Microcystic adenoma and cysts of the pancreas occur sporadically or as a part of von Hippel-Lindau (VHL) disease. The pathology of pancreatic cystic disease in VHL patients has not been well characterized. Furthermore, it is presently unknown whether the alteration of the VHL gene is responsible for the development of the entire spectrum of pancreatic serous cystic lesions. We performed a histopathological analysis of 21 cysts and 98 microcystic adenomas in nine VHL patients with a known germline mutation. In addition, PCR-amplified DNA from 27 pancreatic cystic lesions in three informative patients was studied for allelic deletions with polymorphic markers spanning the VHL gene locus. In all patients, pancreatic lesions were multiple: 21 benign serous cysts, 63 microscopic microcystic adenomas (size <0.4 cm), and 35 macroscopic microcystic adenomas (size >0.5 cm). The average number of lesions per patient was 2.1 benign cysts (range, 0–8), 7.7 (1–37) microscopic microcystic adenomas, and 3 (0–21) macroscopic microcystic adenomas. All lesions showed similar histology and contained prominent fibrous stroma, clear and/or amphophilic, glycogen-rich epithelial cells, endothelial and smooth muscle cells. VHL deletions were detected in all types of pancreatic cystic lesions. The presence of VHL gene allelic deletions in the spectrum of multifocal pancreatic cystic lesions provides direct molecular evidence of their neoplastic nature and integral association with VHL disease. The histopathological and molecular data establish a serous cyst-microcystic adenoma continuum in the development of pancreatic cystic neoplasia in VHL disease.
