Insulinoma

Forest Washington, MD
The Operative Review of Surgery. 2023; 1:155-161.

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Table of Contents

Pathophysiology
Presentation
Diagnosis
Treatment

References

Pathophysiology

Also Known as “Beta Cell Neoplasm”, “Beta Cell Tumor of the Pancreas”, or “Pancreatic Insulin-Producing Tumor”

Definition

  • Insulin Secreting Neuroendocrine Tumor 1
  • Due to an Abnormal Growth of the Beta Islet-Cells of the Pancreas 1
    • There is a Single Report of an Insulin-Secreting Small Cell Carcinoma of the Cervix 2
  • Is the Most Common Functional Pancreatic Neuroendocrine Tumor (PNET) 3
  • *See Pancreatic Neuroendocrine Tumor (PNET)

Distribution and Size

  • Evenly Distributed Throughout Pancreas 4
  • 7% are Multiple 5
  • Most are Small (< 3 cm): 6
    • < 1 cm: 24%
    • 1-2 cm: 42%
    • 2-3 cm: 30%
    • > 3 cm: 4%

Malignancy

  • Most are Benign (93%) 5
  • 6% Have Multiple Endocrine Neoplasia Type 1 (MEN-1) 7

Epidemiology

  • Median Age: 47-50 Years 6-8
  • 57-60% are Female 6-8

Insulinoma After Resection 9

Presentation

Symptoms 10-12

  • Neuroglycopenic Symptoms:
    • Confusion
    • Visual Changes
    • Unusual Behavior
  • Sympathoadrenal Symptoms:
    • Palpitations
    • Diaphoresis
    • Tremulousness
  • Amnesia
  • Weight Gain

Symptom Association with Diet 7

  • Only Fasting Symptoms – 73%
    • Often in the Morning Before Breakfast After Fasting Overnight
  • Only Postprandial Symptoms – 6%
  • Both Fasting and Postprandial Symptoms – 21%

Whipple’s Triad

  • Used in the Diagnosis of Symptomatic Hypoglycemia (Not Exclusive to Insulinoma) 13,14
  • Triad: 15
    • Fasting Hypoglycemia (< 55 mg/dl)
    • Symptoms of Hypoglycemia
    • Symptomatic Relief with Glucose Correction
  • Presence Suggests that Symptoms are Directly the Result of Hypoglycemia

Factitious Hypoglycemia

  • Definition: Hypoglycemia Due to Exogenous Insulin Administration 16
  • Often Due to Munchausen’s Syndrome 17
  • Can Have a Similar Presentation and Should Be Excluded in the Workup of Insulinoma 18

Diagnosis

Diagnosis

  • Primary Diagnosis Made by Demonstrating High Insulin Levels During a Spontaneous or Provoked Episode of Hypoglycemia 4
    • Can Provoke by a 72-Hour Fast or Mixed-Meal Test
  • Rule Out Factitious Hypoglycemia with a C-Peptide Level 19
    • C-Peptide Levels Should be Elevated in the Setting of Insulinoma Commiserate with Insulin Secretion 19
    • Low C-Peptide Levels Raises Concern for Exogenous Insulin Secretion
    • Additionally Screen with Sulfonylurea and Meglitinide Levels

TNM Staging

Localization

  • Initial Imaging: Noninvasive (CT or MRI) 21
  • Somatostatin Receptor Imaging 22
    • Consider if Initial Imaging Fails to Localize
    • Insulinomas Demonstrate Relatively Low Somatostatin Receptor Expression (May Be More Difficult to Detect than Other PNETs) 23,24
    • Options:
      • Somatostatin (Octreotide) Receptor Scintigraphy (SRS) – Classic Test Used
      • Functional PET Scan (Ga-68 DOTATATE) – Becoming More Prevalent with Higher Sensitivity
  • If Noninvasive Imaging Fails: Invasive Imaging
    • Endoscopic Ultrasound (EUS) – Generally Preferred Next Step 25
    • Selective Arterial Calcium Stimulation Test (SACST) with Hepatic Venous Sampling 26

PNET on Imaging: (A) CT, (B) EUS, (C) SRS, (D) Functional PET 27

Treatment

Surgical Resection (Treatment of Choice) 4,28

  • < 2-3 cm: Enucleation
    • Additional Requirements:
      • Single Lesion
      • ≥ 2-3 mm From the Main Pancreatic Duct (Reduce Leak Risk)
      • Well-Encapsulated
      • No Local Invasion
    • The Preferred Approach if Able
  • > 2-3 cm: Surgical Resection
    • Head/Neck: Pancreaticoduodenectomy
    • Body/Tail: Distal Pancreatectomy (Concurrent Splenectomy if Malignancy is Suspected)
    • Entire Pancreas: Total Pancreatectomy

Medical Management to Control Symptomatic Hypoglycemia

  • Options:
    • Diazoxide (Inhibits Insulin Release) – Preferred Agent 29-31
    • Octreotide 31,32
    • Everolimus 33
    • Verapamil 31
    • Phenytoin 34
  • Used Preoperatively or for Patients that are Not Surgical Candidates or in Unresectable Metastatic Disease

Liver-Directed Therapy

  • Resection of Metastases if Able
  • Radiofrequency Ablation (RFA) or Cryoablation 35
  • Hepatic Artery Embolization 36

Additional Options in Surgically Unresectable Disease

  • Tumor Embolization
  • Chemotherapy 4
  • Radiation Therapy 37,38
    • Pancreatic Neuroendocrine Carcinomas Were Previously Considered to be Resistant to Radiation

References

  1. National Cancer Institute. NIH.
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  3. Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013 Jun;32(6):312-24.
  4. Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, Kobayashi M, Hanazaki K. Diagnosis and management of insulinoma. World J Gastroenterol. 2013 Feb 14;19(6):829-37.
  5. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinoma–incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc. 1991 Jul;66(7):711-9.
  6. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical approach to insulinomas. Assessing the need for preoperative localization. Arch Surg. 1992 Apr;127(4):442-7.
  7. Placzkowski KA, Vella A, Thompson GB, Grant CS, Reading CC, Charboneau JW, Andrews JC, Lloyd RV, Service FJ. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73.
  8. Shao S, Zeng Z, Hu S. An observational analysis of insulinoma from a single institution. QJM. 2018 Apr 1;111(4):237-241.
  9. Alabraba E, Bramhall S, O’Sullivan B, Mahon B, Taniere P. Pancreatic insulinoma co-existing with gastric GIST in the absence of neurofibromatosis-1. World J Surg Oncol. 2009 Feb 13;7:18. (License: CC BY 2.0)
  10. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med. 1999 Mar;106(3):307-10.
  11. Service FJ, Dale AJ, Elveback LR, Jiang NS. Insulinoma: clinical and diagnostic features of 60 consecutive cases. Mayo Clin Proc. 1976 Jul;51(7):417-29.
  12. Harrington MG, McGeorge AP, Ballantyne JP, Beastall G. A prospective survey for insulinomas in a neurology department. Lancet. 1983 May 14;1(8333):1094-5.
  13. Martens P, Tits J. Approach to the patient with spontaneous hypoglycemia. Eur J Intern Med. 2014 Jun;25(5):415-21.
  14. Cazabat L, Chanson P. Hypoglycémie et insulinome [Hypoglycemia and insulinoma]. Ann Endocrinol (Paris). 2009 Sep;70 Suppl 1:S2-11.
  15. Desimone ME, Weinstock RS. Hypoglycemia. 2018 May 5. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext.
  16. Bansal N, Weinstock RS. Non-Diabetic Hypoglycemia. 2020 May 20. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext.
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  19. Pfützner A, Löbig M, Fortunato A, Forst T. Evaluation of a new fully automated one-step C-peptide chemiluminescence assay (LIAISON C-Peptid). Clin Lab. 2003;49(5-6):227-32.
  20. Bergsland EK, Woltering EA, Rindo G. Neuroendocrine tumors of the pancreas. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), AJCC, Chicago 2017. p.407. Corrected at 4th printing, 2018.
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  23. Portela-Gomes GM, Stridsberg M, Grimelius L, Rorstad O, Janson ET. Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas – predominance of receptor subtype 4. Endocr Pathol. 2007 Summer;18(2):79-85.
  24. Peltola E, Vesterinen T, Leijon H, Hannula P, Huhtala H, Mäkinen M, Nieminen L, Pirinen E, Rönty M, Söderström M, Arola J, Jaatinen P. Immunohistochemical somatostatin receptor expression in insulinomas. APMIS. 2023 Apr;131(4):152-160.
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