World J. Surg. 8, 583-589, 1984 of 1984 by the Soci(~t~ lnternationale de Chirurgie Prevalence of Diffuse Pancreatic Beta Islet Cell Disease with Hyperinsulinism: Problems in Recognition and Management Timothy S. Harrison, M.D., Stefan S. Fajans, M.D., John C. Floyd, Jr., M.D., Norman W. Thompson, M.D., Dennis A. Rasbach, M.D., Richard J. Santen, M.D., and Cynthia Cohen, M.D. Departments of Surgery, Internal Medicine (Endocrinology), and Pathology, The Milton S. Hershey Medical Center; The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, U.S.A.; and Departments of Internal Medicine (Division of Endocrinology and Metabolism) and Surgery, The University of Michigan Medical Center, Ann Arbor, Michigan, U.S.A. Among 77 patients with endogenous hyperinsulinism seen disease poses many problems. We recognize 3 ma- in 2 medical centers, diffuse islet cell disease accounted for jor diffuse islet cell disorders associated with 17 (22%) patients. Since diffuse islet cell disease poses spe- hyperinsulinism: beta islet cell adenomatosis, cial problems in management, its prevalence is empha- which can often be recognized by the operating sur- sized in this report. geon; nesidioblastosis, and pancreatic beta cell Among these patients with diffuse islet cell disease, there hyperplasia, both of which defy operative recog- were 11 patients with adenomatosis, 4 with nesidioblas- nition. In addition, multiple macroadenomas may tosis, and 2 with islet cell hyperplasia. Six of the 77 pa- or may not co-exist with microadenomatosis or tients were found in multiple endocrine neoplasia, type I hyperplasia in certain patients with hyperinsulin- kindreds; diffuse islet cell disease was documented in 4 of ism. Multifocal islet cell disorders are particularly these patients. frequent in patients with multiple endocrine We outline principles of management in patients with neoplasia, type I (MEN I). Other than to recognize diffuse islet cell disease. Frozen section microscopy failed its occurrence, we do not include in this review of to identify nesidioblastosis or islet cell hyperplasia. diffuse islet cell disorders an analysis of sporadic beta islet cell carcinoma. In many patients, the re- sults of preoperative transhepatic venous catheteri- A continuing problem for surgeons operating on pa- zation (THVC) should draw attention to the pos- tients with endogenous hyperinsulinism is what to sible presence of diffuse islet cell disease. do when no diseased tissue is found at surgery af- ter a preliminary exploration of the pancreas. Soli- tary beta islet cell adenomas can be overlooked when not palpable; identification of diffuse islet cell Case Material Seventy-seven patients with hyperinsulinism were cared for, 69 at the University of Michigan Medi- cal Center since 1960 and 8 at The Milton S. Her- Presented at the International Association of Endo- shey Medical Center of The Pennsylvania State crine Surgeons at Hamburg, September 1983. University since 1973. Infants and young children Supported in part by U.S. Public Health Service under the age of 9 years are not included in this re- Grants AM-02244 and AM-0888; and NIH-5 M01 RR-42 port. General Clinical Research Centers, The University of Michigan, Ann Arbor, Michigan. Reprint requests: Timothy S. Harrison, M.D., Profes- sor of Surgery and Physiology, The Milton S. Hershey Solitary Islet Cell Adenoma Medical Center, The Pennsylvania State University Col- lege of Medicine, P.O. Box 850, Hershey, Pennsylvania While not the major focus of this report, solitary 17033, U.S.A. hyperfunctioning islet cell adenoma was the most 584 World J. Surg. Vol. 8, No. 4, August 1984 Table 1. Endogenous hyperinsulinism. Table 2. Successful intraoperative identification at first exploration. U of M" Adenomatosis 5/11 Without With Ne sidioblastosis 0/4 MEN MEN I MSHMC C Total Hyperplasia 0/2 All patients 63 6 8 77 Solitary adenoma 51 1 4 56 Table 3. Endogenous hyperinsulinism: Multiple endo- Adenomatosis 5b 4 2 11 crine neoplasia I [6/77 patients (8%)]. Nesidioblas- tosis 3 0 1 4 Solitary adenoma Hyperplasia 1 0 1 2 Double adenoma Carcinoma Adenoma plus microadenomatosis Sporadic 3 0 0 3 Adenoma plus hyperplasia MEN I 0 1 0 1 Multicentric beta cell carcinoma ~University of Michigan Medical Center. bOne patient with macroadenomas only, 1 patient with macroadenomas + microadenomatosis, 3 patients with percent pancreatectomy has resulted in an accept- microadenomas + hyperplasia. 'Milton S. Hershey Medical Center, Pennsylvania able but by no means ideal course in that 100 mg State University College of Medicine. diazoxide is required twice daily and fasting plasma glucose levels 10 years postoperatively are often around 50 mg/100 ml. frequent lesion seen--56 (73%) of the 77 patients In a 20-year-old female, a 1.0-cm diameter ad- (Table 1). In 1 patient, the adenoma was not found enoma was removed from the pancreatic head in in a blind distal 85% pancreatic resection. For 16 the belief that this was the patient's only lesion. years her hyperinsulinism has been well controlled Since surgery, she has been able to control symp- with 150 mg of diazoxide daily. toms of hypoglycemia on diet alone, but abnormal Two other patients with solitary adenoma de- plasma insulin/glucose ratios persist in excess of serve special comment. One, a 60-year-old male, 0.3 [1]. During the first trimester of a recent preg- had a 10-g adenoma removed from the pancreatic nancy, occasional overnight fasting plasma glucose tail. There was microadenomatosis in the pancreas levels were between 40 and 50 mg/100 ml. As the surrounding the lesion but it is thought to be of no pregnancy progressed, a typical fasting plasma glu- functional significance since the patient has re- cose of 94 mg/100 ml and concomitant insulin level quired no treatment for 9 years since surgery. of 75 jxU/ml gave an insulin/glucose ratio of 0.8. Plasma glucose, plasma insulin, and insulin/glucose Hypoglycemia in the 40 mg/100 ml range at deliv- ratios are normal during repeated 72-hour fasts. ery has subsided and the patient remains well con- The other solitary adenoma of special interest trolled on diet alone. The diagnosis of adenoma- was in a patient with MEN I. Her plasma glucose tosis is presumptive in this patient and she is the and insulin levels and insulin/glucose ratios are nor- only one in whom there is no microscopic confir- mal since removal of her solitary adenoma 10 years mation. ago. There have been other lesions in the remaining 5 patients with sporadically occurring adenomatosis. One patient had a macroscopic adenoma plus mi- Adenornatosis croadenomatosis and 4 had visible adenomas plus Eleven (14%) of 77 patients had adenomatosis (Ta- hyperplasia. ble 1). In 4 patients the diagnosis was made intra- Patients with adenomatosis have received operatively by the recognition of multiple macroad- 75-85% distal pancreatectomy and vary from re- enomas and confirmed by frozen section micros- quiring no treatment postoperatively to requiring as copy. In one additional patient the diagnosis was much as 200 mg diazoxide daily to prevent symp- made by the endocrinologist in the operating room tomatic hypoglycemia. while sectioning an 80% distally resected pancre- Four of the 11 adenomatosis patients are from 3 atic segment (Table 2). He saw multiple small ad- MEN I kindreds and had differing lesions associ- enomas, and microscopic adenomatosis was con- ated with their adenomatosis (Tables 1 and 3). In firmed by frozen section. Hyperinsulinism had per- two, 2 macroadenomas were present, in another a sisted following our initial operation with removal single macroadenoma co-existed with microad- of a 2.5-cm diameter adenoma thought to be a soli- enomatosis, and in another multiple adenomas co- tary adenoma in the neck of the pancreas. Eighty existed with islet cell hyperplasia. These patients T.S. Harrison et al.: Diffuse Islet Cell Disease 585 have all responded adequately to 75-85% pancre- atectomy. x,'" " Nesidioblas tosis In our 4 patients with nesidioblastosis, there was no evidence of MEN I (Tables 1 and 3). Distal 75-85% pancreatectomy was done but in none did frozen section microscopy identify the lesion (Ta- '\ 73 8! .... ~---" ble 2). Three of these patients have been reported before [2]. Two patients were cared for before the availability of transhepatic portal venous sampling. One was an 1 l-year-old girl with a 2-year history of %--:10 hypoglycemia for whom an 80% blind distal pan- createctomy was done. While she leads an active life as a college student, medical control of her hyperinsulinism with diazoxide is not ideal be- cause of erratic fasting plasma glucose levels often Fig. 1. Plasma insulin values in txU/100 ml during trans- hepatic venous catheterization (THVC) in a patient with below 50 mg/100 ml. A 47-year-old man was cured proven nesidioblastosis. The preoperative interpretation by a 70-80% distal pancreatectomy. Plasma glu- of a solitary adenoma in the pancreatic head may not be cose, plasma insulin, and insulin-to-glucose ratios correct. An adenoma could not be found. Concomitant are normal during a 72-hour fast 6 years postopera- systemic insulin levels are not available for comparison tively. with those obtained during THVC. Mean insulin concen- In a 66-year-old male, results of portal venous tration of values obtained from the splenic vein, superior mesenteric vein, confluence and portal veins is 76 (65-86) sampling done preoperatively were compatible p~U/ml. Venous blood draining the head of the pancreas with, but not necessarily diagnostic of, a solitary had concentrations of 108,910, and 102 ~xU/ml in 3 sepa- adenoma in the pancreatic head (Fig. 1). In spite of rate locations suggesting multifocal hyperinsulinism. vigorous exploration of the pancreatic head, an ad- Five weeks before this study, systemic venous fasting enoma was not found.