Metastatic insulinoma: case report and review of the literature.

Abstract: A 64-year-old nondiabetic woman presented with spells of lightheadedness and diaphoresis associated with lethargy and hunger of 2 weeks' duration. Physical examination was unremarkable; however, her fasting plasma glucose was 66 mg/dl, with concurrent plasma insulin of 171 [mu]IU/ml (normal, 5-27 [mu]IU/ml). Her C-peptide and proinsulin levels were elevated, with negative insulin antibody and negative urinary sulfonylurea levels. Abdominal computed tomographic scan demonstrated a 5 X 4-cm mass in the tail of the pancreas and many liver metastases. She underwent resection of the pancreatic mass, radiofrequency ablation, and cauterization of hepatic lesions. Histology confirmed pancreatic insulinoma. Ten months later, she was free of hypoglycemic symptoms, with normal plasma insulin C-peptide and significantly decreased proinsulin levels. Insulinomas are rare, predominantly benign tumors. Surgery is the only curative treatment. Octreotide can be used to control hormone secretion and tumor growth. Other treatments include hepatic embolization, radiotherapy, chemotherapy, and liver transplantation.

Key Words: hypoglycemia, insulinoma, metastatic

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Insulinomas occur in 4 per 1 million persons per year. They are usually benign and solitary tumors. Metastatic insulinomas are rare and are associated with a higher risk of recurrence and mortality. We report a woman with metastatic insulinoma and review some of the different diagnoses of high insulin state in the place of hypoglycemia with emphasis on the diagnosis and treatment of insulinoma.

Discussion

Hypoglycemia and Hyperinsulinemia

The characteristic signs and symptoms of insulinoma are diaphoresis, palpitation, weakness, and neurologic abnormalities such as confusion, behavior change, loss of consciousness, blurred vision, and seizures. (1), (2) During these episodes, patients become hypoglycemic, and these symptoms improve with food intake. The diagnosis of insulinoma is suggested by hyperinsulinemia in the presence of hypoglycemia. The standard test is a 72-hour supervised fasting study with monitoring of serial plasma glucose and insulin levels. (3) Most patients with insulinoma will become symptomatic during the first 24 hours of the test, with an inappropriately elevated plasma insulin-to-glucose ratio.

Plasma C-peptide and urinary sulfonylurea panels are necessary to differentiate the causes of hyperinsulinemic hypoglycemia. Sulfonylurea stimulates the pancreas to increase insulin production, leading to a lower plasma glucose level. Under these circumstances, serum insulin and C-peptide levels are elevated and sulfonylurea can be detected in the urine. Occasionally, elevated plasma insulin with a normal to low C-peptide level is seen in hypoglycemic patients, suggestive of factitious use of insulin.

Syndromes of autoimmunity and some malignancies can mimic hyperinsulinemia, resulting in hypoglycemia. Patients with these conditions may have antibodies to insulin receptors. These antibodies can cause hypoglycemia by acting as insulin molecules, directly stimulating [beta] cells of the pancreas despite a normal plasma glucose level (4) and by competing with insulin for insulin receptors. The antibodies prevent insulin from binding to its receptors, which in turn inhibits cytoplasmic internalization clearance of insulin-receptor complexes. The persistent high serum insulin level causes fasting hypoglycemia and suppresses insulin secretion. (5) In this situation, the plasma C-peptide level is not elevated.

Some patients can spontaneously develop antibodies against insulin. One model hypothesizes that the antibodies bind to insulin in an equilibrium state in which insulin molecules and the antibodies are reactants. (6) In the fasting state, there are fewer free insulin molecules and more free antibodies. In the fed state, insulin secretion increases, shifting the equilibrium to favor more antibody-insulin complexes, which act as a reservoir of insulin molecules. During the postprandial period, the free insulin level falls after decreased plasma glucose. The equilibrium reverses into the direction of free insulin. The dissociation of the complexes helps to maintain plasma insulin level, causing postprandial or reactive hypoglycemia.

Insulinoma

Insulinomas are the most common tumors arising from the pancreatic islets of Langerhans. (7) A 60-year cohort study from the Mayo Clinic reported an incidence of 4 cases per 1 million person-years. (8) The highest incidence is in people between 40 and 60 years of age, and women are affected slightly more often than men. (2), (8)

Insulinomas are usually benign and relatively small (<2 cm) solitary tumors; (7) however, 5.8 to 15% of the tumors are malignant. (2), (8) Multiple endocrine neoplasia Type I is present in 7.6 to 16% of patients (2), (8) and is associated with a greater risk of recurrence. (8) The 10-year survival rate is estimated at 91% and 29% for benign and malignant insulinoma, respectively. (8)

Although most insulinomas are in the pancreas, (9) localization of the tumors is difficult at diagnosis. Dual-phase contrast spiral CT scan is more sensitive than other noninvasive imaging studies. In a group of seven patients with tumors that were biochemically proven but not previously located by ultrasonography, CT scan, or magnetic resonance imaging, six of seven tumors ranging from 6 to 18 mm were detected by dual-phase spiral CT scan. (10) Endoscopic ultrasonography has detected small pancreatic tumors of 5 mm with a sensitivity ranging from 82 to 86%. (11), (12) Because of the highly vascular nature of these tumors, angiography has been used successfully. In a small series of patients, stimulation using intra-arterial calcium gluconate with venous sampling of insulin release detected up to 100% of insulinomas. (13) The combination of intraoperative palpations and ultrasonography identified most tumors that had not been located before surgery. (14), (15)

Resection of insulinoma is curative in 93 to 100% of benign cases. (1), (2) Postoperative complications such as fistula, hemorrhage, sepsis, and pleural effusion range from 28 to 43% and increase with reoperation. (1), (2) Surgical mortality is approximately 4%; (1), (2) however, metastases reduce survival rates by 60%. (8)

Several medical treatments of insulinoma have been used. Diazoxide, which inhibits insulin secretion from pancreatic [beta] cells, (16) has been used successfully. (2), (17) Boukhman et al (2) reported a response rate of 29 (71%) of 41 patients, but severe complications required its discontinuation in 5 patients. The main side effects were palpitations, hirsutism, edema, and nausea. A gradual increase in dose can minimize anorexia. A diuretic can help reduce peripheral edema. The somatostatin analogue octreotide has also been used in the treatment of insulinoma. Alberts and Falkson (18) reported a case of a 52-year-old man with metastatic insulinoma who responded rapidly to octreotide and remained responsive 4 months later. However, the response rate varies among patients and may be correlated with the degree of expression of somatostatin receptor Subtypes 2 and 3. (19), (20) Octreotide also inhibits glucagon and growth hormone secretion. In subjects without diabetes, renal failure, or insulinoma, octreotide suppression of nocturnal growth hormone did not appear to be an important regulator of carbohydrate tolerance the morning after drug intake. (21) However, it was demonstrated that octreotide treatment lowered endogenous insulin, growth hormone, and glucagon in all 12 type 2 diabetic patients with and without chronic renal failure. Insulin requirements were reduced in only six patients who had chronic renal failure and elevated baseline glucagon after a 5-day treatment with octreotide. (22) Octreotide, therefore, may blunt gluconeogenesis response to decreased plasma glucose and worsen hypoglycemia when used in insulinoma patients.

In contrast, several chemotherapy regimens have shown disappointing results. Combination treatment with streptozocin and doxorubicin is the favored first-line therapy in advanced disease. (23) An open-label prospective trial showed that the addition of interferon alfa to octreotide might prolong survival in a subgroup of patients with metastatic diseases unresponsive to octreotide. (24) In contrast, the combination of interferon alfa and fluorouracil failed to demonstrate significant efficacy over either individual agent alone. (25)

Conclusion

Metastatic insulinoma is a rare disease with an indolent course. Although the disease is currently not curable, available modalities can provide long symptomatic remissions. Patients with malignant insulinoma should be followed closely, and those not responding to standard therapy should be enrolled in chemotherapy trials.

KEY POINTS

* Insulinomas present with hypoglycemia, hyperinsulinemia, elevated C-peptide levels, and a negative urinary sulfonylurea screen.

* Liver is the most common site of metastasis.

* Surgery is the only curative treatment, and palliation can be achieved with octreotide, diazoxide, chemotherapeutic agents, and radioablation.

Accepted July 14, 2003.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9702-0199

References

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(6.) Taylor SI, Barbetti F, Accili D, et al. Syndromes of autoimmunity and hypoglycemia: Autoantibodies directed against insulin and its receptor. Endocrinol Metab Clin North Am 1989;18:123-143.

(7.) Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am Coll Surg 1994;178:187-211.

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(10.) King AD, Ko GT, Yeung VT, et al. Dual phase spiral CT in the detection of small insulinomas of the pancreas. Br J Radiol 1998;71:20-23.

(11.) Lightdale CJ, Botet JF, Woodruff JM, et al. Localization of endocrine tumors of the pancreas with endoscopic ultrasonography. Cancer 1991;68:1815-1820.

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(13.) Aoki T, Sakon M, Ohzato H, et al. Evaluation of preoperative and intraoperative arterial stimulation and venous sampling for diagnosis and surgical resection of insulinoma. Surgery 1999;126:968-973.

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(15.) Huai JC, Zhang W, Niu HO, et al. Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound. Am J Surg 1998;175:18-21.

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(17.) Shaer AJ. Management of hyperinsulinemia with diazoxide in an elderly hemodialysis patient. Nephron 2001;89:337-339.

(18.) Alberts AS, Falkson G. Rapid reversal of life-threatening hypoglycaemia with a somatostatin analogue (octreotide): A case report. S Afr Med J 1988;74:75-76.

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RELATED ARTICLE: Case Report

A 64-year-old nondiabetic woman presented with complaints of episodes of lightheadedness and diaphoresis of 2 weeks' duration. During these episodes, she was tired, sleepy, and hungry. The symptoms resolved after eating. However, these episodes gradually increased in frequency and sometimes awakened her from sleep. She denied having seizures but noticed weight gain of 4 lb in the previous 2 weeks. Her fasting plasma glucose had been normal 1 year earlier. She had no family history of diabetes. Physical examination revealed an obese woman weighing 234 lb (106 kg) and with a body mass index of 43 kg/[m.sup.2]. She had predominance of fat in her abdominal area. She had Acanthosis nigricans around the eyes, lips, axillae, and groin.

Laboratory evaluation showed low overnight fasting plasma glucose of 44 mg/dl, elevated insulin of 171 [mu]IU/ml (normal range, 5-27 [mu]IU/ml), C-peptide of 11.7 ng/ml (normal range, 1.1-4.6 ng/ml), and proinsulin of 5,413 pmol/ml (normal range, 2.1-26.8 pmol/ml). These levels were similarly elevated 1 week later. Her insulin antibody was normal at 0.3 kronus units/ml (normal range, 0-1.0 kronus units/ml) and her urinary sulfonylurea panel was negative (immunoassay performed by Specialty Laboratories, Inc., Los Angeles, CA). Her pituitary-adrenal axis was intact. Plasma thyroid-stimulating hormone and insulin-like growth factor-1 and -2 levels were all within normal ranges. An abdominal computed tomographic (CT) scan demonstrated a 5.0 X 4.0-cm mass in the tail of the pancreas and many ill-defined masses in the liver that were highly suspicious for metastases.

The patient underwent exploratory laparotomy, with resection of the pancreatic mass and three hepatic lesions. Eight hepatic lesions were ablated by radiofrequency and 10 other hepatic lesions were cauterized. Surgical pathology reported a primary neuroendocrine carcinoma of the pancreas (insulinoma) and metastatic neuroendocrine carcinomas to the liver. Ten months after surgery, she had no symptoms of hypoglycemia. Her fasting plasma glucose ranged from 89 to 95 mg/dl. Plasma insulin, C-peptide, and proinsulin had decreased to 8.3 [mu]IU/ml, 4.8 ng/ml, and 862 pmol/ml, respectively.

Tuan-Huy Tran, MD, Ram D. Pathak, MD, and Amelita L.P. Basa, MD

From the Department of Internal Medicine, Section on Endocrinology and Related Diseases, Ochsner Clinic Foundation, New Orleans, LA.

No author has any financial, commercial, or proprietary interest in any drug, device, or equipment mentioned in this article. There is no conflict of interest.

Reprint requests to Amelita L.P. Basa, MD, Ochsner Clinic Foundation, New Orleans, LA 70121. Email: [e-mail]