Central JSM Thyroid Disorders and Management Bringing Excellence in Open Access Case Series *Corresponding author G Bano, Thomas Addison Unit, St George’s Hospital, Blackshaw Road, London, SW17 0QT, UK, Tel: Glucagon Secreting Tumors and 442087251027; Fax: 442087250240; Email: Submitted: 15 October 2016 Glucagonoma Syndrome Accepted: 09 February 2017 Yasmeen Khalid1, Faisal Ozair1, John Du Parc2, Nigel Beharry3, Published: 10 February 2017 Satvinder Mudan4, and Gul Bano1* Copyright 1Department of Diabetes and Endocrinology, St George’s Hospital, UK © 2017 Bano et al. 2 Department of Cytopathlogy, St George’s Hospital, UK OPEN ACCESS 3Department of Radiology, St George’s Hospital, UK 4 Department of Surgery, St George’s Hospital, UK Keywords • Glucagonoma Abstract • Glucagonoma syndrome • Multiple endocrine neoplasia Glucagonomas are the functioning neuroendocrine tumors. These arise from pancreatic • Necrolytic migratory erythema islet α-cells. These tumors are extremely rare and have an annual incidence of 1 per 20-40 • Biomarkers million population 80% of glucagon-expressing tumors are sporadic, and 20% are associated with genetic syndromes such as Multiple Endocrine Neoplasia-type 1. Glucagonoma typically occurs in the distal pancreas, and around 85% are in the body or tail. It tends to be large at the time of diagnosis. Most reported cases of glucagonoma are malignant and about 65- 75% patients present with metastatic disease. The liver is usually the first site of metastases, followed by the involvement of peripancreatic lymph nodes. The term Glucagonoma syndrome and glucagonoma are often interchangeably used, but in fact, these are two distinct entities. Glucagonoma syndrome comprises of necrolytic migratory erythema, hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, diarrhea, venous thrombosis and neuropsychiatric disturbances in the presence of a glucagon-producing tumor of the pancreas. Tumors secreting glucagon can occur without the glucagonoma syndrome. The glucagonoma secretion depends on the expression of protein convertase enzyme PC1/3 or PC2 within the tumor itself. As a result of this expression, the clinical manifestations can be variable. The tumor can either present with hyperinsulinemic hypoglycemia in a patient with a previous history of diabetes or with the features of the glucagonoma syndrome. In cases where a tumor is localized surgery is the curative treatment. Reduction of the tumor bulk, removal of the primary by surgery and targeted therapy for the hepatic metastases are the favored approach even when there is the metastasis. ABBREVIATIONS 80% of glucagon-expressing tumors are sporadic, and 20% are related to genetic syndromes such as Multiple Endocrine GEP: Gastroenteropancreatic (GEP); NETs: Neuroendocrine Neoplasia-type 1 (MEN1) [1]. Mahvash disease, a rare inherited Tumors, PGDP: Proglucagon-Derived Peptides; MEN-1: Multiple tumor predisposition syndrome, due to inactivating mutations in Endocrine Neoplasia-Type 1; GLP-1: Glucagon-Like Peptide-1 the glucagon receptor (GCGR) gene is associated with pancreatic INTRODUCTION syndrome and glucagonoma is interchangeably used, but these Gastroenteropancreatic (GEP) neuroendocrine tumors areα-cell two hyperplasia distinct entities. and glucagonoma [2]. The term Glucagonoma (NETs) can be either nonfunctioning or functioning. Functioning tumors can result in an endocrine syndrome due to inappropriate CASE PRESENTATION Case 1 on the hormone production that results in a particular syndrome. GEPhormone NETs secretion. are rare with The anclassification annual incidence of these rate tumors of less depends than 10 64 years old Caucasian male presented with a maculopapular per million population. Glucagonomas are the functioning NETs. pruritic rash on his legs that settled with topical steroid treatment. A year later he developed a rash on his legs, arm, chest secrete proglucagon-derived peptides (PGDP). These tumors and back (Figure 1). His skin biopsy was suggestive of necrolytic areThese extremely arise from rare pancreaticand have an islet annual α-cells incidence that synthesize of 1 per 20-40 and migratory erythema (NME). He had six months history of million population. The frequency of islet cell tumors expressing abdominal pain, bloating, frequent diarrhea and weight loss. His glucagon is reported to be approximately 1% in autopsy studies, investigations showed high glucagon, chromogranin A, and B. His suggesting that many of tumors are either not diagnosed and other gut peptides and hormones, including serum calcium and associated with a sub-clinical disease. parathyroid hormone were normal (Table 1). His oral glucose Cite this article: Khalid Y, Ozair F, Parc JD, Beharry N, Mudan S, et al. (2017) Glucagon Secreting Tumors and Glucagonoma Syndrome. JSM Thyroid Disord Manag 2(1): 1008. Bano et al. (2017) Email: Central Bringing Excellence in Open Access Glucagonoma typically occurs in the distal pancreas. Around 85% of these tumors are in the body or tail of the pancreas. It tends to be large at the time of diagnosis. Most reported cases of glucagonoma are malignant, and about 65-75% patients present with metastatic disease in the liver and this is followed by the involvement of peripancreatic lymph node [4]. Glucagon secreting tumors can also occur without the glucagonoma syndrome. Glucagonoma may occur in patients with MEN-1 and other genetic syndromes, although this association is rare. The tumors in these cases are usually multifocal and, slow growing. Figure 1 Table 1: Generalized skin rash. Peptide Value Range PP 108pmol/l large pancreatic mass with involvement of lymph nodes and Gastrin 9pmol/l 0-40 tolerance confirmed him to be diabetic. His CT scan showed a 0-300 Glucagon 0-50 (Figure 4). He had distal pancreatectomy and splenectomy. His Somatostatin 0-150 histologylocal infiltration showed (Figurenormal tubular2,3). This and mass acinar was morphology octreotide within avid 348pmol/l a vascular stroma. There was modest nuclear pleomorphism with Chromogranin A 33pmol/l74pmol/l 0-60 some chromatin aggregation, prominent nucleoli and abundant Chromogranin B 257pmol/l 0-150 granular cytoplasm (Figure 5). The lymph node showed normal PTH 1.1-6.9 small lymphocytes in a vascular stroma with a small aggregate Prolactin 110mIU/l of tumor cells (Figure 6). He was started on somatostatin analog 2.3pmol/l treatment. His symptoms, including his rash, settled and diabetes IGF-1 18.1nmol/l 86-324 VIP= Vasoactive intestinal peptide, PP= Pancreatic polypeptide, PTH= improved. His genetic test for MEN 1 mutation was negative. 5.6-25.3 parathyroid hormone, IGF-1= Insulin like growth factor Case 2 A 25- year old male presented with recurrent renal calculi. He was diagnosed with primary hyperparathyroidism. He was MEN- 1 mutation positive. He had a total parathyroidectomy but developed hyperparathyroidism an year later. He had an accessory parathyroid gland in the mediastinum and removal of this gland annual blood tests. Four years later his gut peptides including glucagon,normalized pancreatic his serum polypeptide calcium. He and was Chromogranin under surveillance B started with to increase. He had occasional diarrhea. His results are documented in Table 2. His CT and MRI scan showed a cystic abnormality 4.0 x 1.8 cm arising from the posterior aspect of the tail of the pancreas. This cystic lesion was Octreotide avid. His endoscopic ultrasound scan (EUS) showed a lesion in the tail of the pancreas. Figure 2 Pancreatic mass with lymph node involvement. had distal pancreatectomy and splenectomy and remains well. The fine needle aspiration (FNA) of the lesion was inadequate. He DISCUSSION Glucagonoma is a slowly growing PNET, frequently malignant and an extremely rare neuroendocrine tumor of the α-cells of (NME),the pancreas. hyperglucagonemia, Glucagonoma diabetessyndrome mellitus, was first anemia, described weight in loss,1942 glossitis,[3] and is steatorrhea,characterized diarrhea, by Necrolytic venous migratory thrombosis erythema and neuropsychiatric disturbances. These features are present in the settingPseudoglucagonoma of a glucagon-producing syndrome α-cell is thetumor presence of the ofpancreas. NME in the absence of a pancreatic tumor. These conditions include Liver disorders (i.e., coeliac disease) and other malignancies. Figure 3 Pancreatic mass with local tissue invasion. disease, Inflammatory bowel disease, Pancreatitis, Malabsorption JSM Thyroid Disord Manag 2(1): 1008 (2017) 2/5 Bano et al. (2017) Email: Central Bringing Excellence in Open Access improves [6]. Glucagonoma that produces GLP-1 and GLP-2 are After normalization of glucagon level, this clinical entity tends to with hypoglycemia and hyperinsulinemia. These patients can alsounusual have and gastrointestinal not well recognized. dysfunction Such (refractory tumors tend constipation, to present reduced motility, gross structural abnormalities of the small intestine). This type of presentation is mostly described as a paraneoplastic syndrome in the literature [7]. Glucagonomas produce proglucagon-derived peptide (GRP). The variable clinical phenotypes associated with these tumors Figure 4 Positive Octreotide scan. proglucagon in that particular tumor. The proglucagon processing may be related to the specific secreted peptide derived from proglucagon is cleaved to glucagon by prohormone convertase 2happens (PC2). inGlucagon a cell type-specific is cleaved manner.to glucagon-like In α-cells peptide-1 of the pancreas, (GLP- 1) and GLP-2 by PC1 in the intestinal