Treatment Approach for Neuroendocrine Tumors Associated with the INSM1 Gene
Surgical resection is the primary treatment approach for localized neuroendocrine tumors associated with INSM1 gene expression, as this offers the best chance for cure and improved outcomes. 1
Diagnostic Approach
- INSM1 (Insulinoma-associated protein 1) is a zinc-finger transcription factor that serves as a superior, sensitive, and specific biomarker for neuroendocrine tumors 2
- For proper diagnosis, synaptophysin and/or INSM1 staining should be performed in tumors with solid, trabecular, gyriform or regular glandular growth pattern, uniform nuclei and coarsely stippled ('salt and pepper') chromatin 1
- INSM1 shows nuclear positivity in neuroendocrine tumors with high sensitivity and specificity, making interpretation easier than cytoplasmic markers like chromogranin and synaptophysin 3
- Multiphase contrast-enhanced CT or MRI should be performed to identify the primary tumor and assess for metastatic disease 1
- Somatostatin receptor scintigraphy (Octreoscan) should be considered for tumor localization, except in insulinomas which are less consistently octreotide-avid 1
Preoperative Management
- Before surgical excision, any symptoms of hormonal excess must be treated 1
- For insulinomas, stabilize glucose levels with diet and/or diazoxide 1
- For gastrinomas, treat gastrin hypersecretion with proton pump inhibitors 1
- Octreotide or lanreotide can be considered for symptom control in most pancreatic NET subtypes, but should be used with caution in patients with insulinoma as they can worsen hypoglycemia by suppressing counterregulatory hormones 1
- All patients who might require splenectomy should receive preoperative trivalent vaccine (pneumococcus, haemophilus influenzae b, meningococcus group c) 1
Surgical Management
For Localized Disease
- For nonfunctioning pancreatic NETs >2 cm: complete resection with negative margins and regional lymph node dissection 1
- For nonfunctioning pancreatic NETs 1-2 cm: resection with lymph node dissection should be considered due to small but real risk of lymph node metastases 1
- For insulinomas: enucleation for peripheral tumors; distal pancreatectomy or pancreatoduodenectomy for deeper tumors 1
- For gastrinomas: duodenotomy with local resection or enucleation of tumors and periduodenal node dissection; pancreatoduodenectomy for tumors in the head of the pancreas 1
- For glucagonomas and VIPomas: distal pancreatectomy with splenectomy and lymph node resection for tumors in the tail; pancreatoduodenectomy for tumors in the head 1
For Metastatic Disease
- Surgical resection should be considered in selected patients with liver metastases and potentially resectable disease 1
- Macroscopic radical resection can be achieved in 80% of cases if carried out by experienced surgeons 1
- Cholecystectomy is recommended when performing surgery for advanced NETs in patients anticipated to receive long-term octreotide therapy 1
Management of Unresectable Disease
- Treatment options include somatostatin analogues, biotherapy, radionuclides, ablation therapies, and chemotherapy 1
- Chemotherapy may be used for inoperable or metastatic pancreatic and bronchial tumors, or poorly differentiated NETs 1
- External beam radiotherapy may relieve bone pain from metastases 1
- Novel strategies targeting INSM1-associated signaling pathways (Sonic Hedgehog, PI3K/AKT, MEK/ERK1/2) may facilitate the suppression of neuroendocrine tumor growth 2
Common Pitfalls and Caveats
- Using octreotide in insulinoma patients without confirming octreotide-avidity can precipitously worsen hypoglycemia and result in fatal complications 1
- Failure to perform adequate lymph node dissection during surgery can lead to recurrence, as NETs often have lymph node metastases 1
- Planned cytoreductive, incomplete (R2) resection of advanced disease in patients with asymptomatic or nonfunctional disease remains controversial 1
- Liver-directed therapies following pancreatoduodenectomy are associated with increased risk for perihepatic sepsis and liver abscess 1
- INSM1 staining alone is insufficient as a diagnostic marker for small cell carcinoma when expression is weak and focal 4