Endocrine Manifestations of von Hippel–Lindau Disease

Abstract

von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

Primary Renal Carcinoid with Bilateral Multiple Clear Cell Papillary Renal Cell Carcinomas

“…However, these tumors differ in their molecular and immunohistochemical profiles [23]. In addition, VHL disease may present with endocrine manifestations including pheochromocytomas, extra-adrenal paragangliomas, and pancreatic neuroendocrine tumors [24]. Though VHL syndrome was a consideration with the constellation of findings described in this case, this was effectively ruled out through immunohistochemistry and genetic testing.…”

Deregulated expression of VHL mRNA variants in papillary thyroid cancer

“…Loss-of-function mutations cause the so-called VHL disease, an autosomal dominant disorder characterized by retinal angioma, cerebellar and spinal hemangioblastomas, clear-cell renal cell carcinoma (ccRCC), pheochromocytoma and pancreatic neuroendocrine tumor (Maher et al 2011). Besides, a number of sporadic cancers, including ccRCC, are strongly associated with VHL reduced expression and/or loss-of-function mutations (Gnarra et al 1994;Cassol and Mete, 2015). The best characterized pVHL function is ubiquitination followed by proteasome degradation of target proteins (Robinson and Ohh, 2014).…”

Diagnosing clear cell neuroendocrine tumors on cytological specimens: Report of two cases and brief literature review

“…It has even been proposed that the two entities are indeed the same, with clear cell NET representing the coalescence of multiple small lipid vacuoles into one large vacuole, which clears out the cytoplasm of the cell. 3,11 Singh et al studied 11 pancreatic NETs with foamy, microvesicular cytoplasm, and confirmed in three cases, by electron microscopy, that the cytoplasmic vesicles were lipid vacuoles. Only one of the eleven cases involved a patient who had VHL.…”

“…However, we will continue to use the term clear cell NET to refer to both clear cell NET and lipid‐rich NET, as they seem to be used interchangeably in most studies, and there does not appear to be sufficient evidence to separate them. It has even been proposed that the two entities are indeed the same, with clear cell NET representing the coalescence of multiple small lipid vacuoles into one large vacuole, which clears out the cytoplasm of the cell …”

“…It is due to a mutation in the VHL gene, which is a tumor suppressor gene, on chromosome 3 (3p25‐26) . The most common manifestations of the disease are well known and include craniospinal hemangioblastomas, clear cell renal cell carcinoma, visceral cysts, hemangiomas, papillary cystadenomas, and neuroendocrine neoplasms such as pheochromocytomas, paragangliomas, pancreatic neuroendocrine tumors (NET), and endolymphatic sac tumors . The most common cause of death in these patients is complications from renal cell carcinoma and CNS disease, although the expected survival time for affected individuals has been greatly extended due to routine screening and advanced imaging techniques…”