Insulinoma Guidelines

Updated: Jan 07, 2022
  • Author: Zonera Ashraf Ali, MBBS; Chief Editor: Lawrence T Kim, MD, FACS, FACE  more...
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Guidelines Summary

Guidelines contributor:  Evan S Ong, MD, MS Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona College of Medicine

The following organizations have issued clinical guidelines for the management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs):

  • National Comprehensive Cancer Network (NCCN)
  • North American Neuroendocrine Tumor Society (NANETS)
  • European Neuroendocrine Tumor Society (ENETS)
  • European Society for Medical Oncology (ESM0)

Grading and Staging

Grading schemes for neuroendocrine tumors (NETs) use mitotic count; the level of the nuclear protein Ki-67, which is associated with cellular proliferation; and assessment of necrosis. The World Health Organization (WHO) and the European Neuroendocrine Tumor Society (ENETS)  both incorporate mitotic count and Ki-67 proliferation for the classification of gastroenteropancreatic NETs (GEP-NETs). [66, 67, 68]

Tumors fall into one of the following three grades [69] :

  • G1: Mitotic count < 2/2 mm 2 (10 high-power fields); Ki-67 index < 3%
  • G2: Mitotic count < 2-20/2 mm 2; Ki-67 index 3-20%
  • G3: Mitotic count > 20/2 mm 2; Ki-67 index > 20%

G1 and G2 NETs are well differentiated; as a rule, G3 NETs are poorly differentiated, but rarely may be well differentiated. [48]

The National Comprehensive Cancer Network (NCCN) recommends that tumor differentiation, mitotic rate, and Ki-67 rate be included in the pathology report and that the specific classification and grading scheme be noted to avoid confusion. Clinicians are advised to view histologic grade as a general guide and use clinical judgment to make treatment decisions, particularly in cases of discordance between differentiation and Ki-67 proliferation results. [48]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. [49]

For staging of GEP-NETs, the European Society for Medical Oncology (ESMO) guidelines, updated in 2020, utilize the tumor-node-metastasis (TNM) classification created by the ENETS and the 2019 WHO grading system. [69]

In 2013, the North American Neuroendocrine Tumor Society (NANETS) concluded that while the criteria differ among the various classification systems, the underlying data are similar and pathology reports should include notation of the systems and parameters used to assign the grade and stage. [70]



For the evaluation of insulinoma, National Comprehensive Cancer Network guidelines recommend abdominal multiphasic CT or MRI and measurement of serum insulin, pro-insulin, and C-peptide levels during concurrent hypoglycemia. The following studies may also be performed, as appropriate [48] :

  • Endoscopic ultrasound (EUS)
  • Other biochemical evaluation as clinically indicated 
  • Somatostatin receptor–based imaging;  68Ga-dotatate imaging preferred (PET/CT or PET/MRI) or somatostatin receptor scintigraphy
  • Chest CT ± contrast
  • Consider testing for inherited genetic syndromes

European Neuroendocrine Tumor Society guidelines note that "the exact criteria for the diagnosis of insulinoma continue to evolve and vary in different consensus documents and reviews", but cite proposed diagnostic criteria from a consensus report from the US Endocrine Society, which include endogenous hyperinsulinism documented by symptoms, signs, or both, and plasma findings as follows [16] :

  • Glucose < 55 mg/dl (3.0 mmol/L)
  • Insulin ≥3.0 μU/ml (18 pmol/L)
  • C-peptide ≥0.6 ng/ml (0.2 nmol/L)
  • Proinsulin ≥5.0 pmol/L

Evaluation of serum chromogranin A (CgA) levels are frequently not helpful for diagnosing insulinoma, as an elevated CgA value has only a 73% specificity, compared with 92% specificity for non-insulinoma pancreatic NETs. [16]



National Comprehensive Cancer Network (NCCN) guidelines recommend resection as the primary treatment for most localized pancreatic neuroendocrine tumors (NETs). Exceptions include patients with life-limiting comorbidities or high surgical risk. In addition, observation may be appropriate for incidentally discovered tumors < 1 cm, depending on the site. [48]

Prior to surgery, NCCN recommends that symptoms of hormonal excess be treated with octreotide or lanreotide; however, such treatment is contraindicated in patients with insulinoma because of the potential for fatal complications. Specific recommendations vary by tumor subtype.Cholecystectomy is recommended during surgical resection if treatment with octreotide or lanreotide is planned, due to the increased rate of biliary problems associated with long-term use of these agents. [48]

Additional NCCN recommendations for insulinoma treatment include the following [48] :

  • Stabilize glucose levels with diet and/or diazoxide; everolimus may be considered

  • Primary treatment is enucleation; consider laparoscopic resection for solitary tumors

  • Deeper or invasive tumors or those with proximity to the main pancreatic duct require pancreatoduodenectomy if located in the head and laparoscopic distal pancreatectomy if in a distal location, with preservation of the spleen for smaller tumors

European Neuroendocrine Tumor Society guidelines include the following minimal consensus statements on treatment of insulinomas [16] :

  • Surgery remains the preferred treatment whenever possible, but medical treatment is needed prior to surgery, in recurrent cases, and in malignant insulinomas.
  • In additional to diazoxide, frequent small meals, somatostatin analogs, and the mTOR inhibitor everolimus has been effective in controlling hypoglycemia; sunitinib also has been effective in a few patients. In malignant insulinomas, peptide receptor–targeted radiotherapy (PRRT) or chemoembolization can help control the hypoglycemia.
  • Surgical exploration for possible cure should be performed in all patients with insulinomas if non-resectable metastatic disease is not present, with or without MEN1.
  • A laparoscopic approach is generally recommended in patients with sporadic disease with imaged tumors.
  • In the uncommon patient who is not thought to be a surgical candidate, successful treatment of localized insulinomas with ablative therapy, either endoscopically directed or percutaneously with radiologic direction, has been reported but further data are required. Successful use of EUS-directed ablation using ethanol injection or CT-guided radiofrequency ablation has also been reported.