Pancreatic cyst development: insights from von Hippel-Lindau disease

Pancreatic cysts are frequent, with a prevalence of 2.4 to 13.5% in patients without known pancreatic disease. Due to increased use of cross-sectional imaging techniques, physicians are more frequently confronted with pancreatic cysts [1]. Various types of pancreatic cysts can occur, which can be benign or have malignant potential. An expectative policy is accepted for benign cysts and surgery is indicated for malignant lesions. Currently, accurate diagnostics are not available to identify malignant cysts [1]. Despite the need for mechanistic insight, little is known about the origin and pathophysiology of pancreatic cysts in general.Von Hippel-Lindau (VHL) disease (MIM #193300) is a rare hereditary tumor syndrome that results from a germline mutation in the VHL gene. The reported incidence is 1 per 36,000 live births and a >90% penetrance is present by the age of 65 years [2]. VHL disease can lead to the development of hemangioblastomas of the central nervous system, retinal angiomas, endolymphatic sac tumors, epididymis or broad ligament cystadenomas, renal cysts and renal cell carcinomas (RCCs), pheochromocytomas, pancreatic cysts and pancreatic neuroendocrine tumors (pNETs) [3] (Figure 1). Currently, RCC and hemangioblastomas are the main causes of death [4,5]. VHL patients undergo screening for early detection of manifestations [6]. Understanding the role of the VHL gene in the oxygen-sensing pathway in the tumor micro-environment of RCC has led to major pharmaceutical successes through targeted therapies for many cancer types, such as humanized antibodies targeting vascular endothelial growth factor (VEGF), mTOR- and VEGF receptor tyrosine kinase inhibitors [7]. As a result, first-line treatment of metastasized RCCs has entirely changed in the last decade.pNETs are present in 10 to 17% of VHL patients [8,9] and pancreatic cysts occur in about 70% [10,11]. Because of this high prevalence, it is worthwhile examining the early cellular events that result in pancr