Glucagonoma

Glucagonoma is a tumor of the alpha cells of the pancreas that secretes glucagon, causing hyperglycemia and a characteristic skin rash. Diagnosis is established by elevated glucagon levels and instrumental studies. The tumor is identified by CT and endoscopic ultrasound. Treatment consists of surgical resection.

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Epidemiology

Glucagonomas are rare, but like other islet cell tumors, the primary tumor and metastatic lesions are slow growing: survival is usually about 15 years. Eighty percent of glucagonomas are malignant. The average age at onset of symptoms is 50 years; 80% are women. Some patients have multiple endocrine neoplasia type I.

A clinical description of a glucagon-secreting tumor was given by chance by dermatologists back in 1942. However, it was not until 1966 that the first strictly proven case of glucagonoma was published. The final idea of this disease was formed by 1974. At that time, the term "glucagonoma syndrome" appeared. Currently, there are descriptions of more than 150 similar observations in the literature. The disease rarely affects people under 30 years of age; 85% of patients are 50 years or older at the time of diagnosis.

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Symptoms glucagonomas

Because glucagonomas secrete glucagon, symptoms are similar to diabetes mellitus. Weight loss, normochromic anemia, hypoaminoacidemia, andhypolipidemia are common, but the major distinguishing clinical feature is a chronic rash affecting the extremities, often associated with a smooth, shiny, bright red tongue and cheilitis. The scaling, hyperpigmented, erythematous lesions with superficial necrolysis are called necrolytic migratory erythema.

The clinical picture of glucagonoma is dominated by skin manifestations, so the vast majority of patients are diagnosed by dermatologists. Dermatitis is called necrolytic migratory erythema. The process is cyclical, lasting from 7 to 14 days. It begins with a spot or group of spots, which successively pass through the stage of papule, vesicle, erosion and crust or scale, after which a hyperpigmentation area remains. A feature of dermatitis is polymorphism, i.e. the presence of lesions that are simultaneously at different stages of development, which gives the skin a mottled appearance. Often, a secondary infection joins the main process.

Most often, dermatitis develops on the lower extremities, in the groin area, perineum, perianal area, and lower abdomen. On the face, the process manifests itself as angular cheilitis. Necrotic migratory erythema in most patients is resistant to therapy, both locally and internally, including corticosteroids. This is its second feature. The cause of dermatitis is a pronounced catabolic process under conditions of tumor hyperglucagonemia, which leads to a disruption in the metabolism of proteins and amino acids in tissue structures.

Mucous membrane damage in glucagonoma is characterized by stomatitis, gingivitis, glossitis. The tongue is characteristic - large, fleshy, red, with smoothed papillae. Balanitis and vaginitis are observed less often. The cause of changes in the mucous membranes is similar to the process on the skin.

Among the factors influencing carbohydrate metabolism disorders, the role of glucagon, a recognized hyperglycemic peptide, causes the greatest controversy. In most cases, it is difficult to show a direct relationship between the glucagon level and the magnitude of glycemia. Moreover, even after radical tumor removal, signs of carbohydrate metabolism disorders persist for a long time, despite the normalization of glucagon in the first hours and days. In some cases, diabetes mellitus remains after surgery, despite complete remission of other manifestations of the syndrome.

Diabetes in glucagonoma syndrome is mild in 75% of patients, and diet is sufficient to compensate for it. A quarter of patients require insulin therapy, the daily dose of which in half of the cases does not exceed 40 U. Another feature of diabetes is the rarity of ketoacidosis and the absence of traditional complications in the form of nephro-, angio- and neuropathy.

Expressed catabolic changes in glucagonoma, regardless of the nature of the tumor process (malignant or benign), are also the cause of weight loss, the distinctive feature of which is weight loss in the absence of anorexia. Anemia in glucagonoma syndrome is characterized as normochromic and normocytic. The main indicators are low hemoglobin and hematocrit. Sometimes a decrease in serum iron is noted.

As for folic acid and vitamin B ₁₂, their levels remain within the normal range. The second feature of anemia is resistance to vitamin therapy and iron preparations. Thrombosis and embolism in glucagonoma occur in 10% of patients, and it is still unclear whether they are a property of the syndrome or a result of the tumor process as such, which is often observed in oncological practice in general. More than 20% of patients have diarrhea, rarely steatorrhea. The former is usually periodic, and can range in severity from minor to debilitating.

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Diagnostics glucagonomas

Most patients with glucagonoma have glucagon levels greater than 1000 pg/mL (normal is less than 200). However, moderate increases in the hormone may be seen in renal failure, acute pancreatitis, severe stress, and starvation. Correlation with symptoms is necessary. Patients should undergo abdominal CT and endoscopic ultrasound; if CT is uninformative, MRI may be used.

Among laboratory parameters, a special place is occupied by the study of immunoreactive glucagon. The latter may be elevated in diabetes mellitus, pheochromocytoma, liver cirrhosis, glucocorticoid hypercorticism, renal failure, but glucagon levels exceeding its normal values by tens and hundreds of times are currently known only in glucagon-secreting neoplasms of the pancreas. Other laboratory parameters characteristic of glucagonoma syndrome are hypocholesterolemia, hypoalbuminemia, hypoaminoacidemia. The latter has a special diagnostic value, since it is detected in almost all patients.

Glucagonomas are usually large. Only 14% do not exceed 3 cm in diameter, while in more than 30% of patients the primary lesion is 10 cm or more. In the vast majority of cases (86%), alpha-cell neoplasms are malignant, 2/3 of which already have metastases at the time of diagnosis. Most often (43%), the tumor is detected in the tail of the pancreas, less often (18%) - in its head. Topical diagnostics of glucagonoma and its metastases does not cause any particular difficulties. The most effective in this regard are visceral arteriography and computed tomography.

A glucagon-secreting tumor may be part of the syndrome of multiple endocrine neoplasia type I. Some features of the glucagonoma syndrome, such as diabetes or dermatitis, are observed in enteroglucagon-secreting neoplasms of other organs.

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Treatment glucagonomas

Tumor resection results in regression of symptoms. Inoperable tumors, presence of metastases or recurrent tumors are treated with combination therapy with streptozocin and doxorubicin, which reduce circulating immunoreactive glucagon levels, result in regression of symptoms and improve the condition (50%), but are unlikely to affect survival time. Octreotide injections partially suppress glucagon secretion and reduce erythema, but glucose tolerance may also decrease due to decreased insulin secretion.

Octreotide quite quickly leads to the disappearance of anorexia and weight loss caused by the catabolic effect of excess glucagon. If the drug is effective, patients can be transferred to prolonged octreotide at 20-30 mg intramuscularly once a month. Patients taking octreotide should additionally take pancreatic enzymes due to the suppressive effect of octreotide on the secretion of pancreatic enzymes.

Topical, oral, or parenteral zinc causes regression of the erythema, but the erythema may resolve with simple hydration or intravenous administration of amino or fatty acids, suggesting that the erythema is definitely not caused by zinc deficiency.

Treatment of patients with glucagonoma is surgical and chemotherapeutic. A quarter of all surgical interventions end with exploratory laparotomy due to the metastatic process, but an attempt to remove the primary lesion should be made under any circumstances, since a decrease in tumor mass creates more favorable conditions for chemotherapy. The drugs of choice for glucagonoma are streptozotocin (streptozocin) and dacarbazine, which allow for years to maintain remission of the malignant process.