# Extrapulmonary neuroendocrine carcinoma

Source: https://onco.cc/cancers/extrapulmonary-nec/  
OnCo record `extrapulmonary-nec` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Extrapulmonary neuroendocrine carcinoma is the fast-growing, poorly differentiated form of neuroendocrine cancer arising outside the lung, most often in the bowel, oesophagus, stomach or pancreas. It behaves like small-cell lung cancer and is treated the same way, with platinum and etoposide chemotherapy, and drugs against the DLL3 protein are now in phase 3 trials.

## Summary

Neuroendocrine carcinoma is a different disease from the well-differentiated tumours it shares a name with. The WHO classification defines it by poorly differentiated small-cell or large-cell morphology with a Ki-67 above 20 percent and usually far higher, and its genetics follow small-cell lung cancer, with loss of TP53 and RB1 rather than the MEN1, DAXX and ATRX mutations of neuroendocrine tumours; a subset of colorectal carcinomas carry BRAF V600E and a few are microsatellite unstable. Somatostatin receptor expression is usually weak, so FDG PET stages the disease where somatostatin receptor PET stages tumours, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) combine a carcinoma component with adenocarcinoma or squamous carcinoma. Merkel cell carcinoma of the skin and neuroendocrine prostate cancer are covered on their own pages.

Treatment is borrowed wholesale from small-cell lung cancer. Moertel showed in 1991 that cisplatin with etoposide produced responses in most anaplastic neuroendocrine carcinomas, and platinum-etoposide has been first-line therapy since; the NORDIC NEC series (Annals of Oncology 2013) of 305 patients confirmed that most respond but relapse quickly, and found that carcinomas with a Ki-67 below 55 percent responded less often to platinum yet lived longer, an observation that helped separate grade 3 well-differentiated tumours from true carcinoma. Randomised evidence is scarce: the ECOG-ACRIN EA2142 trial compared capecitabine-temozolomide with platinum-etoposide in high-grade gastroenteropancreatic neoplasms and did not show the oral regimen superior, and the Italian SENECA trial found both CAPTEM and FOLFIRI active in the second line. Localised disease is resected or given chemoradiotherapy with perioperative platinum-etoposide, as in limited-stage small-cell lung cancer.

Immunotherapy and DLL3 are the two openings. The DART basket trial (SWOG S1609) reported responses to nivolumab with ipilimumab in high-grade neuroendocrine carcinoma but not in low-grade tumours, and PD-1 or PD-L1 antibodies are added to first-line chemotherapy by extrapolation from IMpower133 and CASPIAN while dedicated phase 2 trials such as NICE-NEC test the combination directly. DLL3, the surface protein behind tarlatamab's approval in small-cell lung cancer, is expressed by most neuroendocrine carcinomas: the T-cell engagers obrixtamig (DAREON-5, and the phase 3 DAREON-NEC-1 with carboplatin-etoposide in DLL3-positive extrapulmonary carcinoma), peluntamig and ZG006 are in trials that enrol these tumours alongside small-cell lung cancer.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Extrapulmonary NEC; Gastroenteropancreatic neuroendocrine carcinoma; GEP-NEC; Extrapulmonary small-cell carcinoma; Large-cell neuroendocrine carcinoma of the gut; Poorly differentiated neuroendocrine carcinoma
- Tags: subtype-page; endocrine
- Group: endocrine
- Burden: A minority of neuroendocrine neoplasms but the one with the shortest survival; the gastrointestinal tract (colon and rectum, oesophagus, stomach, pancreas) and unknown primary are the commonest sites, most patients present with metastases, and survival is measured in months rather than years.
- Subtypes: Small-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract; Large-cell neuroendocrine carcinoma (NEC) of the gastrointestinal tract; Colorectal NEC (the commonest gut site, BRAF V600E in a subset); Oesophageal and gastric NEC; Pancreatic NEC (distinguish from grade 3 well-differentiated pancreatic NET); Neuroendocrine carcinoma of unknown primary; Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN); Small-cell carcinoma of the cervix, bladder and other extrapulmonary sites
- Biomarkers: Ki-67 above 20 percent, usually far higher, with poorly differentiated morphology; Synaptophysin, chromogranin and INSM1 by immunohistochemistry (chromogranin may be weak); p53 and Rb by immunohistochemistry (abnormal in carcinoma, retained in grade 3 tumour); FDG PET (somatostatin receptor PET usually negative); DLL3 expression (trial eligibility); BRAF V600E and microsatellite instability in colorectal NEC; Ki-67 above or below 55 percent (platinum sensitivity, NORDIC NEC)

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/extrapulmonary-nec/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/extrapulmonary-nec/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/extrapulmonary-nec/#what-it-is [8 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/extrapulmonary-nec/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/extrapulmonary-nec/#treating-it [5 settings, 5 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/extrapulmonary-nec/#evidence [4 trials, 3 key papers, 7 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/extrapulmonary-nec/#science [9 targets, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/extrapulmonary-nec/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/extrapulmonary-nec/#living-with-it [19 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/extrapulmonary-nec/coming/ [17 medicines, 4 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/extrapulmonary-nec/data/ [61 connected records]

## Standard of care

- Diagnosis and staging: Biopsy with Ki-67, morphology and p53 or Rb immunohistochemistry to separate carcinoma from grade 3 tumour; FDG PET and CT; somatostatin receptor PET only if radioligand therapy is contemplated. ([Neuroendocrine tumour grade (Ki-67) and WHO classification](https://onco.cc/terms/net-grade-ki67/), [Tumour differentiation (well / moderately / poorly differentiated)](https://onco.cc/terms/tumour-differentiation/), [PET (positron emission tomography)](https://onco.cc/technologies/pet/), [CT (computed tomography)](https://onco.cc/technologies/ct/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [TP53](https://onco.cc/targets/tp53/))
- Localised disease: Resection or definitive chemoradiotherapy with perioperative platinum-etoposide, following the limited-stage small-cell lung cancer model. ([Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Etoposide](https://onco.cc/drugs/etoposide/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Radiotherapy](https://onco.cc/terms/radiotherapy/))
- Metastatic, first line: Platinum with etoposide (cisplatin or carboplatin), with a PD-1 or PD-L1 antibody added by extrapolation from small-cell lung cancer or within a trial. ([Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Etoposide](https://onco.cc/drugs/etoposide/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Durvalumab](https://onco.cc/drugs/durvalumab/))
- Second line: FOLFIRI, FOLFOX, capecitabine-temozolomide or topotecan; nivolumab with ipilimumab in selected patients (DART); DLL3-directed T-cell engagers in trials. ([FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/), [Topotecan](https://onco.cc/drugs/topotecan/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [DART (SWOG S1609): nivolumab plus ipilimumab in rare tumours](https://onco.cc/trials/dart-s1609/), [DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy](https://onco.cc/trials/nct07544654/), [DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers](https://onco.cc/trials/nct05882058/), [DLL3](https://onco.cc/targets/dll3/))
- Ki-67 near 20 to 55 percent with well-differentiated features: Reclassify as grade 3 neuroendocrine tumour and treat accordingly. ([Neuroendocrine tumour grade (Ki-67) and WHO classification](https://onco.cc/terms/net-grade-ki67/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/))

## State of the art

- Platinum-etoposide remains the backbone after more than three decades, with immunotherapy added by extrapolation from small-cell lung cancer.
- The 2019 WHO split of grade 3 tumour from carcinoma has stopped many slower tumours receiving platinum they would not respond to.
- DLL3-directed T-cell engagers have reached a phase 3 trial specific to extrapulmonary carcinoma.

## Open problems

- No randomised trial has improved on platinum-etoposide in first line.
- Whether adding a PD-1 or PD-L1 antibody helps, as it does in small-cell lung cancer, is untested in a phase 3.
- Second-line therapy has no standard.
- The disease is too rare and too heterogeneous by site for site-specific trials, so basket designs dominate.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Neuroendocrine_tumor
- NORDIC NEC (Annals of Oncology 2013): https://doi.org/10.1093/annonc/mds276
- DART neuroendocrine cohort (Clinical Cancer Research 2020): https://doi.org/10.1158/1078-0432.CCR-19-3356
- Wikipedia: https://en.wikipedia.org/wiki/Neuroendocrine_tumor

## Connected records

- cancers: [Cancer of unknown primary, favourable subsets](https://onco.cc/cancers/cup-favourable-subsets/), [Grade 3 well-differentiated neuroendocrine tumour](https://onco.cc/cancers/grade-3-net/), [Lung neuroendocrine tumours (typical and atypical carcinoid)](https://onco.cc/cancers/lung-net/), [Neuroendocrine carcinoma of the gallbladder](https://onco.cc/cancers/gallbladder-neuroendocrine-carcinoma/), [Neuroendocrine neoplasms of the breast](https://onco.cc/cancers/neuroendocrine-neoplasms-breast/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Pancreatic neuroendocrine tumours](https://onco.cc/cancers/pancreatic-net/), [Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma](https://onco.cc/cancers/sinonasal-undifferentiated-carcinoma/), [Small cell neuroendocrine carcinoma of the cervix](https://onco.cc/cancers/cervical-small-cell-neuroendocrine-carcinoma/), [Small intestinal neuroendocrine tumours](https://onco.cc/cancers/small-intestinal-net/), [Thymic carcinoma](https://onco.cc/cancers/thymic-carcinoma/)
- technologies: [CT (computed tomography)](https://onco.cc/technologies/ct/), [PET (positron emission tomography)](https://onco.cc/technologies/pet/), [Somatostatin receptor PET (68Ga/64Cu-DOTATATE)](https://onco.cc/technologies/sstr-pet/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [DLL3](https://onco.cc/targets/dll3/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Capecitabine + temozolomide (CAPTEM)](https://onco.cc/drugs/capecitabine-temozolomide/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Etoposide](https://onco.cc/drugs/etoposide/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Lutetium-177 dotatate](https://onco.cc/drugs/lutathera/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Obrixtamig](https://onco.cc/drugs/obrixtamig/), [Peluntamig](https://onco.cc/drugs/peluntamig/), [Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/), [Topotecan](https://onco.cc/drugs/topotecan/), [ZG006](https://onco.cc/drugs/zg006/)
- pathways: [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/)
- terms: [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Neuroendocrine tumour grade (Ki-67) and WHO classification](https://onco.cc/terms/net-grade-ki67/), [Radiotherapy](https://onco.cc/terms/radiotherapy/), [Tumour differentiation (well / moderately / poorly differentiated)](https://onco.cc/terms/tumour-differentiation/)
- trials: [A Study of Peluntamig (PT217) in Patients With Neuroendocrine Carcinomas Expressing DLL3 (the SKYBRIDGE Study)](https://onco.cc/trials/nct05652686/), [DAREON®-NEC-1: A Study in People With Advanced Extrapulmonary Neuroendocrine Cancer (epNEC) to Compare Obrixtamig Plus Carboplatin and Etoposide Treatment With Standard Chemotherapy](https://onco.cc/trials/nct07544654/), [DAREON™-5: A Study to Test Whether Different Doses of BI 764532 Help People With Small Cell Lung Cancer or Other Neuroendocrine Cancers](https://onco.cc/trials/nct05882058/), [DART (SWOG S1609): nivolumab plus ipilimumab in rare tumours](https://onco.cc/trials/dart-s1609/)
- key papers: [A common classification framework for neuroendocrine neoplasms (IARC and WHO expert consensus)](https://onco.cc/key-papers/paper-rindi-common-classification-framework-mod-pathol-2018/), [DART (SWOG 1609): nivolumab plus ipilimumab in rare tumours, non-pancreatic neuroendocrine neoplasms cohort](https://onco.cc/key-papers/paper-dart-nivolumab-ipilimumab-nec-patel-ccr-2020/), [NORDIC NEC: predictive and prognostic factors in 305 patients with advanced gastrointestinal neuroendocrine carcinoma](https://onco.cc/key-papers/paper-nordic-nec-sorbye-ann-oncol-2013/)

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JSON: https://onco.cc/api/v1/entities/extrapulmonary-nec.json