INTRODUCTION

Insulinomas, the most common cause of endogenous hypoglycemia related to endogenous hyperinsulinism, occur in 1-4 persons per million people.1–3 Insulinomas are characterized by episodic hypoglycemia related to tumor insulin secretion.4 Up to 90% are benign, solitary, intrapancreatic, and or less than 2 cm in diameter.3,5–7 Insulinomas may be characterized as solitary, Multiple endocrine neoplasia type 1–associated, or rarely insulinomatosis (synchronous and metachronous insulinomas).8 The standard treatment of insulinomas is surgical excision, although patients with recurrent insulinomatosis may need medical management and advanced surgical management.9 Medical management includes diazoxide, somatostatin analogs, or everolimus; verapamil, steroids, and phenytoin have also been used; however, in 95% of cases, surgical management is ultimately required.10–16 We present a case of recurrent insulinomatosis requiring total pancreatectomy after recurrence of disease almost 20 years after enucleation and failure of medical management without any known underlying familial genetic predisposition.

CASE REPORT

Our patient, now 72 years old, began experiencing hypoglycemic symptoms at age 30 years (Figure 1). She had no family history of neuroendocrine tumors including multiple endocrine neoplasia type 1 or gastrointestinal cancer. Thirteen years after the onset of symptoms, fasting laboratory tests revealed a serum glucose level of 38 mg/dL, insulin level of 3.7 μIU/mL, c-peptide levels between 330 and 470 ng/mL, proinsulin of 23 pmol/L, and a negative sulfonylurea screen. Six years later, computer tomography showed an area of enhancement in the anterior body of the pancreas; endoscopic ultrasound (EUS) showed 2 nodules in the anterior body, 2 in the head, and 1 in the tail. The largest of these was in the tail and measured 1 × 0.7 cm. She was taken for abdominal exploration, where 5 separate insulinomas from the head and body were removed by enucleation. The largest of these was 1 cm in the body of the pancreas.

Figure 1.:

Timeline of symptoms, medical, and surgical management. EUS, endoscopic ultrasound; PET, positron emission tomography.

Twenty years later, the patient presented to our institution because of persistent hypoglycemic symptoms. A gallium-dotatate positron emission tomography scan detected multiple radiotracer-avid foci in the postoperative pancreatic head and body, raising concerns of recurrence (Figure 2). Initially, she was managed medically by frequent snacking and diazoxide. The full diazoxide dose was cost-prohibitive, so everolimus was added. She reported improved symptom management, so diazoxide was discontinued a few months later; her hypoglycemia threshold improved to t50 mg/dL.

Figure 2.:

Positron emission tomography showing multiple radiotracer avid foci in the postoperative pancreatic head and body region, concerning for underlying recurrent malignant involvement.

Several months later, surveillance magnetic resonance imaging showed no recurrent disease, which was inconsistent with the previous positron emission tomography scan. Thus, EUS was performed revealing 3 lesions in the pancreatic head and 2 in the body/tail, the largest measuring 1 cm. EUS-guided fine-needle sampling confirmed the recurrence of insulinoma. Everolimus had to be discontinued because of a rash, altered taste, and unintentional 25-pound weight loss. Scheduled diazoxide was resumed, but the patient reported severe daily hypoglycemia symptoms. She experienced low (40 mg/dL) morning blood glucose readings, multiple episodes of loss of consciousness, and one episode of unresponsiveness with convulsions. Because of the severity of symptoms and the likelihood that the lesions were confined to the pancreas, medical management with octreotide was not selected, and she chose total pancreatectomy. Surgical histopathology revealed focal chronic pancreatitis with multiple well-differentiated stage G1 neuroendocrine tumors positive for synaptophysin, chromogranin, INSM1, and AE1/3 but negative for trypsin, with a Ki-67 of 1%. The largest of these tumors measured 0.8 cm. No metastasis was found in the 19 resected lymph nodes. Her postoperative course was uncomplicated. Four days after surgery, her C-peptide level was undetectable. She is now managed as a functional type 1 diabetic with insulin. With 10 months of postop follow-up, she has not experienced any episodes of hypoglycemia symptoms, and surveillance imaging did not reveal recurrence.

DISCUSSION

To the best of our knowledge, this report is one of the first cases of recurrent insulinomatosis to recur 20 years after enucleation in the absence of a known familial syndrome. This should prompt reflection on the diagnosis and management of this rare entity. Failure of initial surgical intervention such as enucleation or partial pancreatectomy and medical therapy such as diazoxide, somatostatin analogs, or everolimus necessitating definitive surgery for recurrent insulinomatosis is seen in 95% of cases reviewed.10,14 Octreotide was not attempted in our patient because of her severe hypoglycemia but has been noted to help in other cases.11,13,16 As our case demonstrates, magnetic resonance imaging is not always the best test for diagnosis of recurrence of insulinomas; EUS is an accurate modality for diagnosis.12,19 EUS-guided ablation therapies may be a promising technique for definitive management of insulinomatosis especially in patients where surgery is a prohibitive risk or technically not feasible. The risks of total pancreatectomy include fistulas, abscesses, bleeding, delayed gastric emptying, and diabetes.12,13,17,18 EUS-guided ablations carry their own risks including pancreatitis, duodenal perforation, and bleeding. However, this technique should be explored in long-term prospective studies of recurrent insulinomatosis.10,19 Finally, somatic mutation analysis was not performed on the surgical specimen, and recent research has implicated variants of a triad of genes, CEBPA, FOXL2, and IRS2 as well as the MAFA protein in the pathogenesis of recurrent insulinomatosis.15,20–22 Hence, it is imperative to explore these genetic factors in future cases of recurrent insulinomatosis, particularly in those lacking a known familial syndrome.

DISCLOSURES

Author contributions: E. Gill: project development, data collection, manuscript writing, and manuscript editing; A. Pusateri: project development, data collection, and manuscript editing; SG Krishna: project development and manuscript editing and is the article guarantor.

Financial disclosure: SG Krishna has research grant support (investigator-initiated studies) from Mauna Kea Technologies, Paris, France, and Taewoong Medical, USA.

Informed consent was obtained for this case report.

REFERENCES 1. Okabayashi T, Shima Y, Sumiyoshi T, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013;19(6):829–37. 2. Chang F, Chandra A, Culora G, Mahadeva U, Meenan J, Herbert A. Cytologic diagnosis of pancreatic endocrine tumors by endoscopic ultrasound-guided fine-needle aspiration: A review. Diagn Cytopathol. 2006;34(9):649–58. 3. Sotoudehmanesh R, Hedayat A, Shirazian N, et al. Endoscopic ultrasonography (EUS) in the localization of insulinoma. Endocrine. 2007;31(3):238–41. 4. Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005;19(5):753–81. 5. Doi R, Komoto I, Nakamura Y, et al. Pancreatic endocrine tumor in Japan. Pancreas. 2004;28(3):247–52. 6. Mittendorf EA, Liu YC, McHenry CR. Giant insulinoma: Case report and review of the literature. J Clin Endocrinol Metab. 2005;90(1):575–80. 7. Kondo T, Tomita S, Adachi H, et al. A case of hyperinsulinemia of undetermined origin, successfully treated with long-acting octreotide. Endocr J. 2005;52(5):511–7. 8. Anlauf M, Bauersfeld J, Raffel A, et al. Insulinomatosis: A multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia. Am J Surg Pathol. 2009;33(3):339–46. 9. Snaith JR, McLeod D, Richardson A, Chipps D. Multifocal insulinoma secondary to insulinomatosis: Persistent hypoglycaemia despite total pancreatectomy. Endocrinol Diabetes Metab Case Rep. 2020;2020:20-0091. 10. Grimaldi F, Fazio N, Attanasio R, et al. Italian Association of clinical endocrinologists (AME) and Italian AACE chapter position Statement for clinical practice: Assessment of response to treatment and follow-up in gastroenteropancreatic neuroendocrine neoplasms. Endocr Metab immune Disord Drug Targets. 2018;18(5):419–49. 11. Tartaglia A, Busonero G, Gagliardi L, Boddi V, Pieri F, Nizzoli M. Complete remission of recurrent multiple insulin-producing neuroendocrine tumors of the pancreas with somatostatin analogs: A case report and literature review. Discover Oncol. 2022;13(1):66. 12. Mehrabi A, Fischer L, Hafezi M, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014;43(5):675–86. 13. Vezzosi D, Bennet A, Rochaix P, et al. Octreotide in insulinoma patients: Efficacy on hypoglycemia, relationships with octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur J Endocrinol. 2005;152(5):757–67. 14. Jaramillo Chacón H, González Devia D, López Panqueva RP, et al. Insulinomatosis: una causa muy rara de tumor neuroendocrino pancreático. Revista Colombiana de Endocrinología Diabetes Metabolismo. 2020;7(2):76–85. 15. Iacovazzo D, Flanagan SE, Walker E, et al. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proc Natl Acad Sci USA. 2018;115(5):1027–32. 16. Paz-Ibarra J, Siles A, Siles A, Alvarez J, Ruiz G, Diaz R. Abstract# 1397268: A rare case of insulinomatosis in a 58-year-old woman with recurrent symptoms of hypoglycemia. Endocr Pract. 2023;29(5):S5–S6. 17. Sauvanet A. Surgical complications of pancreatectomy [in French]. J Chir (Paris). 2008;145(2):103–14. 18. Del Chiaro M, Rangelova E, Segersvärd R, Arnelo U. Are there still indications for total pancreatectomy? Updates Surg. 2016;68(3):257–63. 19. El Sayed G, Frim L, Franklin J, et al. Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: A systematic literature review. Ther Adv Gastroenterol. 2021;14:17562848211042171. 20. Anoshkin K, Vasilyev I, Karandasheva K, et al. New regions with molecular alterations in a rare case of insulinomatosis: Case report with literature review. Front Endocrinol (Lausanne). 2021;12:760154. 21. Fottner C, Sollfrank S, Ghiasi M, et al. Second MAFA variant causing a phosphorylation defect in the transactivation domain and familial insulinomatosis. Cancers (Basel). 2022;14(7):1798. 22. Mintziras I, Peer K, Goerlach J, et al. Adult proinsulinomatosis associated with a MAFA germline mutation as a rare cause of recurrent hypoglycemia. Pancreas. 2021;50(10):1450–3.