Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Glucagon Cell Hyperplasia and Neoplasia

  • Wenzel M. Hackeng
  • Claudio LuchiniEmail author
  • Lodewijk A. Brosens
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_5509-1

Synonyms

Definition

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.

Clinical Features

  • Incidence

    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.

  • Site

    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.

  • Treatment

    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.

  • Outcome

    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).

Macroscopy

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).

Microscopy

The pancreas may be diffusely involved and contain several microadenomas (<5 mm) and PanNETs (>5 mm), in which a typical neuroendocrine tumor histology can be observed (Fig. 1). Tumors can grow in a solid pattern, and calcifications can be found. Numerous (glucagon cell) hyperplastic islets and areas of nesidioblastosis within ductulo-insular structures are scattered through and around the neoplastic lesions. In reactive GCHN, more hyperplastic islets and microadenomas (mean 6.03–8.42/50 mm2) have been reported compared with nonreactive “wild-type GCGR” GCHN (3–5.16/50 mm2) (Sipos et al. 2015).
Fig. 1

Pancreas with multiple neuroendocrine tumors, microadenomas, and hyperplastic islets, at different magnifications (a, 4×; b, 20× original magnifications)

Immunophenotype

Tumors are mostly positive for the neuroendocrine markers, such as synaptophysin (Fig. 2) and chromogranin A. Usually all tumors are positive (at least weakly) for glucagon (Fig. 3), although glucagon-negative tumors have been reported. Pancreatic polypeptide is occasionally positive; all are negative for gastrin and insulin. All hyperplastic islets show predominant or exclusive glucagon expression, while some smaller islets keep normal peptide hormone expression. Ki-67 labeling index is usually less than 2% for all micro- and macrotumors, although 5% has been reported in larger tumors.
Fig. 2

Intense positivity for synaptophysin (10× original magnification)

Fig. 3

Pancreas with multiple glucagon-positive pancreatic neuroendocrine tumors, microadenomas, and hyperplastic islets. Germline MEN1 or VHL mutations were ruled out in this case. Although GCGR germline mutation status is unknown, asymptomatic hyperglucagonemia is present and the phenotype is consistent with GCHN (10× original magnification; glucagon immunohistochemistry with hematoxylin counterstaining)

Molecular Features

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.

Differential Diagnosis

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

  1. Anlauf, M., Schlenger, R., Perren, A., et al. (2006). Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. The American Journal of Surgical Pathology, 30, 560–574.CrossRefPubMedCentralGoogle Scholar
  2. Lubensky, I. A., Pack, S., Ault, D., et al. (1998). Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: Histopathological and molecular genetic analysis. The American Journal of Pathology, 153, 223–231.CrossRefPubMedCentralGoogle Scholar
  3. 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
  4. Sipos, B., Sperveslage, J., Anlauf, M., et al. (2015). Glucagon cell hyperplasia and neoplasia with and without glucagon receptor mutations. The Journal of Clinical Endocrinology and Metabolism, 100, E783–E788.CrossRefPubMedCentralGoogle Scholar
  5. Solloway, M. J., Madjidi, A., Gu, C., et al. (2015). Glucagon couples hepatic amino acid catabolism to mTOR-dependent regulation of alpha-cell mass. Cell Reports, 12, 495–510.CrossRefPubMedCentralGoogle Scholar
  6. Yu, R., Nissen, N. N., Dhall, D., et al. (2008). Nesidioblastosis and hyperplasia of alpha cells, microglucagonoma, and nonfunctioning islet cell tumor of the pancreas: Review of the literature. Pancreas, 36, 428–431.CrossRefPubMedCentralGoogle Scholar

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Authors and Affiliations

  • Wenzel M. Hackeng
    • 1
  • Claudio Luchini
    • 2
    Email author
  • Lodewijk A. Brosens
    • 1
  1. 1.Department of PathologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Section of Pathology, Department of Diagnostics and Public HealthUniversity and Hospital Trust of VeronaVeronaItaly