Evaluation and Treatment of Glucagonoma

What is a glucagonoma?

Glucagonomas are third in occurrence of all the pancreatic neorendocrine tumors (5 to 10 %).  It is estimated that one person in 20 million will present with glucagonoma each year. Glucagon is normally secreted from the islet cells of the pancreatic gland, and is responsible of counterregulatory function in glucose metabolism, antagonizing insulin function.

Patients present the disease typically between 40 and 70 years of age, and is equally distributed for gender. While some may develop in the setting of MEN1 syndrome, 60 % of glucagonomas are sporadic. They typically originate in the pancreas, usually in the body or tail of the gland.

Clinically, patients present with the “5D´s” or Sweet Syndrome which comprises Diabetes, Dermatitis, Diarrhea, Depression and Deep Vein Thrombosis. Not all symptoms co-exist at the time of diagnosis. While most patients develop Diabetes (75 to 95 %), the majority are referred by dermatologists when presenting weight loss and necrolytic migratory erythema (70%). The skin condition begins as red lumps and plaques in the perineum, groins or abdomen, and it may migrate to the extremities. While the center of these plaques eventually clears and leaves bronze colored skin, the edges become blistered and crusted. The rash is itchy and painful. Most patients may develop cheilitis in the corners of the mouth.

Diagnosis is confirmed with a significant elevation of glucagon (>50 pmol/l), glucose and chromogranin-A values in plasma. Patients are frequently anemic. If not for the dermatosis, patients may usually go underdiagnosed for years.

What radiologic tests are helpful preoperatively?

Glucagonomas are usually solitary intrapancreatic large tumors (>6 cm). Hepatic metastases are present in 60 to 90  % of patients at diagnosis.

As with other pancreatic neuroendocrine tumors, glucagonomas are well identified and staged by computed tomography and/or Magnetic resonance imaging. Complementary radioisotope imaging can be performed to the two aforementioned studies, and can detect small foci of primary tumors and metastases since 55 to 95 % of these lesions express somatostatin receptors.

Positron Emission Tomography in combination with CT imaging have been shown to have higher detection rates when compared to standard scintigraphy and standard CT in lesions of less than 3 cm in diameter (96%).

Endoscopic ultrasound is the study of choice when screening patients with asymptomatic, genetically proven MEN-1 patients.

What is the treatment of glucagonoma?

Surgery is the mainstay of treatment for patients with glucagonoma, although preoperative preparation is of paramount importance to control symptoms of hormone hypersecretion before surgery.

The skin rash resolves within a few days in about 90% of patients who are treated with octreotide. Enteral or parenteral nutrition may be also beneficial to those who have lost a substantial amount of weight, and this can also help relieve the rash. Blood sugar management is another critical consideration. Importantly, patients with glucagonomas are at risk (up to a 30% chance) of developing deep vein thrombosis and/or pulmonary embolism. Prophylactic anticoagulation is indicated. If contemplating spleen resection, vaccinations are also recommended.

The primary treatment for a glucagonoma is surgical removal, and this offers the only chance for cure. An operation involves a full exploration of the abdomen, either through a standard laparotomy, or with laparoscopy if immediate preoperative imaging studies permit otherwise. Complete resection offers the only chance for cure. Thus, resection of the tumor and metastasis including adjacent lymph nodes, should be included in the specimen.

Because most glucagonomas are located in the pancreas tail or body, a distal pancreatectomy may be performed. Spleen preserving techniques have been described but practiced by experienced groups only. As most glucagonomas are malignant in nature; distal pancreatectomy, splenectomy and surrounding tissue is the preferred surgical approach.

A pancreatoduodenectomy or Whipple procedure is the preferred approach for tumors in the head of the pancreas. It is often difficult to establish whether a glucagonoma is benign or malignant, based on microscopic features alone. As a result, some tumors are confirmed to be malignant only when tumor is discovered outside the pancreatic gland (lymph nodes, liver, lungs).

While cure for glucagonomas is possible if the tumor can be completely excised,  the resection of at least 90% of the tumoral burden can produce as much as 60%-80% five year survival rates, with good control of symptoms.