Pancreatic Neuroendocrine Tumours

Name: Pancreatic Neuroendocrine Tumours: Mini Review for Clinicians, Algorithms & Cases
Creator: Dr. Haritha Chiramana
License: https://creativecommons.org/licenses/by-nc-nd/4.0/

Upper GI & Pancreas, part 2 · Well-differentiated NETs G1–G3 · Functioning syndromes · MEN1 and VHL · Surveillance or surgery · SSA, PRRT, CAPTEM and targeted drugs · Neuroendocrine carcinoma · Key points for clinicians · Last updated 16 October 2026

For health professionals. This section uses clinical terms and is general education for doctors, nurses and students, not advice for an individual patient. Patients and families: please read our patient guides instead, Cancer Myth Busters · Understanding your cancer report · Living through cancer treatment, or speak with your own doctor.

Who this page is for, and where to start

Printable PDFs for this moduleMini reviews, slides, algorithms, quick references and the MCQ booklet are on the Printable Teaching Resources page. No PDF downloads are kept on this page.

Printable Teaching Resources →

For your patientsPlain-language Telugu–English answers for patients and families: the Pancreatic cancer Myth Busters (20 myths), symptoms and warning signs and the Telugu handouts.

Open the pancreatic cancer myths →

SurgeonsScreening and workup (03), local therapy with surgery types (05), algorithms (07), cases (11)

Physicians & oncologistsBiomarkers (04), systemic therapy (06), algorithms (07), survivorship (08), cases (11)

Postgraduate residentsOncology and other specialities: case vignettes (11), landmark trials (09) and 0 cited trials (12) for exams and journal clubs

Medical studentsAt a glance (01), presentation and common traps (02), the figures, and follow-up (08)

Prepared and reviewed by Dr. Haritha Chiramana, MD, DM, Senior Medical Oncologist & Hemato-Oncologist, C.R. Reddy Cancer Center, Nellore, Andhra Pradesh, India. She teaches oncology to postgraduates and medical students; colleges and departments may write to info@drharitha.co.in for teaching sessions. Printable Teaching Resources and how to cite → Phone 0861 232 5344 · WhatsApp +91 79896 42272.

01 At a glance

Pancreatic neuroendocrine tumours (PanNETs) arise from islet cells. They are rare (about 1.3 per 100,000 people a year, 1–2% of pancreatic tumours) but rising, mostly because scans done for other reasons now find small ones. Most present in the fourth to sixth decades.
Two questions decide almost everything: is the tumour well differentiated (NET G1, G2 or G3) or poorly differentiated (NEC), and what is its grade by Ki-67 (WHO 2022^[1])? A NET and an NEC of the pancreas are different diseases with different staging, treatment and outlook.
50–85% are non-functioning and present as an incidental mass or with symptoms of size. The rest cause a hormone syndrome (insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma) that must be controlled before and during tumour treatment.
Outlook is usually measured in years: even with distant spread, median survival for G1–G2 pancreatic NETs was about 50 months in US registry data (Dasari 2017^[2]), against about 11 months for metastatic NEC (NORDIC NEC^[3]).
Not every tumour needs an operation: most sporadic, asymptomatic non-functioning tumours of 2 cm or less can be watched (ASPEN^[4]); larger, functioning or higher-grade tumours are resected.
Think inherited: MEN1, VHL, NF1 and tuberous sclerosis account for a minority of cases but change thresholds for surgery and require family testing.
India: Ga-68 DOTA PET and Lu-177 PRRT are available in larger Indian centres; India has produced Lu-177 and given PRRT since about 2008, which keeps this treatment more affordable than in many countries (IJMPO 2019^[5]; AJNMMI 2020^[6]).

Figure 1. Pancreatic neuroendocrine neoplasms at a glance. Well-differentiated tumours (NET G1–G3) and poorly differentiated carcinomas (NEC) share a name but not a biology, a staging system or a treatment (WHO 2022; incidence from US registry data).

02 Clinical presentation, common traps & causes

How pancreatic NETs come to attention

Type	How often (new cases per million a year)	Typical story	Spread at diagnosis
Non-functioning	Most PanNETs (50–85%)	Incidental on CT, MRI or endoscopic ultrasound; or pain, weight loss, jaundice, a palpable mass, or liver metastases with an unknown primary	Depends on size and grade; many small ones never spread
Insulinoma	1–3 (about 4 per million in the Mayo series, Service 1991^[7])	Fasting hypoglycaemia: confusion, odd behaviour, visual change, sweating, palpitations, seizure-like episodes; often weight gain from eating to avoid symptoms	About 1 in 10
Gastrinoma (Zollinger-Ellison)	0.5–2	Severe, recurrent or post-bulbar ulcers; reflux; diarrhoea that settles on a PPI; complications such as bleeding, stricture or perforation	Often nodes; liver spread in a minority at diagnosis
VIPoma	0.05–0.2 (about 1 per million)	Large-volume watery, tea-coloured, odourless diarrhoea that continues when fasting; low potassium, dehydration, flushing in 20%	60–80%
Glucagonoma	0.01–0.1	Necrolytic migratory erythema, weight loss, diabetes, anaemia, cheilitis and glossitis, venous clots, neuropsychiatric change	50–80%
Somatostatinoma	About 1 in 40 million	Usually a mass (pain, weight loss, jaundice); the syndrome of diabetes, gallstones and steatorrhoea is rare (under 10%)	Most

Figure 2. Functioning syndromes. Suspect them from the symptoms, prove them with the hormone in the right conditions, then find the tumour. Do not order hormone panels in patients without symptoms (UpToDate topic reviews; ENETS 2023 functioning-tumour guidance).

Inherited syndromes

Syndrome	Lifetime PanNET risk	Clues	Practical point
MEN1	80–100%	Hypercalcaemia (often the first sign), pituitary tumour, multiple pancreatic or duodenal tumours, gastrinoma at a young age	Every gastrinoma patient is screened for MEN1 (Niederle 2021^[8]; Brandi 2021^[9])
Von Hippel-Lindau	Up to 20%	Retinal or cerebellar haemangioblastoma, kidney cancer, phaeochromocytoma, many pancreatic cysts	Missense or exon 3 variants carry more metastatic risk
Neurofibromatosis 1	About 10%	Café-au-lait spots, neurofibromas; ampullary or duodenal somatostatin-rich tumours	Seldom a hormone syndrome; less likely to metastasise than sporadic somatostatinoma
Tuberous sclerosis	About 1%	Skin, brain and kidney lesions	Treat the PanNET by the usual rules

Figure 3. Inherited syndromes. Hereditary PanNETs are usually multiple and more indolent, so surgery is reserved for larger or growing tumours and pancreas-sparing operations are preferred (MEN1 and VHL UpToDate reviews; international MEN1 consensus).

Common traps

Hypoglycaemia mislabelled as epilepsy, a psychiatric illness or "giddiness": check a glucose during an episode; insist on Whipple's triad (symptoms, low glucose, relief with glucose).
Zollinger-Ellison hidden by PPIs: suspect it with ulcers beyond the bulb, multiple or refractory ulcers, ulcers without H. pylori or NSAIDs, thick gastric folds, or chronic diarrhoea. Do not stop a PPI casually to test: complications can follow.
Necrolytic migratory erythema treated as eczema or fungal infection for months; it is not specific (zinc deficiency, liver disease and other cancers mimic it), so measure glucagon.
VIPoma treated as infective diarrhoea: secretory diarrhoea (stool osmotic gap under 50) that persists on fasting points away from infection and laxatives.
Chromogranin A used for diagnosis: PPIs, kidney failure, atrophic gastritis, heart failure and inflammatory disease raise it. Histology makes the diagnosis.
A positive hormone stain is not a syndrome: tumours staining for somatostatin, gastrin or insulin are called functioning only when the patient has the clinical syndrome.
Not every hypervascular pancreatic mass is a NET: think of renal cell carcinoma metastasis (especially in VHL), solid pseudopapillary neoplasm, adenocarcinoma, lymphoma, focal or autoimmune pancreatitis. Physiological SSTR uptake in the uncinate process can mimic a tumour.
Liver metastases from an "unknown primary" with neuroendocrine histology: SSTR PET, multiphasic imaging and EUS usually find a small pancreatic or intestinal primary.

03 Screening, workup & staging essentials

Diagnostic approach

Tissue confirms the diagnosis, from the primary (EUS-guided fine-needle biopsy) or the safest, most aggressive-looking metastasis. Ask the pathologist for differentiation, Ki-67 and mitotic count on the sample.
Stage with multiphasic imaging: triple-phase CT (non-contrast, arterial, portal venous) or multiphasic MRI with diffusion. Arterial images show the hypervascular primary and liver metastases; MRI is more sensitive for small liver deposits.
Add SSTR PET (Ga-68 DOTATATE or DOTANOC, or Cu-64 DOTATATE) at baseline in most well-differentiated tumours: whole-body staging, occult primaries and eligibility for SSA and PRRT (Sadowski 2016^[10]; Hope 2018^[11]). It may be omitted for a very small (under 1–1.5 cm) G1 tumour at low risk of spread.
FDG PET for NET G3 and NEC, before surgery for NEC, and when a low-grade tumour behaves aggressively.
Functioning tumours not seen on CT, MRI or SSTR PET: EUS (detects 2–3 mm lesions), GLP-1 receptor (exendin) PET for insulinoma, and rarely selective arterial calcium stimulation with hepatic venous sampling. Modern imaging finds nearly all of them.

Figure 4. Matching the test to the tumour. Multiphasic CT or MRI stages almost every patient; SSTR PET adds whole-body staging and decides SSA and PRRT eligibility; FDG PET marks aggressive disease (UpToDate diagnosis, insulinoma, gastrinoma and G3 reviews).

Proving a hormone syndrome (only when symptoms suggest one)

Syndrome	Test	Diagnostic finding	Cautions
Insulinoma	Supervised 72-hour fast (mixed-meal test if symptoms are after meals)	Glucose under 55 mg/dL with inappropriately high insulin, C-peptide and proinsulin, and a glucose rise after glucagon	Screen for sulfonylureas; exogenous insulin suppresses C-peptide
Gastrinoma	Fasting gastrin after holding the PPI for 7–14 days (H2-blocker cover, specialist supervision) + gastric pH at endoscopy	Gastrin above 10 times the upper limit (≈1000 pg/mL) with gastric pH under 2 (Berna 2006^[12])	Atrophic gastritis, H. pylori and PPIs raise gastrin; secretin test only if equivocal
Glucagonoma	Fasting plasma glucagon	Above 500 pg/mL	A normal level does not exclude it in the classic syndrome
VIPoma	Serum VIP, repeated	Raised VIP with secretory diarrhoea over 0.7 L a day	Follow the laboratory's collection rules
Somatostatinoma	Plasma somatostatin	Over 3 times the upper limit with the clinical syndrome	Somatostatin staining alone is not a diagnosis

Who needs germline testing

Everyone with a family history suggesting MEN1, VHL, NF1 or tuberous sclerosis; every patient with gastrinoma; multiple pancreatic NETs; associated tumours (hyperparathyroidism, pituitary tumour, haemangioblastoma, kidney cancer, phaeochromocytoma).
Consider it for apparently sporadic tumours in people under 50, regardless of family history. About 1 in 10 MEN1 variants arise new, so a clean family history does not exclude it.
MEN1 surveillance (international consensus): yearly clinical review with calcium, PTH and prolactin; pancreatic imaging (MRI or EUS, avoiding radiation) every 2–3 years; urgent work-up of new symptoms.

Staging

Well-differentiated pancreatic NETs use their own AJCC system (version 9), separate from pancreatic cancer; T categories follow size (≤2, >2–4, >4 cm) and invasion. Poorly differentiated NECs are staged like pancreatic adenocarcinoma.
Gastrinomas of the duodenum use the duodenal/ampullary NET system.

Figure 5. TNM for pancreatic NETs (AJCC version 9, 2023), redrawn in our own words. Size thresholds also drive surgical decisions (section 05).

04 Biomarkers that change treatment

Figure 6. Grading. Ki-67 bands follow the WHO 2022 classification; the 55% re-review rule and the immunostains for the grey zone follow the UpToDate pathology review.

Marker	What it tells you	What it changes
Differentiation (morphology ± p53, Rb, DAXX/ATRX)	NET versus NEC. DAXX or ATRX loss in about half of pancreatic NETs (including G3); Rb loss or abnormal p53 favours NEC	NET treatments versus platinum-etoposide; prognosis
Ki-67 index and mitotic count	Grade G1 (under 3%), G2 (3–20%), G3 (over 20%)	Surveillance versus surgery for small tumours; SSA alone (low Ki-67) versus PRRT (Ki-67 10–55%, NETTER-2^[13]) or chemotherapy; above 55%: NEC-type treatment
SSTR expression (PET uptake)	Target for somatostatin analogues and PRRT	SSA and PRRT need uptake in every significant lesion; SSTR-negative disease goes to CAPTEM or targeted drugs
FDG avidity	Glycolytic, more aggressive clones	Shorter intervals, earlier chemotherapy; re-biopsy if discordant with grade
Hormones (insulin, gastrin, glucagon, VIP, somatostatin)	Functional status; marker of activity if raised at baseline	Hormone control; checked with imaging every 6–12 months after resection
Chromogranin A	Weak: rises with PPIs, kidney failure, atrophic gastritis; falls with SSAs regardless of tumour size	Not for diagnosis or routine follow-up after surgery; a ≥50% rise predicted progression with sensitivity only 34% in a prospective study
NETest (blood RNA signature)	High accuracy in pooled studies	Investigational: not yet a basis for changing treatment without imaging
Germline MEN1, VHL, NF1, TSC	Inherited syndrome	Surgical thresholds, pancreas-sparing surgery, belzutifan (VHL), family testing
Tumour NGS (NEC, NET G3 in later lines)	MSI-H/dMMR, TMB-high, BRAF V600E, NTRK and RET fusions	Immune checkpoint inhibitors, dabrafenib + trametinib, TRK or RET inhibitors after chemotherapy

05 Local therapy: surgery, liver-directed therapy & radiotherapy

Surgery for localised disease

Figure 7. Who needs an operation. The UpToDate topic on surgery for sporadic PanNETs was not in the source set: the ≤2 cm surveillance rule is from the prospective ASPEN cohort and ENETS/NCCN guidance (web-verified, October 2026); red flags summarise guideline criteria. Please check against local surgical practice.

Small, sporadic, non-functioning tumours (2 cm or less): active surveillance is now preferred for most asymptomatic patients. The prospective international ASPEN cohort concluded this at its interim analysis (Partelli 2022^[4]), and its final report (ESMO 2025, more than 860 patients under surveillance) found survival similar to surgery, with relevant growth infrequent and distant spread rare. ENETS and NCCN accept observation up to 2 cm; NANETS individualises tumours of 1–2 cm.
Red flags that favour surgery at any size: symptoms, jaundice or main-duct dilatation, clear growth on serial imaging, higher grade, suspicious nodes, and patient preference after counselling (younger patients face decades of surveillance).
Larger tumours (over 2 cm): formal resection (pancreaticoduodenectomy for the head, distal pancreatectomy for the body and tail, central pancreatectomy in selected cases) with removal of regional lymph nodes. Total pancreatectomy is rarely needed.
Enucleation suits small, benign-appearing tumours, especially insulinomas, away from the main pancreatic duct. In one series of head lesions it caused more clinically relevant fistulas than a Whipple (40% vs 14%) but spares pancreatic function. It is not used for tumours over 2 cm or when malignancy is possible, because no nodes are removed.
Functioning tumours: complete resection to negative margins is the standard. Insulinoma surgery cures more than 90%; persistent hypoglycaemia after surgery means repeat localisation and reoperation. Sporadic gastrinoma: PPI, then exploration with duodenotomy and lymph-node dissection; small duodenal tumours may be resected endoscopically by experts. Failure to control symptoms after resection predicts earlier relapse (Zaidi 2019^[14]).
Hereditary tumours: MEN1 non-functioning tumours are resected at 2 cm or more or if growing or higher grade; MEN1 gastrinoma is controlled with a PPI and surgery is debated; MEN1 insulinoma is resected (often local excision of head tumours plus distal subtotal pancreatectomy). VHL: resect head tumours over 2 cm and body or tail tumours over 3 cm; pancreas-sparing operations because more tumours may follow.
After complete resection of a G1–G2 tumour, no adjuvant therapy has been shown to help; NET G3 is also followed after surgery. Localised NEC needs perioperative platinum-etoposide (section 06).

Metastatic disease: surgery and liver-directed therapy

Figure 8. Liver-directed therapy. Survival figures come from observational surgical series (no randomised trials); embolization choices are made by an experienced interventional team (UpToDate local-options review).

Resect when everything can be removed: when both the primary and liver-predominant metastases are resectable, surgery is preferred to systemic therapy. Five-year survival after liver resection is 61–77% in series and symptoms improve in most, though relapse is the rule (84% at 5 years in the Mayo series, Sarmiento 2003^[15]).
Debulking: a 90% cytoreduction threshold gave longer progression-free survival than 70% in observational studies, with similar overall survival; selection bias is large and there are no randomised trials.
Unresectable liver-predominant disease: bland embolization, chemo-embolization or Y-90 radioembolization control symptoms and tumour growth (responses over 50%). Drug-eluting beads cause more biliary injury; late liver fibrosis has been reported after Y-90, and its safety before later PRRT is not established. Ablation suits lesions under about 3 cm.
Liver transplantation is investigational for neuroendocrine liver metastases and is considered only in highly selected patients in expert programmes.
Before any procedure in a functioning tumour: control the hormone (SSA, fluids, potassium, glucose) because tumour breakdown can release a surge.

Radiotherapy

External-beam radiotherapy has a limited role in well-differentiated pancreatic NETs: palliation of painful bone metastases or a bleeding or obstructing mass. Most "radiation" for these tumours is delivered internally, as PRRT (section 06).
NEC: for unresectable locoregional disease, chemotherapy plus radiotherapy is suggested over either alone; prophylactic cranial irradiation is not used.

06 Systemic therapy: indications & options

First, control the hormone

Figure 9. Hormone control by syndrome. No doses are given: use local protocols. Based on the UpToDate insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma and systemic-therapy reviews.

Insulinoma: diazoxide is more predictable than SSAs; SSAs can worsen hypoglycaemia by suppressing glucagon, so start them only with monitoring. Everolimus can control refractory hypoglycaemia.
Gastrinoma: high-dose PPI for every patient, usually reducible later; potassium-competitive acid blockers are an alternative; SSA if refractory.
VIPoma: replace fluid and potassium first (some patients need several litres a day), then an SSA; steroids or antidiarrhoeals for refractory diarrhoea.
Glucagonoma and somatostatinoma: SSA, nutrition, diabetes control; watch for clots in glucagonoma.
Continue the SSA after progression in functioning tumours (hormone control); in non-functioning tumours it can be stopped when a second-line therapy starts.

Well-differentiated G1–G2 tumours: controlling growth

Watch asymptomatic, low-volume, slowly growing disease: there is no proof that early treatment prolongs life (NANETS^[16]).
Somatostatin analogues are first line for SSTR-positive, low-volume disease: in CLARINET^[17], lanreotide prolonged progression-free survival (median not reached vs 18 months; 2-year 65% vs 33%) in G1–G2 non-functioning GEP-NETs, including pancreatic primaries, without an overall survival difference; octreotide showed the same principle in midgut NETs (PROMID^[18]).
PRRT with Lu-177 dotatate is the usual next step after SSA progression in SSTR-positive disease. In OCLURANDOM^[19] (pancreatic NETs, phase 2) it gave a median progression-free survival of 21 vs 11 months over sunitinib with less severe toxicity (44% vs 72%); in a large Dutch cohort, pancreatic NETs had a 55% response and median survival of 71 months (Brabander 2017^[20]). NETTER-1^[21] (midgut only) established PRRT plus SSA over high-dose SSA. In COMPETE^[22], Lu-177 edotreotide beat everolimus (24 vs 14 months; HR 0.67) in G1–G2 GEP-NETs; edotreotide remains investigational for pancreatic NETs.
First-line PRRT for higher G2 and G3: in NETTER-2^[13] (Ki-67 10–55%, 54% pancreatic), Lu-177 dotatate plus SSA gave 23 vs 9 months over high-dose octreotide (HR 0.28; response 43% vs 9%); the pancreatic subgroup benefited (HR 0.34).
Capecitabine plus temozolomide (CAPTEM) is preferred for bulky, symptomatic or rapidly progressive disease because responses are frequent: in E2211^[23], progression-free survival 23 vs 15 months over temozolomide alone, response 40%, at the cost of more grade 3–4 toxicity (44% vs 22%). Streptozocin-based regimens are an alternative where available (Moertel 1992^[24]).
Targeted drugs for progressive disease: everolimus (RADIANT-3^[25]: 11 vs 5 months; overall survival 44 vs 38 months, not significant, Yao 2016^[26]), sunitinib (Raymond 2011^[27]: 12 vs 6 months) and cabozantinib after prior therapy (CABINET^[28] pancreatic cohort: 14 vs 4 months; response 19%).
Sequencing (Algorithm 3): SSTR-positive, low volume → SSA; high volume → SSA + PRRT (Ki-67 10–20%), SSA + liver-directed therapy, or CAPTEM; rapid progression → CAPTEM. SSTR-negative → CAPTEM if rapid, otherwise cabozantinib, everolimus or sunitinib. After SSA → PRRT; after SSA and PRRT → CAPTEM (bulky or fast) or a targeted drug; repeat PRRT in selected patients, ideally in a trial.

Figure 10. Progression-free survival in the trials behind today's choices (rounded medians as reported in the UpToDate reviews; NETTER-2 and COMPETE included pancreatic and intestinal primaries).

High-grade disease: NET G3 and NEC

Figure 11. NET G3 versus NEC. Distinguishing them changes the first treatment; survival figures are from observational cohorts quoted in the UpToDate G3 and NEC reviews.

NET G3 (Ki-67 20–55%), SSTR-positive: SSA alone only for minimal, asymptomatic disease; moderate burden → PRRT + SSA or chemotherapy (CAPTEM or FOLFOX); major burden or symptoms → chemotherapy first (faster onset, easier to start). SSTR-negative → CAPTEM or FOLFOX. In a retrospective series of NET G3 treated with CAPTEM, response was 41% and median survival 32 months. Ki-67 over 55% or rapid progression: treat as NEC.
Localised NEC: surgery with platinum-etoposide (neoadjuvant preferred for locoregionally advanced tumours); chemoradiation for unresectable locoregional disease.
Metastatic NEC: platinum (cisplatin or carboplatin) plus etoposide first (NORDIC NEC^[3]: response 31%, progression-free 4 and overall 11 months); platinum plus irinotecan is equivalent (TOPIC-NEC^[29]). Send tumour NGS at diagnosis.
After first-line NEC therapy: relapse 6 months or more after stopping → re-treat with platinum; earlier → irinotecan- or oxaliplatin-based regimens or temozolomide ± capecitabine (nal-IRI + 5-FU and docetaxel were tested in NET-02^[30]). MSI-H/dMMR → checkpoint inhibitor (KEYNOTE-158^[31]); BRAF V600E → dabrafenib + trametinib (NCI-MATCH^[32]); NTRK or RET fusion → matched inhibitor.

India now (October 2026)

PRRT: Lu-177 has been produced in India (BARC, BRIT) and used for PRRT since about 2008, so PRRT is offered at larger nuclear medicine centres at lower cost than imported products; one centre reports more than 4,000 treatments (AJNMMI 2020^[6]).
Ga-68 DOTA PET is available in metropolitan centres; tracer logistics limit it elsewhere, so plan scans with the nuclear medicine team.
Available in India (October 2026): octreotide LAR, lanreotide, everolimus, sunitinib, cabozantinib, streptozocin and belzutifan; capecitabine and temozolomide (CAPTEM) are oral and widely used. Discuss cost and scheme or insurance cover before planning a long sequence.
Lu-177 edotreotide is investigational here as elsewhere.

Quick reference (also as a printable PDF on the Printable Teaching Resources page)

Table A. Diagnosis and staging tests and what they change

Test	When	What it changes	Pitfalls
Multiphasic CT (non-contrast, arterial, portal venous) or MRI with diffusion	Every patient at diagnosis; follow-up	Finds the hypervascular primary and liver metastases; resectability; MRI is more sensitive for small liver deposits	Small insulinomas and duodenal gastrinomas can be missed
SSTR PET-CT (Ga-68 DOTATATE, DOTANOC or Cu-64 DOTATATE)	Most well-differentiated tumours at baseline; occult primary; before SSA or PRRT	Whole-body staging; changes management more often than CT, MRI or older scintigraphy; uptake = SSA and PRRT eligibility	Less sensitive for insulinoma and high grade; physiological uptake in the uncinate process; meningiomas, healing fractures and inflammation also take it up
FDG PET-CT	NET G3, NEC, or a tumour behaving faster than its grade	FDG-avid disease predicts aggressive behaviour; staging before surgery for NEC	Low-grade NETs are often FDG-negative
EUS with fine-needle biopsy	Tissue diagnosis; small or occult functioning tumours; distance from the main duct before enucleation	Detects lesions of 2–3 mm; gives Ki-67 grade on a core	Small samples can under-grade a heterogeneous tumour; less useful for duodenal gastrinoma
Hormone tests (only with symptoms)	Suspected syndrome	Insulin/C-peptide/proinsulin during hypoglycaemia; gastrin off PPI with gastric pH; glucagon; VIP; somatostatin	PPIs, atrophic gastritis and H. pylori raise gastrin; random insulin levels mislead
Chromogranin A	Not for diagnosis or routine post-surgery follow-up	At most a trend marker in metastatic disease with a high baseline, same assay each time	PPIs, renal failure, atrophic gastritis, heart failure and SSAs alter it
Germline testing	Family history; all gastrinomas; multiple tumours; consider under 50	MEN1, VHL, NF1, TSC: changes surgical thresholds, surveillance and family testing	A negative family history does not exclude MEN1 (about 10% de novo)
Tumour NGS	NEC and NET G3 needing later lines	MSI-H/dMMR, TMB-high, BRAF V600E, NTRK and RET fusions open targeted or immune therapy	Rare in well-differentiated NETs

Table B. Treatment by setting

Setting	Usual plan	Alternatives and notes
Sporadic non-functioning ≤2 cm, no red flags	Active surveillance: MRI or EUS at 6–12 months, then yearly	Resect if growth, duct dilatation, jaundice, higher grade or patient preference after counselling (ASPEN^[4])
Non-functioning >2 cm or with red flags	Formal resection with lymph-node removal	Enucleation only for small, low-grade tumours away from the main duct; no proven adjuvant therapy for G1–G2
Insulinoma	Enucleation or limited resection; cure in more than 90%	Diazoxide or SSA while waiting or if unfit; ablation in selected high-risk patients
Sporadic gastrinoma	High-dose PPI, then duodenal exploration + lymph-node dissection ± pancreatic resection	Small duodenal tumours: endoscopic resection in experienced hands
MEN1	PPI for gastrinoma; surgery for insulinoma and non-functioning ≥2 cm or growing	Pancreas-sparing operations; parathyroid surgery first when hypercalcaemic
VHL	Surveillance if head ≤2 cm or body/tail ≤3 cm; resect above these	Belzutifan for fast growth (doubling time under 500 days), to delay surgery, or if unresectable
Metastatic, liver-only, resectable	Resect primary and liver (± ablation)	Debulking ≥70–90% only in selected patients; transplant investigational
Metastatic G1–G2, unresectable	By SSTR status, burden and pace (Algorithm 3)	Watch, SSA, PRRT, CAPTEM, everolimus, sunitinib, cabozantinib, liver-directed therapy
NET G3	CAPTEM or FOLFOX; PRRT + SSA if SSTR-positive (NETTER-2^[13])	Ki-67 >55% or rapid progression: treat as NEC
NEC, localised	Surgery with perioperative platinum-etoposide, or chemoradiation	No prophylactic cranial irradiation
NEC, metastatic	Platinum + etoposide (or irinotecan)	Second line FOLFIRI, FOLFOX, CAPTEM or nal-IRI + 5-FU; immunotherapy for MSI-H/TMB-high; BRAF, NTRK, RET drugs

Table C. Systemic options for well-differentiated pancreatic NETs: evidence and best fit

Option	Key evidence	Best fit	Watch for
Somatostatin analogue (octreotide LAR, lanreotide)	CLARINET^[17]: PFS not reached vs 18 months (HR 0.47); PROMID^[18] in midgut NETs	SSTR-positive, low volume, slow; any functioning tumour for symptoms	Gallstones, steatorrhoea, B12 deficiency, mild hyperglycaemia; may worsen insulinoma hypoglycaemia
PRRT (Lu-177 dotatate) + SSA	OCLURANDOM^[19] (21 vs 11 months vs sunitinib); NETTER-2^[13] first line G2–G3 (23 vs 9 months); COMPETE^[22] (Lu-177 edotreotide vs everolimus, 24 vs 14 months)	SSTR-positive in every lesion, after SSA, or first line for Ki-67 10–55%	Nausea, cytopenias, renal function; rare therapy-related MDS/AML; radiation precautions at home
Capecitabine + temozolomide (CAPTEM)	E2211^[23]: PFS 23 vs 15 months vs temozolomide; response 40%	Bulky, symptomatic or rapidly progressing; SSTR-negative; NET G3	Cytopenias (check counts), nausea, vomiting, diarrhoea, fatigue
Everolimus	RADIANT-3^[25]: PFS 11 vs 5 months	Progressive disease, any SSTR status; refractory insulinoma hypoglycaemia	Stomatitis, hyperglycaemia, infection, pneumonitis
Sunitinib	Phase III^[27]: PFS 12 vs 6 months	Progressive pancreatic NET (not intestinal)	Hypertension, hand-foot reaction, diarrhoea, hypothyroidism
Cabozantinib	CABINET^[28]: pancreatic cohort PFS 14 vs 4 months	After everolimus, sunitinib or PRRT	Hypertension, fatigue, clots, diarrhoea, palmar-plantar reaction
Streptozocin-based chemotherapy	Moertel 1992^[24]; Kouvaraki 2004^[33]	Where available (mainly Europe); bulky disease	Kidney toxicity, nausea

Table D. Managing common problems during treatment

Problem	Likely cause	First steps	When to act fast
Confusion, sweating or a fit before breakfast	Hypoglycaemia (insulinoma, or SSA unmasking it)	Glucose now; frequent meals; diazoxide; review SSA	Any loss of consciousness: emergency care
Watery diarrhoea, cramps, weakness	VIPoma crisis, SSA failure, enzyme deficiency or bile-acid loss after surgery	Fluids and potassium; check stool volume; SSA; enzymes if fatty stools	Dizziness, low urine output, potassium below normal
Ulcer pain, black stools, vomiting	Acid hypersecretion (gastrinoma), PPI stopped or under-dosed	Restart high-dose PPI; endoscopy	Bleeding or perforation signs
Fever, cough or breathlessness on everolimus	Infection or pneumonitis	Hold drug; chest imaging; treat infection	Low oxygen saturation
Falling counts after PRRT or CAPTEM	Marrow toxicity	Counts before each cycle; adjust or delay	Fever with neutropenia; persistent cytopenia months after PRRT (think MDS)
High blood pressure on sunitinib or cabozantinib	VEGF-pathway inhibition	Home BP log; antihypertensives	Headache, chest pain, BP ≥180/110
Pain, fever or nausea after embolization	Inflammatory reaction to the treated tumour; biliary injury is more frequent with drug-eluting beads	Analgesia, fluids; imaging if symptoms persist	Rigors, rising bilirubin
New hormone symptoms after a procedure	Hormone release from tumour breakdown	SSA cover; correct glucose, fluids, potassium	Haemodynamic instability

07 Management algorithms

These decision paths pull together sections 02–06. Colours: teal for favourable paths, purple for intermediate, rose for advanced or high-risk paths.

Algorithm 1Suspected pancreatic NET: from first suspicion to a staged, graded diagnosis

Hypervascular pancreatic mass, a hormone syndrome, or neuroendocrine liver metastases → multiphasic CT or MRI → NET multidisciplinary team

Hormone symptoms

Prove the syndrome first: 72-hour fast, gastrin off PPI with gastric pH, glucagon, VIP or somatostatin

Control the hormone (diazoxide, PPI, fluids, SSA)

Localise: CT/MRI → SSTR PET (GLP-1R PET for insulinoma) → EUS

Every gastrinoma: test for MEN1

Incidental or mass symptoms

EUS-guided biopsy: differentiation, Ki-67, mitoses

NET G1–G2 → SSTR PET (may skip if <1–1.5 cm, G1)

NET G3 / NEC → FDG PET ± SSTR PET

AJCC version 9 stage

No hormone panel without symptoms; no chromogranin A for diagnosis

Liver metastases first

Biopsy the safest metastasis (grade on the hottest area)

SSTR PET, multiphasic imaging and EUS to find the primary

Go to Algorithm 3 (G1–G2) or 4 (G3, NEC)

All patients: family history and germline testing when indicated (all gastrinomas, multiple tumours, consider under 50) · photograph and record the hormone symptoms · discuss in a NET multidisciplinary team.

Algorithm 2Localised disease: who needs an operation?

No distant metastases → function, size, grade, duct and nodes, hereditary status → fitness and patient preference

Sporadic, non-functioning ≤2 cm

No red flags → active surveillance: MRI or EUS at 6–12 months, then yearly

Growth, duct dilatation, jaundice, higher grade, nodes → resection

Shared decision: ASPEN supports surveillance; young patients may choose surgery

Non-functioning >2 cm or functioning

Formal resection + nodes (Whipple, distal, central)

Insulinoma → enucleation if away from the duct

Sporadic gastrinoma → duodenotomy + nodes

G1–G2 complete resection → follow-up (no adjuvant)

Control the hormone before surgery

Hereditary

MEN1 → PPI for gastrinoma; resect insulinoma and non-functioning ≥2 cm or growing

VHL → resect head >2 cm, body/tail >3 cm; belzutifan for fast growth or unresectable

Pancreas-sparing surgery; lifelong surveillance; family testing

All patients: high-volume pancreatic surgeon · vaccines and fever plan if splenectomy · diabetes and digestion check after resection · follow-up for 10 years.

Algorithm 3Metastatic well-differentiated G1–G2 disease: what first, what next

Unresectable or metastatic NET G1–G2 → resectable? (surgery preferred) → SSTR PET, burden, pace, symptoms, liver predominance

SSTR-positive

Asymptomatic, minimal → watch

Low volume → SSA

High volume → SSA + PRRT (Ki-67 10–20%), SSA + liver-directed therapy, or CAPTEM

Rapid progression → CAPTEM

Liver-predominant symptoms: add embolization

SSTR-negative

Rapid progression → CAPTEM

Slower → cabozantinib, everolimus, sunitinib, CAPTEM or liver-directed therapy

No SSA or PRRT for tumour control (SSA may still help hormone symptoms)

After progression

On SSA → PRRT (or targeted drug if PRRT unsuitable; CAPTEM if bulky)

After SSA + PRRT → CAPTEM if bulky or fast; otherwise cabozantinib, everolimus or sunitinib

After CAPTEM → PRRT if SSTR-positive

Re-biopsy if the pace changes: grade may have risen

All patients: hormone control first · keep SSA after progression only in functioning tumours · CT/MRI every 3–6 months on treatment · trial at every line · bone and quality-of-life care.

Algorithm 4High-grade disease: NET G3 versus NEC

Ki-67 over 20% → pathology review (morphology, p53, Rb, DAXX/ATRX) → SSTR and FDG PET → NGS

NET G3 (Ki-67 20–55%)

SSTR+, moderate burden → PRRT + SSA or CAPTEM/FOLFOX

Major burden or symptoms → chemotherapy first

SSTR-negative → CAPTEM or FOLFOX

Localised → resection, then follow-up

Ki-67 >55% or rapid pace → treat as NEC

NEC, localised

Resectable → surgery + platinum-etoposide (neoadjuvant if locally advanced)

Unresectable locoregional → chemotherapy + radiotherapy

No prophylactic cranial irradiation

NEC, metastatic

First line → platinum + etoposide (or irinotecan)

Relapse ≥6 months → platinum again; <6 months → FOLFIRI, FOLFOX or CAPTEM

MSI-H/TMB-high → immunotherapy; BRAF, NTRK, RET → matched drug

Early palliative care; goals of care

All patients: FDG PET before surgery for NEC · NGS on tissue (or ctDNA) · scans every 2–3 months on treatment · trial where available.

08 Survivorship, follow-up & reducing recurrence

Figure 12. A simple follow-up rhythm, adapted from NCCN as quoted in the UpToDate functioning-tumour reviews: history, examination, marker if initially raised, and multiphasic imaging from 3–12 months, then every 6–12 months up to 10 years.

Follow-up after resection (NCCN, as quoted in the UpToDate reviews; adapt to grade and resources)

Situation	What and how often	Notes
After resection, any functioning or non-functioning NET	History, examination, hormone level if it was raised, multiphasic CT or MRI at 3–12 months; then every 6–12 months up to 10 years	Low-grade, small, node-negative tumours can be imaged less often; NEC needs closer imaging
Small tumour under active surveillance	MRI or EUS at 6–12 months, then yearly while stable	Resect if it grows, the duct dilates or the grade rises
Metastatic disease on treatment or watch-and-wait	Imaging every 3–6 months (2–3 months for NEC); 6–12-monthly once stable for years	Same imaging technique each time; SSTR PET when the plan may change
MEN1 or VHL	Lifelong programme (MRI or EUS every 1–3 years plus syndrome-specific tests)	Family testing; pancreas-sparing decisions

Figure 13. When relapses happen. Options follow the systemic-therapy and liver-directed algorithms; grade migration at relapse is described in the G3 and pathology reviews.

Digestion and diabetes: exocrine insufficiency after Whipple or total pancreatectomy and with long-term SSAs (fatty stools: enzymes); diabetes after distal or total pancreatectomy. Check glucose, B12, vitamin D and iron.
Somatostatin analogues long term: gallstones, steatorrhoea, B12 deficiency and mild hyperglycaemia; ask about biliary pain.
After PRRT: blood counts for years (therapy-related myeloid neoplasms are the most serious late effect) and kidney function.
Targeted drugs: everolimus (glucose, lipids, mouth ulcers, pneumonitis); sunitinib and cabozantinib (blood pressure, thyroid, proteinuria, wound healing).
After splenectomy: pneumococcal, meningococcal and Hib vaccines; standby antibiotics and urgent care for fever.
Family: share germline results; offer testing to first-degree relatives in MEN1 and VHL families.
Living with a slow cancer: many patients live for years with metastatic disease; plan work, finances and mental health support as for a chronic illness.

09 Landmark trials

Figure 14. How to read a survival curve (illustrative). Use the absolute gap at a fixed time and overall survival, not the median or PFS alone, when weighing benefit against toxicity and cost.

CLARINET^[17]: lanreotide vs placebo in G1–G2 non-functioning GEP-NETs → progression-free survival prolonged (HR 0.47) → SSA as first-line tumour control.
RADIANT-3^[25]: everolimus vs placebo in progressive pancreatic NETs → 11 vs 5 months → mTOR inhibition approved.
Sunitinib phase III^[27]: sunitinib vs placebo in progressive pancreatic NETs → 12 vs 6 months (stopped early) → first antiangiogenic standard.
E2211^[23]: capecitabine + temozolomide vs temozolomide → 23 vs 15 months; response 40% → CAPTEM as the preferred chemotherapy when shrinkage matters.
NETTER-1^[21]: Lu-177 dotatate + SSA vs high-dose SSA in midgut NETs → large progression-free benefit; final overall survival difference not significant (Strosberg 2021^[34]) → PRRT established.
OCLURANDOM^[19]: Lu-177 dotatate vs sunitinib in progressive pancreatic NETs (randomised phase 2) → 1-year progression-free 81% vs 42% → PRRT ahead of sunitinib.
NETTER-2^[13]: first-line Lu-177 dotatate + SSA vs high-dose SSA for Ki-67 10–55% → 23 vs 9 months → PRRT moved to first line for higher-grade tumours.
COMPETE^[22]: Lu-177 edotreotide vs everolimus in G1–G2 GEP-NETs → 24 vs 14 months, less toxicity → second PRRT agent (investigational for pancreatic NETs).
CABINET^[28]: cabozantinib vs placebo after prior therapy → pancreatic cohort 14 vs 4 months → a third targeted option.
TOPIC-NEC^[29]: etoposide-cisplatin vs irinotecan-cisplatin in digestive NEC → similar survival → either platinum doublet first line.
ASPEN (interim analysis^[4]): prospective cohort of sporadic non-functioning tumours ≤2 cm → surveillance safe for most → fewer unnecessary pancreatectomies.

10 Practice pearls & pitfalls

Ask two questions of every pathology report: well or poorly differentiated, and what is the Ki-67? Then decide.
Grade on the hottest area: a small EUS core can under-grade a heterogeneous tumour.
A NET G3 with Ki-67 above 55%, or an NEC with Ki-67 below 55%, deserves a second pathology opinion.
Episodes of confusion or "fits" before breakfast are hypoglycaemia until proved otherwise; check glucose during the episode.
Never stop a PPI casually to measure gastrin in suspected Zollinger-Ellison syndrome: arrange it with a gastroenterologist and H2-blocker cover.
Screen every gastrinoma patient for MEN1, starting with calcium and PTH.
Do not order chromogranin A to diagnose or to follow a resected tumour.
Most sporadic, asymptomatic, non-functioning tumours of 2 cm or less can be watched; explain the plan in writing so the patient does not feel abandoned.
Control the hormone before biopsy, surgery, embolization or PRRT: fluids and potassium in VIPoma, glucose in insulinoma, PPI in gastrinoma.
SSAs can worsen hypoglycaemia in insulinoma: diazoxide first.
PRRT needs uptake in every significant lesion; an FDG-avid, SSTR-negative lesion will escape it.
Choose CAPTEM when you need shrinkage (symptoms, bulk, borderline resectability); choose SSA or watch when you need time.
Keep the SSA after progression only if the tumour is functioning.
A tumour that suddenly speeds up needs a new biopsy: grade can rise over time.
In India, Lu-177 for PRRT is made in-country and larger centres offer it; plan the sequence with the nuclear medicine team early.

11 Case vignettes: lines of management

Case 1Incidental · ≤2 cm · surveillance

A small spot on a kidney-stone CT

58 years, man1.4 cm body lesionNo symptoms

A 58-year-old engineer has a CT for renal colic. It shows a 1.4 cm arterially enhancing lesion in the pancreatic body. He is well; no family history of endocrine disease.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Characterise
Multiphasic MRI: 1.4 cm, well defined, no duct dilatation, no nodes, liver clear. EUS: solid lesion 5 mm from the main duct; fine-needle biopsy shows a well-differentiated NET, Ki-67 2% (G1).
Hormones?
No symptoms: no hormone panel and no chromogranin A. SSTR PET optional for a small G1 tumour at low risk; done here because of uncertainty about nodes: uptake only in the primary.
Decide together
Sporadic, asymptomatic, non-functioning, ≤2 cm, G1, no red flags: active surveillance, as supported by ASPEN, explained in writing with the reasons for surgery if things change.
Follow-up
MRI at 6 months, then yearly. At 3 years the lesion is 1.5 cm and unchanged in character: continue.

Teaching points

Small sporadic non-functioning tumours are usually indolent; a pancreatectomy carries real risk.
Red flags (growth, duct dilatation, jaundice, higher grade, nodes) change the plan.
Surveillance is a plan, not neglect: give dates and reasons.

See: Sections 03 and 05, Figure 7 (surgery), Algorithm 2.

Case 2Functioning · insulinoma · cure

Morning "fits" in a schoolteacher

32 years, womanGlucose 38 mg/dLWeight gain

A 32-year-old teacher has had three episodes of confusion and jerking before breakfast, treated as epilepsy. She has gained 6 kg and carries biscuits. Family members found her glucose 38 mg/dL during an episode; she recovered with sugar.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Prove it
Supervised 72-hour fast: symptomatic hypoglycaemia at 14 hours with inappropriately high insulin, C-peptide and proinsulin; sulfonylurea screen negative; glucose rose after glucagon. Whipple's triad confirmed.
Keep her safe
Frequent meals; glucose at hand; diazoxide while waiting. No SSA (it can deepen hypoglycaemia).
Find it
Multiphasic CT: 1.2 cm hypervascular lesion in the pancreatic head, away from the duct on EUS. Calcium, PTH and prolactin normal (MEN1 unlikely).
Operate
Enucleation at a high-volume centre: well-differentiated NET G1, margins clear. Glucose normal the next morning; antiepileptic stopped with the neurologist.
Follow-up
Clinical review and glucose; imaging only if symptoms return. Recurrence after remission is under 10%.

Teaching points

Hypoglycaemia is often misdiagnosed as epilepsy or a psychiatric disorder.
Biochemistry first, imaging second.
Most insulinomas are small, solitary and curable by enucleation.

See: Sections 02, 03 and 05, Figure 2, Table A.

Case 3Gastrinoma · MEN1

Ulcers that never heal and a kidney stone

36 years, manPost-bulbar ulcersCalcium 11.6 mg/dL

A 36-year-old has had duodenal ulcers for 4 years despite PPIs and H. pylori eradication, chronic diarrhoea, and a kidney stone last year. His mother had "parathyroid surgery".

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Suspect
Post-bulbar and multiple ulcers, diarrhoea and a stone: Zollinger-Ellison with MEN1 until proved otherwise.
Test safely
Endoscopy: thick folds, gastric pH 1.5. Gastrin off PPI for 10 days with H2-blocker cover, arranged by the gastroenterologist: 14 times the upper limit. Calcium high, PTH raised; prolactin normal.
Genetics and imaging
Germline MEN1 pathogenic variant. SSTR PET: two small duodenal lesions and a 1.1 cm pancreatic tail lesion; liver clear.
Treat
High-dose PPI long term (symptoms controlled). Subtotal parathyroidectomy with thymectomy for hyperparathyroidism. Duodeno-pancreatic surgery discussed: not routine for MEN1 gastrinoma; he chooses surveillance.
Family and follow-up
Cascade testing offered to siblings and children; yearly calcium, PTH, prolactin; pancreatic MRI every 2–3 years; resect the tail lesion if it reaches 2 cm or grows.

Teaching points

Every gastrinoma patient is screened for MEN1.
Stopping a PPI for testing must be supervised.
In MEN1, gastrinoma is controlled with a PPI; surgery for non-functioning tumours starts at 2 cm.

See: Sections 02, 03 and 05, Figure 3, Algorithm 2.

Case 4Metastatic G2 · SSA → PRRT

Liver spots on a check-up scan

55 years, womanKi-67 8% (G2)SSTR-positive

A 55-year-old woman has multiple liver lesions on an ultrasound for dyspepsia. She feels well. Liver biopsy: well-differentiated NET, Ki-67 8%. CT: 3 cm pancreatic tail primary, about 15 liver metastases in both lobes.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Stage
Ga-68 DOTATATE PET: intense uptake in the primary and all liver lesions; no other sites. Not resectable (bilobar, many lesions).
Start
Asymptomatic, moderate burden, SSTR-positive: lanreotide (CLARINET); CT or MRI every 3–6 months.
Progression at 26 months
Liver lesions grow; still SSTR-positive in every lesion; Ki-67 on re-biopsy 12%. Lu-177 dotatate PRRT (OCLURANDOM, NETTER-1 principle) at the regional nuclear medicine centre; SSA stopped (non-functioning).
Response
Partial response; counts and kidney function monitored; well 3 years later.

Teaching points

Unresectable low-burden SSTR-positive disease: SSA first.
PRRT is the usual second step after SSA progression.
Non-functioning tumours do not need the SSA continued once PRRT starts.

See: Section 06, Figure 10, Algorithm 3.

Case 5NET G3 · first-line PRRT or CAPTEM

Bulky disease with a Ki-67 of 30%

49 years, manKi-67 30%SSTR + and FDG +

A 49-year-old man has upper abdominal pain and 5 kg weight loss. CT: 6 cm pancreatic head mass with liver metastases (about 30% of the liver). Biopsy: well-differentiated NET, Ki-67 30%, p53 and Rb normal.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Classify
Well differentiated with Ki-67 20–55% and normal p53/Rb: NET G3, not NEC. SSTR PET positive in all lesions; FDG PET also positive.
Choose first line
Symptomatic, moderate-to-major burden: chemotherapy (CAPTEM) chosen for rapid response; PRRT + SSA (NETTER-2) discussed as an equal alternative for moderate burden.
Next
Partial response after 6 months of CAPTEM; at progression a year later, PRRT + SSA.
If things change
If a new biopsy showed Ki-67 above 55% or NEC morphology, switch to platinum-etoposide.

Teaching points

NET G3 and NEC are different diseases; differentiation and immunostains decide.
NETTER-2 makes PRRT a first-line option for Ki-67 10–55%.
Bulky or symptomatic disease: chemotherapy first.

See: Sections 04 and 06, Figure 11, Algorithm 4.

Case 6NEC · platinum-etoposide · NGS

Rapid jaundice and a Ki-67 of 80%

63 years, manLarge-cell NECLiver and bone

A 63-year-old man has jaundice, 8 kg weight loss in 6 weeks, and bone pain. CT: 4 cm pancreatic head mass, many liver lesions, lytic spine lesions. Biopsy: poorly differentiated large-cell neuroendocrine carcinoma, Ki-67 80%, Rb lost.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Relieve and stage
Biliary metal stent; FDG PET: widespread avid disease. Staged like pancreatic adenocarcinoma: stage IV.
Treat
Carboplatin + etoposide (NORDIC NEC; TOPIC-NEC shows irinotecan-cisplatin is equivalent); palliative radiotherapy to the painful spine; early palliative care.
Test the tumour
NGS: MSI-stable, no BRAF, NTRK or RET alteration.
Relapse at 5 months
Within 6 months of stopping: second-line FOLFIRI rather than repeat platinum; goals-of-care discussion with the family.

Teaching points

NEC behaves like small cell cancer; median survival about a year.
Send NGS at diagnosis: MSI-H, BRAF, NTRK and RET change later lines.
Relapse timing guides re-use of platinum.

See: Sections 04 and 06, Algorithm 4.

Case 7VHL · surveillance and belzutifan

A 2.5 cm tail lesion in a young woman with VHL

27 years, womanVHL (exon 3)2.5 cm tail NET

A 27-year-old with known VHL (previous cerebellar haemangioblastoma) has a 2.5 cm solid, arterially enhancing lesion in the pancreatic tail on her surveillance MRI, plus several cysts. A year ago it was 1.6 cm.

Before you open the answer: what is the likely diagnosis, what must be done before treatment, and what is the plan?

Show the line of management

Interpret
Hereditary NET in the body/tail below the 3 cm VHL threshold, but growing fast (doubling time well under 500 days) and with an exon 3 variant (higher metastatic risk).
Options
Resection now (pancreas-sparing) or belzutifan to shrink it and delay surgery; surveillance alone is less suitable given the growth.
Plan
Belzutifan started in a VHL clinic (also helps kidney lesions); MRI in 3 months; resect if it continues to grow or reaches 3 cm.
Family
Siblings offered testing; lifelong VHL surveillance.

Teaching points

VHL thresholds: head over 2 cm, body or tail over 3 cm.
Growth rate and genotype matter as much as size.
Belzutifan can delay or avoid surgery in selected VHL patients.

See: Sections 02 and 05, Figure 3, Algorithm 2.

12 References & guidelines

NCCN Guidelines: Neuroendocrine and Adrenal Tumors (current version); ESMO 2020^[35]; NANETS 2020^[16]; ENETS 2023 functioning-tumour guidance^[36]; AJCC Cancer Staging System version 9 (neuroendocrine tumours of the pancreas); WHO Classification of Tumours, 5th edition (endocrine and neuroendocrine).
Cross-checked in October 2026 against 22 UpToDate topic reviews: pancreatic NEN presentation, diagnosis and staging; pathology and classification of GEP-NENs; systemic therapy for G1–G2 pancreatic and gastrointestinal NETs; well-differentiated G3 GEP-NETs; poorly differentiated GEP-NEC; metastatic GEP-NET imaging, biomarkers and prognosis; local options for liver metastases; tumour biomarkers; insulinoma; gastrinoma (diagnosis and management); glucagonoma; VIPoma; somatostatinoma; MEN1 (manifestations, management, gene test interpretation); von Hippel-Lindau disease (diagnosis, surveillance and management); resection of lesions of the head of the pancreas; total pancreatectomy.
The UpToDate topic on surgery for sporadic pancreatic NENs was not available: surgical selection for small non-functioning tumours rests on the ASPEN study (interim report and ESMO 2025 final results, web-verified 16 October 2026) and guideline positions quoted there. India PRRT facts web-verified on 16 October 2026.
Citations were taken from the UpToDate reference lists, except ASPEN and the two India PRRT papers (web-verified). Brabander 2017 (volume and page) and the Hofland 2023 DOI were web-verified on 16 October 2026. Drug availability in India confirmed by Dr. Haritha Chiramana, October 2026.

Core trials and papers cited on this page (37)

Journal, year, volume and first page (or DOI); each links to the PubMed record by exact citation.

Numbered in order of first citation in the text

WHO 2022 classification (Rindi 2022): Rindi G, Mete O, Uccella S, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol 2022;33:115. PubMed Classification, epidemiology and outcome
SEER survival (Dasari 2017): Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335. PubMed Classification, epidemiology and outcome
NORDIC NEC: Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal NEC (WHO G3): the NORDIC NEC study. Ann Oncol 2013;24:152. PubMed High-grade disease
ASPEN interim analysis (Partelli 2022): Partelli S, et al. Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of the prospective ASPEN trial. Br J Surg. 2022. doi:10.1093/bjs/znac267. PubMed Surgery and liver-directed therapy
PRRT in India (IJMPO 2019): Peptide receptor radionuclide therapy in the management of neuroendocrine tumors: fundamentals and clinical practice points for medical oncologists. Indian J Med Paediatr Oncol. 2019. doi:10.4103/ijmpo.ijmpo_161_19. PubMed Peptide receptor radionuclide therapy
A decade of PRRT in India (AJNMMI 2020): A decade of clinical PRRT services with indigenously produced 177Lu-DOTATATE at a tertiary cancer centre in India. Am J Nucl Med Mol Imaging 2020;10:178. PubMed Peptide receptor radionuclide therapy
Insulinoma 60-year series (Service 1991): Service FJ, McMahon MM, O'Brien PC, Ballard DJ. Functioning insulinoma: incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66:711. PubMed Classification, epidemiology and outcome
MEN1 pancreas consensus (Niederle 2021): Niederle B, Selberherr A, Bartsch DK, et al. MEN1 and the pancreas: diagnosis and treatment of functioning and non-functioning pancreatic and duodenal neuroendocrine neoplasia. An international consensus statement. Neuroendocrinology 2021;111:609. PubMed Hereditary syndromes
MEN1 review (Brandi 2021): Brandi ML, Agarwal SK, Perrier ND, et al. Multiple endocrine neoplasia type 1: latest insights. Endocr Rev 2021;42:133. PubMed Hereditary syndromes
Ga-68 DOTATATE PET (Sadowski 2016): Sadowski SM, Neychev V, Millo C, et al. Prospective study of 68Ga-DOTATATE PET/CT for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol 2016;34:588. PubMed Diagnosis and imaging
SSTR PET appropriate use (Hope 2018): Hope TA, Bergsland EK, Bozkurt MF, et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J Nucl Med 2018;59:66. PubMed Diagnosis and imaging
Fasting gastrin in ZES (Berna 2006): Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger-Ellison syndrome I: prospective study of fasting serum gastrin in 309 patients. Medicine (Baltimore) 2006;85:295. PubMed Diagnosis and imaging
NETTER-2: Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose octreotide for newly diagnosed advanced grade 2–3 GEP-NETs (NETTER-2). Lancet 2024;403:2807. PubMed Peptide receptor radionuclide therapy
Symptom control after resection (Zaidi 2019): Zaidi MY, Lopez-Aguiar AG, Poultsides GA, et al. The impact of failure to achieve symptom control after resection of functional neuroendocrine tumors: an 8-institution study. J Surg Oncol 2019;119:5. PubMed Surgery and liver-directed therapy
Liver resection series (Sarmiento 2003): Sarmiento JM, Heywood G, Rubin J, et al. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg 2003;197:29. PubMed Surgery and liver-directed therapy
NANETS pancreatic NET guideline (Halfdanarson 2020): Halfdanarson TR, Strosberg JR, Tang L, et al. NANETS consensus guidelines for surveillance and medical management of pancreatic neuroendocrine tumors. Pancreas 2020;49:863. PubMed Guidelines
CLARINET: Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224. PubMed Somatostatin analogues and targeted drugs
PROMID: Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in metastatic neuroendocrine midgut tumors (PROMID). J Clin Oncol 2009;27:4656. PubMed Somatostatin analogues and targeted drugs
OCLURANDOM: Baudin E, Durand A, Beron A, et al. [177Lu]Lu-dota-tate versus sunitinib in metastatic progressive pancreatic neuroendocrine tumours (OCLURANDOM): a randomised phase 2 trial. Lancet Oncol 2026;27:699. PubMed Peptide receptor radionuclide therapy
Lu-177 dotatate Rotterdam cohort (Brabander 2017): Brabander T, van der Zwan WA, Teunissen JJ, et al. Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in GEP and bronchial NETs. Clin Cancer Res 2017;23:4617. PubMed Peptide receptor radionuclide therapy
NETTER-1: Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 2017;376:125. PubMed Peptide receptor radionuclide therapy
COMPETE: Walter T, Jann H, Ansquer C, et al. [177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3 trial. Lancet 2026;408:234. PubMed Peptide receptor radionuclide therapy
E2211: Kunz PL, Graham NT, Catalano PJ, et al. Randomized study of temozolomide or temozolomide and capecitabine in advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol 2023;41:1359. PubMed Chemotherapy
Streptozocin-doxorubicin (Moertel 1992): Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in advanced islet-cell carcinoma. N Engl J Med 1992;326:519. PubMed Chemotherapy
RADIANT-3: Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514. PubMed Somatostatin analogues and targeted drugs
RADIANT-3 overall survival (Yao 2016): Yao JC, Pavel M, Lombard-Bohas C, et al. Everolimus for advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from RADIANT-3. J Clin Oncol. 2016. PubMed Somatostatin analogues and targeted drugs
Sunitinib phase III (Raymond 2011): Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501. PubMed Somatostatin analogues and targeted drugs
CABINET: Chan JA, Geyer S, Zemla T, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med 2025;392:653. PubMed Somatostatin analogues and targeted drugs
TOPIC-NEC: Morizane C, Machida N, Honma Y, et al. Etoposide and cisplatin vs irinotecan and cisplatin for advanced digestive NEC: the TOPIC-NEC phase 3 randomized trial. JAMA Oncol 2022;8:1447. PubMed High-grade disease
NET-02: McNamara MG, Swain J, Craig Z, et al. NET-02: nal-IRI/5-FU or docetaxel as second-line therapy in poorly differentiated extrapulmonary NEC. EClinicalMedicine 2023;60:102015. PubMed High-grade disease
KEYNOTE-158 non-colorectal MSI-H (Marabelle 2020): Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in non-colorectal high microsatellite instability/mismatch repair-deficient cancer (KEYNOTE-158). J Clin Oncol 2020;38:1. PubMed High-grade disease
NCI-MATCH subprotocol H (BRAF V600E): Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in BRAF V600E-mutated tumors: NCI-MATCH subprotocol H. J Clin Oncol 2020;38:3895. PubMed High-grade disease
FAS chemotherapy (Kouvaraki 2004): J Clin Oncol 22:4762. PubMed Other studies cited in the text
NETTER-1 final overall survival (Strosberg 2021): Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-dotatate plus long-acting octreotide versus high-dose octreotide in midgut NETs (NETTER-1): final overall survival and long-term safety. Lancet Oncol 2021;22:1752. PubMed Peptide receptor radionuclide therapy
ESMO GEP-NEN guideline (Pavel 2020): Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines. Ann Oncol 2020;31:844. PubMed Guidelines
ENETS 2023 functioning PanNETs (Hofland 2023): Hofland J, Falconi M, Christ E, et al. European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol. 2023. doi:10.1111/jne.13318. PubMed Guidelines

Further reading (not cited in the text above)

LITESPARK-004: Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med 2021;385:2036. PubMed Hereditary syndromes
LITESPARK-004 pancreatic lesions (Else 2024): Else T, Jonasch E, Iliopoulos O, et al. Belzutifan for von Hippel-Lindau disease: pancreatic lesion population of the phase 2 LITESPARK-004 study. Clin Cancer Res 2024;30:1750. PubMed Hereditary syndromes

How to cite this page

VancouverChiramana H. Pancreatic Neuroendocrine Tumours: a mini review for clinicians. Oncology Knowledge Hub [Internet]. Nellore (India): drharitha.co.in; 2026 [updated 2026 Oct 16; cited year month day]. Available from: https://drharitha.co.in/professionals/pancreatic-neuroendocrine-tumours

APA 7Chiramana, H. (2026, October 16). Pancreatic Neuroendocrine Tumours: A mini review for clinicians. Oncology Knowledge Hub. Retrieved Month Day, Year, from https://drharitha.co.in/professionals/pancreatic-neuroendocrine-tumours

Free to use and share for education with attribution; please do not alter or use commercially (CC BY-NC-ND 4.0). Replace the italic parts with the date you accessed the page.

Educational summary for health professionals, written in our own words from current guidelines and primary trials. No drug doses are given. Exocrine pancreatic cancer (ductal adenocarcinoma) has its own module in the Upper GI & Pancreas series; oesophageal and gastric cancers will follow. Verify current guidelines, Indian regulatory approvals and individual patient factors before treatment decisions.

Written by Dr. Haritha ChiramanaSenior Medical Oncologist & Hemato-Oncologist · MD, DM (Medical Oncology) · C.R. Reddy Cancer Center, Nellore, Andhra Pradesh, India

Medically reviewed by Dr. Haritha Chiramana on 16 October 2026. This page is general education and cannot replace an individual consultation.