Pancreatic Involvement in von Hippel Lindau Disease: A Single‐Center Experience

Von Hippel Lindau (VHL) disease is an autosomal dominant genetic disorder, which is characterized by the development of benign and malignant tumors and cysts in multiple organs. Most commonly affected organs are cerebellum, eyes, spinal cord, kidneys, adrenal glands, and pancreas [1]. Pancreatic manifestations range from simple cysts and serous cystadenomas to potentially malignant pancreatic neuroendocrine tumors (PNETs) [2, 3]. This study describes the clinical features and pancreatic manifestations of VHL patients with pancreatic involvement managed at our center. This is a retrospective observational study conducted at the Department of Gastroenterology and Hepatology, Istanbul University, Istanbul Medical Faculty. All patients with genetically or clinically confirmed VHL disease were screened. 15 patients with confirmed pancreatic involvement were included in the study. Written informed consent was obtained from each patient. Data regarding demographic characteristics, family history, age at VHL diagnosis, and pancreatic and extra-pancreatic organ involvement were extracted from electronic health records. This study was descriptive in nature. Categorical variables were summarized using counts and percentages, while continuous variables were reported as means with ranges. No inferential statistical analyses were performed due to the small sample size. Our cohort of 15 VHL patients with pancreatic involvement is from five distinct families with a distribution of 6, 5, 2, 1, and 1 patient per family. Four patients are index cases within their families. One patient died from necrotizing pneumonia at age 51. The remaining 14 patients have a mean age of 40.4 years (Table 1). 13 patients had multiple cysts in the pancreas, while one patient had two cysts, and the other had one PNET. Pancreatic cysts were evaluated through a combination of clinical assessment, imaging studies, biochemical, and cytological cyst fluid analysis. Body and neck were the most frequently involved parts, each with 13 patients, followed by the head with 12 patients. Tail was the least involved part with 11 patients. 10 patients had cysts in all parts of the pancreas. The largest cyst in each patient was analyzed according to its size (based on MRI), the part of the pancreas where it was located, and its radiological features (Table 1). The largest pancreatic cysts were most located in the head of the pancreas (n = 4, 28.6%). All cysts except one cyst appeared hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging without a solid component or a contrast enhancement on the post-contrast dynamic series. In one cyst, post-contrast dynamic series revealed an 8 mm polypoid lesion within the cyst, connected to the cyst wall by a stalk and demonstrating contrast enhancement during the arterial phase. This lesion exhibited mild contrast uptake in the portal and venous phases and showed washout characteristics. In addition to the cysts, MRI of one patient revealed an approximately 1 cm lesion with well-defined borders in the uncinate process, that showed contrast enhancement. Subsequent Gallium PET-CT showed intense Ga-68 uptake in the same lesion, consistent with somatostatin receptor expression, and PNET. In this patient, serum Chromogranin A was measured at 81 ng/mL (reference range: 0–100), and neuron-specific enolase (NSE) at 18.2 ng/mL (reference range: 0–16). Considering cyst features on imaging, cyst growth rate, symptomatic status, and history of pancreatitis, EUS guided fine needle aspiration (FNA) was performed on a total of seven cysts of five patients, and on one lesion, which showed Ga-68 uptake on PET scan. Pathology of the lesion was consistent with low-grade PNET. Given the tumor's grade, size, and its clinically nonfunctional status, a watchful waiting approach with serial imaging was chosen. All aspirates were watery in consistency. Four samples were clear, two samples were xanthochromic, and one sample was dark. Five samples contained hypocellular material with sparse macrophages and lymphocytes. Two samples showed benign epithelial cells with serous characteristics. CEA was normal in all cysts, ranging 0.2–1.96 ng/mL. Amylase was normal in all but 1 cyst, that showed amylase level of 1034 U/L. This cyst was considered a pseudocyst. Consequently, six cysts were defined as serous cystadenomas and one cyst was defined as pseudocyst (Table 1). Three patients in our cohort had a history of pancreatitis, one iatrogenic post FNA, and two recurrent. Type 3c diabetes developed in one patient due to recurrent pancreatitis. The other patient also had exocrine pancreatic insufficiency in addition to endocrine insufficiency. Most patients in our cohort were found to have multiple cysts. Among those who underwent cyst sampling, the majority were diagnosed with serous cystadenoma, while one patient was diagnosed with PNET. Another noteworthy finding was the development of pancreatic insufficiency in two patients, secondary to the loss of pancreatic parenchyma due to cysts. Pancreatic involvement is highly prevalent in VHL disease, and this case series describes the spectrum of pancreatic manifestations observed in affected patients [1]. Although most lesions are cystic, PNETs, which carry malignant potential and can increase mortality, also occur. Given this risk, early detection through systematic screening imaging is essential. [4] Notably, pancreatic malignancies in VHL are almost exclusively PNETs [5]. In our cohort, 1 of 15 patients (6.7%) developed a biopsy-confirmed, nonfunctional, low-grade PNET measuring < 2 cm, which is currently managed with active surveillance. Consequently, VHL is a rare disease, and thus it is quite challenging to find enough cases for comprehensive research, especially at a single center. This increases the importance of case series specific to this disease. Better understanding the findings of pancreatic involvement and the characterization of cysts will positively impact the diagnosis and follow-up process of VHL patients. The authors would like to express their gratitude to the following colleagues from Istanbul University Istanbul Medical Faculty for their contributions to this research: Prof. Dr. Filiz Akyüz, Prof. Dr. Kadir Demir, Prof. Dr. Fatih Beşişik, and Prof. Dr. Sabahattin Kaymakoğlu. Their expertise and support were invaluable in the completion of this work. The authors have nothing to report. Written informed consent was obtained from all participants. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.