 is highly conserved among various species and a number of studies have demonstrated the presence of mutations at this position (6,28–30). However, in previous cases involving this mutation, patients were reported to have a positive family history of VHL disease. In addition, no relatives of the patient in the current study were found to carry this mutation or had any clinical indications of VHL disease. Therefore, for the patient discussed in the present study, a de novo mutation may have occurred in a germ cell of either parent or at the embryo stage.

In conclusion, the current study presents a rare case of a de novo VHL patient with advanced RCC at first diagnosis; to the best of our knowledge, the patient discussed in the present study is the first known case of a sporadic de novo germline mutation of VHL at c.194C>G. Current understanding of the molecular genetics and pathophysiology of VHL disease, as well as developments in surgical and target therapies for RCC have advanced in recent years; however, early detection through genetic screening and regular clinical surveillance of VHL disease patients and their families continues to be the predominant mode of disease management. The enhanced sensitivity of imaging techniques and advancements in therapeutic techniques, including radiofrequency ablation and NSS allow for the identification and management of tumors at earlier stages, thereby attenuating the morbidity and mortality rates associated with VHL disease.