Understanding neuroendocrine tumors
Learn about neuroendocrine tumors, including where they occur, risk factors, diagnosis, treatment, and disease progression.
This site is intended for healthcare professionals outside of the United States (US) and the United Kingdom (UK).
This site is created and funded by Novartis.
What are neuroendocrine tumors?
Neuroendocrine tumors (NETs) are a group of neoplastic growths that arise from specialized secretory cells, known as neuroendocrine cells, distributed throughout the body. Neuroendocrine cells have the capacity to produce hormones, as well as proteins that can serve as biomarkers for NETs. 1a 2
Neuroendocrine cells can be predominately found in three broad areas1b 3 4a:
Isolated neuroendocrine cells dispersed throughout most tissues such as the bronchopulmonary system, the pancreas, and the gastrointestinal tract
Aggregates of neuroendocrine cells present in organs such as pancreatic islets
Classic endocrine glands such as the adrenal medulla, parathyroid glands, and the pituitary gland
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The anatomical distribution and nature of NETs
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The risk factors of NETs
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Symptoms of NETs
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Diagnosis of NETs
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The treatment of NETs
NETs are classified according to their anatomical origin, with the majority originating in the gastroenteropancreatic or bronchopulmonary tracts (GEP-NETs and BP-NETs), respectively.
NETs are subclassified according to the embryological origin of their site4b 5a:
Foregut
Midgut
Hindgut
Not only do NETs differ in their anatomical site, they can also vary in their differentiation and grading.
Differentiation
Differentiation describes the degree of similarity between tumor cells and healthy cells within the tissue from which they arose. Well-differentiated cancer cells closely resemble the characteristics of non-neoplastic cells. By definition, NETs are well differentiated.5b
Grading
Grading refers to the histological grade (G) that NETs are given, describing the aggressiveness of the tumor; G1, G2, or G3.5c
Higher-grade tumors are usually associated with negative patient outcomes.
Well-differentiated NETs are usually G1 or G2; poorly differentiated tumors (called neuroendocrine carcinomas [NECs]) are G3.4c
To date the exact cause of NETs is unknown and the vast majority occur sporadically. Some risk factors include the following6:
Family history of cancer
Diabetes
Obesity
Smoking
Alcohol consumption
Hereditary syndromes
When NETs cause clinical symptoms due to the hypersecretion of hormones, they are termed “functioning.”
However, most NETs do not produce a biologically active hormone and are termed “non functioning.” Thus, if symptoms do occur, they are often vague and non specific. 4d 5d 7
Symptoms usually associated with GEP-NETs:
Abdominal pain
Change in bowel habit
Fatigue
Symptoms usually associated with BP-NETs:
Wheezing
Coughing
Hemoptysis
Dyspnea
Chest pain
Recurrent pneumonia
There are several tools, measures, and imaging techniques used to diagnose NETs.
Patient presentation5d: Typically initiated by patient-reported symptoms, often including abdominal pain and changes in bowel habits
Histology8a: Histological evaluation of biopsied tumor tissue. Microscopic assessment using hematoxylin and eosin (HE) staining techniques are used to determine tumor differentiation
Biochemistry: Biomarkers specific to NETs are assessed, such as4e 5e:
- Chromogranin A (CgA), produced by a range of GEP-NETs and BP-NETs
- Plasma pancreatic polypeptide elevated in pancreatic and colonic NETs
- 5-HIAA elevated in blood and urine due to serotonin secretion by midgut NETs
Anatomical imaging4f 5f: Various imaging techniques can be employed such as CT scans, MRI scans, endoscopic ultrasonography and endoscopy
Somatostatin receptor (SSTR) imaging9a: This plays a central role in diagnosis and follow-up. SSTRs are expressed in high density in the majority of GEP-NETs and BP-NETs. SSTR imaging uses radiolabeled somatostatin analogue (SSA) tracers, like octreotide, that bind to SSTRs on NET cells. The radioactive molecule (often gallium-68) allows precise imaging of tumor location and size
The primary aim of treatment is curative surgery, however, it is usually attainable for only a minority of patients. For the remainder, therapy aims to manage symptoms, prevent tumor growth, and extend survival.
Various treatments can help achieve these objectives, such as 4g 5g:
- Surgery
- SSAs
- Liver-directed therapies
- Molecular targeted treatments such as everolimus and sunitinib
- Chemotherapy
- Peptide receptor radionuclide therapy (PRRT), a molecular approach that attaches ligands for peptide hormone receptors to therapeutic radionuclides
Disease progression in GEP-NETs
Disease progression in GEP-NETs profoundly impacts the survival and quality of life of patients. Despite their typically slow growth, most GEP-NETs can advance even with treatment, potentially leading to death. The risk of progression and death in patients with metastatic GEP-NETs rises over time.10a 11
Identifying disease progression
The identification of progression is essential to help improve patient outcomes, as it may offer an opportunity to modify treatment strategies. In clinical practice, multiple factors can be considered when determining the timing for therapeutic adjustments, including the following 8b 10b :
Tumor burden assessment
Evaluation of drug-related toxicity
Monitoring and addressing cancer-related symptoms
Clinician judgment and expertise of the healthcare provider
Recurrent or worsening symptoms may indicate disease progression in GEP-NET patients. Such symptoms may arise from increased tumor burden or secretion of bioactive substances from functional tumors. Evaluating these signs and symptoms can suggest disease progression, prompting the need for imaging scans and other laboratory tests.9b 12 13 14
Find out more about identifying the progression of neuroendocrine tumors – including assessing progression and relevant ENETS and ESMO guidelines.
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Abbreviations
5-HIAA, 5-hydroxyindoleacetic acid
BP-NETs, bronchopulmonary neuroendocrine tumors
CgA, chromogranin A
CT, computed tomography
G, grade
GEP-NETs, gastroenteropancreatic neuroendocrine tumors
HE, hematoxylin and eosin
MRI, magnetic resonance imaging
NECs, neuroendocrine carcinomas
NETs, neuroendocrine tumors
PRRT, peptide receptor radionuclide therapy
RLT, radioligand therapy
SSA, somatostatin analogue
SSTR, somatostatin receptor
References
1a 1b Canadian Cancer Society. What are neuroendocrine tumours? Accessed July 19, 2024. https://cancer.ca/en/cancer-information/cancer-types/neuroendocrine-tumours
2 Kidd M, Modlin IM, Bodei L, Drozdov I. Decoding the molecular and mutational ambiguities of gastroenteropancreatic neuroendocrine neoplasm pathobiology. Cell Mol Gastroenterol Hepatol. 2015;1(2):131-153. doi:10.1016/j.jcmgh.2014.12.008
3 Herrera-Martínez AD, Hofland J, Hofland LJ, et al. Targeted systemic treatment of neuroendocrine tumors: current options and future perspectives. Drugs. 2019;79(1):21-42. doi:10.1007/s40265-018-1033-0
4a 4b 4c 4d 4e 4f 4g Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing but NET: a review of neuroendocrine tumors and carcinomas. Neoplasia. 2017;19(12):991-1002. doi:10.1016/j.neo.2017.09.002
5a 5b 5c 5d 5e 5f 5g Raphael MJ, Chan DL, Law C, Singh S. Principles of diagnosis and management of neuroendocrine tumours. CMAJ. 2017;189(10):E398-E404. doi:10.1503/cmaj.160771
6 Leoncini E, Carioli G, La Vecchia C, Boccia S, Rindi G. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol. 2016;27(1):68-81. doi:10.1093/annonc/mdv505
7 Canadian Cancer Society. Symptoms of neuroendocrine tumours (NETs). Accessed July 19, 2024. http://cancer.ca/en/cancer-information/cancer-types/neuroendocrine-tumours/signs-and-symptoms
8a 8b Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. doi:10.1016/j.annonc.2020.03.304
9a 9b Hope TA, Bergsland EK, Bozkurt MF, et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J Nucl Med. 2018;59(1):66-74. doi:10.2967/jnumed.117.202275
10a 10b Merino-Casabiel X, Aller J, Arbizu J, et al. Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors. Clin Transl Oncol. 2018;20(12):1522-1528. doi:10.1007/s12094-018-1881-9
11 Rinke A, Wittenberg M, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): results of long-term survival. Neuroendocrinology. 2017;104(1):26-32. doi:10.1159/000443612
12 de Mestier L, Dromain C, d'Assignies G, et al. Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art. Endocr Relat Cancer. 2014;21(3):R105-R120. doi:10.1530/ERC-13-0365
13 Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology. 2012;95(2):135-156. doi:10.1159/000335629
14 Grozinsky-Glasberg S, Grossman AB, Gross DJ. Carcinoid heart disease: from pathophysiology to treatment--'something in the way it moves'. Neuroendocrinology. 2015;101(4):263-273. doi:10.1159/000381930
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