Glucagonoma is a tumor of pancreatic islet A cells, where the tumor cells secrete excessive glucagon. Clinically, it primarily manifests as necrolytic migratory erythema of the skin, chronic inflammation of the corners of the mouth, lips, tongue, and other areas, loose nails, vulvovaginitis, anemia, diabetes, etc., hence it is also known as the hyperglycemic cutaneous syndrome. In 1963, Unger used radioimmunoassay to measure glucagon levels in patients' serum for diagnosis. In 1966, McGavran applied electron microscopy to identify A-cell granule characteristics in tumor cells and used radioimmunoassay to confirm high glucagon content in the excised tumor tissue, marking the first definitive diagnosis of this condition. The incidence of glucagonoma remains unclear, with only a few cases reported domestically and no large-scale cases documented internationally, making it a rare disease. Patients range in age from 20 to 73 years, with an average age of 52, and the male-to-female ratio is 1:2 or 1:3, with most female patients being postmenopausal women. Some patients may also present with Multiple Endocrine Neoplasia Type I (MEN-I). Therefore, thorough examinations of patients and their family members are necessary to determine the presence of other endocrine tumors.

bubble_chart Pathological Changes

1. Glucagonomas are larger than other functional endocrine tumors, with diameters ranging from 3 to 35 cm. Most are solitary tumors, with only 2–4% being multiple. Malignancy accounts for 60–82% of cases. Over 50% of patients already have distant metastases at the time of diagnosis, with the liver and lymph nodes being the most common sites of metastasis, though spread to the bones and adrenal glands can also occur. Glucagonomas almost exclusively arise in the pancreas, with 50% located in the pancreatic tail, 38% in the pancreatic body, and 12% in the pancreatic head.
2. Histologically, under microscopy, glucagonomas exhibit well-differentiated endocrine tumor morphology without significant characteristic changes. Although most are carcinomas, mitotic figures or nuclear atypia are uncommon. Immunohistochemical staining reveals positive glucagon granules, indicating the tumor originates from pancreatic islet A cells. Electron microscopy shows varying amounts of secretory granules within the tumor cells, typically abundant in benign cases but markedly reduced in malignant ones.
3. The skin pathology of this disease primarily manifests as necrolytic dissolution of the epidermal spinous cell layer, leading to bullous rupture, with minimal lymphocytic infiltration around blood vessels in the epidermal layer. In chronic lesions, nonspecific dermatitis-like changes are observed, including irregular acanthosis with spongiotic edema, fusiform keratinocytes with pyknotic nuclei, and negative immunofluorescence findings.

bubble_chart Clinical Manifestations

(1) Migratory Necrolytic Dermatitis

This is the most distinctive clinical feature of the disease, occurring in approximately 68% of patients (Table 1). Initially, it primarily manifests as localized erythema or desquamative red papules, often presenting in annular or arc-shaped patterns. These erythematous lesions then spread peripherally in a circular or creeping manner, merging with one another. The erythema becomes raised, with central bullae formation. Subsequently, these bullae erode, necrose, and crust, evolving into necrolytic bullous papules. These skin lesions typically heal within 2–3 weeks, leaving behind areas of hyperpigmentation. The entire pathological process is chronic, recurrent, and migratory in progression. The skin disease often begins in areas prone to friction, such as the mouth, vagina, and perianal regions, and may eventually involve the trunk, buttocks, thighs, arms, and face. Histopathological examination of the surrounding tissue reveals spongiotic edema and necrosis in the stratum spinosum between the stratum corneum and the stratum germinativum of the epidermis, which serves as a diagnostic hallmark of this condition.

Table 1 Clinical Manifestations of Glucagonoma ^*

The mechanism underlying the skin disease in glucagonoma remains incompletely understood. Some suggest it may be due to zinc deficiency; others propose that increased glucagon secretion enhances catabolism, leading to hypoaminoacidemia and malnutrition, which contribute to skin damage. Another theory posits that glucagon itself or other substances secreted by the tumor may directly harm the skin, as evidenced by the complete resolution of skin lesions following tumor resection.

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The most common clinical manifestation of glucagonoma is a certain degree of diabetes, with an incidence rate of 83%. The diabetes caused by this disease is generally mild, rarely requiring insulin treatment, and does not lead to diabetes-related complications. Although the mechanism of diabetes associated with glucagonoma is related to glucagon promoting hepatic glucose production, this effect is transient, as blood sugar levels can return to normal within 90 minutes after glucagon injection. In most cases, this effect is due to reduced glycogenolysis. Some believe it is related to the ratio between glucagon and insulin, as the abnormal outcome of this ratio in diabetes evaluation is very similar to the manifestations seen in patients with hyperglucagonemia due to glucagon tumor diseases.

(3) Anemia and Weight Loss

Approximately 85% of patients experience anemia, which is normochromic and normocytic, making it relatively easy to diagnose. The cause of anemia remains unclear. Patients' serum iron, vitamin B₁₂, and folate levels are all normal, but experiments suggest that glucagon may inhibit the activity of erythropoietin.

About 66% of patients exhibit weight loss, attributed to excessive lipolysis and gluconeogenesis, as well as a reduction in the amino acid pool, including muscle and visceral protein stores. The weight loss is significant, averaging up to 14 kg.

(4) Stomatitis, Glossitis, and Vulvovaginitis

Around 34% of patients develop stomatitis and glossitis, with some experiencing painful perioral dermatitis or fungal superinfections. Approximately 12% of patients suffer from chronic vulvovaginitis.

(5) Thromboembolism

Thromboembolism is another common clinical manifestation in glucagonoma patients, occurring in about 30% of cases and often posing a life-threatening risk. Deep vein thrombosis and pulmonary embolism are the most frequent presentations. The cause of thromboembolism remains unclear, and no coagulation abnormalities have been identified in these patients.

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Between 15–50% of patients may experience diarrhea, though the underlying cause is not well understood. Like other functional endocrine tumors, glucagonomas can secrete—or even oversecrete—other peptides, some of which may induce a hyperfunctional state in the small intestine, leading to diarrhea.

(7) Genetic Predisposition

Glucagonomas may be associated with MEN-I syndrome, so patients and their family members should be screened for other endocrine disorders. Boden reported a family in which one member of the second generation had a glucagonoma. Among the third generation, four individuals exhibited varying degrees of persistent hyperglucagonemia. The first-generation female had mild diabetes, a large goiter, and a refractory skin disease that remained undiagnosed for years, suggesting a probable case of glucagonoma.

The hereditary nature of this disease is considered an autosomal dominant trait with variable penetrance. Radioimmunoassay studies have shown that glucagon exhibits a high cross-reactivity rate with other serum proteins. This abnormal generation and transformation reaction is attributed to the presence of different IgG subclasses in the patient's blood.

bubble_chart Auxiliary Examination

1. Laboratory Tests

Hypoaminoacidemia, elevated blood glucose or decreased glucose tolerance, normocytic normochromic anemia, increased erythrocyte sedimentation rate, significantly decreased serum zinc levels, etc.

2. Plasma Glucagon Measurement

Hyperglucagonemia is the characteristic diagnostic basis for this disease and is crucial for both diagnosis and differential diagnosis.

(1) The normal plasma glucagon level is 25–250 pg/ml, whereas in patients with glucagonoma, it often exceeds 1000 pg/ml. Other conditions such as renal failure, cirrhosis or hepatic failure, and extreme stress reactions can also cause hyperglucagonemia, but these levels typically do not exceed 500 pg/ml. Leichter reported a group of glucagonoma patients with plasma glucagon levels of 2110 ± 334 pg/ml, showing no overlap with the previous group of patients.

(2) Secretin Stimulation Test: For patients with uncertain diagnoses, secretin can be injected to stimulate the secretion of pancreatic alpha cells. After injection, glucagonoma patients exhibit a very significant increase in plasma glucagon levels, whereas non-glucagonoma patients show no such response. However, this reaction can also occur in primary or secondary pancreatic alpha cell hyperplasia, requiring comprehensive clinical analysis for differentiation.

3. Response to Exogenous Glucagon

In normal individuals, intravenous injection of 0.25–0.5 mg glucagon leads to a decrease in plasma insulin and a significant rise in blood glucose concentration. In contrast, glucagonoma patients show no such response, with only a slight increase or no change in blood glucose levels. This is because long-term elevation of endogenous glucagon in these patients desensitizes them to exogenous glucagon, resulting in a blunted glycemic response.

4. Skin Biopsy

A biopsy of the edge of typical skin lesions reveals necrosis and dissolution in the prickle cell layer between the germinal layer and the stratum corneum, with a normal dermal layer.

5. Localization Studies

Due to their typically large size, solid mass, and rich blood supply, glucagonomas are easier to localize compared to other pancreatic endocrine tumors. Non-invasive and painless, ultrasound can diagnose primary pancreatic lesions and metastases, with repeat comparisons as needed and at a lower cost. CT scans are highly accurate and sensitive for glucagonomas. Since approximately 92% of glucagonomas are highly vascularized, selective or superselective abdominal angiography is recommended for patients with negative ultrasound or CT findings, achieving a diagnostic rate of 80%. Percutaneous transhepatic portal venous sampling (PTPS) is significant for diagnosis and localization, though unnecessary for most patients. Additionally, since glucagonomas often secrete glucagon episodically, sampling errors may occur, affecting result analysis and interpretation.

bubble_chart Diagnosis

The characteristic skin lesions of typical migratory necrolytic erythema, combined with common signs such as diabetes, anemia, and weight loss, easily lead to suspicion of this disease. However, it is precisely because the possibility of this condition is only considered after the appearance of specific skin lesions that diagnosis is often delayed, resulting in tumor enlargement and a high metastasis rate. Therefore, when skin erythema appears, especially if accompanied by perioral inflammation or glossitis, this disease should be suspected. As long as a detailed medical history is taken, a comprehensive physical examination is performed, and laboratory and imaging data are combined, differential diagnosis is usually not difficult.

bubble_chart Treatment Measures

1. Surgical Treatment

Surgical intervention is currently the preferred method for treating this condition. Once diagnosed, prompt surgical removal of the tumor is recommended, and exploratory surgery should also be considered for suspected cases. The surgical principles are as follows: for small and isolated tumors, enucleation may be performed; for larger tumors, carcinomas, or cases with multiple lesions, pancreatic resection is necessary. Since most glucagonomas are located in the body or tail of the pancreas, distal pancreatectomy usually suffices, and subtotal pancreatectomy is preferable to total pancreatectomy when required. Postoperative improvement is rapid, with skin lesions disappearing or significantly alleviating within 2–3 weeks, plasma amino acid levels rising, and diabetes or impaired glucose tolerance resolving. Even for patients with large tumors or malignant metastases, radical or debulking surgery should not be abandoned, as glucagonomas grow slowly. There are reports of patients surviving 10 years after resection despite metastatic disease.

For patients with liver metastases, in addition to lobectomy or segmentectomy, hepatic artery embolization may be performed for unresectable cases, as malignant glucagonoma liver metastases are primarily supplied by the hepatic artery. Reported tumor shrinkage post-embolization can reach 50%. Some authors also inject chemotherapeutic agents or streptozotocin via the hepatic artery during embolization to enhance its effects.

2. Pharmacological Treatment

(1) Perioperative Management

Preoperative nutritional support is essential to improve metabolic status. Octreotide acetate (150 μg subcutaneously three times daily) significantly reduces peripheral glucagon levels and enhances the efficacy of total parenteral nutrition. Perioperative heparin administration helps prevent thrombosis.

(2) Systemic Chemotherapy

Streptozotocin shows better efficacy, with a response rate of 33%, while doxorubicin alone has a 20% response rate. Combination therapy may improve outcomes. Octreotide acetate is effective, reportedly reducing blood glucagon levels, alleviating symptoms, and significantly improving skin lesions. However, octreotide does not appear to inhibit tumor growth.

bubble_chart Differentiation

Glucagonoma tumor diseases are primarily characterized clinically by migratory necrolytic erythema of the skin and elevated plasma glucagon levels. Before making a diagnosis, it is sometimes necessary to differentiate from other diseases that may cause similar changes:

1. Skin lesions: Many patients with glucagonoma tumor diseases have skin lesions that were misdiagnosed as psoriasis or chronic eczema before the condition was confirmed. Additionally, similar skin lesions resembling necrolytic migratory erythema can occur in cases of long-term parenteral nutrition, secondary zinc deficiency, and acrodermatitis enteropathica. However, these patients do not have hyperglucagonemia and generally do not exhibit other clinical manifestations associated with glucagonoma tumor diseases.
2. Hyperglucagonemia: A significant increase in plasma glucagon levels is seen only in patients with glucagonoma tumor diseases. However, grade I increases may occur in the following conditions or diseases: starvation, protein intake, intense exercise, renal failure, cirrhosis or hepatic failure, diabetes, Cushing's syndrome, pheochromocytoma, severe infections, and those receiving corticosteroid therapy. As long as a thorough medical history is taken, a comprehensive physical examination is conducted, and laboratory and imaging data are combined, differential diagnosis is usually not difficult.