Tárcia Nogueira Ferreira Gomes1, Lívia de Almeida Costa1*, Luciano Lenz1,3, Giovana Biasia de Sousa1, Ermelindo Della Libera1,2and Frank Shigueo Nakao1,2
1Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil
2Fleury Medicina Diagnóstica, Centro de Medicina Diagnóstica, São Paulo, Brazil
3Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil
Received: 19 April, 2016; Accepted: 16 June, 2016; Published: 17 June, 2016
Lívia de Almeida Costa, Department of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil; 37 Zely Lage Street, Alto dos Passos, Juiz de Fora, Minas Gerais, 36026-430, Brazil, Tel: +55-11-982078393; E-mail:
Ferreira Gomes TN, de Almeida Costa L, Lenz L, de Sousa GB, Libera ED, et al. (2016) Review of Pancreatic Lesions in Von Hippel-Lindau Disease. Arch Clin Gastroenterol 2(1): 038-43. 10.17352/2455-2283.000018
© 2016 Ferreira Gomes TN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Von Hippel-Lindau disease; Endosonography; Pancreatic cyst; Pancreatic neoplasms; Neuroendocrine tumors
CT: Computed Tomography; EUS: Endoscopic Ultrasound; FDG-PET: Fluorodeoxyglucose Positron Emission Tomography; HIF: Hypoxia-Inducible Factor; MEN: Multiple Endocrine Neoplasia; MRCP: Magnetic Resonance Cholangiopancreatography; MRI: Magnetic Resonance Imaging; NET: Neuroendocrine Tumors; PDGF: Platelet-Derived Growth Factor; TGF: Transforming Growth Factor; VEGF: Vascular Endothelial Growth Factor; VHLD: Von Hippel-Lindau Disease
Von Hippel-Lindaudisease (VHLD) is a rare hereditary tumor syndrome, inherited in autosomal dominant manner. Patients diagnosed with VHLD have a high risk of developing neoplasms of various organs (eyes, central nervous system, bone, kidney, adrenal glands, epididymis, broad ligament and pancreas). Due to its rarity, most of the physicians fail to properly diagnose it in time, and they might expose patients to a risk of unnecessary surgeries with important consequences in a long run. When this condition is diagnosed, lifelong follow-up is necessary. Pancreatic involvement it is seen in most patients with VHLD and various pancreatic lesions have been described, including cystic lesions (simple unilocular or serous microcystic or macro/micro-cystic adenomas), neuroendocrine tumors (NET), renal cell cancer metastasis and adenocarcinoma. These lesions are rarely the primary presenting tumor and frequently diagnosed during the screening of family members with VHLD, by imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT). Cystic lesions are the most common, generally asymptomatic and are rarely associated with malignant degeneration, except mucinous cysts. It is recommended follow-up and intervention if these lesions become symptomatic or mucinous aspect. NET are usually multiple, nonfunctional and have malignant potential. The management of NET depends on size, doubling time and underlying genetics. Because of their malignant potential, it is necessary careful observation in a long-term follow-up. If treatment is necessary, more conservative management is preferable. Molecular targets for treatment of NET in VHLD have also been proposed and some drugs are in preclinical or clinical trials.
Von Hippel-Lindau disease (VHLD) is a rare hereditary syndrome, first described in 1911 and 1926 by von Hippel . and Lindau , respectively. It was only named as we know nowadays in 1964 by Melmon and Rosen, who also established clinical criteria for its diagnosis . VHLD reported prevalence is 1:36,000 newborns and between 1:39,000 and 1:93,000 persons in Europe [4-6].
Germline mutations in the VHL gene are responsible for VHLD. The human VHL gene was first identified in 1993. It is located on chromosome 3 (3p26-p25) and it has a tumor suppressor function . It consists of three exons and encodes two different mRNA transcripts of 213 (30 kDa, VHLp30) and 160 amino acids (19 kDa, VHLp19), respectively [8-10]. The molecular pathways related to specific aspects of VHLD has been studied recently . It is widely known that VHL protein regulates the oxygen-sensing pathway, which is responsible for angiogenesis mechanism. Therefore, VHL mutations result in impairment of hypoxia-inducible factor (HIF) degradation, facilitating continuous expression of growth and angiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-α, which is accountable for highly vascular tumors in VHLD [12-14]. Functional loss of VHL protein other than HIF-related process has been reported, such as microtubule instability, which destabilizes cell polarity and cilia maintenance, and defects in the collagen network and misregulation of β1-integrin, which results in disturbance of fibronectin matrix assembly. Those latter mechanisms reported are responsible for renal cysts development. Although it is not confirmed the origin of pancreatic cysts, in vivo studies with knocked-out mouse model suggested that cilia loss is the main mechanism [10,15]. Hyper production of VEGF may favor pancreatic cystic formation in this patients and it is highly suggestive of VHLD .
The inheritance occurs in autosomal dominant manner and it has a high penetrance, as reported that close to 100% of patients with VHL mutation will have any clinical manifestation until 65 years old. Despite being a hereditary disease, de novo cases were detected in approximately 20% of VHLD patients, i.e., with no family history of VHLD . The expression of VHLD is extremely variable: the time of onset, location of tumors and symptoms related are different from case to case [18,19]. Due to its rarity, most of physicians fail to properly diagnose it in time, and they might expose patients to risk of unnecessary surgeries with important consequences in a long run . When this condition is diagnosed, lifelong follow-up is mandatory .
Diagnostic criteria are based mainly on clinical history, but genetic evaluation has been considered. According to the Danish Guideline for VHLD and Massachusetts General Hospital criteria, one should be diagnosed with VHLD if fulfill one or two conditions: 1- At least two of manifestations described below; 2- At least one of manifestations described below, and pathogenic mutation in VHL gene in genetic testing or at least one first-degree relative with VHLD. The manifestations that are considered in clinical diagnostic criteria are: hemangioblastoma of retina, cerebellum, medulla oblongata or spinal cord, endolymphatic sac tumor, clear renal cell carcinomas, pheochromocytoma, paraganglioma and/or glomus tumor, neuroendocrine neoplasms and/or multiple cysts of pancreas. If some of these manifestations are diagnosed in patients without family history of VHLD, the age of onset (< 30 years for hemangioblastoma and <40 years old for clear cell renal cell carcinomas or pheochromocytoma) or the number of lesions (usually bilateral or multiple in clear cell renal cell carcinomas or pheochromocitoma; more than two hemangioblastomas of central nervous system; more than one pancreatic serous cystadenoma or neuroendocrine tumor or multiple pancreatic cysts) should be considered as diagnostic criteria. In sporadic cases that do not satisfy any of these criteria, differential diagnosis should be remembered, such as polycystic kidney disease, multiple endocrine neoplasia (MEN) type 2, neurofibromatosis, hereditary pheochromocytoma-paraganglioma and others [5,13]. The disease can be divided into two types, depending on genotype-phenotype characteristics. Patients classified as type 1 have lower risk to develop pheochromocytomas than type 2. Type 2 is divided into three subgroups (A, B and C), which are defined by presence or not of clear cell renal cell carcinoma and/or hemangioblastoma . Pancreatic neoplasms and cysts can be found in types 1, 2A and 2B, but the subgroup 2C is characterized by the exclusive presence of pheochromocytoma (Table 1) [4,13,20].
Patients diagnosed with VHLD have higher risk for developing malignant and benign neoplasm of various organs, such as eyes and central nervous system (angioma and hemangioblastomas, respectively), petrosal bone (endolymphatic sac tumors), kidney (clear renal cell carcinoma and cysts), adrenal glands (pheochromocytoma), epididymis and broad ligament (cystadenomas) and pancreas (simple cysts, serous cystadenomas, neuroendocrine tumors, metastatic renal cell carcinoma and adenocarcinoma) [4,5,13].
The aim of this paper is highlight the aspects of pancreatic involvement in patients with von Hippel-Lindau disease.
Pancreatic involvement is seen in most patients with VHLD and the frequency varies from 17% to 87.4% [4,12,16,20]. VHL gene mutations are found in 80% of patients with VHLD and pancreatic alterations . They are diagnosed at the mean age of 36 years, ranging from 5 to 70 years old . These lesions rarely are the primary presenting tumor and frequently are diagnosed later than other manifestations . Oftentimes, they are discovered during screening of family members with VHLD . They are commonly reported as a result of increased understanding of the disease and improved imaging technology . Imaging techniques, such as magnetic resonance imaging (MRI) or computed tomography (CT), may provide accurate detection  and play an important role in follow-up of lesions and screening of asymptomatic gene carriers . When the tumor is identified with CT, pancreatic MRI is used to confirm the diagnosis. Endoscopic ultrasound (EUS) and somatostatin receptor scintigraphy, can be useful for complementary diagnosis .
Various pancreatic lesions have been described, including simple unilocular cystic lesions or simple pancreatic cysts, serous microcystic or macro/microcystic adenomas, neuroendocrine tumors (NET), hemangioblastomas, renal cell cancer metastasis and rarely adenocarcinoma [16,21]. The most frequent pancreatic lesions are cystic (simple cysts and serous microcystic adenomas), but solid lesions also occur, including NET and metastatic tumors . Combined lesions occur, but the association of NETs and cystic lesions is rare . High prevalence of pancreatic cystic lesions in patients with VHLD was also described in some studies, with approximately 60% of these patients had severe or moderated cystic disease of the pancreas . These neoplasms tend to be asymptomatic or oligosymptomatic [12,16], non-functional and discovered incidentally [21,23]. Their management can be complex . These patients require a long–term follow-up with abdominal imaging techniques and the MRI is preferable because of the absence of exposure to radiation . Several authors suggest annual surveillance with MRI .
Systematic examination of patients with VHLD by CT scanning, reviewed by specializedradiologists, optimized the detection of pancreatic lesions . CT and MRI have been used to characterize pancreatic lesions, but radiologic criteria alone are generally inadequate for distinguishing between malignant and benign lesions . For this differentiation, the endoscopic ultrasound (EUS) has become preferred for diagnosing and localizing pancreatic lesions. EUS-guided fine-needle aspiration can be useful for differentiation between types of pancreatic lesions .
Simple pancreatic cysts or unilocular pancreatic cystic lesions
Cysts are the most common pancreatic lesions. They may show a single or multiple unilocular cystic lesions, and the latter are more common and may substitute completely the gland . Hyperproduction of VEGF may favor pancreatic cystic formation in this patients and it is highly suggestive of VHLD .
These lesions produce symptoms related to their size and are not associated with malignant degeneration . They are often asymptomatic, usually do not require intervention and it has been recommended conservative management [12,21]. Delman et al. , advocate annual observation of these lesions with MRI or CT. In approximately 50% of patients, lesions size increase during follow-up and in almost 20% of them it is observed compression of neighboring organs or pancreatic duct . They rarely become symptomatic due to endocrine/exocrine pancreatic insufficiency or due to compression of surrounding organs, causing obstructive jaundice, pancreatitis, abdominal discomfort and intestinal sub-occlusion [13,21]. Pancreatic exocrine insufficiency is managed by enzyme replacement . The risk of diabetes mellitus is low, even when the parenchyma is completely replaced by cysts . If the cystic lesion compresses nearby structures , and a patient develops pain or obstructive symptoms, treatment is indicated [13,24].
Pancreatic unilocular cystic lesions are rare in the general population . Hough et al. , suggested that the presence of this lesion in a patient with familiar history of VHLD is sufficient to make the diagnosis of VHLD highly probable .
At MRI these lesions appear hypointense on T1-weighted and hyperintense on T2-weighted images, with no enhancement after contrast administration . Frequently it is difficult to distinguish benign unilocular cystic lesions from a serous microcystic cystadenoma.
Treatment strategies should be individualized. Surgical treatment in patients who have only few cysts is feasible. In case of symptomatic biliary obstruction, endoscopic biliary stent placement as well as radiologically guided percutaneous aspiration with or without injection of sclerosing substance are strategies that can be performed [13,21].
Serous cystadenoma has a lower incidence than pancreatic simple cysts in the VHLD. They are often multiple and generally asymptomatic . Rarely it may produce compressive symptoms and need treatment . This lesion may be diffuse in all pancreatic gland, with parenchyma almost completely replaced by innumerable cysts, with “bunch of grapes” appearance (Figure 1) .
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