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Cited by 268Neuroendocrine Tumor Research AdvancesPituitary Gland Disorders and TreatmentsGastrointestinal Bleeding Diagnosis and Treatment

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers

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O’Toole, Dermot, Grossman, Ashley, Gross, David, Delle Fave, Gianfranco, Barkmanova, Jaroslava, O’Connor, Juan, Pape, Ulrich-Frank, Plöckinger, Ursula·2009·Neuroendocrinology
DOI 10.1159/000225948
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Abstract

Neuroendocrine tumors (NETs) originating from the midgut may result in functional symptoms due to the secretion of various peptides and hormones and most notably 5-hydroxytryptamine (5-HT) or serotonin. This is a tryptophan-derived biogenic amine involved in smooth muscle contraction, blood pressure regulation and both peripheral and central nervous system neurotransmission. Approximately 2% of dietary tryptophan is converted into serotonin. Serotonin is synthesized and stored in enterochromaffin cells of the gastrointestinal tract (80% of total body serotonin content), in dense granules of platelets (storage only) and in the serotoninergic neurons of the central nervous system. The urinary breakdown metabolite of serotonin is 5-hydroxyindole acetic acid (5-HIAA) which is particularly useful in the diagnosis and follow-up of NETs with carcinoid syndrome. Serum measurements of serotonin are possible in these patients; however, large individual variation makes them unreliable for diagnosis and in follow-up. Universally, 5-HIAA is the most frequently performed assay in the clinical setting of the carcinoid syndrome.The overall sensitivity and specificity of urinary 5-HIAA in the presence of the carcinoid syndrome is of the order of 70 and 90%, respectively [1, 2]. Midgut carcinoids are most liable to produce the carcinoid syndrome with 5-HIAA elevation, thus attesting to a high specificity (>90%) in this setting. Fore- and hindgut NETs produce less serotonin than midgut tumors [1, 3]. The sensitivity is lower in patients with midgut carcinoid tumors without the carcinoid syndrome. Urinary 5-HIAA levels may also depend on tumor volume and may be normal in patients with non-metastatic carcinoid tumors. Levels may be normal even in the presence of the carcinoid syndrome, particularly in subjects without diarrhoea; however, this is a rare event [4]. In functional midgut tumors, discriminating performances may vary depending on whether the cut-offs are high or low. Meijer et al. [1] demonstrated that a low level 5-HIAA cut-off value (2.8 mmol/mol creatinine) yielded 68% sensitivity and 89% specificity, whereas a higher cut-off (6.7 mmol/mol creatinine) improved specificity to 98% at the expense of a lower sensitivity (52%). Thus, in order to confidently exclude a carcinoid tumor, a low-level cut-off value may be preferred; to confirm the presence of a carcinoid tumor, a high-level cut-off value is better. Some patients with the carcinoid syndrome excrete non-hydroxylated indole acids, not measured as 5-HIAA. There appears to be an inconstant correlation between 5-HIAA level and the clinical severity of the carcinoid syndrome; this may be related to a fluctuating release of serotonin from tumors such that the correlation may not be reliable. Recent data have examined 5-HIAA as a prognostic factor in these patients: while interesting data have emerged, the expert group felt that data have not confirmed 5-HIAA levels to be a consistently reliable prognosticfactor in this disease. To illustrate this, two studies including 256 and 139 patients with midgut carcinoid tumors showed that while elevated 5-HIAA levels were predictive of poor outcome at univariate analysis, this did not remain significant at multivariate analysis [5, 6]. In another study examining 76 patients, those with persistent moderately increased urinary 5-HIAA levels (≤20 mmol/mol creatinine) had a more favourable outcome compared to those with greatly elevated levels [7]. A further study in a mixed tumor group including 119 patients (53 of midgut origin) interestingly found high 5-HIAA to be an independent survival factor [8].While several assays are available to measure 5-HIAA (thin-layer chromatography, enzyme immunoassay, gas chromatography, gas chromatography-mass spectrometry) [9,10,11,12], the use of high-performance liquid chromatography (HPLC) is most frequently employed. HPLC with electrochemical detection is currently recommended; however, automated assays [13] or those using mass spectrometry [12] may be available in some laboratories. Liquid chromatography tandem mass spectrometry assay appears to be a rapid assay with little necessity for repeat analyses because of chromatographic interference or dilutions [12]. A further automated method with on-line solid-phase extraction and HPLC and fluorometric detection has recently been shown to have increased precision and faster throughput compared to the manual solvent extraction method [14]. Whatever technique is used, it should be performed in accredited laboratories.Conditions for Optimal Assay (fig. 1)Urine should be collected and measured in plastic containers. Acid should be added to ensure sterility and hence stability. The sample should be stored in a refrigerator until analysis. All the urine passed over 24 h should be collected into the container, preferably by using a measuring jug. Collecting should be started at a defined time point following urination, and after that urine should be

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  • Chromogranin A has replaced 24-h urine collection of 5-hydroxyindoleacetic acid and is the most important tumour marker in monitoring neuroendocrine tumours during and after treatment, and is recommended by the European NeuroEndocrine Tumor Society.

    “Chromogranin A (CgA) has replaced the 24-h urine collection of 5-hydroxyindoleacetic acid and has become the most important tumour marker in the monitoring of NET during and after treatment and is recommended by the European NeuroEndocrine Tumor Society (Korse et al, 2009; O'Toole et al, 2009).”

    From Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours (2011) · cites this paper as O'Toole et al, 2009

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  1. Service FJ: Hypoglycemic disorders. N Engl J Med 1995; 332: 1144-1152.
  2. Hirshberg B, Skarulis MC, Pucino F, Csako G, Brennan R, Gorden P: Repaglinide-in- duced factitious hypoglycemia. J Clin Endo- crinol Metab 2001; 86: 475-477.
  3. Jensen RT, Niederle B, Mitry E, et al: Gastri- noma (duodenal and pancreatic). Neuroen- docrinology 2006; 84: 173-182.
  4. O'Connor DT, Deftos LJ: Secretion of chro- mogranin A by peptide-producing endo- crine neoplasms. N Engl J Med 1986; 314: 1145-1151.
  5. Goebel SU, Serrano J, Yu F, Gibril F, Venzon DJ, Jensen RT: Prospective study of the value of serum chromogranin A or serum gastrin levels in the assessment of the presence, ex- tent, or growth of gastrinomas. Cancer 1999; 85: 1470-1483.
  6. O'Toole D: Current trend: endocrine tumors of the stomach, small bowel, colon and rec- tum (in French). Gastroenterol Clin Biol 2006; 30: 276-291.
  7. Levinson SS, Miller JJ: Towards a better un- derstanding of heterophile (and the like) an- tibody interference with modern immuno- assays. Clin Chim Acta 2002; 325: 1-15.
  8. Leon A, Torta M, Dittadi R, et al: Compari- son between two methods in the determina- tion of circulating chromogranin A in neu- roendocrine tumors: results of a prospective multicenter observational study. Int J Biol Markers 2005; 20: 156-168.

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Authors
O’Toole, D., Grossman, A., Gross, D., Delle Fave, G., Barkmanova, J., O’Connor, J., Pape, U.-F., & Plöckinger, U.
Affiliations
  • Uppsala University (SE)
  • Hôpital Beaujon (FR)
  • Hadassah Medical Center (IL)
  • University of Oxford (GB)
  • National Institutes of Health (US)
  • Charité – Universitätsmedizin Berlin (DE)
  • University of Zurich (CH)
ORCID
Venue
Neuroendocrinology
Publisher
S. Karger AG
Published
2009
Volume
90
Issue
2
Pages
194-202
ISSN
  • 0028-3835 (ISSN-L)
  • 1423-0194
DOI
10.1159/000225948
OpenAlex
W1973304341
Cited by
268
References
63
Citations by year
2026: 2 · 2025: 11 · 2024: 13 · 2023: 3 · 2022: 15 · 2021: 16 · 2020: 16 · 2019: 12 · 2018: 20 · 2017: 20 · 2016: 17 · 2015: 20 · 2014: 32 · 2013: 22 · 2012: 22
FWCI
10.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Open Access CRIS of the University of Bern
Funders
  • Università degli Studi di Genova
  • Rigshospitalet
  • Chinese Academy of Medical Sciences
  • Akademiska Sjukhuset
  • Università degli Studi di Torino
  • Uppsala Universitet
  • Università degli Studi di Verona
  • Peking Union Medical College Hospital
  • Peking Union Medical College
  • Erasmus Universitair Medisch Centrum Rotterdam
Topics
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal Bleeding Diagnosis and Treatment
Keywords
neuroendocrine tumors, carcinoid syndrome, 5-hydroxyindoleacetic acid, urinary 5-HIAA, serotonin, biochemical markers, sensitivity and specificity, cut-off values, enterochromaffin cells, follow-up monitoring, standard of care, functional tumors
MeSH terms
Fasting, Humans, Hydroxyindoleacetic Acid, Hypoglycemia, Insulinoma, Secretin, Gastrinoma, Biomarkers, Neuroendocrine Tumors, Chromogranin A

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