Combined Serous Cystadenoma and Well-Differentiated Pancreatic Endocrine Carcinoma in a Patient with von Hippel-Lindau Disease Benoît Terris Service d'Anatomie Pathologique Hôpital Cochin, Paris, France

Case History: This 34-year-old female underwent a computed tomography scan for chronic postprandial abdominal pain. Her past medical history included retinal and cerebellar hemangioblastomas and a resection of a clear cell carcinoma of the kidney. CT scan showed a pancreas entirely replaced by numerous cysts of various sizes compressing the main pancreatic duct. Intermingled within the cysts, an hypervascular mass of 32 mm was present in the head of the pancreas. A duodenopancreatectomy with pancreaticogastric anastomosis was performed. At macroscopic examination the pancreas was entirely involved by multilocular cysts containing serous fluid. Some cystic lesions showed central scars. A solid yellow tumor of more than 3cm was observed in the head of the pancreas at proximity of the duodenal wall. At distance a second centimetric tumor was detected. The selected slide is from the cystic pancreatic lesions and the largest nodule. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Microscopic examination of the pancreatic slide shows a biphasic pattern with alternating cystic areas and solid areas: Cystic areas consist of an aggregation of small cysts irregularly distributed and separated by abundant collagen bands. Typical stellate scar and calcifications are not observed. The cysts are lined by a single layer of monomorphous cuboidal cells with hyperchromatic central nuclei and clear cytoplasm. Small papillary projections are present in some cysts. The cells are rich in intracytoplasmic glycogen on PAS stain and are negative on Alcian Blue stain. Solid areas consist of nest cells arranged in trabecular or lobular or occasionally acinar patterns separated by numerous small vessels and large fibrous bands. The majority of the neoplastic cells are uniform in size and are closely intermingled with cystic lesions. They present an eosinophilic cytoplasm and contain round nuclei with coarse chromatin. Rare pleomorphic cells with irregularly hyperchromatic nuclei are interspersed without necrosis or vascular invasion. Rare mitoses were observed. However a contiguous lymphatic node is infiltrated by tumoral cells. Another peripancreatic lymph node is also invaded. Strong positive cytoplasmic immunoreactivity for chromogranin A and synaptophysin is observed. In contrast no labeling was observed for different hormone peptides (insulin, gastrin, glucagon, somatostatin, calcitonin, VIP, substance P). Based on this histology, additional information was asked to the clinicians. In fact, this patient had a family history of von Hippel-Lindau (VHL) disease with a germline mutation of the VHL gene. The pathologic diagnosis proposed is a combined serous cystadenoma and well-differentiated pancreatic endocrine carcinoma in a patient with von Hippel-Lindau disease. SEROUS CYSTIC NEOPLASMS OF THE PANCREAS Serous cystic neoplasms (SCNs) of the pancreas are benign and cytologically monomorphous neoplasms. Their histologically and immunohistochemically profiles suggest that they differentiate along lines similar to centroacinar cells. SCNs occur in adults (mean age of 61 years) and affect female twice as frequently as males. Most patients are asymptomatic or present non-specific symptoms such as abdominal pain, vomiting or weight loss. Less commonly palpable abdominal mass, obstructive jaundice or recurrent pancreatitis can occur. SCNs usually present as relatively large masses, mostly in the body or tail of the pancreas [1]. Although heterogeneous in their gross appearance, the microscopic features of the tumor cells are remarkably invariable. The cysts which contain proteinaceous fluid are lined by a single layer of clear cuboidal or flattened epithelial cells. They are negative for mucin stains, and the glycogen can be highlighted by the PAS stain [2]. They contain uniform round hyperchromatic nuclei. Immunohistochemistry is usually not necessary to perform the diagnostic. Like centroacinar cells and intra-lobular ducts, SCN express frequently MUC1 (34%) and MUC6 (70%) [3]. They are also positive in 80% and 100% of cases for alpha-inhibin and NSE respectively. Based on their gross appearance five different subtypes of SCN have been described: The most common form is the microcystic SCN. This lesion, well characterized on imaging, correspond to multilocular cystic lesion containing a central stellate scar. They are often large in size (>10cm) and do not communicate with the pancreatic ductal system. They are composed of innumerable tiny cysts with a sponge-like appearance on cross section [1, 2]. The serous oligocystic or macrocystic form of SCN is a well delimitated unilocular or less frequently plurilocular cystic lesion of the pancreas composed of cysts measuring more than 2cm in diameter [2]. No central stellate scar is present. They are difficult to distinguish clinically with pseudocysts or mucinous cystadenoma. Millimetric cysts within the wall of unilocular macrocystic lesions permit their diagnostic by endoscopic ultrasonography [4]. The solid non cystic variant of serous adenoma, usually of small size (<3cm), may be confused with pancreatic endocrine tumor or metastatic renal cell carcinoma [5]. The SCN occurring in patients with von Hippel-lindau disease (see below) are multiple, diffusely distributed in pancreas and show the coexistence of microcystic and oligocystic forms [6]. The exceptionally rare serous cystadenocarcinoma has histological features similar to those of SCN. However they show an aggressive behavior displaying perineural or perivascular invasion, involvement of a regional lymph node and/or the liver [7]. Despite some well documented observations, the interpretation of the tumors as malignant remains controversial. We cannot exclude that some of these cases correspond in reality to VHL patients having complex lesions with voluminous serous cysts associated or not with endocrine pancreatic tumor. Identifying a pancreatic mass as a SCN on imaging is important because this tumor, unlike the other cystic tumors of the pancreas, may not require a systematic surgical resection even if few cases have been reported to metastasize or to show an aggressive local behaviour without evidence of significant cytological atypia. However, because post-operative mortality can be significant in elderly or other patients who are poor operative risks, typical microcystic SCN should be treated conservatively whenever possible. Despite progress of imaging, macrocystic SCN remains difficult to distinguish from mucinous cystadenoma, pseudocyts or rare congenital cysts. PANCREATIC LESIONS ASSOCIATED WITH VON HIPPEL-LINDAU DISEASE VHL disease is an autosomal dominant syndrome that results from a germline mutation in the VHL tumor suppressor gene located on chromosome 3p25 [8]. The main function of VHL protein is the negative regulation of hypoxia-inducible factor-1 (HIF-1). Dysfunction of VHL protein caused by the VHL gene abnormality results in the absence of HIF-1 degradation and consequent overproduction of different growth factors. Affected individuals are predisposed to develop a variety of neoplasms in multiple target organs. These lesions include hemangioblastoma of the central nervous system, retinal angioma, endolymphatic sac tumor, renal cell carcinoma, pheochromocytoma and cyst of the kidneys and epididymis. Pancreatic involvement occurs in 60 to 80% of patients [6, 9, 10]. It can be the unique organ affected in 8% of patients with VHL disease. Majority of pancreatic lesions are usually asymptomatic and discovered during systematic screening of family members with VHL. Most of them correspond to multiple and more rarely isolated cystic lesions corresponding to microcystic and/or macrocystic forms of SCN. Compared with sporadic cases, they show a much wider range of number, size and distribution within the pancreas. The involvement can be limited to a minute cystic dilatation of a centroacinar lumen or in contrast affected the entire pancreatic gland as in our case. Compression of the main pancreatic duct or neighboring organs occurrs in 20% of patients. No malignant forms have been described. Associated to these cystic lesions, pancreatic endocrine neoplasms (PENs) may be encountered in 10 to 17% of VHL patients [9, 11]. Association of these 2 rare tumors within the pancreas is highly suggestive of VHL disease. PENs can be difficult to distinguish on CT scans from a solid form of vascularized SCN. Although the architecture and immunohistochemical profile permit easily the diagnosis of PENs, some particular features suggest VHL associated PEN from their sporadic counterparts. Prominent nuclear atypia are observed as well as a clear cell morphology. This pattern observed in 60% of cases is due to the presence of numerous cytoplasmic lipid droplets [11]. This feature is not specific of PENs associated with VHL as it has recently been described in rare sporadic cases [12]. Like in our observation, PENs in VHL patients are often multiple and disseminated throughout the pancreas making therapeutic decisions difficult. This multiplicity of endocrine lesions raise the differential diagnosis with multiple endocrine neoplasia type 1. However, frequency of PENs and symptomatic hormone hypersecretion appear higher in this later genetic syndrome. 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