Glucagonoma

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]

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, 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. Similar symptoms are present in cases of pseudo-glucagonoma syndrome in the absence of a glucagon-secreting tumor. 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 0.0005 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.

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.

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.

There are no established causes for glucagonoma. Mostly, glucagonomas are sporadic but 20% are associated with the MEN1 syndrome.

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.

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.

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 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.

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.

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, weight loss, glucose intolerance, 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 a serum glucagon concentration of 1000 pg/ml or greater.

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.

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. 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 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 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.

The predominant medical therapy for primary glucagonoma is somatostatin analogs (octreotide). Metastatic tumors need hepatic artery embolization, Radiofrequency ablation, and molecular therapy.

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.

There is no established method for prevention of glucagonoma.

Secondary prevention measures of glucagonoma include routine glucagon levels and imaging at scheduled intervals after treatment.

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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]

Glucagonoma was first described in 1942 by Becker. In 1966, McGavran was the 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.

• In 1942, glucagonoma was first described by Becker.
• Between 1942 and 1966, many authors tried to make associations between high level of glucagon and skin eruptions.
• In 1966, The first well-documented case of glucagonoma was reported by McGavran in a female with skin lesions and glucose intolerance. The author was the first to describe a correlation between skin lesions and islet-cell tumors.^[1]
• In 1970, Wilkinson described the typical skin eruption in glucagonoma as necrolytic migratory erythema.^[1]

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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]

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.

• Glucagonoma is a rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Glucagonomas are neuroendocrine tumors derived from multipotential stem cells.^{[1][2][3][4][5][6]}
  • Glucagon increases glycogenolysis, gluconeogenesis from amino acid substrates and inhibits glycolysis. This causes weight loss due to the catabolic action of glucagon.
  • When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms.
  • Glucagonoma causes hyperglucagonemia, zinc deficiency, fatty acid deficiency, hypoaminoacidemia that may cause necrolytic migratory erythema.
  • The mechanism for necrolytic migratory erythema involves excessive inflammation in the epidermis in response to trauma and to the necrolysis.
  • Necrolytic migratory erythema (NME) probably results from hyponutrition and amino acid deficiency. It can be caused by the loss of tryptophan in cutaneous tissues as a result of the excess circulating glucagon. Tryptophan is responsible for niacin function, which regulates cell turnover and the maturation of the epidermis and mucosal epithelia.
  • Diarrhea may result from the secretion of gastrin which occurs with glucagonoma.

Glucagonoma may be part of type 1 multiple endocrine neoplasia. It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene.^{[1][2][3][4][5][6][7]}

• It is characterized by the development of the following tumors:
  • Pituitary adenomas
  • Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma)
  • Parathyroid hyperplasia with resulting hyperparathyroidism
• The gene locus causing multiple endocrine neoplasia type 1 has been localized to chromosome 11q13 by studies of loss of heterozygosity on multiple endocrine neoplasia type 1-associated tumors and by linkage analysis in multiple endocrine neoplasia type 1 families. MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
• MEN1 gene is a tumor suppressor gene and causes type 1 multiple endocrine neoplasia by Knudson’s “two hits” model for tumor development.
• Two hits model for tumor development suggests that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele. This “two hits” model gives cells the survival advantage needed for tumor development.

The gross pathology of glucagonoma may show:^[7][8][9]

• Large tumors at diagnosis with a mean diameter of 5 cm. About 50 to 82% have evidence of metastatic spread at presentation.

• Nearly 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.
• In few patients, location can be extrapancreatic, such as in kidney, duodenum, lung, accessory pancreatic tissue.

• Metastasis usually occurs to the liver. Other sites are lymph nodes, bone, lung, and adrenals.

• Tumors smaller than 2 cm in diameter are associated with a very low chance of malignancy.

The microscopic pathology of glucagonoma tumors in pancreas usually show intense staining for glucagon.^[10][11]

• Many glucagonomas are pleomorphic with cells containing granules that stain for other peptides, most frequently pancreatic polypeptide.
• Immunoperoxidase staining can detect glucagon within the tumor cells and glucagon mRNA also may be detected.
• Electron microscopy shows secretory granules indicating the origin of glucagonoma from alpha cells.
• Benign tumors are usually fully granulated and malignant cells have fewer granules.
• Skin biopsy may depict epidermal necrosis.

• 
  Histology of confluent epidermal necrosis (high mag),Source:By Nephron – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
• 
  Histology of confluent epidermal necrosis (very high mag)Source:By Nephron – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]
• 
  Histology of confluent epidermal necrosis (intermed mag)Source:By Nephron – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16874054^[12]

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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]

There are no established causes for glucagonoma. Mostly, glucagonomas are sporadic but 20% are associated with the MEN1 syndrome.

There are no established causes for glucagonoma. Mostly, glucagonomas are sporadic but 20% are associated with the MEN1 syndrome.^[1][2]

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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]

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 hyperglycemia include infection, diabetes mellitus, Cushing syndrome, renal failure, acute pancreatitis, severe stress, and prolonged fasting.

Glucagonoma must be differentiated from certain skin lesions in which necrolytic migratory erythema can be found such as:^[1]

• Pemphigus foliaceus 
• Pustular psoriasis
• Chronic eczema
• Acrodermatitis enteropathica
• Pellagra

Disease	Clinical Picture			Investigations	Pictures
	History	Symptoms	Signs
Glucagonoma[2][3][4][5]	A family history of multiple endocrine neoplasia type 1	Necrolytic migratory erythema characterized by the spread of erythematous blisters and swelling across areas subject to greater friction and pressure Skin lesions involving the lower abdomen, buttocks, perineum, and groin Weight loss Glucose intolerance	Rash: Erythematous, ring shaped rash that blisters, erodes, and crusts over suggesting necrolytic migratory erythema Muscle atrophy Unilateral calf or thigh erythema and swelling Hyporeflexia Unilateral/bilateral sensory loss in the upper/lower extremity	Serum glucagon Increased plasma glucagon levels (>500 pg/mL) Concentrations above 1000 pg/mL are diagnostic of glucagonoma CT scan is used to determine: The location of the tumor Metastasis (usually liver metastasis) Appear isodense with the liver on a non-contrasted study
Pemphigus foliaceus.[6][2][7][8]	Autoimmune blistering disease of the skin with characteristic lesions that are scaly, crusted erosions, often on an erythematous base.[1] Mucosal involvement is absent even with widespread disease	Cutaneous lesion that usually develops in a seborrheic distribution The scalp, face, and trunk are common sites of involvement Skin lesions may remain localized or may coalesce to cover large areas of skin Pain or burning sensations frequently accompany the cutaneous lesions Systemic symptoms are usually absent	The skin lesions usually consist of small, scattered superficial blisters Lesions rapidly evolve into scaly, crusted erosions Positive Nikolsky sign Occasionally, pemphigus foliaceus progresses to involve the entire skin surface as an exfoliative erythroderma	Autoimmune IgG build up in the epidermis, then nearly almost all of the antibodies are aimed against desmoglein 1
Pustular psoriasis[2][3]	Positive family history of psoriasis Frequent association with histocompatibility antigen (HLA)- Cw6 A history of a long-term erythematous scaly area with ocular and joint involvement Past medical history of the patient may include:  Viral or bacterial infection  Diabetes  Hypertension  Chronic kidney disease  Obesity	Pain(unpleasant, superficial, sensitive, itchy, hot or burning)  Pruritus High fever Dystrophic nails Recent presentation of arthralgia	Papulosquamous disease with variable morphology, distribution, severity, and course Scaling papules and plaques Koebner phenomenon: appearance of new psoriatic lesions at the site of skin injury Woronoff’s ring: ring of peripheral blanching skin around a psoriatic plaque Auspitz’s sign: Small bleeding points are seen upon disruption of a psoriatic scale	Skin biopsy Perivascular and dermal inflammatory cell infiltration Vascular dilation Absent granular layer Elongation of dermal papillae Parakeratosis Spongiform pustules of Kogoj (pathognomic of psoriasis) Munro’s micro abscesses (pathognomic of psoriasis) Edema of dermal papillae Basal cell layer is expanded Leukocytosis
Acrodermatitis enteropathica[9][10][11]	An autosomal recessive disorder characterized by: Periorificial and acral dermatitis, alopecia, and diarrhea The genetic base is a mutation of SLC39A4 which encodes a transmembrane protein that serves as a zinc uptake protein	Symptoms appear in infants after breast milk weaning The appearance of erythematous patches and plaques of dry, scaly skin Diarrhea	Erythematouspatches/plaques of dry and scaly skin The lesions may appear eczematous or may evolve into crusted vesicles, bullae or pustules The lesions are frequent in: Mouth/ perioral Anus/ Peri-anal Also involves hands, feet, and scalp Paronychia  Alopecia of the scalp, eyebrows, and eyelashes	Measurement of zinc in plasma, erythrocytes, neutrophils, lymphocytes, and hair A low plasma zinc usually is defined as a value less than 60 mcg/dL The criteria for zinc deficiency are decreased zinc level in lymphocyte Depressed serum alkaline phosphatase levels
Pellagra[12][13]	Niacin deficiency disease characterized by Photosensitivity Pigmented dermatitis Diarrhea Dementia. Hisotry of: Alcoholics Bariatric surgery Anorexia nervosa Malabsorptive disease Dietary deficiency especially in infants Past history of Carcinoid syndrome Prolonged use of isoniazide A family history of Hartnup disease	Photosensitivity Pigmented dermatitis in sun-exposed areas Diarrhea Dementia	Symmetric hyperpigmented rash, similar in color and distribution to a sunburn, which is present in the exposed areas of skin	Niacin status can be assessed by measuring urinary N-methylnicotinamide or by measuring the erythrocyte NAD/NADP ratio
Chronic eczema (atopic dermatitis)	Chronic pruritic inflammatory skin disease Occurs most frequently in children but also affects adults Family history of: Atopy (Eczema Asthma Allergic rhinitis) History of dermatitis involving the skin creases Personal or family history of asthma or hay fever	Symptoms beginning in a child before the age of 2 years or, in children <4 years Dermatitis affecting the cheeks or dorsal aspect of extremities Dry skin and severe pruritus that is associated with cutaneous hyperactivity to various environmental stimuli Exposure to: Food and inhalant allergens Irritants Infection	Visible dermatitis involving flexural surfaces Presence of generally dry skin within the past year Erythema, papulation, oozing and crusting, excoriation	Raised IgE or an eosinophilia Radioallergosorbent Test: Blood is mixed separately with many different allergens and the antibody levels measured Skin biopsy: A procedure that removes a small piece of the affected skin and sent for microscopic examination in a pathology laboratory

Glucagonoma can be differentiated from other causes of hyperglycemia which include:^[14][15][16]

• Type1 DM

• Type 2 DM
• MODY-DM
• Psychogenic polydipsia
• Diabetes insipidus
• Transient hyperglycemia
• Steroid therapy
• Renal tubular acidosis type-1
• Glucagonoma
• Cushing’s syndrome
• Hypothyroidism
• Wolfram syndrome
• Alstrom syndrome

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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]

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.

• Annual incidence is 0.01 to 0.1 new cases per 100,000.^[1]
• Most glucagonomas are sporadic but up to 20 percent may be associated with the multiple endocrine neoplasia syndrome type 1. Glucagonomas occur in only 3 percent of MEN1 patients.^[2][3]

• Patients typically present in their fifth decade with lesions mainly located in the tail of the pancreas,
• When associated with MEN 1, patients present at a younger age of around 33 years.^[4][5]

• Glucagonoma affects men and women equally.

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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]

The most common risk factor in the development of glucagonoma is a positive family history of multiple endocrine neoplasia type1 which is characterized by the presence of pituitary adenomas, islet cell tumors of the pancreas, and hyperparathyroidism.

• The most common risk factor in the development of glucagonoma is a positive family history of multiple endocrine neoplasia type 1.^[1][2]
  • It is an autosomal dominant syndrome that is usually caused by mutations in the MEN1 gene.
  • It is characterized by the development of the following tumors:^[1]
    • Pituitary adenomas
    • Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma)
    • Parathyroid hyperplasia with resulting hyperparathyroidism

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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]

Screening of multiple endocrine neoplasia type 1 associated glucagonoma improves morbidity and survival rates of patients. Biochemical screening depends on measuring gastrointestinal hormones such as 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 is positive, patients should have a periodic clinical, biochemical, and radiological screening program.

• Screening of multiple endocrine neoplasia type 1 associated glucagonoma improves morbidity and survival rates of patients.
• The survival rate of early diagnosed and treated glucagonoma is 85% while this rate falls to 60% in patients with malignant disease.
• Sporadic cases present in their fifth decade whereas patients with MEN I present at the younger age of 33 years. So, familiar cases of glucagonoma should be diagnosed and treated as soon as possible.^[1][2]

• A first-degree relative of family member with known MEN1 mutation.
• Asymptomatic first-degree relative.
• First-degree relative with familial MEN1, for example, one MEN1-associated tumor.
• Suspicious multiple parathyroid adenomas before the age of 40 years, recurrent hyperparathyroidism, gastrinoma or multiple pancreatic NET at any age.
• Atypical features for MEN1 (i.e. development of two nonclassical MEN1-associated tumors, e.g. parathyroid and adrenal tumor).

• Patients should be screened as early as possible, before 5 years of age for asymptomatic patients.
• Biochemical screening for the development of MEN1 tumors in asymptomatic members of families with MEN1 is likely to be of benefit in as much as earlier diagnosis and treatment of these tumors may help reduce morbidity and mortality. Screening for MEN1 tumors is difficult because clinical and biochemical manifestations in members of any one family are not uniformly similar.^[3]

• Biochemical screening depends on measurement of:^[4]
  • Serum concentrations of calcium in all patients as the earliest manifestation for MEN1 is hyperparathyroidism.
  • Gastrointestinal hormones: Gastrin, insulin, glucagon, pancreatic polypeptide, chromogranin A, prolactin, and IGF-1 in all patients.

• Pancreatic involvement in asymptomatic patients has been detected by measuring fasting plasma concentrations of gastrin, pancreatic polypeptide, glucagon, and chromogranin A and by abdominal imaging.^[5]
• Screening should be done at least once annually and also have baseline pituitary and abdominal imaging which should then be repeated at 1- to 3-year intervals and it should be repeated throughout life because the disease may not manifest in some patients until the eighth decade.

• Radiological screening should include an MRI of the pancreas, adrenal glands, and pituitary and repeated every 2 years.^[6]

• All high-risk patients should be offered genetic counseling and MEN1 mutation testing. If the genetic tests result are positive, patients should have a periodic clinical, biochemical, and radiological screening program.^[3]
  • This may include examination for mutations in genes associated with familial hyperparathyroidism including CDC73 associated with the HPT-JT and the calcium sensing receptor (CASR), or cyclin-dependent kinase 1B (CDKN1B) and AIP which are rarely identified in those with clinical MEN1.

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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]

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.

• If left untreated, patients with glucagonoma may progress to develop necrolytic migratory erythema, cheilosis, stomatitis, diarrhea, polyuria, and polydipsia.
• Glucagonoma has a very slow growth rate compared to most malignant tumors.

Complications of glucagonoma include:

• Metastasis:
  • Glucagonomas are generally slow-growing but are usually advanced by the time of diagnosis.
  • Metastasis occurs mainly in the liver but in few cases, it can occur in lymph nodes, peritoneum, lung, and adrenals.
• Weight loss: due to the catabolic effect of glucagon, most patients lose weight.
• Anemia
• Neuropsychiatric manifestations include depression, dementia, psychosis, and agitation
• Reversible dilated cardiomyopathy^[1]

Prognosis of glucagonoma depends on the following:

• Whether or not the tumor can be removed by surgery.
• The stage of the tumor, the size of the tumor, whether cancer has spread outside the pancreas.
• The patient’s general health.
• Whether the tumor has just been diagnosed or has recurred.
• 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.

Additionally:

• Age, grade, and distant metastases are the most significant predictors of survival.
• Five and 10-year survival rates for patients undergoing resection of gastroenteropancreatic neuroendocrine tumors.^[2]
• Sixty percent of glucagonomas are malignant. Once the tumor is metastatic, the cure is rare.^[3]

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