THERAPY of insulinoma

solitary benign insulinoma Therapy of a solitary benign insulinoma, which has been biochemically and endocrinologically proven without doubt, should be the surgical intervention / operation ( - if vital contraindications against surgery in general are not present). Safe medical therapy without unwanted side-effects by means of inhibition of insulin secretion do not exist. Diazoxide™ or somatostatin-analogues (octreotide™) should only be reserved for selected situations without other options left. Similar to other endocrine tumors potential development of malignancy should be in mind with any neuroendocrine tumor of the pancreas. Endocrine surgery of the pancreas definitely requires s surgeon skilled in insulinoma surgery. The following surgical options exist : 1. enucleation of the mostly palpable or visible tumor 2. partial pancreatic resection (left resection) if tumor is localized near the tail of the pancreas or anatomically close to the main pancreatic duct and enucleation not feasible (spleen and its vessels 3. modified resection of the pancreatic head without removal of the duodenum if tumor is localized in the center of the pancreatic head (modified Whipple's operation)

Malignant Metastatic Insulinoma Adaequate therapy of metastatic malignant insulinoma is a demanding challenge for endocrinological oncologists or oncological endocrinologists, respectively ! "Streptozotocin", a glucosamine derivative of an alkylating N-nitrosourea has been first applied to a patient with malignant insulinoma in 1968. The substance has been known as a chemical used in experimental animals in diabetes research. Due to the rarity of the disease relevant studies concerning the therapy of metastatic malignant insulinoma and including a sufficient number of patients do not (!) exist. Published studies addressing therapy of malignant insulinoma only contain sporadic observations. Any attempt to present these data in a meaningful statistical context should be regarded as an unserious personal interpretation, which does not take into account the clinically relevant problems of the patients. The multicenter study published by Moertel et al. (Mayo-Clinic, N Engl J Med 1992*) contained only 6 patients with malignant insulinoma in a series of advanced islet cell carcinomas.. Since 1992 we use transarterial high-dose streptozotozin therapy of the liver by means of transhepatic perfusion (TACP) in the range of grams or in combination with liver embolisation (TACE) - pharmacological short name: Streptozocin / Zanosar® (Pharmacia & Upjohn Co. USA) Surgical options: The primary option of malignant insulinoma is always surgical resection of the tumor. Inoperability is rare ! 1. partial pancreatic resection / extended left resection if tumor is localized in the tail or the body of pancreas 2. tumor resection if localized in the pancreatic head, modified Whipple-surgery saving the duodenum 3. partial hepatic metastasectomy or hemi-hepatectomy 4. lymph node resection Radiological and oncological options: see also www.gep-net.com "neuroendocrine GEP-Tumors" "chemoembolisation" "octreoscan" "radiofrequency ablation / RFTA" 1. transarterial hepatic chemoperfusion (TACP) - high-dose streptozotozin intraarterially 2. transarterial (selective) hepatic chemoembolisation (TACE) - high-dose streptozotozin intraarterially in combination with Contour®-PVA particles or polyacryl mikrospheres (Embospheres®) 3. ablative procedures in case of single lesions - RFTA / RITA (radiofrequency thermoablation) + post-interventional chemoperfusion 4. permanent hepatic embolisation - (NBCA / n-butylcyanoacrylat) 5. radionuklid therapy by means of 90-Yttrium-DOTA-octreotide oder 177-Lutetium-DOTA-octreotate (somatostatin analogs) with pos. Octreoscan / DOTATOC-therapy (www.gep-net.com "octreoscan") Due to its numerous side effects, streptozotocin therapy, should be in the hands of the few experts. This applies equally to hepatic and renal toxicity depending upon single and cumulative dosages via intraarterial pathways.

1. Moertel CJ: Streptozotocin-Doxorubicin, Streptozotocin-Fluorouracil or Chlorozotocin in the treatment of advanced islet-cell-carcinoma. N Engl J Med 1992, 336; 519-523 2. Starke A.: Streptozotocin chemotherapy in patients with malignant metastatic insulinoma. Exp Clin Endocrinol Diabetes 103 A53, 1995 3. Simon, Starke et al: Treatment of benign and malignant insulinoma - 10-year results from one center. Eur J Clin Invest 27, Suppl 1, A34, 1997 4. Saddig et al: 10-year update of of benign and malignant insulinoma. Bioscientifica Congr. Ser., 4. ECE Sevilla, Spain 1998

Multiple Insulinoma multiple endocrine neoplasia type 1 (MEN 1) In genetically determined multiple endocrine neoplasia type 1 (MEN 1) endocrine tumors are found in the parathyroid gland, the pancreas and the pituitary gland. In the pancreas the manifestation often presents with insulinomas. These are diagnosed and treated similar to sporadic insulinomas. In contrast to sporadic insulinoma in MEN 1 multiple tumors are found more often which also tend to relapse. Sporadic single insulinomas normally do not relapse. It is unclear if insulinomas in MEN 1 are tend to present as malignant tumors. This is discussed but not proven.

Islet cell hyperplasia pancreatogenous hyperinsulinemic Non-Insulinoma-Hypoglycemia Focal islet cell hyperplasia (Beta cell hyperplasia, microadenomatosis; "nesidioblastosis" in adults; PHHI: "persistent hyperinsulinemic hypoglycemia of infancy") Islet cell hyperplasia or beta cell hyperplasia is known in infants as "nesidioblastosis" together with hypertrophy of islet cells. the familiar form is genetically determined with mutations of the SUR-1 gene and the Kir6.2 gene. In recent years in adults hyperinsulinemic hypoglycemia not caused by insullinoma has been observed independent of genetic markers. John Servive from the Mayo Clinic in Rochester coined the term "pancreatogenous hyperinsulinemic non-insulinoma hypoglycemia". We have observed 5 cases during recent years. The biochemical diagnosis of the disease is difficult and demanding. Differential fasting test diagnosis usually allows the correct diagnosis preoperatively.