Glucagonoma overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2], Mohammed Abdelwahed M.D[3]
Overview
A glucagonoma is a tumor of the alpha cells of the pancreas that results in overproduction of the hormone glucagon. Glucagonoma was first described in 1942 by Becker. On microscopic examination, glucagonoma's consist of pleomorphic cells containing granules that stain for other peptides, most frequently pancreatic polypeptide. Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon. Similar symptoms are present in cases of pseudo-glucagonoma syndrome in the absence of a glucagon-secreting tumor. Further, glucagonoma must be differentiated from certain skin lesions (acrodermatitis enteropathica, psoriasis, pellagra, eczema) and other causes of hyperglucagonemia (infection, diabetes mellitus, Cushing syndrome, renal failure, acute pancreatitis, severe stress, and prolonged fasting). The incidence of glucagonoma is approximately .0005 per 100,000 individuals worldwide. Glucagonoma affects men and women equally. The median age at diagnosis of glucagonoma is 52.5 years. The most potent risk factor in the development of glucagonoma is a positive family history of multiple endocrine neoplasia type 1. If left untreated, patients with glucagonoma may progress to develop necrolytic migratory erythema, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia.The presence of metastasis is associated with a particularly poor prognosis among patients with glucagonoma. The 10-year event-free survival rate is less than 51.6% with metastasis and 64.3% without metastasis. According to The American Joint Committee on Cancer (AJCC), there are four stages of glucagonoma based on the TNM staging system. Symptoms of glucagonoma include necrolytic migratory erythema, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia. A positive family history of multiple endocrine neoplasia type 1 may be present. Common physical examination findings of glucagonoma include tachycardia, fever, rash, muscle atrophy, cotton wool spots, flame hemorrhage, and dot and blot hemorrhage on fundoscopic examination of the eye may be present. Laboratory findings consistent with the diagnosis of glucagonoma include serum glucagon concentration of 1000pg/ml or greater. Findings on abdominal CT scan suggestive of glucagonoma include reinforced mass in the arterial phase of the enhanced CT scan. Abdominal MRI is helpful in the diagnosis of glucagonoma. On abdominal MRI, glucagonoma is characterized by a mass which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI. The abdominal ultrasound scan may be helpful in the diagnosis of glucagonoma. Findings on ultrasound scan suggestive of glucagonoma is a hypoechoic tumor in the distal pancreas. Other imaging studies for glucagonoma include positron emission tomography scan and somatostatin receptor scintigraphy. Other diagnostic studies for glucagonoma includes biopsy, which demonstrates epidermal necrosis, subcorneal pustules, either isolated or associated with necrosis of the epidermis, confluent parakeratosis, epidermal hyperplasia, and marked papillary dermal angioplasia and suppurative folliculitis. The predominant therapy for glucagonoma is surgical resection. Adjunctive chemotherapy may be required. Surgery is the mainstay of treatment for glucagonoma. The feasibility of surgery depends on the stage of glucagonoma at diagnosis. Secondary prevention measures of glucagonoma include routine glucagon levels and imaging at scheduled intervals after treatment.
Historical Perspective
Glucagonoma was first described in 1942 by Becker. In 1966, McGavran was first to report a case of hyperglucagonemia associated with cutaneous changes. In 1970, Wilkinson described the typical skin eruption in glucagonoma as necrolytic migratory erythema.
Pathophysiology
Glucagonoma is a tumor of the alpha cells of the pancreas characterized by the excessive secretion of glucagon and necrolytic migratory erythema. Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema. Glucagonoma may be a part of type 1 multiple endocrine neoplasia. It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene. MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for tumor development. All glucagonomas are located in the pancreas, 50–80% occur in the pancreatic tail, 32.2% in the body and 21.9% in the head. Glucagonoma can metastasize mainly to the liver. Glucagonomas consist of pleomorphic cells containing granules that stain for other peptides, most frequently pancreatic polypeptide. Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon.
Causes
There are no established causes for glucagonoma. Mostly, glucagonomas are sporadic but 20% are associated with the MEN1 syndrome.
Differential Diagnosis
Glucagonoma must be differentiated from certain skin lesions in which necrolytic migratory erythema can be found such as acrodermatitis enteropathica, psoriasis, pellagra, and eczema. Glucagonoma should be differentiated from other causes of hyperglucagonemia include infection, diabetes mellitus, Cushing syndrome, renal failure, acute pancreatitis, severe stress, and prolonged fasting.
Epidemiology and Demographics
The incidence of glucagonoma is approximately 0.0005 per 100,000 individuals worldwide. Glucagonoma affects men and women equally. The median age of diagnosis is the fifth decade.
Risk Factors
The most common risk factor in the development of glucagonoma is a positive family history of multiple endocrine neoplasia type 1, which is characterized by the presence of pituitary adenomas, islet cell tumors of the pancreas, and hyperparathyroidism.
Screening
Screening of multiple endocrine neoplasia type 1 associated glucagonoma improves morbidity and survival rates of patients. Biochemical screening depends on measuring gastrointestinal hormones: gastrin, insulin, glucagon, VIP, pancreatic polypeptide, chromogranin A, prolactin, and IGF-1 in all patients. Radiological screening should include an MRI of the pancreas, adrenal glands, and pituitary and repeated every 2 years. All high-risk patients should be offered genetic counseling and MEN1 mutation testing. If the genetic tests result patients should have a periodic clinical, biochemical, and radiological screening program.
Natural History, Complications and Prognosis
If left untreated, patients with glucagonoma may progress to develop necrolytic migratory erythema, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia. The presence of metastasis is associated with a particularly poor prognosis among patients with glucagonoma. The 10-year event free survival rate is less than 51.6% with metastasis and 64.3% without metastasis. Glucagonomas are generally slow-growing but are usually advanced by the time of diagnosis. Age, grade, and distant metastases are the most significant predictors of survival.
Staging
According to The American Joint Committee on Cancer (AJCC), there are four stages of glucagonoma based on the TNM staging system.
History and Symptoms
Symptoms of glucagonoma include necrolytic migratory erythema, weight loss, glucose intolerance, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia. A positive family history of multiple endocrine neoplasia type 1 may be present.
Physical Examination
Common physical examination findings of glucagonoma include tachycardia, fever, rash, muscle atrophy, cotton wool spots, flame hemorrhage, and dot and blot hemorrhage on fundoscopic examination of the eye may be present.
Laboratory Findings
Laboratory findings consistent with the diagnosis of glucagonoma include a serum glucagon concentration of 1000 pg/ml or greater.
CT
Findings on abdominal CT scan suggestive of glucagonoma include a reinforced mass in the arterial phase of the enhanced CT scan. Symptomatic, but nonfunctioning, glucagonoma is usually large (>3 cm) at the time of diagnosis.
MRI
Abdominal MRI is helpful in the diagnosis of glucagonoma. On abdominal MRI, glucagonoma is characterized by a mass which is hypointense on T1-weighted MRI and hyperintense on T2-weighted MRI.
Ultrasonography
The abdominal ultrasound scan may be helpful in the diagnosis of glucagonoma. Finding on ultrasound scan suggestive of glucagonoma is a hypoechoic tumor in the pancreas. US-guided fine-needle aspiration biopsy is a non-operative histologic diagnosis. Intraoperative ultrasonography is used as an adjunct to intraoperative palpation.
Other Imaging Findings
Other imaging studies for glucagonoma include positron emission tomography scan and somatostatin receptor scintigraphy. Scintigraphy is less sensitive than PET scan but still useful.
Other Diagnostic Studies
Other diagnostic studies for glucagonoma include venous sampling after a selective injection of a stimulating secretin. Biopsy, which demonstrates epidermal necrosis, subcorneal pustules, either isolated or associated with necrosis of the epidermis, confluent parakeratosis, epidermal hyperplasia and marked papillary dermal angioplasia, and suppurative folliculitis.
Medical Therapy
The predominant medical therapy for primary glucagonoma is somatostatin analogs (octreotide). Metastatic tumors need hepatic artery embolization, Radiofrequency ablation, and molecular therapy.
Surgery
Surgery is the mainstay of treatment for glucagonoma. The feasibility of surgery depends on the stage of glucagonoma at diagnosis. Hepatic resection is indicated for the treatment of metastatic liver disease in patients who are candidates for surgery with no extensive extrahepatic metastases.
Primary Prevention
There is no established method for prevention of glucagonoma.
Secondary Prevention
Secondary prevention measures of glucagonoma include routine glucagon levels and imaging at scheduled intervals after treatment.