Small Bowel Neuroendocrine Tumors (NETs)

See Small Bowel Neoplasms for the general small-bowel-tumor overview. Most content below is from a textbook reference chapter (Sabiston Ch50 - Infectious Enteritis & Small Bowel Neoplasms), not primary literature — the Medical therapy section’s four pivotal trials (PROMID, CLARINET, RADIANT-4, NETTER-1) are now independently backed by their primary publications; see those source pages for full trial-by-trial detail.

Origin and classification

Intestinal NETs arise from enterochromaffin cells (Kulchitsky cells), considered neural-crest-derived cells at the base of the crypts of Lieberkühn. First described by Lubarsch in 1888; Oberndorfer coined the term Karzinoide in 1907 to indicate the carcinoma-like appearance with presumed lack of malignant potential — however, the term “carcinoid” has become a misnomer, as all NENs have malignant potential. Most patients with small bowel NENs are in their 7th decade of life (median age at gastroenteric NET of 63 years).

NENs are divided into NETs and neuroendocrine carcinomas. NETs may be benign or well-differentiated malignant, further subdivided into three grades based on appearance, mitotic rate, behavior, and Ki-67 proliferative index: low-grade (grade 1, G1), intermediate-grade (grade 2, G2), or high-grade (grade 3, G3). Neuroendocrine carcinomas are all G3, poorly differentiated malignant tumors. The distinction between a G3 well-differentiated NET and a G3 poorly differentiated NEC can be difficult and may require additional pathologic confirmation/immunohistochemical staining.

Embryologic origin categorization: foregut (respiratory tract, thymus), midgut (jejunum, ileum, proximal duodenum), and hindgut (distal colon, rectum) NETs. Foregut NETs characteristically produce low levels of serotonin (5-hydroxytryptamine) but may secrete 5-hydroxytryptophan or adrenocorticotropic hormone. Midgut NETs are characterized by high serotonin production. Hindgut NETs rarely produce serotonin but may produce other hormones such as somatostatin and peptide YY. After the appendix, the small intestine is the second most frequently affected GI site for NETs; within the small intestine, NETs almost always occur in the last two feet of the ileum.

NETs are composed of multipotential cells able to secrete numerous humoral agents, most prominently serotonin and substance P (Table 50.9 in the source lists secretory products by category — amines, tachykinins, peptides, other). NETs have also been found to secrete corticotropin, histamine, dopamine, neurotensin, prostaglandins, kinins, gastrin, somatostatin, pancreatic polypeptide, calcitonin, and neuron-specific enolase.

Pathology

70–80% of NETs are asymptomatic and found incidentally at surgery. In the GI tract, >90% of NETs are in five typical sites: small intestine (38%), rectum (34%), colon (16%), stomach (11%), unknown sites (1%) — the recent US incidence rise is attributed to improved diagnostic detection of both rectal and gastric tumors; in Korea, the rectum is the most common NET site.

Malignant potential (metastatic ability) relates to location, size, depth of invasion, and growth pattern. Only ~3% of appendiceal NETs metastasize, but >35% of ileal NETs are associated with metastasis. Most (~75%) GI NETs are smaller than 1 cm in diameter, and about 2% of these are associated with metastasis; NETs 1–2 cm are associated with metastasis in 50%, and >2 cm in 80–90% of cases.

Grossly, these tumors are small, firm, submucosal nodules, usually yellow on the cut surface — may be subtle, seen as a small whitish plaque on the antimesenteric border of the small intestine. They are often associated with a larger mesenteric mass caused by nodal disease and desmoplastic invasion of the mesentery, often mistaken for the primary tumor. They grow very slowly, but after invasion of the serosa the intense desmoplastic reaction produces mesenteric fibrosis, intestinal kinking, and intermittent obstruction. Small bowel NETs are multicentric in 20–30% of patients — this tendency to multicentricity exceeds that of any other GI malignant neoplasm. Another unusual observation is frequent coexistence of a second primary malignant neoplasm of a different histologic type — usually a synchronous adenocarcinoma (most commonly in the large intestine), occurring in 10–20% of NET patients. Multiple endocrine neoplasia type 1 is associated with NETs in ~10% of cases.

Clinical manifestations

In the absence of carcinoid syndrome, symptoms are similar to those of other small bowel tumor histologic types — most common is abdominal pain, variably associated with partial/complete small bowel obstruction. Obstructive symptoms can be caused by intussusception but usually occur secondary to a local desmoplastic reaction, apparently produced by humoral agents from the tumor. Diarrhea and weight loss may also occur — diarrhea in this setting is a result of partial bowel obstruction rather than the secretory diarrhea seen with malignant carcinoid syndrome.

Malignant carcinoid syndrome

A relatively rare syndrome, occurring in <10% of patients with NETs. Usually associated with GI NETs, particularly from the small bowel, but NETs at other sites (bronchus, pancreas, ovary, testes) have also been described in association. Because of first-pass hepatic metabolism of the vasoactive peptides responsible, hepatic metastasis or extraabdominal disease is necessary to elicit the syndrome (tumors that bypass the liver — ovarian and retroperitoneal NETs — may produce the syndrome without liver metastasis). Classic description: vasomotor, cardiac, and GI manifestations. Humoral factors implicated include serotonin, 5-hydroxytryptophan, histamine, dopamine, tachykinin, kallikrein, substance P, prostaglandin, and neuropeptide K. Most patients with carcinoid syndrome have massive hepatic replacement by metastatic disease.

Common symptoms/signs: cutaneous flushing (80%), diarrhea (76%), hepatomegaly (71%), cardiac lesions (most commonly right-sided heart valvular disease, 41–70%), and asthma (25%). Cutaneous flushing has four varieties: (1) diffuse erythematous — short-lived, face/neck/upper chest; (2) violaceous — similar but longer, may become permanent cyanotic flush with watery eyes/conjunctivitis; (3) prolonged flushes — up to 2–3 days, may involve the entire body with lacrimation, hypotension, facial edema; (4) bright-red patchy flushing — typically seen with gastric NETs. Diarrhea is episodic (usually postprandial), watery, often explosive, thought caused by increased circulating serotonin (the serotonin antagonist methysergide effectively controls the symptom). Cardiac lesions usually involve the right heart, but left-sided lesions occur in 15% of symptomatic patients and can lead to symptomatic left-sided heart failure; the three most common cardiac lesions are pulmonary stenosis (90%), tricuspid insufficiency (47%), and tricuspid stenosis (42%). Asthmatic attacks occur during flushing episodes, with serotonin/bradykinin implicated. Malabsorption and pellagra (dementia, dermatitis, diarrhea) occasionally present, thought caused by excessive dietary tryptophan diversion.

Diagnosis

Elevation of various humoral factors forms the basis for diagnostic tests. Serotonin is metabolized in the liver/lung to the pharmacologically inactive 5-hydroxyindoleacetic acid (5-HIAA); elevated 24-hour urinary 5-HIAA (measured by HPLC) is highly specific although not sensitive. Chromogranin A (CgA) has been a well-established marker for carcinoid disease for the last decade — elevated in

80% of NET patients, specificity 95%, but sensitivity only ~55% (some investigators suggest combining with other tests). Serum CgA + 24-hour urine 5-HIAA is an acceptable diagnostic combination with increased sensitivity. Serum CgA + N-terminal pro-brain natriuretic peptide may also be combined for diagnosis and surveillance — increased levels of both are associated with worse overall survival than elevated CgA alone. CgA levels have proven efficacy over urine 5-HIAA for surveillance after resection or as a prognostic marker. Plasma serotonin, substance P, neurotensin, neurokinin A, and neuropeptide K can be measured but are not elevated in all patients. Provocative tests using pentagastrin, calcium, or epinephrine can reproduce NET symptoms; pentagastrin can differentiate NETs from chronic atrophic gastritis but is generally not used for NET diagnosis given the diagnostic reliability of 5-HIAA, CgA, and N-terminal pro-brain natriuretic peptide.

Small bowel NETs are rarely diagnosed preoperatively. Barium studies may show multiple filling defects from bowel kinking/fibrosis (Fig. 50.31). A combination of anatomic and functional imaging is routinely performed to optimize sensitivity/specificity.

• CT was traditionally the imaging modality of choice for identifying disease site and lymphatic/ hematogenous metastasis presence — findings depend on size, degree of mesenteric invasion/ desmoplastic reaction, and regional lymph node invasion; if these entities are not well defined, CT has limited diagnostic capability. A solid mass with spiculated borders and radiating surrounding strands associated with linear strands in the mesenteric fat and bowel kinking allows a fairly confident diagnosis. CT angiography may help identify encasement/pseudoaneurysm formation typical of a malignant mesenteric process.
• MRI is not generally used for GI NETs but helpful for metastatic disease, especially hepatic — liver metastases have low T1 signal, high T2 signal, peripherally enhance in the hepatic arterial phase after gadolinium, and appear as hypointense defects in the portal venous phase. Diffusion-weighted MRI and dynamic contrast-enhanced techniques are promising but not yet validated for monitoring therapy.
• Octreotide scintigraphy: octreotide is a synthetic somatostatin analogue; indium (111In)-labeled pentetreotide specifically binds somatostatin receptor subtypes 2 and 5. Functional nuclear imaging capitalizes on somatostatin receptor positivity; higher sensitivity than CT for delineation/localization, particularly useful for extraabdominal metastatic disease or when the primary tumor cannot be identified by CT.
• 18F-FDG PET: limited capability because FDG is taken up only in high-grade NETs (high Ki-67), whereas most NETs have low Ki-67 and are not well seen by this modality.
• 68Ga-DOTATATE PET/CT: increasingly used for preoperative staging — DOTATATE binds somatostatin receptors, directing radioactivity into the tumor; clinically useful for localizing primary tumors of unknown origin in NET-metastasis patients and for defining metastatic extent. Combining 68Ga-DOTATATE with 18FDG PET/CT may be even more helpful. In a study of 27 NET patients, sensitivity of 68Ga-DOTATATE vs. 18FDG PET/CT was 95% vs. 37% overall; for liver, lymph node, bone metastases and primary lesion, 95%/95%/90%/93% vs. 40%/28%/28%/75% respectively. 64Cu-DOTATATE is a newer, FDA-approved radionuclide with better true positive lesion detection, longer shelf life, and wider scanning window than 68Ga-DOTATATE. Lutetium-177 (177Lu) peptide receptor radionuclide therapy is both diagnostic and therapeutic (theranostic), developed for compounds with high affinity for somatostatin receptors 2, 3, and 5.

Since resection is the only curative treatment, accurate preoperative imaging is critical to surgical management.

Treatment

Surgical therapy

Based on tumor size, location, and presence of metastatic disease. Primary tumors <1 cm without regional lymph node metastasis: segmental intestinal resection is adequate. Tumors >1 cm, with multiple tumors, or with regional lymph node metastasis regardless of primary size: wide excision of bowel and mesentery required. Terminal ileum lesions are best treated by right hemicolectomy. Small duodenal tumors can be excised locally; more extensive lesions may require pancreaticoduodenectomy. A single-center prospective longitudinal study showed a laparoscopic approach is safe and feasible in selected patients, with similar R0 resection rates but shorter hospital stay vs. laparotomy; progression-free survival at 1/3/5 years was 95%/83%/75% for R0 patients without liver metastasis, 92%/83%/57% for R0 patients with resected liver metastasis, and 82%/58%/30% for R2 resection (residual tumor on visual examination). Overall/progression-free survival did not differ significantly between laparoscopic and open groups.

Caution should be exercised in anesthetic management of NET patients — anesthesia may precipitate a carcinoid crisis (hypotension, bronchospasm, flushing, tachyarrhythmias). Carcinoid crisis is treated with IV octreotide (bolus 50–100 μg, may continue as infusion at 50 μg/hr).

The abdomen should be thoroughly explored for multicentric lesions in addition to treating the primary tumor. A large desmoplastic reaction causing mesenteric shortening/folding/pleating results in intestinal angina and obstruction. If the mesenteric disease appears to involve a large portion of the mesentery, dissection of the tumor off the mesenteric vessels with preservation of blood supply to unaffected bowel is appropriate, albeit technically demanding; extensive small bowel mesentery mobilization is often required for a difficult resection. Removal of the mesenteric disease provides a survival advantage, and mesenteric debulking ensures the most durable palliation. Aggressive surgical resection/debulking achieves relief of obstruction in 93% and mesenteric vessel encasement in 83% of cases.

In patients with widespread metastatic NET disease, surgery may still be indicated — surgical debulking often provides beneficial symptomatic relief. In limited hepatic involvement, metastasectomy provides the most durable survival benefit vs. other treatment modalities; an option so long as there are no extrahepatic metastases, liver function is not compromised, and there is no diffuse bilobar involvement. Unfortunately, most patients are not liver-resection candidates because of extensive disease at diagnosis; even with resection there is still a high recurrence rate (75%). In these cases, transarterial chemoembolization or radioembolization provide liver-directed disease control. Resection of the primary tumor, with or without mesenteric resection, has been shown to improve survival/slow progression of hepatic metastases in patients with unresectable disease. Hepatic transplantation for extensive liver metastases has been evaluated in small studies but with unacceptably high recurrence rates limiting this approach. Given treatment complexity, all surgical resections should be performed at a high volume center.

Medical therapy

Primarily directed toward relief of symptoms from excess humoral factor production (Table 50.10 in the source summarizes NET medical therapies by category — approved, off-label, investigational). Somatostatin analogs (SSAs) are standard of care for controlling functional NET symptoms, controlling symptoms in >70% of carcinoid syndrome patients. Octreotide (Sandostatin) and lanreotide (Somatuline), including depot formulations (Sandostatin LAR, Somatuline depot), relieve carcinoid symptoms (diarrhea, flushing, antisecretory effect) in most patients and delay cancer progression (antiproliferative effect) — demonstrated in two randomized phase 3 trials, both now independently ingested. Rinke 2009 - PROMID Trial (85 treatment-naive patients with midgut NETs, near- exclusively Ki-67 ≤2%) found octreotide LAR significantly delayed tumor progression vs. placebo (median time to progression 14.3 vs 6.0 months; HR 0.34) and identified low hepatic tumor burden and a resected primary as predictors of the strongest antiproliferative response; the overall-survival analysis was underpowered and explicitly not confirmatory (only 16 deaths at the planned interim analysis). Caplin 2014 - CLARINET Trial (204 patients, broader enteropancreatic population, Ki-67 up to 10%, mostly stable disease at baseline) found lanreotide associated with significantly prolonged progression-free survival vs. placebo (median not reached vs 18.0 months; HR 0.47), with no significant OS or quality-of-life difference (confounded by placebo-to-lanreotide crossover). No guideline currently exists for choosing octreotide LAR vs. lanreotide as first-line therapy — the two trials studied somewhat different populations (PROMID: midgut-only, near-exclusively grade 1; CLARINET: broader enteropancreatic, grade 1-2) rather than head-to-head. Asymptomatic patients with low-volume/ unresectable disease require an individualized decision between observation (with close imaging monitoring every 3–6 months) or SSA initiation.

For SSA-refractory disease progression, emerging options: everolimus (mTOR inhibitor, initially developed as immunosuppressant therapy) approved for unresectable/locally advanced/metastatic nonfunctional GI NETs — Yao 2016 - RADIANT-4 Trial (302 patients with advanced non-functional lung/GI NETs, excluding pancreatic and carcinoid-syndrome tumors) showed median progression-free survival improved from 3.9 to 11.0 months with everolimus vs. placebo (HR 0.48), though significant tumor reduction is rarely obtained (objective response only 2%; benefit mainly from disease stabilization) and an interim overall-survival analysis (HR 0.64) did not reach statistical significance; targeting multiple signaling pathways may provide better tumor control than single-pathway targeting. Peptide receptor radionuclides: Strosberg 2017 - NETTER-1 Trial (229 patients with SSA-progressive midgut NETs, a second-line population) demonstrated a 79% lower risk of progression or death with 177Lu-Dotatate vs. high-dose octreotide (HR 0.21; median PFS not reached vs. 8.4 months), with an interim overall-survival signal (HR 0.40) that had not yet crossed the trial’s statistical-significance boundary at time of publication. Interferon alpha — used since 1983, elicits cell cycle inhibition at G1/S, antiangiogenesis via VEGF downregulation, and somatostatin receptor upregulation; tumor regression in ~10%, stabilization in 65%, but chronic fatigue, pancytopenia, thyroiditis, and lupus erythematosus side effects have led to it falling out of use; pegylated interferon alpha-2b has comparable efficacy with more tolerable side effects; combination with SSAs may be efficacious given upregulated somatostatin receptors, though trial results are mixed. For SSA-resistant carcinoid diarrhea: increasing SSA dose or adding short-acting antidiarrheals; telotristat etiprate (serotonin synthesis inhibitor) is indicated for SSA-refractory carcinoid syndrome diarrhea — the TELESTAR trial showed reduced daily bowel movements by 35%. Serotonin receptor antagonists used with limited success (methysergide no longer used due to retroperitoneal fibrosis risk; ketanserin/cyproheptadine provide some symptom control; ondansetron also has a role.

Historically, cytotoxic chemotherapy (streptozotocin, 5-FU, cyclophosphamide combinations) was the only available treatment for metastatic NETs, with median survival ~2 years; currently chemotherapy’s role is confined predominantly to G2 metastatic disease that is symptomatic, unresponsive to other therapies, or has high tumor proliferation rates. Temozolomide as monotherapy has acceptable toxicity and antitumoral effects; in combination with capecitabine, shown to prolong survival in well-differentiated metastatic NETs progressing on prior therapies. Cisplatin/etoposide shown some promise but only in poorly differentiated neuroendocrine carcinomas. Treatment of metastatic NENs requires a multidisciplinary approach; combined modalities (surgical debulking, hepatic artery embolization, chemoembolization/radioembolization, medical therapy) may be best. Sunitinib (a multitargeted/selective tyrosine kinase inhibitor active against PDGFR-α/β and VEGFR) decreases angiogenesis and prolongs progression-free survival in pancreatic NETs in multiple trials, most notably those with exon 9/11 mutations.

Prognosis

NETs have the best prognosis of all small bowel tumors, localized or metastatic. Resection of a NET localized to its primary site approaches 100% survival. Five-year survival rates are ~65% with regional disease, 25–35% with distant metastases. Metastatic disease at diagnosis is present in 20–50% of patients, and tumors recur in 40–60%. When widespread metastatic disease precludes cure, extensive resection for palliation may be indicated — long-term palliation can be obtained because these tumors are relatively slow growing. An elevated level of CgA, an independent predictor of adverse prognosis, is probably the most useful factor identified before surgery.

Open items / gaps

• PROMID, CLARINET, RADIANT-4, and NETTER-1 are now independently backed by their primary publications (see Medical therapy section and their source pages). TELESTAR is still not independently ingested — the telotristat-etiprate figure above (35% reduction in daily bowel movements) remains sourced only from the textbook’s narrative summary.
• Theranostic use of 177Lu (diagnostic + therapeutic PRRT) is flagged as an emerging approach but not developed in depth here.
• NETTER-1’s reported overall-survival benefit (interim HR 0.40) and RADIANT-4’s (interim HR 0.64) were both non-mature/non-confirmatory interim analyses at time of publication — if either trial’s final OS analysis is ever ingested, this page’s framing should be revisited.