Neuroendocrine tumors (NETs)

Overview

• Definition: neuroendocrine neoplasms, a heterogeneous group arising from enterochromaffin/neuroendocrine cells. Broadly divided into pancreatic and nonpancreatic (GI, lung) NETs.
• Epidemiology: gastroenteropancreatic (GEP) NET incidence ~3.56/100,000 in the US and rising over >40 years (broader NET incidence often cited ~7/100,000). Sites: lung (most common single site overall), small bowel and rectum (most common GEP sites), pancreas, appendix. 5-yr survival for metastatic grade 1/2 GEP NET ranges from ~28% (rectal) to ~69% (small intestine).
• Functionality: most NETs are nonfunctional (about 60 to 90% of pNETs); patients are often asymptomatic and found incidentally on imaging.

Grading and classification (WHO 2019 / 2017)

• IHC: chromogranin A, synaptophysin, INSM1, CD56. Site-specific markers (TTF-1 for lung, CDX-2 for GI). Staging follows general TNM/AJCC principles, slightly different by site.
• Hereditary syndromes (most pNETs are sporadic, but associations exist):
  • MEN1: pancreatic NETs + parathyroid + pituitary (3 P's).
  • MEN2: medullary thyroid + pheo + parathyroid (2A) or marfanoid + mucosal neuromas (2B). RET-mutated.
  • VHL: pNETs + RCC + pheo + hemangioblastomas.
  • NF1: duodenal somatostatinoma, pheochromocytoma.
  • Tuberous sclerosis (TSC1/2): pNETs.

Functional syndromes

• Carcinoid syndrome (small bowel NET with liver mets, from serotonin/vasoactive substances that bypass hepatic clearance):
  • Symptoms: flushing, diarrhea, bronchospasm, right-sided heart valve fibrosis. TIPS = Tricuspid Insufficiency, Pulmonic Stenosis (carcinoid heart disease).
  • Diagnosis: 24-hr urinary 5-HIAA (serotonin metabolite); avoid serotonin-rich foods for ~3 days before and throughout the 24-hr collection (per lab instructions).
  • Carcinoid crisis: perioperative; pretreat with octreotide.
• Insulinoma (pNET): hypoglycemia + Whipple triad. Tx: surgery; diazoxide for symptoms; everolimus.
• Gastrinoma (pNET, duodenal): Zollinger-Ellison (recurrent peptic ulcers, diarrhea). Often MEN1-associated. Tx: PPI + surgery.
• Glucagonoma: necrolytic migratory erythema, diabetes, weight loss, DVT.
• VIPoma: WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria).
• Somatostatinoma: diabetes + steatorrhea + cholelithiasis. Often duodenal in NF1.

• Carcinoid heart disease occurs in ~20 to 50% of carcinoid syndrome patients, predominantly tricuspid regurgitation; overt right heart failure develops in a subset and valve disease can be initially asymptomatic. Markedly elevated 5-HIAA predicts carcinoid heart disease.
• Severe right-sided heart failure adds major operative risk (elevated central venous pressure → catastrophic bleeding during liver resection). Pursue thorough cardiac workup and correct valvular disease FIRST, with interval liver resection afterward.
• Valve surgery is indicated for progressive right-sided failure with moderate-to-severe right-valve insufficiency on echo. Continue a somatostatin analog for tumor control while managing the heart disease; right colectomy does not help carcinoid heart disease.

Workup & staging

• Functional (SSTR) imaging: Ga-68 (or Cu-64) DOTATATE PET is preferred; has largely replaced In-111 OctreoScan (somatostatin-receptor scintigraphy) for better sensitivity/specificity.
• Anatomic imaging: CT with arterial-phase liver, or MRI with gadoxetate disodium (preferred). If primary not identified, use upper/lower endoscopy, pancreatic EUS, and/or CT/MRI enterography.
• FDG-PET for high-grade or NEC (lower SSTR expression).
• Markers: serum chromogranin A (limited specificity), 24-hr urine 5-HIAA for carcinoid; for pNETs, hormone-specific markers (insulin, gastrin, VIP, glucagon) as clinically indicated.
• Pathology: reviewed by expert pathologists; report Ki-67 (preferred) and/or mitotic rate.
• Echocardiogram if carcinoid syndrome.

Treatment

• Surgery is the main treatment for nonmetastatic tumors; there is NO role for adjuvant therapy after complete resection.
• Appendiceal NET <2 cm: appendectomy curative. Rectal NET <1 cm: polypectomy curative.
• In advanced disease, cytoreductive (debulking) surgery is palliative/controversial; may help refractory hormone-producing tumors and bowel obstruction/mesenteric fibrosis. Upfront resection of primary and liver metastases (e.g. metastatic disease confined to one lobe/segment) can give durable control (reported 5-yr OS ~40 to 100%).
• Liver-directed therapy: bland embolization, TACE, Y-90 radioembolization, RFA, or surgical debulking for liver-predominant disease; useful for symptom/hormone control and as nonsurgical debulking, with prolonged tumor regression in some.

• SSAs are a usual first-line option for indolent, SSTR-positive G1/G2 NETs (and hormone control); rapidly progressive, bulky, or well-differentiated G3 disease may need PRRT (NETTER-2) or chemotherapy first (and control hormone-related symptoms). Tumor response rates are low; benefit is disease stabilization. In asymptomatic, low-burden metastatic disease, watch-and-wait is appropriate (note the excellent 18-mo placebo PFS in CLARINET).
• Octreotide LAR (PROMID, midgut NET, n=85): 30 mg IM monthly vs placebo. median TTP 14.3 vs 6.0 mo (HR 0.34); SD at 6 mo 66.7% vs 37.2%; OS HR 0.81 (NS).
• Lanreotide (CLARINET, GEP-NET, Ki-67 <10%, n=204): mPFS not reached vs 18 mo (HR 0.47); 2-yr PFS 65.1% vs 33.0%. FDA Dec 2014. AEs: diarrhea, abdominal pain, cholelithiasis.
• Refractory carcinoid syndrome diarrhea: increase octreotide dose (to 60 mg) or frequency (q3 wk), add short-acting octreotide (100 to 500 mcg q8h), or add telotristat ethyl (tryptophan hydroxylase inhibitor). Telotristat (250 mg PO TID added to an SSA) reduced bowel movements by ≥30% (durable response) in 44% vs placebo 20%; supported for diarrhea, flushing reduction was not statistically significant (Kulke JCO 2017).

• NETTER-1 (progressive SSTR+ midgut NET after octreotide LAR, n=230): 177Lu-DOTATATE q8wk × 4 + octreotide 30 mg vs octreotide 60 mg. mPFS not reached (updated 28.4 mo) vs 8.4 mo (HR 0.21); ORR 18% vs 3%; mOS 48 vs 36.3 mo (HR 0.84, NS, ~36% crossover). FDA Jan 2018.
• NETTER-2 (high-grade 2 / G3 GEP-NET, 1L vs octreotide HD): mPFS 22.8 vs 8.5 mo (HR 0.276). Supports 1L use (NCCN); the existing Lutathera label (SSTR+ GEP-NET, no line restriction) covers it, and the Apr 2024 FDA action extended use to children ≥12 yr.
• Eligibility: SSTR+ on Ga-68 DOTATATE PET.
• Administration: 7.4 GBq (200 mCi) IV over 30 min q8wk × 4. IV amino-acid solution is given for renal protection 30 min before, during, and 3 hr after each infusion; these amino-acid solutions are emetogenic (main cause of NETTER-1 nausea), so give a 5-HT3 antagonist. Hold long-acting SSAs 4 to 6 wk before each infusion; resume 4 to 24 hr after.
• Toxicity: myelosuppression (mostly mild thrombocytopenia ~25%, lymphopenia ~18%, anemia ~14%, leukopenia ~10%; nadir 4 to 6 wk, resolves by ~8 wk), irreversible myelotoxicity, MDS 2 to 3%, acute leukemia ~0.5%, hepatic toxicity, infertility, carcinoid crisis, nausea/vomiting, embryo-fetal toxicity.

• Everolimus (mTOR inhibitor): RADIANT-3 (pNET): mPFS 11.0 vs 4.6 mo (HR 0.35); OS 44.0 vs 37.7 mo (NS). FDA 2011. RADIANT-4 (nonfunctional GI/lung NET): mPFS 11.0 vs 3.9 mo (HR ~0.48; OS HR 0.73 NS). FDA Feb 2016. (RADIANT-2, everolimus + octreotide in carcinoid syndrome: only borderline PFS benefit.)
• Sunitinib (advanced pNET only, n=171, progression within 12 mo): 37.5 mg/day vs BSC/placebo. mPFS 11.4 vs 5.5 mo (HR 0.42); mOS 38.6 vs 29.1 mo (NS). FDA 2011.
• Cabozantinib (CABINET, Chan NEJM 2025, previously treated advanced well-diff NET): pNET mPFS 13.8 vs 4.4 mo (HR 0.23); extra-pancreatic (epNET) 8.4 vs 3.9 mo (HR 0.38). FDA Mar 26, 2025 for adults and children ≥12 with previously treated unresectable/metastatic well-diff pNET and epNET. NCCN Cat 1/2A preferred.
• Surufatinib (China): SANET-p (pNET) mPFS 10.9 vs 3.7 mo (HR 0.49); SANET-ep (extrapancreatic) 9.2 vs 3.8 mo (HR 0.33).
• Belzutifan (Welireg), HIF-2α inhibitor: LITESPARK-004 (Jonasch NEJM 2021, PMID 34818478) in VHL-associated tumors, VHL-pNET cohort ORR 91% (n=22). FDA Aug 13, 2021 for adult VHL patients with RCC, CNS hemangioblastoma, or pNET not requiring immediate surgery. Toxicity: anemia (~90%), hypoxia (monitor SpO2 and Hgb). Not for sporadic (non-VHL) pNET.
• Chemotherapy: pNETs are more chemo-sensitive than other GEP NETs (respond to alkylators: streptozocin, dacarbazine, temozolomide). CAPTEM (capecitabine + temozolomide; ECOG-ACRIN E2211, pNET, n=144): mPFS 22.7 vs 14.4 mo (HR 0.58) and ORR 39.7% vs 33.8% with temozolomide alone (not significant); PFS was the positive endpoint: good option when radiographic response is needed. Well-differentiated G1/G2 midgut NETs have low chemo response, so cytotoxics are not routinely favored; high-grade/G3 and NEC respond to platinum-etoposide, and selected progressive G3 tumors may respond to CAPTEM or oxaliplatin-based regimens.
• Poorly differentiated NEC: treat like small-cell lung cancer with platinum + etoposide; interest in adding immunotherapy.
• Sequencing: after SSA failure in nonpancreatic GI NET, choose everolimus or 177Lu-DOTATATE (many favor PRRT for its long PFS; phase III COMPETE showed 177Lu-edotreotide > everolimus PFS, but head-to-head 177Lu-DOTATATE vs everolimus level-I data are still lacking and sequencing is unsettled); optimal sequence of everolimus, sunitinib, cabozantinib, PRRT, and CAPTEM in pNET is not established: shared decision-making by toxicity and response needs.

*Bevacizumab patients also received octreotide.

Site-specific management summary

• Pancreatic NET (pNET): most chemo-sensitive; options after SSAs include everolimus, sunitinib, cabozantinib (CABINET), CAPTEM (for response), PRRT, and surufatinib (China). Belzutifan for VHL-associated pNET.
• Nonpancreatic GI (midgut/carcinoid) NET: SSAs 1L (PROMID/CLARINET); after progression, everolimus (RADIANT-4) or PRRT (NETTER-1). Not responsive to cytotoxic chemo. Cabozantinib now approved for epNET.
• Lung NET: everolimus (RADIANT-4, lung/GI). PRRT for SSTR+ disease.
• Any high-grade NEC (poorly diff): platinum + etoposide (SCLC-like).

Pheochromocytoma / paraganglioma (PPGL)

• Catecholamine secretion: episodic HTN, headaches, palpitations, sweating.
• Diagnosis: plasma free metanephrines or 24-hr urine fractionated metanephrines.
• Imaging: MRI/CT, then MIBG scan or Ga-68 DOTATATE PET.
• Genetic testing for ALL: RET, VHL, NF1, SDHx (B/C/D), TMEM127, MAX, FH. ~40% have a germline mutation.
• Pre-op management: α-blockade (phenoxybenzamine) for ~7 to 14 days before surgery; add a β-blocker for tachycardia only after adequate α-blockade (never before).
• Surgery: minimally invasive adrenalectomy for localized noninvasive adrenal pheo (open for large/invasive tumors); paragangliomas need site-specific resection. All PPGLs have metastatic potential (no benign/malignant split).
• Metastatic: no curative tx. Belzutifan (HIF-2α inhibitor; FDA May 2025 for unresectable/metastatic PPGL, adults and children ≥12; LITESPARK-015 ORR 26%, mDOR 20.4 mo). Sunitinib, cabozantinib, lutetium-177 DOTATATE, MIBG-131 (iobenguane I-131; Azedra, FDA 2018; since discontinued, no longer available in the US), CVD chemo.

High-yield NET pearls

• Grade by Ki-67 (G1 <3%, G2 3 to 20%, G3 >20%); well-diff G3 is treated more like NET, poorly-diff NEC like SCLC.
• Ga-68 DOTATATE PET is the imaging of choice for SSTR+ NETs; FDG-PET for high-grade/NEC.
• SSAs (octreotide, lanreotide) = 1L for advanced well-diff NET (PROMID, CLARINET); watch-and-wait if asymptomatic/low-burden.
• Telotristat ethyl for SSA-refractory carcinoid diarrhea.
• 177Lu-DOTATATE (NETTER-1; NETTER-2 expanded to 1L high-grade 2/G3). Hold SSA 4 to 6 wk before; amino acids for nephroprotection; watch MDS/AML.
• Everolimus (RADIANT-3 pNET, FDA 2011; RADIANT-4 GI/lung, FDA 2016); sunitinib (pNET only, FDA 2011). Cabozantinib (CABINET, FDA Mar 2025) for previously treated pNET + epNET.
• CAPTEM (E2211) for pNET when response is needed; nonpancreatic GI NET not chemo-responsive.
• Carcinoid heart disease: right-sided fibrosis (TIPS); treat valve disease before major liver surgery.
• 5-HIAA is the urine biomarker for serotonin/carcinoid; markedly elevated predicts heart disease.
• Pheo: α-block FIRST, then β-block; ~40% germline.
• Whipple triad for insulinoma. NEC (poorly diff) → platinum + etoposide.