Glucagon Cell Hyperplasia and Neoplasia
Glucagon cell hyperplasia and neoplasia (GCHN) is the histological phenotype of various rare underlying conditions. By pathogenesis it can be divided into reactive, functional, and nonfunctional GCHN.
Reactive GCHN is characterized by germline loss-of-function mutations in the glucagon receptor gene (GCGR) on chromosome 17q25.3, inherited in an autosomal recessive fashion (Mahvash syndrome (Yu et al. 2008)). Hyperaminoacidemia, the result of absent glucagon signaling specifically in the liver, causes pancreatic alpha cell hyperplasia and/or neoplasia, which in turn results in hyperglucagonemia without glucagonoma syndrome due to the defective or absent GCGR (Solloway et al. 2015). Because of this, glucagon-producing pancreatic neuroendocrine tumors (PanNETs) are per definition nonfunctional in reactive GCHN.
Functional and nonfunctional GCHN lack GCGR mutations, and several other genes in the glucagon signaling pathway have been suggested as pathogenic candidates. Functional GCHN presents with hyperglucagonemia and glucagonoma syndrome, while nonfunctional GCHN lacks both.
About half of reported cases of GCHN have been classified as reactive GCHN. While the incidence is unknown, the prevalence of reactive GCHN has been estimated to be about one in four million (Lucas et al. 2013).
Age and Sex
Patients with GCHN present around middle age with gross PanNETs (range 25–74 years). Recently a young girl (7 years) was diagnosed with reactive GCHN after a period of persistent hyperaminoacidemia. Both sexes are equally affected.
So far, only endocrine pancreatic tissue has been reported to be affected in GCHN. As islets transplanted into the renal capsule of a murine GCHN model also are affected, heterotopic pancreas or metaplasia might also be.
There are no guidelines for treatment. Because of the neoplastic potential, treatment and follow-up as recommended for PanNET syndromes like MEN1 has been suggested. PanNETs should be resected following guidelines for nonfunctional PanNET. Restoring GCGR function would be an attractive treatment but has not been reported yet.
Although cases are very rare, PanNETs develop in most reactive GCHN patients and less commonly in functional/nonfunctional GCHN. Lymph node and liver metastases are rare but have been reported in reactive and nonreactive GCHN. In the murine model of reactive GCHN, all mice developed microadenomas, most developed macroscopic PanNETs, and liver metastases were occasionally seen (Lucas et al. 2013).
Usually GCHN is not suspected clinically; surgical resections are performed only in case of mass-effect. Solid and/or cystic, well-circumscribed tumors can be found on gross examination in an enlarged pancreas. In reactive GCHN, a higher number of (larger) macrotumors can be found (between 2 and 12), while fewer macrotumors are seen in nonreactive GCHN (Sipos et al. 2015).
Germline MEN1 and VHL mutations should be excluded for the diagnosis GCHN. In rare cases somatic mutations and allelic loss of MEN1 have been reported in reactive GCHN microadenomas. It is expected that secondary driving mutations contribute to neoplastic progression.
MEN1 and VHL syndrome are two germline genetic conditions with multiple neuroendocrine proliferations throughout the pancreas and usually have additional clinical manifestations. Pancreatic disease in VHL syndrome is characterized by pancreatic serous cysts, mostly glucagon-negative microadenomas and PanNETs, and no glucagon cell hyperplasia (Lubensky et al. 1998). In MEN1 syndrome, more than half of microadenomas and PanNETs can be glucagon-positive, and glucagon cell hyperplasia has been reported, but, in contrast to GCHN, other peptide hormone expression can also be observed in micro- and macrotumors. In MEN1 as well as VHL syndrome, the number of hyperplastic islets and microadenomas is less than in GCHN (Anlauf et al. 2006).
References and Further Reading
- Lucas, M., Yu, V., & Yu, R. (2013). Mahvash disease: Pancreatic neuroendocrine tumor syndrome caused by inactivating glucagon receptor mutation. Journal of Molecular and Genetic Medicine, 7, 4.Google Scholar