Treatment Guideline Chart
Neuroendocrine tumors are rare, small, slow-growing epithelial neoplasms with predominant neuroendocrine differentiation found in most organs of the body.
They arise from cells throughout the diffuse endocrine system.
Carcinoid tumors and pancreatic neuroendocrine tumors are the most common.
Carcinoid tumors arise from the lungs & bronchi, stomach, small intestine, appendix, rectum or thymus.
Majority of the neuroendocrine tumors are sporadic but some tumors are caused by inherited genetic syndromes such as multiple endocrine neoplasia, Von-Hippel Lindau disease, tuberous sclerosis complex and neurofibromatosis.
They have the ability to store and secrete various peptides and neuroamines.

Surgical Intervention

  • Surgical management should be individualized with the ultimate therapeutic decisions and approaches decided after a full multidisciplinary evaluation
  • Surgery can be curative or palliative
  • It can be primary tumor resection or tumor debulking
  • It has curative potential and can improve survival
    • It can lessen or remove the risk of progressive symptoms such as bowel obstruction
  • Early intervention can also increase the chance of successful surgery and decrease technical complications
  • Definitive resection of the primary tumor should always be performed whenever technically feasible
    • It is the primary treatment approach for most localized carcinoid tumors and pancreatic NETs
    • Primary tumor removal by segmental resection and lymphadenectomy are recommended
  • Prophylactic cholecystectomy is also advised in patients undergoing surgery for NETs of the digestive tract in order to mitigate biliary toxicity of somatostatin analogs and prevent chemical cholecystitis if transcatheter arterial chemoembolization is done
  • Ensure that Octreotide is given preoperatively and intraoperatively to avoid intraoperative carcinoid crisis in patients with functional tumors
  • Trivalent vaccine (eg H influenzae b, meningococcal group C, pneumococcus) should be given preoperatively to patients who will require splenectomy
Curative Surgery
  • Resection of the primary tumor should be accompanied by a thorough intraoperative evaluation for synchronous tumors or metastatic disease
    • Resectable liver metastasis should be removed
    • Selective portal vein embolization is considered in patients with borderline liver reserve in order to induce liver hypertrophy
    • Liver transplantation is an option in young patients <50 years old if:
      • Primary tumor originates from the gastrointestinal tract
      • Tumor is drained by the venous portal system
      • Disease progression is controlled for at least 6 months before transplantation
Palliative Surgery
  • Cytoreductive surgery is recommended in patients when complete resection of the tumor is not possible
  • Consists of combination of multiple techniques such as hepatectomy, local ablative therapies (eg radiofrequency ablation, cryotherapy, or microwave therapy), intra-abdominal organ resection, and bypass procedures
  • Aims to stabilize or improve symptoms and decrease or normalize hormone levels
  • Can reduce tumor bulk, prevent or delay complications from local or distant disease, decrease hormone levels, and prolong survival
  • Requires the assessment by a multidisciplinary team to ensure care and provide case-specific palliative options
  • Hepatic arterial embolization [eg bland transarterial embolization (TAE), chemoembolization (TACE), radioembolization (TARE)] with or without chemotherapy is another cytoreductive option for patients who are not surgical candidates, especially for patients with unresectable metastatic liver-dominant, well-differentiated NETs
    • Indicated for patients symptomatic or with disease progression on somatostatin analog therapy or other forms of systemic therapy, or those with bulky hepatic disease
Localized NETs
  • Most appendiceal carcinoids are found after appendectomy and majority are located at the tip of the appendix
  • Careful pathological investigation of the specimen is required
  • Simple appendectomy is sufficient for low-grade appendiceal NETs ≤2 cm confined to the appendix
  • Completely excised, small, well-differentiated carcinoid measuring ≥1 cm and confined to the tip of the appendix can be considered as cured if there is no evidence of lymphovascular invasion or invasion into the mesoappendix
  • Right hemicolectomy is considered in the following conditions:
    • Appendiceal carcinoids with evidence of tumor invasion at the base of the appendix
    • Tumors >2 cm
    • Undetermined tumor size
    • Incompletely resected tumors
    • Tumors with lymphovascular or mesoappendix invasion
    • Intermediate to high-grade tumors
    • Mixed histology (eg goblet cell carcinoid, adenocarcinoid)
    • Obvious mesenteric nodal involvement
  • Lobectomy or other anatomic pulmonary resection (eg segmentectomy, bilobectomy, pneumonectomy) with lymph node resection/sampling is recommended for localized or locoregional resectable disease
  • Carcinoids of cecum are frequently metastatic at the time of diagnosis
  • Usually present as silent, large, bulky tumors manifesting with gastrointestinal hemorrhage or obstruction
  • More aggressive than appendiceal carcinoid
  • Surgical excision with adequate resection of mesenteric lymph-node bearing tissue is recommended
  • Careful pathological examination is required especially in small lesions
  • If feasible, endoscopic resection is recommended and if performed, follow-up esophagogastroduodenoscopy (EGD) as indicated
  • For nonmetastatic duodenal carcinoid tumors other options include:
    • Transduodenal local excision with regional lymphadenectomy
    • Pancreatoduodenectomy
      • May also be considered for ampullary tumors not amenable to local or endoscopic excision
  • Bowel resection with regional lymphadenopathy is recommended
    • Manual palpation of the entire bowel to assess presence of synchronous tumors 
    • Intra-operative assessment of the superior mesenteric artery and vein is also recommended
  • Local resection or enucleation of pancreatic NETs is recommended whenever feasible
    • More advanced surgical resections such as Whipple resections are not routinely performed and should only be done in carefully selected patients
  • All insulinomas regardless of size should undergo resection due to hypoglycemic complications 
  • Pancreatic NETs, except for insulinomas, are surgically managed by a laparotomy to allow an extensive exploration of the abdomen and look for lymph node metastases
  • Intrapancreatic single tumors if localized preoperatively can be cured in almost all cases using laparoscopic approach
    • Surgical cure rates are high for insulinomas and for sporadic gastrinomas
    • Cure rates of other pancreatic NETs are lower because they are diagnosed during advanced disease state
  • It is recommended to have endoscopic or transanal excision in tumors ≤2 cm
    • For tumors 1-2 cm, consider radical resection if with tumor invasion in muscularis propria or node positive
  • Low anterior resection or abdominoperineal resection (APR) is recommended for tumors >2 cm with tumor invasion of the muscularis propria or tumors associated with lymph node metastases
  • Endoscopic removal with biopsy and subsequent follow-up is recommended for superficial, low-grade tumors <1 cm
    • Wedge resection may also be used for patients with tumors <2 cm and with normal gastrin levels
  • Local surgical resection is done for tumors >2 cm with recurrent tumors or with >6 polyps
  • Radical gastric resection with lymphadenectomy is recommended for patients with solitary or multiple tumors >2 cm in size and with normal gastrin levels
  • Antrectomy may be performed in patients with type 1 gastric NETs and chronic atrophic gastritis to eliminate the source of gastric production
  • Endoscopic resection is recommended for patients with locoregional type 1 and 2 gastric NETs
  • Radical resection and regional lymph node dissection should be done to patients with non-metastatic gastric NETs and normal gastrin levels (type 3) because of its more aggressive quality
  • Partial gastrectomy and lymph node dissection are required for type 3 isolated sporadic gastric NETs considered only in selected patients
    • Clinical benefit is not clearly established in patients with asymptomatic small-volume disease and may not be applicable in patients with large-volume liver metastatic disease
  • Generally treated with surgical resection (thymectomy via median sternotomy and/or thoracotomy with lymph node dissection) without adjuvant therapy for localized and resectable disease with negative margins
Metastatic NETs
  • Pancreatic NETs have highly variable growth patterns
    • Almost all of insulinomas are benign while more than half of other symptomatic pancreatic NETs and nonfunctional pancreatic NETs have hepatic metastasis
    • High 5-year survival rates are noted in patients with resected pancreatic NETs, with incomplete resections and with diffuse hepatic disease
  • Surgical resection of all visible tumor is only feasible in a few number of patients with pancreatic NETs with liver metastasis
    • Studies showed no evidence of symptom control or prolonged survival
    • Despite this, surgical resection should still be attempted because of the low efficacies of other tumor treatments
  • Hepatic arterial embolization is also recommended in patients with pancreatic NETs with hepatic metastasis who are not surgical candidates, disease limited to the liver with patent portal vein, and preserved functional status
    • Similar response rates of more than half is also observed with gastric and carcinoid tumors
    • Especially considered in patients with functional pancreatic NETs in which hormone excess state cannot be controlled by other treatment modalities
  • Radiofrequency ablation and cryoablation, with or without cytoreductive surgery, via percutaneous or laparoscopic approach are considered in selected patients with advanced pancreatic NETs
  • Hepatic resection provides long-term symptomatic relief and prolongs survival in patients with hepatic metastasis localized to one lobe
  • Orthotopic liver transplantation is only attempted in a small number of patients
    • There is a 5-year survival rate if there are poor prognostic factors such as prior extensive upper abdominal surgery, neuroendocrine primary tumor in the duodenum or pancreas, and hepatomegaly
    • There is an increased 5-year survival rate in the absence of risk factors
    • Thus, liver transplantation cannot be routinely performed in patients with liver-isolated metastatic NETs but it can be an option for some young patients without risk factors
  • Hepatic arterial embolization is recommended as a palliative option in patients with liver metastasis who cannot undergo surgical resection but have preserved performance status, disease confined to the liver with patent portal vein
    • Considered in patients with functional carcinoid tumors in which hormone excess cannot be controlled by other methods
    • Response rates are decreased hormonal secretion or radiographic regression by half
    • Techniques used are bland embolization, chemoembolization, embolization with chemotherapy beads, and embolization using radioisotopes
  • Radiofrequency ablation and cryoablation, used alone or in combination with surgical debulking, should be considered only in selected patients
    • Clinical benefit is not clearly established in patients with asymptomatic small-volume disease and may not be applicable in patients with large-volume liver metastatic disease
Functional Pancreatic NETs
  • For patients with >2 cm in size pancreatic NETs or malignant-appearing non-functional and functional pancreatic NETs, resection should include total removal of the tumor with negative margins and regional lymph nodes
  • Exploratory surgery including duodenotomy and intraoperative ultrasound with enucleation or local resection of tumors and removal of periduodenal nodes is recommended
  • Pancreatoduodenectomy is recommended for invasive/deep gastrinomas located within the head of the pancreas or proximal to the main pancreatic duct
  • Distal pancreatectomy with splenectomy with removal or regional nodes may be considered for distal tumors
  • Enucleation is the primary treatment for exophytic or peripheral insulinomas as they are primarily benign
  • Peripheral insulinomas may have an open or laparoscopic enucleation/local resection or spleen-preserving distal pancreatectomy
  • If enucleation is not possible because of deeper or invasive tumors and those in proximity to the main pancreatic duct, options include:
    • Pancreatoduodenectomy for tumors in the head of the pancreas
    • Distal pancreatectomy with preservation of the spleen for small tumors not involving the splenic vessels
  • Mostly malignant, calcified and located in the tail of the pancreas
  • Distal pancreatectomy with resection of the peripancreatic lymph nodes and splenectomy is recommended
    • Enucleation or local excision with peripancreatic lymph nodes resection may be considered for peripheral tumors <2 cm
  • Pancreatoduodenectomy with peripancreatic lymphadenectomy may be done for tumors in the head of the pancreas (rare) 
  • Perioperative anticoagulation should be considered due to increased risk of pulmonary emboli
  • Enucleation or local excision with peripancreatic lymph node dissection may be considered peripheral tumors <2 cm 
  • Distal pancreatectomy with resection of the peripancreatic lymph nodes with or without splenectomy is recommended
  • Pancreatoduodenectomy with peripancreatic lymph nodes dissection is suggested for tumors within the head
Nonfunctional Pancreatic NETs
  • Surgical resection is recommended except in:
    • Patients with other life-limiting comorbidities
    • High surgical risk
    • Widely metastatic disease
  • For non-functional tumors ≤2 cm in size, may have an open or laparoscopic enucleation/local resection with or without regional lymphadenectomy
    • Patients who have non-functional pancreatic NETs that are 1-2 cm in size with small but measurable risk to have lymph node metastases, lymph node resection is considered and serial imaging is recommended
  • For patients with >2 cm in size pancreatic NETs or malignant-appearing non-functional and functional pancreatic NETs, resection should include total removal of the tumor with negative margins and regional lymph nodes
    • If the head of the pancreas is involved, may do pancreatoduodenectomy with regional lymphadenectomy
    • If the distal part of the pancreas is involved, may do distal pancreatectomy with splenectomy and regional lymphadenectomy
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