Adult-Onset Nesidioblastosis Causing Hypoglycemia an Important Clinical Entity and Continuing Treatment Dilemma

PAPER Adult-Onset Nesidioblastosis Causing Hypoglycemia An Important Clinical Entity and Continuing Treatment Dilemma Ronald M. Witteles, MD; Francis H. Straus II, MD; Sonia L. Sugg, MD; Mahalakshmana Rao Koka, MD; Eduardo A. Costa, MD; Edwin L. Kaplan, MD Hypothesis: Nesidioblastosis is an important cause of insulin-dependent diabetes mellitus, pancreatic exo- adult hyperinsulinemic hypoglycemia, and control of this crine insufficiency, and need for reoperation. disorder can often be obtained with a 70% distal pancreatectomy. Results: Of 32 adult patients who underwent surgical ex- ploration for hyperinsulinemic hypoglycemia at our insti- Design: The records of all adult patients operated on tution, 27 (84%) were found to have 1 or more insulino- for hypoglycemia between 1974 and 1999 were mas, and 5 (16%) were diagnosed with nesidioblastosis. reviewed retrospectively. Patients with the pathologic Each patient with nesidioblastosis underwent a 70% distal diagnosis of nesidioblastosis were contacted for pancreatectomy. Follow-up duration for the 5 patients follow-up (1.5-21 years) and are presented. Patients’ ranged from 1.5 to 21 years, with 3 patients (60%) asymp- results were compared with those of 36 other individu- tomatic and taking no medications, and 2 patients (40%) als with this disorder who were previously reported in experiencing some recurrences of hypoglycemia. The 2 pa- the literature. tients with recurrences are now successfully treated with a calcium channel blocker, an approach, to our knowledge, Setting: The University of Chicago Medical Center (Chi- never before reported for adult-onset nesidioblastosis. cago, Ill), a tertiary care facility. Conclusions: Nesidioblastosis is an uncommon but clini- Patients: A consecutive sample of all patients operated cally important cause of hypoglycemia in the adult popu- on for hypoglycemia. lation, and must always be considered in a patient with a presumptive preoperative diagnosis of insulinoma. This Interventions: Seventy percent distal pancreatectomy study indicates that a 70% distal pancreatectomy is of- for all patients with nesidioblastosis, and maintenance ten successful in controlling hypoglycemia, and rarely therapy with verapamil hydrochloride for 2 patients. results in diabetes mellitus. However, the optimal treatment of this disorder remains to be determined. Main Outcome Measures: Achievement of normo- glycemia with and without medication, development of Arch Surg. 2001;136:656-663 EORGE F. LAIDLAW coined been reported in the literature; most have the term “nesidioblasto- short or no follow-up data. Though From the Departments of sis” in 1938, combining throughout the years there has been some Pathology (Dr Straus) and Surgery (Drs Witteles, Koka, the Greek words for is- confusion regarding the terminology, it is and Kaplan), University of let (nesidion) and builder now generally accepted that the terms “en- Chicago Pritzker School of G(blastos) to emphasize that in this condi- docrine cell dysplasia,” “islet cell hyper- Medicine, Chicago, Ill; and the tion cells differentiate and bud from the plasia,” “islet cell hypertrophy,” “micro- Department of Oncologic and pancreatic ductal epithelium to form new adenomatosis,” and “islet hypertrophy” are Endocrine Surgery, Medical islet tissue.1 While nesidioblastosis is rec- included in the diagnosis of nesidioblas- College of Wisconsin, ognized as the most common cause of neo- tosis.4 While most patients with an insu- Milwaukee (Dr Sugg). During natal hyperinsulinemia, it is believed to be linoma have a discrete lesion in one por- the time of this study, Dr Costa rare in adults, accounting for 0.5% to 7% tion of the pancreas, and multiple was a visiting scholar in of all cases of hyperinsulinemic hypogly- insulinomas are usually associated with Endocrine Surgery at the cemia. The first case report was by Sand- multiple endocrine neoplasia type 1 University of Chicago Pritzker 2 School of Medicine. Dr Witteles ler et al in 1975, and the largest case se- (MEN-1) syndrome, nesidioblastosis is al- 3 is presently a resident at ries was reported by Harness et al in 1981. most always characterized by a prolifera- Stanford University School of To our knowledge to date, only 36 total tion of abnormal B cells throughout the Medicine, Stanford, Calif. cases of adult-onset nesidioblastosis have entire pancreas.5 We report on the cases (REPRINTED) ARCH SURG/ VOL 136, JUNE 2001 WWW.ARCHSURG.COM 656 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 PATIENTS AND METHODS I PD The medical records of all adult patients operated on for hypoglycemia at the University of Chicago Medi- cal Center between 1974 and 1999 were reviewed. Of 32 cases identified, 27 (84%) were diagnosed with 1 or more insulinomas, and 5 (16%) were diagnosed with nesidioblastosis without an accompanying insulinoma. The patients with nesidioblastosis were contacted for follow-up, and appropriate laboratory test- ing was performed when possible. I Reports of adult-onset nesidioblastosis in the literature were found by a search of MEDLINE, and these patients were analyzed by symptoms, extent of I pancreatectomy, and outcome. Outcome was mea- sured by control of hypoglycemia and hypoglycemic symptoms with and without medication, need for reoperation, evidence of pancreatic exocrine insufficiency, and development of insulin-dependent Figure 2. Patient 4. A site of proliferating pancreatic ductules (PD), some of diabetes mellitus. which are lined by cuboidal cells with a similar morphology to islet cells in the 3 closely associated islets (I) (hematoxylin-eosin, original magnification 3 250). PD Figure 3. Patient 2. Several small islet cells (arrows) forming from and around proliferating small ductules (PD) (hematoxylin-eosin, original magnification 3 150). Figure 1. Patient 5. Concentration of medium-sized islets (arrows) on small Figures 2 3 4 integrally associated ductules (hematoxylin-eosin, original magnification 3 and proliferating pancreatic ductules ( , , , 100). and 5). Four of the 5 cases did exhibit foci of dilated pancreatic ducts or ductules, suggesting focal areas of duct obstruction (Figure 6), which might be a factor in stimu- of 5 individuals with adult-onset nesidioblastosis who we lating islet hyperplasia and nesidioblastosis. Many me- have treated at the University of Chicago Medical Cen- dium- and large-sized islets showed irregular non-oval ter (Chicago, Ill) and present a review of the literature outlines. Scattered islets of varying size contained large pertaining to this disease. hyperchromatic islet cell nuclei (dysplasia, Figure 7). Some of these were 6 to 8 times larger than smaller ad- RESULTS jacent nuclei. Immunohistochemical staining showed that the increased number of islet cells still contained the usual In each of the following 5 cases of hyperinsulinism, no ratios of insulin-, glucagon-, somatostatin-, and poly- islet cell tumor was found in multiple sections of the 60% peptide-secreting cells. to 80% distal pancreatectomy specimens examined. All cases showed a diffuse increase in islet tissue, forming CASE 1 islets that varied in size (Figure 1). Some pancreatic sections showed that nearly 50% of the cross-sectional area In 1979, a 22-year-old man was admitted to the Univer- was made up of islet tissue. Many small- and medium- sity of Chicago Medical Center, having experienced diz- sized islets were present in close association with small ziness, lightheadedness, and headaches for 3 months. His (REPRINTED) ARCH SURG/ VOL 136, JUNE 2001 WWW.ARCHSURG.COM 657 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 4. Patient 3. Small ductule with a very closely associated (arrow) Figure 6. Patient 3. A dilated pancreatic duct filled with acellular mucoid medium-sized, irregularly shaped islet cell containing one large hyperchromatic material. Similar-appearing ducts were present in 4 of the 5 described islet cell nucleus (hematoxylin-eosin, original magnification 3 400). patients (hematoxylin-eosin, original magnification 3 400). Figure 5. Patient 1. Another ductule with a very closely associated Figure 7. Patient 4. A large islet cell occupying most of the field containing medium-sized islet cell with considerable variation in islet cell nuclear size one very large and several larger than usual hyperchromatic islet cell nuclei and chromisity (hematoxylin-eosin, original magnification 3 450). (hematoxylin-eosin, original magnification 3 550). blood glucose level was 2.3 mmol/L (42 mg/dL), and at at the time of operation. A 70% distal pancreatectomy that time, his insulin levels were inappropriately high. was performed, removing all pancreatic tissue to the left A 70% distal pancreatectomy was performed, removing of the superior mesenteric vessels. Pathological analysis all pancreatic tissue to the left of the superior mesen- was consistent with nesidioblastosis (Figure 3), and no teric vessels. Pathological examination results were con- insulinoma was found grossly or microscopically. sistent with nesidioblastosis (Figure 5), and no insuli- Postoperatively, the patient was initially asymptom- noma was found grossly or microscopically. atic and normoglycemic, and she was discharged with- At 21 years’ follow-up, the patient was found to be out any complications. Soon afterwards, she developed normoglycemic and generally asymptomatic, and with- recurrence of symptomatic hypoglycemic episodes.

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