Interesting Case - Insulinoma

A 50 year old male presented with fatigability and increased appetite of 15 years duration. He reported that, he has to have a meal every 2 – 3 hours or else he would feel tired: tiredness would decrease after food intake. There was no history of weight loss, loose stools or palpitations. There was no history of fever, convulsions or loss of consciousness. He was not a diabetic and he gave no history of any drug intake.

Patient was of good built and afebrile. His vital parameters were stable. He had no thyromegaly, tremors or edema. Systemic examination was clinically normal. Once while the patient was symptomatic in the hospital, his glucose level was checked and was found to be less than 50mg/dl. His symptoms improved with IV dextrose.

He was then evaluated for causes of recurrent hypoglycemia. Causes like insulin or sulfonylurea intake, sepsis, cardiac, renal and hepatic failure were ruled out. He was then evaluated for Insulinoma. C peptide levels was done, which was elevated two fold. MRI abdomen was done. It showed a mass lesion at the tail of the pancreas? A possible diagnosis of Insulinoma was considered.

He was consequently put on continuous intra venous dextrose saline infusion. He is awaiting surgery now.

INSULINOMA

Insulinomas are rare pancreatic islet cell tumors (incidence of 1 case per 250,000 person-years); while most are sporadic, some are associated with the MEN1 syndrome. The characteristic clinical manifestation of an insulinoma is fasting hypoglycemia, (although some patients also have postprandial hypoglycemia), with neuroglycopenic symptoms which may or may not be preceded by sympathoadrenal (autonomic) symptoms. The neuroglycopenic symptoms of insulinoma include confusion, visual change, and unusual behavior. Sympathoadrenal symptoms may include palpitations, diaphoresis, and tremulousness. Amnesia for hypoglycemia is common. The median duration of symptoms before diagnosis was less than 1.5 years in one Mayo Clinic series. However, a few patients had probably been symptomatic for decades. As many as 20 percent of patients had been misdiagnosed with a neurological or psychiatric disorder before the insulinoma was recognized. Seizure disorder is another common misdiagnosis. Weight gain was described in 18 percent of patients. Most insulinoma are solitary and benign. Multiple insulinomas are less common, and tend to be associated with MEN1. Malignant insulinomas are also less common.

The diagnosis of insulinoma is established by demonstrating inappropriately high serum insulin concentrations during a spontaneous or induced episode of hypoglycemia (eg, 72-hour fast).

Imaging techniques are then used to localize the tumor. Accurate preoperative localization of an insulinoma is desirable. The procedures available include spiral CT, arteriography, ultrasonography (transabdominal and endoscopic), and 111-In-pentetreotide imaging. Transabdominal ultrasonography and CT are preferred initial tests, followed by endoscopic ultrasonography or arterial stimulation with hepatic venous sampling when an insulinoma has not been localized by noninvasive techniques.

There are a few disorders in which the biochemical findings simulate those of an insulinoma because they are also associated with primary overproduction of insulin:

• Familial persistent hyperinsulinemic hypoglycemia of infancy
• Primary islet-cell hyperplasia (also called nesidioblastosis)
• Noninsulinoma pancreatogenous hypoglycemia syndrome
• Post gastric bypass hypoglycemia.

The latter two conditions have the characteristic feature of producing primarily postprandial hypoglycemia.

The recommended initial treatment of patients with benign, solitary insulinoma is the surgical excision of the tumor (Grade 1A). The approach and extent of surgery should be determined based upon tumor location. Patients with multiple insulinomas (typically in the setting of MEN1), the recommended treatment is local excision of any tumors found in the head of the pancreas plus a distal subtotal pancreatectomy (Grade B). Patients with persistent hypoglycemia after surgery in whom solitary or multiple tumors are identified after additional localization procedures; a repeat operation (Grade 1A) is resorted to. In patients whom insulinoma cannot be located during pancreatic exploration, who are not candidates for or refuse surgery, diazoxide therapy for the medical management of hypoglycemia (Grade 2C) is recommended. Diazoxide (which diminishes insulin secretion and is given in divided doses of up to 1200 mg/day) sometimes used for controlling hypoglycemia. However, it can cause marked edema (which may require high doses of loop diuretics) and hirsutism.

Octreotide, an analog of somatostatin , inhibits GH secretion, but in large doses, also inhibits the secretion of TSH, insulin, and glucagon. Octreotide is highly effective in controlling the symptoms associated with glucagonomas, VIPomas, and carcinoid tumors, efficacy is less predictable for symptomatic patients with insulinoma. However, it could be a reasonable choice for patients with persistent hypoglycemia that is refractory to diazoxide. Lanreotide, another somatostatin analog is reported to have similar clinical efficacy as octreotide, and is also available in a long-acting depot form (Lanreotide-SR). Verapamil and phenytoin have also been used with some success. However, none of these drugs are as effective as tumor resection.

A patient with potentially resectable liver-isolated metastatic insulinoma, surgical resection of the hepatic metastases along with the primary tumor (Grade 1B) is the preferred option. Although the majority of cases will not be cured by surgery, given the slow-growing nature of the tumor, extended survival is sometimes possible. Other treatment options for patients with unresectable hepatic-predominant symptomatic metastatic disease include embolization, chemoembolization, radio frequency ablation, and cryoablation. The efficacy of somatostatin analogs for patients with diazoxide-refractory symptomatic hypoglycemia is unpredictable. Octreotide, as well as other systemic therapy approaches (interferon, chemotherapy, targeted radiotherapy) are tried but with variable outcomes. The traditional chemotherapy regimen of choice in malignant insulinomas has been streptozocin and doxorubicin: with objective response rates as high as 69 percent for metastatic islet cell tumors, the true radiologic response rate is probably lower, between 10 and 40 percent. Alternative regimen comprising of orally active alkylating agent temozolomide are being tried.

Novel therapeutic approaches for patients with advanced islet cell tumors include the use of targeted radiotherapy, as well as regimens incorporating inhibitors of angiogenesis, small molecule tyrosine kinase inhibitors, and inhibitors of the mammalian target of rapamycin (mTOR)

There are no evidence-based guidelines for follow-up after resection of a malignant insulinoma. Consensus-derived guidelines from the National Comprehensive Cancer Network following treatment for an islet cell tumor include:

• Three and six months postresection — History and physical examination, tumor markers,
• CT/MRI Long-term — History and physical examination with tumor markers every 6 to 12 months for years 1 to 3, and as clinically indicated thereafter. Imaging studies are recommended only as clinically indicated