Intestinal Carcinoid Tumor Guidelines

Updated: Dec 20, 2021
  • Author: Rachel E Lewis, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  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)
  • UK and Ireland Neuroendocrine Tumour Society (UKI NETS)

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). [61, 62, 63]  

Tumors fall into one of the following three grades:

  • G1: well differentiated, low grade
  • G2: well differentiated, intermediate grade
  • G3: poorly differentiated, high grade

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. [60]

NCCN guidelines recommend staging according to the 8th edition of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. [60]  The AJCC uses separate staging systems for carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix. [64]

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. [65]  

In 2012, the UK and Ireland Neuroendocrine Tumour Society (UKI NETS) released updated guidelines for the management of GEP-NETs. Recommendations for grading and staging are as follows [66] :

  • For grading: WHO 2010 grading system
  • For staging: 8 th edition of the AJCC Cancer Staging Manual
  • Also stage NETs of the stomach, pancreas and appendix with the ENETS site-specific T-staging system
  • The TNM classification used should be specified
  • Underlying features of the T-stage classification (e.g., tumor size, extent of invasion) should be documented to allow for translation between different classification systems

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. [67]




Treatment for locoregional disease

NCCN guidelines recommend resection as the primary treatment for most carcinoid tumors of the gastrointestinal (GI) tract. Specific recommendations vary by tumor subtype. However, for neuroendocrine tumors at any site, cholecystectomy is recommended during surgical resection if treatment with a somatostatin analog (ie, octreotide, lanreotide) is planned, due to the increased rate of biliary problems associated with long-term use of these agents. [60]

Gastric tumors

For gastric tumors, the NCCN recommendations are as follows [60] :

  • With hypergastrinemia and tumors ≤ 2 cm: Endoscopic resection of prominent tumors with endoscopic surveillance every 2-3 years
  • With hypergastrinemia and tumors > 2 cm: Resection of primary gastrinoma or consider endoscopic surveillance and/or octeotide or lanreotide and manage gastric hypersecretio with high-dose proton pump inhibitors (PPIs)
  • With normal gastrin levels: Radical gastric resection and regional lymphadenectomy (preferred); endoscopic or wedge resection can be considered for tumors ≤ 2 cm

NANETS 2010 guidelines subclassify gastric carcinoids into the following three distinct groups [68] :

  • Type I – Those associated with chronic atrophic gastritis/pernicious anemia (70-80%)
  • Type II – Those associated with Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (MEN I) (5%)
  • Type III – Sporadic NETs of the stomach (15-20%)

NANETS 2013 updated guidelines include the following recommendations for treatment of gastric carcinoid tumors by subtype [67] :

  • Type I or II, < 1 cm: Surveillance or endoscopic removal
  • Type I, 1 cm to < 2 cm: Surveillance with repeat endoscopy every 3 years or endoscopic resection
  • Type II, 1 cm to < 2 cm: Endoscopic resection
  • Type I, ≥2 cm (≤6 polyps), or type II ≥2 cm: Endoscopic resection, if possible, or open surgical resection
  • Type I, ≥2 cm (>6 polyps): Individualized treatment required; surveillance, endoscopic resection, or surgical resection
  • Type III: Partial gastrectomy and lymph node dissection

The 2016 revised ENETS guidelines prefer conservative management strategies over surgery for type I tumors. The guidelines recommend resection of tumors ≥ 10 mm performed by experienced endoscopists in gastric tumors using either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). [69]

For type II tumors, local or limited excision can be recommended, but this should be patient tailored at multidisciplinary NET centers of excellence. Type III tumors should be treated similarly to gastric adenocarcinoma with surgery (partial or total gastrectomy with lymph node dissection). Systemic therapies is required for inoperable or stage 4 disease. [69]

Duodenal tumors

For duodenal tumors, the NCCN recommends the following treatments [60] :

  • Endoscopic resection with follow-up upper endoscopy
  • Transduodenal local excision with or without lymph node sampling
  • Pancreatoduodenectomy

ENETS guidelines provide the following recommendations for treatment of duodenal tumors [69] :

  • All localized tumors should be removed
  • Endoscopic resection for tumors ≤1 cm confined to the submucosal layer, without lymph node or distant metastasis
  • Surgical resection with lymphadenectomy for tumors in the periampullary region
  • Surgical resection for tumors >2 cm and tumors of any size with lymph node metastases

Bowel tumors

NCCN recommendations are as follows [60] :

  • Surgical resection with lymphadenectomy
  • Careful examination of the entire bowel and assessment of proximity to or involvement of the superior mesenteric artery and superior mesenteric vein
  • Prophylactic cholecystectomy if further treatment with octreotide or lanreotide is planned

The NANETS guidelines include the following recommendations [67] :

  • Tumors of the cecum: Right hemicolectomy with node dissection
  • Tumors of the jejunal or ileum: Resection with node dissection; full bowel examination required
  • Distal colon and rectum tumors < 1 cm: Endoscopic resection (polypectomy, endoscopic mucosal resection, endoscopic submucosal dissection) for mucosal or submucosal tumors
  • Distal colon and rectum tumors 1-2 cm: Transanal excision via rigid or flexible dissection; could also be considered after endoscopic resection with positive margins
  • Distal colon and rectum tumors >2 cm: Surgical resection (low anterior resection or abdominoperineal resection) for larger tumors, tumors invading muscularis propria, or those with lymphadenopathy

The ENETS guidelines provide following recommendations [70, 71] :

Rectal Tumors  [70]

  • Endoscopic resection by simple polypectomy, endoscopic mucosal resection (EMR) with modified EMR band ligation, endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEMS).
  • For lesions < 10 mm and no involvement of the muscularis propria, EMR is adequate, but EMR band-assisted ligation may improve the number of complete resections 
  •  If EMR results in an incomplete resection, then ESD or TEMS may be indicated as salvage therapy

 Jejunum and Ileum  Tumors  [71]

  • Curative resection of the primary tumor and dissection of the locoregional lymph node metastasis along the superior mesenteric root and around the mesentery
  • Lymphatic mapping it is not a standardized procedure and not generally recommended 

Appendix tumors

NCCN recommendations for appendix NETs are as follows [60] :

  • Tumors ≤ 2 cm confined to the appendix: Appendectomy
  • Tumors ≤ 2 cm with lymphovascular or mesoappendiceal invasion or atypical histologic features: More aggressive treatment can be considered
  • Incomplete resection or tumors > 2 cm: Staging with abdominal/pelvic CT or MRI; if no distant disease, reexploration with a right hemicolectomy

The NANETS guidelines include the following recommendations [67] :

  • Excision for tumors ≤ 2 cm; consider right hemicolectomy with node dissection if high- risk features are present
  • Tumors > 2 cm: Right hemicolectomy with node dissection

The 2016 ENETS revised guidelines recommendations include [72] :

  • Tumors ≤ 2 cm: simple appendectomy unless incompletely resected
  • Right hemicolectomy with node dissection only in rare tumors measuring 1–2 cm but with positive or unclear margins or with deep mesoappendiceal invasion (ENETS T2), higher proliferation rate (G2) and/or vascular invasion
  • Tumors > 2 cm: right hemicolectomy with node dissection

Metastatic disease

NCCN recommendations for the treatment of unresectable and/or metastatic carcinoid tumors of the GI tract include the following [60] :

  • Somatostatin scintigraphy to assess sites of metastases and somatostatin receptor status if octreotide or lanreotide is considered
  • Limited hepatic metastases: Complete resection of primary tumor and metastases with curative intent; noncurative debulking surgery in select cases
  • Unresectable hepatic progressive disease: Radiofrequency ablation or cryoablation or hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization)
  • Palliative small bowel resection for patients with abdominal pain from bowel obstruction or ischemia related to the primary tumor
  • Octreotide or lanreotide to control tumor growth in patients with clinically significant tumor burden or progressive disease; everolimus can be considered for advanced tumors
  • Consider capecitabine if no other options are feasible (category 3)
  • Malignant carcinoid syndrome: Octreotide or lanreotide; cardiology consultation, and echocardiogram to assess for heart disease. If poorly controlled, consider telotristat for persistent symptoms.
  • Liver transplantation is investigational and not recommended as routine care

Note that the use of ablative techniques for hepatic disease is associated with increased infectious complications. Although the NCCN guidelines cite category 2b evidence for cryoablation and radiofrequency ablation, most centers use radiofrequency or microwave ablation. Cryoablation is generally used only in centers providing ablation for renal cell cancers, and it is associated with a small but definite risk of subsequent acute respiratory distress syndrome. [73]