Pocket Oncology (Pocket Notebook Series), 1st Ed.


Jean K. Lee and Diane Reidy-Lagunes


• Prevalence of neuroendocrine tumors (NETs) in US may exceed 100000 (likely 2° to ↑ imaging & endoscopy surveillance)

• pNETs are 1% of pancreatic CA by incidence; 10% of pancreatic CA by prevalence

• Peak incidence of pNET between ages 40–69


• NETs: Heterogeneous group of neoplasms composed of pancreatic neuroendocrine tumors (pNETs) & carcinoid tumors. Carcinoid tumors arise from enterochromaffin cells generally of the GI & pulm tract but can also arise in the GU & GYN systems. Tx is dependent on the site of origin

• Approximately 2/3 of carcinoid tumors arise from the GI system (sites of origin include stomach, small intestine, appendix, rectum)

• The WHO classification system distinguishes well-differentiated & poorly differentiated neoplasm to prognostically stratify NETs. These are further classified by the TNM grading system by the ENETS

• NET pathology is defined by cell differentiation (ie, cell morphology) & grading (divided into low, intermediate, & high grades & based on proliferative activity of the tumor, measured by Ki-67 index and/or mitoses)

Risk Factors and Genetics

• Majority of NETs are sporadic; RFs are poorly understood

• Rarely a/w MEN type 1 (autosomal dominant), w/Mts in the tumor suppressor gene MEN1 that encodes protein menin, (tumors involving the pancreas, pituitary, & parathyroid glands), MEN type 2, (Mts in RET proto-oncogene w/medullary thyroid CA, pheochromocytoma, & hyperparathyroidism (HPT))

• Cases also a/w VHL disease, tuberous sclerosis complex, neurofibromatosis; Rare pancreatic CAs as part of Lynch Syndrome (LS) also seen

Clinical Presentation

• Frequently asx (ie, nonfunctional tumors); sx usu. related to hormonal hypersecretion (ie, functional): Intermittent flushing, diarrhea, rarely tricuspid regurg/pulm stenosis in pts w/carcinoid syn, & sx related to secretion of insulin, glucagon, gastrin, & other peptides in pts w/pNETs

Diagnostic Evaluation

• Multi-phasic CT & MRI recommended to assess extent of disease & possible 1° location

• Octreotide scan (radiolabeled somatostatin analog [111In-DTPA]-octreotide may also be used given majority of carcinoid tumors express receptors for somatostatin; octreoscan positive tumors have better prognosis

• Other imaging studies: EUS or EGD used for suspected duodenal & gastric NETs & pNETs; proctoscopic examination for rectal carcinoids; Bronchoscopy as needed for thymic & bronchopulm carcinoids

• Lab work: R/o MEN1 syn in pts w/suspected FHx. Serum chromogranin A (may be spuriously elevated in pt using PPIs, renal or liver failure) may be a useful biomarker; hormone markers based on clinical sx (ie, 24-h 5-HIAA if suspected carcinoid syn)

Management: Locoregional Disease

• Depends on location of 1° site & tumor size; Surgery is mainstay tx for resectable tumors for healthy pts

Management: Unresectable Locoregional Disease or Metastatic Disease

• Many pts can often be followed w/o intervention for long periods of time given slow-growing nature of many carcinoid tumors; therefore pts should be monitored closely to determine rate of disease growth & active surveillanceapproach should be considered

• Octreotide & analogue Rx: Used to control sx in hormonally active NETs. Analogs have tumorstatic rather than tumoricidal effect. Use of monthly octreotide LAR a/w delay in tumor progression (14.3 vs. 6 mos) in small bowel NETs (NEJM 1986;315:663; PROMID study, J Clin Oncol 2009;27:4656)

• Use of interferon for tx of differentiated carcinoid tumors under debate given significant toxicities

• Debulking cytoreductive surgery should be considered in some cases for palliative purposes to ↓ hormone-producing tissue & sx

• Systemic chemotherapy: Consider in pt w/heavy tumor burden. Traditional cytotoxic chemotherapeutic regimens for carcinoid tumors are ineffective. In pNET cases, can consider streptozotocin plus doxorubicin (RR 69%, OS 2.2 y; NEJM 1992;326:519) or temozolomide-based therapies (Strosberg, Cancer 2011;117(2):268)

• Biologically targeted therapies: VEGF inhibitors (sunitinib) & mTOR inhibitors shown to have efficacy in pNETs & FDA-approved for pNETs in 2011. Phase III study w/mTOR inhibitor everolimus showed improved median PFS (4.6 mos to 11 mos, HR 0.35) compared to placebo (NEJM 2011;364:514) Placebo-controlled phase III trial of sunitinib vs. best supportive care in adv pNET pts showed ↑ PFS (5.5 mos to 11.4 mos, HR 0.42) (NEJM 2011;364:501)

• Liver-directed therapies: Hepatic artery (bland or chemo) embolization or high-frequency radioablation commonly used. Useful for reducing sx of the tumor-associated hormone production & w/prolonged tumor regression

• Radiolabeled octreotide Rx (PRRT): Currently ongoing studies show potential benefits but not approved by FDA at this time