Extrapulmonary Neuroendocrine Cancers

Extrapulmonary neuroendocrine cancers, which can also be referred to as extrapulmonary neuroendocrine carcinomas (epNECs), are rare, highly aggressive cancers that develop from neuroendocrine cells outside the lungs. They are characterized by rapid growth, early spread, and poor prognosis.

epNECs are typically diagnosed around  60 years of age and are slightly more common in men. Their rarity and non-specific symptoms mean they are frequently misdiagnosed or mistaken for other neuroendocrine diseases, such as neuroendocrine tumors (NETs).

epNECs can develop in several organs, most commonly in the:

• Gastroenteropancreatic (GEP) tract
• Breast
• Genitourinary tract
• Skin
• Head and neck

"The symptoms related with extrapulmonary neuroendocrine carcinomas (epNECs) depend on the site of origin. When we are talking about extrapulmonary, so outside the lungs, this means that they can arise from the gastrointestinal tract, the pancreas, the genitourinary tract, or gynecological organs. There is also a proportion of cases with an unknown primary."

Jaume Capdevila
Medical Oncologist at Vall d'Hebron University Hospital, Barcelona

Diagnosing extrapulmonary neuroendocrine carcinomas (epNECs)

Because epNECs are uncommon and share symptoms with many other gastrointestinal and systemic conditions, diagnosis is often delayed and challenging. Healthcare professionals can have limited experience with the disease, and epNEC may initially be misclassified as less aggressive and slower growing neuroendocrine tumors (NETs) or benign condition such as irritable bowel syndrome.

What are the symptoms of extrapulmonary neuroendocrine carcinoma (epNEC)?

Symptoms vary depending on where the cancer begins but can include:

Unexplained weight loss

Persistent tiredness

Localized pain or discomfort

Loss of appetite

Changes in digestion or breathing

General decline in wellbeing

In more advanced stages, symptoms often intensify rapidly, reflecting the aggressive nature of the disease.

Treatments for extrapulmonary neuroendocrine carcinomas (epNEC)

Because epNECs can occur across multiple organs, care is often fragmented, which can lead to delayed treatment. On average, a person may attend 11 primary care visits (non-specialist clinicians) and three secondary care (specialist clinicians who manage complex, acute conditions) referrals before diagnosis.

Prognosis is poor even after a person receives chemotherapy treatment, which is the recommended standard of care for initial treatment. Currently, there are no approved therapies that have been developed to specifically treat epNEC, and there is an urgent need for personalized therapies that can deliver durable benefit and meaningful improvements in people’s lives.

Biomarker testing in cancer: Biomarkers in extrapulmonary neuroendocrine carcinomas (epNEC)

Every cancer is unique and the growth of cancer may be influenced by molecules, called biomarkers. They can include gene mutations, proteins or other substances, which provide key information about the cancer. Understanding how the cancer behaves through biomarkers is essential for improving diagnosis and guiding future treatment. Research is exploring several biomarkers and genetic alterations that may influence tumor behavior and identify patients who could benefit from targeted therapies.

What is DLL3?

DLL3 (Delta-like ligand 3) is emerging as a key biomarker in epNEC. It is highly expressed in neuroendocrine carcinoma cells while showing minimal expression in normal tissues, making it a promising therapeutic target. DLL3 can be detected using immunohistochemistry (IHC), and new assays are in development to better identify DLL3-positive tumors.

Studies are also examining frequent genetic alterations, including TP53 and RB1, which may help define disease mechanisms and support biomarker-guided treatment in the future.

"Biomarker testing is so important for those living with extrapulmonary neuroendocrine carcinomas (epNEC) because biomarker testing allows for more information about people's specific cancer cells. That means instead of taking a one-size-fits all treatment route, people can be treated personally in a way that's best going to impact their cancer."

Lisa Walker
CEO of Neuroendocrine Cancer UK

References

1. Sethi S, et al. Epidemiology and retrospective analysis in extrapulmonary neuroendocrine carcinoma. Cureus. 2020;12(11):e11331
2. Frizziero M, et al. Is the morphological subtype of extra-pulmonary poorly differentiated neuroendocrine carcinoma clinically relevant? Cancers (Basel). 2021;13(16):398
3. Sorbye H, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma: current management and future perspectives. Cancer. 2014;120(18):2814-2823
4. Clarke CN, et al. Real-world analysis of neuroendocrine tumor misdiagnosis and associated costs. Surg Oncol Insight. 2024;1(4):100105
5. International Neuroendocrine Cancer Alliance (INCA). Diagnosis & Misdiagnosis of NET/NEC. Available from: https://incalliance.org/diagnosis-and-misdiagnosis. Accessed: April 2026.
6. Hallet J, et al. Patterns of Symptoms Burden in Neuroendocrine Tumors: A Population-Based Analysis of Prospective Patient-Reported Outcomes. Oncologist. 2019 Oct;24(10):1384-1394.
7. Macmillan Cancer Support. Signs and symptoms of lung cancer. 2025. Available from: www.macmillan.org.uk/cancer-information-and-support/lung-cancer/signs-and-symptoms-of-lung-cancer. Accessed: April 2026.
8. Oronsky B, et al. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia. 2017;19(12):991-1002.
9. Basuroy R, et al. Delays and routes to diagnosis of neuroendocrine tumours. BMC Cancer. 2018;18.
10. McGarrah PW, et al. Pancreas 2020;49(4):529–33.
11. Apostolidis L, et al. Cancer Med 2016;5(9):2261–7.
12. Gosain R, et al. Cancers (Basel) 2022;14(6):1428.
13. Stumpo S, et al. Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives. J Clin Med. 2023 Dec 15;12(24):7715.
14. Liverani C, Bongiovanni A, Mercatali L, et al. Diagnostic and Predictive Role of DLL3 Expression in Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Pathol. 2021;32(2):309-317.
15. Peddio A, et al. DLL3 as a potential diagnostic and therapeutic target in neuroendocrine neoplasms. Critical Reviews in Oncol Hematol. 2025;204:104524.