Regression of Type II Gastric Carcinoids in Multiple Endocrine Neoplasia Type 1 Patients with Zollinger-Ellison Syndrome after Surgical Excision of All Gastrinomas Melanie L. Richards, M.D., 1 Paul Gauger, M.D., 2 Norman W. Thompson, M.D., 2 Thomas J. Giordano, M.D., Ph.D. 3 1 Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA 2 Department of General Surgery, Division of Endocrine Surgery, University of Michigan Hospital, 1500 E. Medical Drive, Ann Arbor, Michigan 48109, USA 3 Department of Pathology, University of Michigan Hospital, 1500 E. Medical Drive, Ann Arbor, Michigan 48109, USA Published Online: June 16, 2004 Abstract. Enterochromaffin-like (ECL) tumors are documented in pa- tients with hypergastrinemia secondary to chronic atrophic gastritis or with Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 (ZES-MEN-1). In patients with ECL tumors and atrophic gastritis, nor- mogastrinemia after antrectomy has resulted in resolution, regression, or stabilization of ECL tumors. The natural history of ECL tumors associated with ZES-MEN-1 following normalization of gastrin levels after gastri- noma resection has not been previously reported. The purpose of this study was to determine the course of ECL tumors in patients with ZES-MEN-1 following normalization of serum gastrin levels after gastrinoma resection. Two patients with ZES-MEN-1 had biopsy-proven ECL tumors on endo- scopic evaluation. They then underwent surgical exploration that included distal pancreatectomy, enucleation of pancreatic head tumors, duode- notomy with excision of submucosal tumors, and peripancreatic lymphad- enectomy. Gastric ECL tumors larger than 1.0 cm were locally excised. Pa- tients underwent long-term follow-up with biochemical and endoscopic surveillance. Normogastrinemia was achieved and sustained following gas- trinoma resection in two patients with ZES-MEN-1. Periodic endoscopic surveillance over a 6-year period showed complete resolution of the ECL tumors. The development of ECL tumors associated with ZES-MEN-1 is multifactorial. Studies identified a genetic influence on tumor growth with loss of heterozygosity at the MEN-1 gene locus in ECL tumors. The reso- lution of ECL tumors in ZES-MEN-1 patients who are normogastrinemic indicates that an elevated gastrin level is a primary initiator for develop- ment of these tumors. Therefore both genetic defects and hypergastrinemia are causative agents. Normalization of serum gastrin levels is critical for the prevention of aggressive forms of ECL tumors. Enterochromaffin-like (ECL) tumors are primarily documented in patients with hypergastrinemia; they are secondary to chronic atro- phic gastritis or are seen in patients with the Zollinger-Ellison syn- drome (ZES) and multiple endocrine neoplasia type 1 (MEN-1) [1]. These endocrine cell neoplasms are frequently referred to as multiple gastric carcinoids in both conditions. Hyperplasia of the ECL cells, as well as tumors, develop primarily as the result of the trophic effect of chronic hypergastrinemia on all of the neuroendo- crine cells of the proximal stomach. A literature review of 224 ECL tumors found them to be associ- ated with chronic atrophic gastritis in 79% of patients; 10% of pa- tients had ZES, and 11% were sporadic [1]. The sporadic tumors were solitary, and they were larger and more biologically aggressive than those that are gastrin-dependent. Of patients with ZES, 92% had documented MEN-1. The incidence of ECL tumors in ZES- MEN-1 patients may be as high as 30%, compared to 5% in patients with chronic atrophic gastritis and hypergastrinemia [2–5]. Because of the rarity of ECL tumors in sporadic cases of ZES, a genetic factor related to the gene mutation has been considered an impor- tant contributing, if not primary, cause of their occurrence in MEN-1 patients. In patients with ECL tumors, atrophic gastritis, and hypergas- trinemia, normogastrinemia after antrectomy has resulted in reso- lution, regression, or stabilization of ECL tumors [6–8]. The natu- ral history of ECL tumors in ZES-MEN-1 patients following normalization of gastrin levels after gastrinoma resection has not been previously reported. We report two patients with ZES- MEN-1 and ECL tumors who underwent operative treatment for their gastrinomas resulting in normalization of gastrin levels. We also document the effect on the remaining ECL tumors. Patients and Methods Two patients with ZES-MEN-1 had biopsy-proven ECL tumors on endoscopic evaluation. Endoscopic evaluation was performed for surveillance and diagnostic purposes. Smaller tumors were not completely excised because of their extent. Both patients then un- derwent surgical exploration that included distal pancreatectomy, enucleation of pancreatic head tumors, duodenotomy with excision of submucosal tumors, and peripancreatic lymphadenectomy. Gas- tric ECL tumors larger than 1.0 cm were locally excised. All pa- tients were then followed biochemically and with endoscopic sur- veillance. Correspondence to: Melanie L. Richards, M.D. WORLD Journal of SURGERY © 2004 by the Socie ´te ´ Internationale de Chirurgie World J. Surg. 28, 652–658, 2004 DOI: 10.1007/s00268-004-7345-0