Inhibin-expressing clear cell neuroendocrine tumor of the ampulla: an unusual presentation of von Hippel–Lindau disease

Abstract

von Hippel-Lindau (VHL) disease is a hereditary autosomal dominant disorder associated with deletions or mutations in the VHL tumor suppressor gene. Characteristically, up to 60 % of neuroendocrine tumors (NETs) associated with VHL disease display a spectrum of clear cell morphology including multivacuolated lipid-rich cell change. Unlike neurofibromatosis type 1 and multiple endocrine neoplasia type 1 syndromes, ampullary NETs have not been described in association with VHL disease. In this report, we discuss the features of an incidental ampullary clear cell NET occurring in a patient with pancreatic VHL disease including multiple pancreatic NETs. The ampullary lesion consisted of epithelial cells resembling lipoblasts or signet ring cells. In our case, all NETs showing clear cell change were positive for inhibin. While the underlying mechanism of this finding is largely unknown, it is of note that positivity for inhibin has not been observed in clear cell NETs associated with multiple endocrine neoplasia type 1 syndrome. Our case proves that NETs can develop in the ampullary region in patients with VHL; clear cell change can occur in these lesions and can mimic signet ring cell carcinoma. This issue is of clinical significance especially in small biopsy samples; thus, positivity for keratin alone should not be taken as evidence of an adenocarcinoma. Moreover, demonstration of inhibin expression in a NET with clear cell change along with other clinical stigmata should alert the diagnostician to the possibility of VHL disease. However, further larger series examining inhibin expression in both syndrome-related and sporadic clear cell NETs are needed to confirm our findings.

Endocrine Manifestations of von Hippel–Lindau Disease

“…6 Interestingly, none have shown gastrin positivity, 6 which is in contrast with MEN1-associated NETs, which are gastrin producing in up to 50% of cases. 17 Interestingly, inhibin positivity has been reported in clear cell NETs associated with VHL disease 15 (Figure 2, G). While the underlying mechanism of this finding is largely unknown, this phenomenon is attributed to the status of pseudohypoxia resulting in HIF-1a increase in the setting of VHL disease, 15 since positivity for inhibin has not been observed in other clear cell NETs associated with MEN1 syndrome.…”

“…17 Interestingly, inhibin positivity has been reported in clear cell NETs associated with VHL disease 15 (Figure 2, G). While the underlying mechanism of this finding is largely unknown, this phenomenon is attributed to the status of pseudohypoxia resulting in HIF-1a increase in the setting of VHL disease, 15 since positivity for inhibin has not been observed in other clear cell NETs associated with MEN1 syndrome. 22 Thus, positivity for inhibin is used to suggest the possibility of VHL disease underlying multifocal clear cell NETs.…”

“…23 Furthermore, glycogen synthesis is induced in hypoxia by HIF-1 and promotes tumor cell survival. 24 This phenomenon can sometimes mimic a signet ring cell carcinoma 15 ( Figure 2, E). These neoplasms are positive for chromogranin A and synaptophysin by immunohistochemistry and can be focally positive for somatostatin, pancreatic polypeptide (Figure 2, F), vasoactive intestinal peptide, insulin, and/or glucagon.…”

“…VHLrelated pancreatic NETs and paragangliomas/pheochromocytomas will be discussed in detail in this section. Other rare neuroendocrine tumors reported in patients with VHL include clear cell NETs in the ampulla and gallbladder, 15,16 a clinically functioning duodenal D cell NET, 17 a NET of the common bile duct, 18 an aggressive growth hormoneprolactin-producing pituitary adenoma, 19 and a parathyroid adenoma with primary hyperparathyroidism. 20 …”

“…22 This phenomenon is also attributed to the activation of HIF1-a, leading to a status of pseudohypoxia resulting in lipid and glycogen accumulation in tumor cells. 15 It has been shown that HIF-mediated stimulation of lipin 1 expression causes triglyceride accumulation. 23 Furthermore, glycogen synthesis is induced in hypoxia by HIF-1 and promotes tumor cell survival.…”