ENETS Guidelines

Neuroendocrinology 2009;90:194–202 Received: August 27, 2008

Accepted after revision: October 24, 2008
DOI: 10.1159/000225948
Published online: August 28, 2009

ENETS Consensus Guidelines for the

Standards of Care in Neuroendocrine Tumors:
Biochemical Markers
Dermot O’Toolea Ashley Grossmanb David Grossc Gianfranco Delle Faved
Jaroslava Barkmanovae Juan O’Connorf Ulrich-Frank Papeg Ursula Plöckingerg
and all other Mallorca Consensus Conference participants
a
Department of Gastroentereology and Clinical Medicine, St. James’s Hospital and Trinity College, Dublin, Ireland;
b
St. Bartholomew, West Smithfield, London, UK; cDepartment of Endocrinology and Metabolism, Hadassah University
Hospital, Jerusalem, Israel; dOspedale S. Andrea, Rome, Italy; eDepartment of Oncology, University Hospital,
Prague, Czech Republic; fInstituto Alexander Fleming, Buenos Aires, Argentina; gDepartment of Hepatology and
Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany

Standards for the Detection and Interpretation of Performance of 5-HIAA in Diagnosis

5-Hydroxyindole Acetic Acid The overall sensitivity and specificity of urinary 5-
HIAA in the presence of the carcinoid syndrome is of the
Background/Definition order of 70 and 90%, respectively [1, 2]. Midgut carcinoids
Neuroendocrine tumors (NETs) originating from the are most liable to produce the carcinoid syndrome with
midgut may result in functional symptoms due to the se- 5-HIAA elevation, thus attesting to a high specificity
cretion of various peptides and hormones and most no- (190%) in this setting. Fore- and hindgut NETs produce
tably 5-hydroxytryptamine (5-HT) or serotonin. This is less serotonin than midgut tumors [1, 3]. The sensitivity
a tryptophan-derived biogenic amine involved in smooth is lower in patients with midgut carcinoid tumors with-
muscle contraction, blood pressure regulation and both out the carcinoid syndrome. Urinary 5-HIAA levels may
peripheral and central nervous system neurotransmis- also depend on tumor volume and may be normal in pa-
sion. Approximately 2% of dietary tryptophan is convert- tients with non-metastatic carcinoid tumors. Levels may
ed into serotonin. Serotonin is synthesized and stored in be normal even in the presence of the carcinoid syn-
enterochromaffin cells of the gastrointestinal tract (80% drome, particularly in subjects without diarrhoea; how-
of total body serotonin content), in dense granules of ever, this is a rare event [4]. In functional midgut tumors,
platelets (storage only) and in the serotoninergic neurons discriminating performances may vary depending on
of the central nervous system. The urinary breakdown whether the cut-offs are high or low. Meijer et al. [1] dem-
metabolite of serotonin is 5-hydroxyindole acetic acid (5- onstrated that a low level 5-HIAA cut-off value (2.8
HIAA) which is particularly useful in the diagnosis and mmol/mol creatinine) yielded 68% sensitivity and 89%
follow-up of NETs with carcinoid syndrome. Serum mea- specificity, whereas a higher cut-off (6.7 mmol/mol cre-
surements of serotonin are possible in these patients; atinine) improved specificity to 98% at the expense of a
however, large individual variation makes them unreli- lower sensitivity (52%). Thus, in order to confidently ex-
able for diagnosis and in follow-up. Universally, 5-HIAA clude a carcinoid tumor, a low-level cut-off value may be
is the most frequently performed assay in the clinical set- preferred; to confirm the presence of a carcinoid tumor,
ting of the carcinoid syndrome. a high-level cut-off value is better. Some patients with the

© 2009 S. Karger AG, Basel Dermot O’Toole

0028–3835/09/0902–0194$26.00/0 Department of Gastroenterology and Clinical Medicine
Fax +41 61 306 12 34 St. James’s Hospital and Trinity College Dublin, James’s Street
E-Mail karger@karger.ch Accessible online at: Dublin 8 (Ireland)
www.karger.com www.karger.com/nen Tel. +353 1 410 3815, Fax +353 4 410 3492, E-Mail otooled1@tcd.ie
carcinoid syndrome excrete non-hydroxylated indole ac-
ids, not measured as 5-HIAA. There appears to be an in- U On day 1, urinate into the container upon rising in the
morning.
constant correlation between 5-HIAA level and the clin- U Collect all subsequent urine for the next 24 h.
ical severity of the carcinoid syndrome; this may be re- U On day 2, urinate into the container upon rising in the
lated to a fluctuating release of serotonin from tumors morning.
such that the correlation may not be reliable. Recent data U Keep the sample in the refrigerator or a cool place during
have examined 5-HIAA as a prognostic factor in these the collection period. Upon completion, return it as in-
structed as soon as possible.
patients: while interesting data have emerged, the expert
group felt that data have not confirmed 5-HIAA levels to Some foods contain high levels of serotonin which may increase
be a consistently reliable prognostic factor in this disease. the levels of urinary 5-HIAA and consumption should be avoided
To illustrate this, two studies including 256 and 139 pa- 3 days prior to urine collection: plums, pineapples, bananas, egg-
tients with midgut carcinoid tumors showed that while plants, tomatoes, avocados, and walnuts.
elevated 5-HIAA levels were predictive of poor outcome Certain medications may also interfere with the assay. If on med-
at univariate analysis, this did not remain significant at ications this should be discussed with your specialist physician
multivariate analysis [5, 6]. In another study examining who will give further advice.
76 patients, those with persistent moderately increased
urinary 5-HIAA levels (^20 mmol/mol creatinine) had
Fig. 1. Procedure for collection of a 24-hour urine sample.
a more favourable outcome compared to those with great-
ly elevated levels [7]. A further study in a mixed tumor
group including 119 patients (53 of midgut origin) inter-
estingly found high 5-HIAA to be an independent sur- collected until the same time point the next day (a precise
vival factor [8]. 24-hour collection). Written instructions should be
handed out including food and medication precautions
Assays for 5-HIAA (fig. 1).
While several assays are available to measure 5-HIAA
(thin-layer chromatography, enzyme immunoassay, gas Care in Interpreting 5-HIAA Levels
chromatography, gas chromatography-mass spectrome- Intraindividual variation of 5-HIAA is also possible
try) [9–12], the use of high-performance liquid chroma- and this variation may be high, therefore two consecutive
tography (HPLC) is most frequently employed. HPLC 24-hour collections should be performed and the mean
with electrochemical detection is currently recommend- value of these two can be taken, especially when the col-
ed; however, automated assays [13] or those using mass lection is required for diagnosis. A single specimen may
spectrometry [12] may be available in some laboratories. be sufficient for follow-up purposes. Certain co-morbid-
Liquid chromatography tandem mass spectrometry as- ities or associated disorders may have effects on the con-
say appears to be a rapid assay with little necessity for centration of 5-HIAA. Falsely low 5-HIAA levels may be
repeat analyses because of chromatographic interference encountered in patients with renal impairment and those
or dilutions [12]. A further automated method with on- on haemodialysis. In addition, 5-HIAA may be increased
line solid-phase extraction and HPLC and fluorometric in untreated patients with malabsorption, who have in-
detection has recently been shown to have increased pre- creased urinary tryptophan metabolites. Such patients
cision and faster throughput compared to the manual sol- include those with gluten-sensitive enteropathy (coeliac
vent extraction method [14]. Whatever technique is used, disease), tropical sprue, Whipple disease, intestinal stasis
it should be performed in accredited laboratories. and cystic fibrosis (chronic intestinal obstruction) [1, 15];
plasma 5-HT, but not urinary 5-HIAA, have been elevat-
Conditions for Optimal Assay (fig. 1) ed in diarrhoea-predominant irritable bowel syndrome
Urine should be collected and measured in plastic [16]. A small number of normal individuals may have el-
containers. Acid should be added to ensure sterility and evated urinary 5-HIAA and therefore other objective
hence stability. The sample should be stored in a refrig- findings should be used in conjunction with tumor mark-
erator until analysis. All the urine passed over 24 h should er analysis to support the diagnosis of a carcinoid [17].
be collected into the container, preferably by using a mea- The following food substances are rich in dietary trypto-
suring jug. Collecting should be started at a defined time phan and therefore patients should abstain from these for
point following urination, and after that urine should be 3 days prior to urinary collection: plums, pineapples, ba-

Standards of Care in NETs – Biochemical Neuroendocrinology 2009;90:194–202 195

Markers
nanas, eggplants (aubergines), tomatoes, avocados and ture similar to patients with insulinoma and may be di-
walnuts [2, 18, 19]. Certain medications may increase or agnosed by a positive drug screen [21]. An overall ap-
decrease 5-HIAA urinary levels as follows: proach to diagnosing and managing insulinoma has been
– Increased: acetanilide, phenacetin, glyceryl guaiaco- provided elsewhere in a recent consensus statement [22].
late (found in many cough syrups), methocarbamol,
and reserpine, cisplatin, fluorouracil, melphalan, rau- Supervised 72-Hour Fast
wolfia. This test has been verified as the gold standard in estab-
– Decreased: chlorpromazine, heparin, imipramine, lishing a biochemical diagnosis of insulinoma [23]. Pa-
isoniazid, levodopa, monoamine oxidase inhibitors, tients should be hospitalized in a specialist unit experi-
methenamine, methyldopa, phenothiazines, prometh- enced in performing the test. A 72-hour period is univer-
azine, and tricyclic antidepressants, chlorophenylala- sally recognized as the most appropriate duration [22]
nine, corticotrophin, guanfacine, imipramine, isocar- although some groups have proposed a shorter fast of 48 h
boxazid, isoniazid, levodopa, MAO inhibitors, mo- [24, 25]. Symptoms appear within 12 h for one third of pa-
clobemide, octreotide. tients, 80% within 24 h, 90% with 48 h and approaching
Patients are frequently treated with somatostatin ana- 100% within 72 h [26]. Absolute values of glucose and in-
logues and these are known to decrease levels of 5-HIAA; sulin are the most important variables and any measurable
where possible, assays for diagnostic purposes should be insulin is abnormal when blood glucose drops to 2.5
made in patients not on somatostatin analogues, while in mol/l (45 mg/dl). Assays used for the determination of in-
the follow-up setting, comparisons should be performed sulin, pro-insulin, C-peptide and ␤-hydroxybutyrate may
in patients on stable or comparable doses. vary but should be performed in accredited laboratories.
Very occasionally, an insulinoma is only revealed by hypo-
glycaemia induced by a mixed meal rather than fasting.
Insulinoma: 72-Hour Fast
Patient Information Scheme
NETs secreting insulin are termed insulinomas and A detailed description of the fast should be provided
are almost exclusively intrapancreatic in nature. Exces- to all patients with an information card to help in symp-
sive insulin secretion leading to hypoglycaemia usually tom identification. Patients should stay off all foods ex-
results in a combination of neurologic (diplopia, blurred cept for plain water, black tea or coffee and essential med-
vision, confusion, abnormal behavior and amnesia, sei- ications (particularly hypoglycaemic agents, e.g., sulpho-
zures, coma, etc.) and autonomic (sweating, weakness, nylureas).
hunger, tremor, nausea, feelings of warmth, anxiety, pal-
pitations) symptoms. Symptoms are usually related to the Procedure
degree of insulin-induced hypoglycaemia but may be The timing of the 72-hour fast is not critical – some
non-specific. Hypoglycaemia-induced clinical signs are teams prefer to perform the test early in the week when
classically present in the early morning preprandial phase staffing levels may be higher and avoiding prolonging the
or may be exercise-induced. The diagnosis is suggested in test into the weekend. An oral glucose tolerance or mixed
the presence of: (1) symptoms of hypoglycaemia; (2) glu- meal test can be performed before the fast. The patient
cose !2.2 mmol/l (40 mg/dl; others use a threshold of !3 should be monitored in a supervised environment and
mmol/l, 50 mg/dl), and (3) relief of symptoms with ad- fasting should be accompanied by an intravenous line.
ministration of glucose [20]. This is known as Whipple’s – Absolute blood (venous) determinations should be
triad. The 72-hour fast is the gold standard for diagnos- performed at least 2–4 times per day and when the
ing insulinoma and relates to the integrity of patients’ patient describes symptoms. The test interpretation
endogenous suppression of insulin in the face of hypogly- should be made using laboratory blood glucose assays;
caemia. The fast attests to autonomous insulin secretion bedside measurements can be used in the presence of
and the failure of appropriate insulin suppression in the clinical symptoms to determine if more definitive
presence of hypoglycaemia. Factitious hypoglycaemia measurements should be made.
secondary to exogenous use of insulin is suspected on the – Blood should also be drawn for insulin measurement
finding of high (often very high) serum insulin in com- concurrently with glucose estimations, and assay for
bination with suppression of C-peptide. Sulphonylureas insulin and C-peptide when the hypoglycaemia is
and related insulin secretagogues result in a clinical pic- confirmed.

196 Neuroendocrinology 2009;90:194–202 O’Toole /Grossman/Gross /Delle Fave/

Barkmanova /O’Connor /Pape /Plöckinger
– ␤-Hydroxybutyrate (or urinary ketones) should be ZES. Indeed, in a recent prospective analysis, up to two-
measured at the end of the test in order to confirm the thirds of gastrinoma patients were found to have FSG val-
validity of the fast. A low level of hydroxybutyrate in ues !10-fold normal [27]. The gold standard is the secre-
the presence of hypoglycaemia confirms inappropri- tin test [27–31]. This hormone, when given intravenously
ate insulin or insulin-like hormone secretion. provokes an increase in serum gastrin and secondarily in
– A urinary assay for sulphonylureas should be per- gastric acid secretion. The most reliable data concerning
formed as a specific request. the secretin test have emanated from the National Insti-
• Not all drugs are detected, e.g. repaglinide [21]; tute of Health studies in patients with sporadic and mul-
false positive results may also occur, e.g. on para- tiple endocrine neoplasia type-I (MEN1)-associated gas-
cetamol. trinomas [27–31]. Recent consensus guidelines have de-
• The results need to be confirmed with the local lab- scribed the criteria used for establishing the diagnosis of
oratory. gastrinoma [31]; however, according to the expert com-
mittee, acid output studies are available to only a limited
Definition of Hypoglycaemia number of groups (including those experts’ groups). For
The endpoint of the test is documented hypoglycae- the NIH group the secretin test was useful in diagnosing
mia. ZES regardless of the extent or locations of the tumor, the
– Documented blood glucose levels ^2.2 mmol/l (^40 presence or absence of MEN1 or the level of FSG (less
mg/dl; according to some !3 nmol/l, 50 mg/dl; levels than or greater than 1,000 pg/ml) [28]. In patients with
may depend on age and sex); fasting gastrin !1,000 pg/ml, the sensitivity of the secre-
– Concomitant insulin levels 16 ␮U/l (636 pmol/l; 63 tin test using the criterion delta (increase from prestimu-
␮U/l by ICMA); lation level) gastrin of 6110 pg/ml was 93% (CI 76–99%)
– A ␤-hydroxybutyrate level ^2.7 mmol/l can be used and for a delta gastrin of 200 pg/ml sensitivity was 85%
as a surrogate marker to confirm the validity of the fast (CI 66–96%) (p 1 0.05) [28]. The same group recently re-
and inappropriate insulin suppression; ported their prospective experience on gastrin provoca-
– A glucagon test immediately after 72-hour fasting in tive tests in 293 patients from the NIH with ZES and com-
patients without definite results has also been recom- pared with 537 ZES patients in the literature and 462 non-
mended; ZES patients (again from the literature) [30]. This group
– Exercise test immediately after 72-hour fasting in pa- established a delta gastrin of 6120 pg/ml in patients with
tients without definitive results may be performed in !10-fold increase as having the highest sensitivity and
a supervised setting; specificity (94 and 100%, respectively) [30]. They also
– Use of a ratio of insulin to glucose to aid in the diag- demonstrated the clear superiority of the secretin provo-
nosis is not recommended. cation test compared to the calcium test (94 vs. 62%).
However, in ZES patients with a negative secretin test the
calcium provocation test may be helpful [30]. The expert
Standards for the Diagnosis of a Gastrinoma: group noted that certain groups had difficulty in obtain-
Secretin Test ing secretin, hindering accurate diagnosis.

The diagnosis of Zollinger-Ellison syndrome (ZES) Indications for Gastrin Provocative Tests: Secretin Test
can be established by the demonstration of elevated fast- – The secretin test is performed to confirm a biochemi-
ing serum gastrin (FSG) in the presence of low gastric pH. cal diagnosis of gastrinoma. The test may be repeated
FSG alone is not adequate to make the diagnosis of ZES during the follow-up after curative surgery. FSG should
because hypergastrinaemia can be seen in patients with be performed prior to secretin test; if FSG 11,000 pg/
achlorhydria associated with chronic atrophic fundus ml a secretin test is not necessary. When FSG lies be-
gastritis (e.g., pernicious anaemia) and in other condi- tween 200 and 1,000 pg/ml, a secretin test should be
tions with hyperchlorhydria (e.g., Helicobacter pylori in- performed;
fection, gastric outlet obstruction, renal failure, antral G- – The following conditions should also be document-
cell syndromes, short bowel syndrome, retained antrum). ed:
In addition, the use of chronic proton pump inhibitors ] Absence of fundic atrophic gastritis
(PPIs) leads to high FSG levels and therefore gastrin pro- • Antral and fundic biopsies (8 serology for anti-
vocative tests are needed to establish the diagnosis of parietal and intrinsic factor antibodies);

Standards of Care in NETs – Biochemical Neuroendocrinology 2009;90:194–202 197

Markers
 • 24-hour pH-metry (loss of diurnal pH course); Serum Chromogranin A
basal acid output is recommended pre and post
secretin where possible; BAO 115 mmol/h is Chromogranin A (CgA) is an acid glycoprotein with
highly suggestive of diagnosis of ZES; a random 439 amino acids that is present in the secretory dense core
pH analysis during upper gastrointestinal en- granules of most neuroendocrine cells [32]. The chromo-
doscopy was also suggested (this requires fur- granin family consists of at least three different water-
ther evaluation); soluble acidic glycoproteins (CgA, CgB, and secreto-
• Helicobacter pylori testing; granin II, sometimes called chromogranin C). Upon
] Other conditions leading to high FSG should be stimulation, CgA and other peptide hormones and neu-
considered, including: gastric outlet obstruction, ropeptides are released. CgA is also secreted from neuro-
renal failure, antral G-cell syndromes, short bowel endocrine-derived tumors including foregut, midgut and
syndrome, retained gastric antrum. hindgut gastrointestinal NETs, pheochromocytomas,
neuroblastomas, medullary thyroid carcinomas, some
Preparation for Secretin Test pituitary tumors, functioning and non-functioning pan-
– If possible, PPIs should be interrupted 10 days to 2 creatic NETs and other amine precursor uptake and de-
weeks prior to the test (PPIs for 2 weeks can be re- carboxylation tumors. CgA has also been widely used as
placed by H2 blockers); interruption of H2 blockers for an immunohistochemical marker in NETs [33] and is rec-
approximately 48 h prior to test, however, interruption ognized as the most effective. CgA has been recognized
of all anti-secretory medications should be individu- as a general serum marker, as it is co-secreted in tumors
ally adapted and patients should be warned of re-ap- with the amines and peptides that are present in the neu-
parition of symptoms and should have sufficient anti- rosecretory granules [34] and can be elevated in both
secretory medications to start should they become functionally active and non-functional NETs. Specificity
symptomatic; certain patients may have to be hospital- of elevated CgA is related to tumor type and is almost
ized during anti-secretory therapy withdrawal; universally elevated in patients with gastrinoma [35–37].
– Heparinized vacutainers are used and should be la- It is often high in NETs from midgut origin and non-
beled and placed in ice. functioning pancreatic NETs. Differences in tumor cell
type, histological differentiation and tumor volume may
Secretin Test influence the level of CgA and interpretation may also
– Patient fasting overnight, 12–14 h. depend on the assay used in measurement.
– Site indwelling i.v. cannula.
– Kabi-secretin (2 U/kg body weight) is given by intra- Reliability of CgA in Patients with NETs
venous bolus. Overall CgA has been found to be clinically informa-
– Serum gastrin tive and moderately sensitive in the majority of studies
] baseline measured at –15, and –1 min before test; devoted to this topic. CgA was found to be more sensitive
] 2, 5, 10, 15, 20, and 30 min after secretin. than neurone-specific enolase in all subgroups of a large
– Samples stored on ice (immediate transfer to labora- mixed NET patient cohort (n = 128) [38]. While perfor-
tory). mances have been limited in low-level cut-offs due to the
Possible side effects of the secretin test include flush, overlap with control populations, very high levels of se-
allergic reaction. rum CgA are rarely found outside the setting of NETs
with the exception of patients on gastric acid secretory
Interpretation of Results blockers, especially PPIs (see below) [39] or those with
– Delta gastrin at least 200 pg/ml any time during the hypergastrinaemia. Specificity of CgA in the diagnosis of
test is considered as positive. NETs depends on the tumor type and burden (100% spec-
– The NIH has recently published a delta gastrin of ificities have been reported in patients with metastatic
6120 pg/ml as having a high sensitivity and specific- disease [40–43]), the quality of the control populations
ity (94 and 100%, respectively) [30]. used and the cut-off values employed [36, 44]. Elevated
CgA was found to be more sensitive than high urinary 5-
HIAA levels in patients with metastatic midgut lesions
(87 vs. 76%, respectively) [5]. Nobels et al. [35] demon-
strated a significant positive relation between the serum

198 Neuroendocrinology 2009;90:194–202 O’Toole /Grossman/Gross /Delle Fave/

Barkmanova /O’Connor /Pape /Plöckinger
levels of CgA and the tumor mass in NETs; however, the for the diagnosis of NET than the measurement of frag-
distinction between high and low tumor volume may be ments [34, 59]. Stridsberg et al. [44] compared the three
open to question. This study also confirmed tissue speci- commercially available kits in a group of NET patients
ficities as high CgA concentrations were found in all pa- and found sensitivities to vary between 67 and 93%,
tients with gastrinoma, although small in size and tumor while specificities were 185% for all three. A recent mul-
volume [35]. In a mixed series of 128 patients with NET, ticentre prospective comparison between two methods,
increased CgA levels were found in 29 and 67% of patients immunoradiometric and ELISA, found a 36% clinical
with locoregional or metastatic disease, respectively [38]. discordance rate [60]. These results were mirrored with
Nonetheless, the prognostic value of CgA in patients with a difference of 5-fold inter-laboratory variation rate in a
NET has not been confirmed to date. recent Italian study aimed at assessing CgA detection
False-positive elevation of CgA may occur in the fol- performance as applied to immunoradiometric and ELI-
lowing circumstances: SA assays [61]. A further prospective analysis underlined
– Impaired renal function [45, 46]; CgA to be a practical marker in patients with NET, how-
– Parkinson disease, untreated hypertension and preg- ever, with limited diagnostic power; using RCO curves,
nancy; a cut-off of 53 ng/ml for IRMA and 16 U/l for ELISA for
– Steroid treatment or glucocorticoid excess, which can discriminating between healthy controls and NET pa-
lead to up-regulation of CgA mRNA [47, 48]; tients yielded only moderate sensitivities (71.3 and 83%,
– Chronic atrophic gastritis (type A) [49]; respectively) and specificities (71 and 85%, respectively)
– Treatment with anti-secretory medications, especially [43].
PPIs [39].
Chronic elevation of gastrin levels provokes hyperpla-
sia of the neuroendocrine cells of the stomach, and these
cells are able to secrete CgA [50]. In patients with chron- General Remarks on CgA
ically elevated CgA and ZES, Stabile et al. [51] demon- – CgA is the most practical and useful general serum tu-
strated that the CgA concentrations can be normalized mor marker in patients with NET;
by gastrectomy alone, without resection of the gastrin- – Elevated CgA can occur in normal individuals and in
producing tumor. A more recently described case report patients with non-NET tumors although the levels are
usually lower than in patients with NET;
of false-positive CgA was due to the presence of hetero-
– Sensitivity of elevated CgA varies according to NET tu-
phile antibodies (HAb), which can bind to animal anti- mor type and volume.
gens and may be present in up to 40% of the normal pop-
ulation [52]; in the CgA immunometric assays, HAb CgA Assays and Interpretation
interferences may be circumnavigated by using a HAb- – Reference laboratories should be preferred for clinical
blocking tube [53]. samples assays;
– Reference intervals and individual patient results differ
significantly between different chromogranin A assays
Assays for CgA and cannot be directly compared;
A recognized international standard for CgA assay is – Serial measurements should be performed using the
not available and variations in assay types may influence same assay;
results. Several assays for measurements of intact CgA – If assays are changed, patients should undergo a new
and cleavage products have been developed [34, 54]. The baseline measurement;
– False-positive results are possible in patients with hy-
complexity of assays is explained by the presence of sev- pergastrinaemia (especially on anti-secretory medica-
eral CgA-related peptides from human and other species tions or chronic atrophic gastritis type A) and in the
[55] and CgA processing varies according to neuroendo- presence of heterophile antibodies (care in patients au-
crine cells/tissue [56, 57]. A competitive radioimmuno- toimmune disease or those sensitized to rodent proteins
assay can detect circulating CgA, with the use of purified (mouse monoclonal antibodies));
– Where possible, proton pump inhibitors should be in-
full-length human CgA [41, 58]. Commercial CgA kits terrupted, leaving a clearance of at least 3 half-lives, pri-
differ in the types of antibodies used (monoclonal vs. or to CgA plasma sampling.
polyclonal) and include enzyme detection (ELISA) and
radioimmunoassay. Differences in methods of standard-
ization have also led to heterogeneity. Generally, mea-
surement of intact CgA in plasma has greater sensitivity

Standards of Care in NETs – Biochemical Neuroendocrinology 2009;90:194–202 199

Markers
 List of Participants Dik Kwekkeboom, Department of Nuclear Medicine, Erasmus
University Medical Center, Rotterdam (The Netherlands); Ra-
List of Participants of the Consensus Conference on the chida Lebtahi, Nuclear Medicine Department, Bichat Hospital,
ENETS Guidelines for the Standard of Care for the Paris (France); Val Lewington, Royal Marsden, NHS Foundation
Diagnosis and Treatment of Neuroendocrine Tumors, Trust, Sutton (UK); Anne Marie McNicol, Division of Cancer Sci-
Held in Palma de Mallorca (Spain), November 28 to ences and Molecular Pathology, Pathology Department, Royal
December 1, 2007 Infirmary, Glasgow (UK); Emmanuel Mitry, Hepatogastroenter-
Göran Åkerström, Department of Surgery, University Hospi- ology and Digestive Oncology, Hôpital Ambroise-Paré, Bou-
tal, Uppsala (Sweden); Bruno Annibale, University Sapienza logne (France); Ola Nilsson, Department of Pathology, Sahlgren-
Roma, Rome (Italy); Rudolf Arnold, Department of Internal ska sjukhuset, Gothenburg (Sweden); Kjell Öberg, Department of
Medicine, Philipps University, Munich (Germany); Emilio Ba- Internal Medicine, Endocrine Unit, University Hospital, Uppsa-
jetta, Medical Oncology Unit B, Istituto Nazionale Tumori, Mi- la (Sweden); Mauro Papotti, Department of Biological and Clini-
lan (Italy); Yuan-Jia Chen, Department of Gastroenterology, Pe- cal Sciences, University of Turin/St. Luigi Hospital, Turin (Italy);
king Union Medical College Hospital, Chinese Academy of Med- Marianne Pavel, Department of Hepatology and Gastroenterol-
ical Sciences, Beijing (China); Frederico Costa, Hospital Sirio ogy, Campus Virchow-Klinikum, Charité-Universitätsmedizin
Libanes, Centro de Oncologia, São Paulo (Brazil); Anne Couve- Berlin, Berlin (Germany); Aurel Perren, Institut für Allgemeine
lard, Service de Gastroentérologie, Hôpital Beaujon, Clichy Pathologie und Pathologische Anatomie der Technischen Uni-
(France); Joseph Davar, Department of Cardiology, Royal Free versität München, Klinikum r.d. Isar, Munich (Germany); Marco
Hospital, London (UK); Wouter de Herder, Department of Inter- Platania, Istituto Nazionale dei Tumori di Milano, Milan (Italy);
nal Medicine, Section of Endocrinology, Erasmus MC, Rotter- Guido Rindi, Department of Pathology and Laboratory Medi-
dam (The Netherlands); Barbro Eriksson, Medical Department, cine, Università degli Studi, Parma (Italy); Philippe Ruszniewski,
Endocrine Unit, University Hospital, Uppsala (Sweden); Massi- Service de Gastroentérologie, Hôpital Beaujon, Clichy (France);
mo Falconi, Medicine and Surgery, University of Verona, Verona Ramon Salazar, Institut Català d’Oncologia, Barcelona (Spain);
(Italy); Diego Ferone, Departments of Internal Medicine and En- Aldo Scarpa, Department of Pathology, University of Verona, Ve-
docrinological and Metabolic Sciences, University of Genoa, Ge- rona (Italy); Klemens Scheidhauer, Klinikum rechts der Isar, TU
noa (Italy); Björn Gustafsson, Medisinsk avd, Gastroseksjon, St München, Munich (Germany); Jean-Yves Scoazec, Anatomie
Olavs Hospital, Trondheim (Norway); Rudolf Hyrdel, II. Internal Pathologique, Hôpital Edouard-Herriot, Lyon (France); Anders
Medical Department, University Hospital Martin, Martin (Slo- Sundin, Department of Radiology, Uppsala University Hospital,
vakia); Diana Ivan, Endocrinology and Diabetology, Klinikum Uppsala (Sweden); Waldemar Szpak, Westville Hospital, May-
der Philipps-Universität, Marburg (Germany); Gregory Kaltsas, ville (South Africa); Babs Taal, Netherlands Cancer Centre,
G. Genimatas Hospital, Athens (Greece); Reza Kianmanesh, UFR Amsterdam (The Netherlands); Pavel Vitek, Institute of Radia-
Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, tion Oncology, University Hospital, Prague (Czech Republic);
Hôpital Louis Mourier, Colombes (France); Günter Klöppel, In- Marie-Pierre Vullierme, Service de Gastroentérologie, Hôpital
stitut für Pathologie, TU München, Munich (Germany); Ulrich- Beaujon, Clichy (France); Bertram Wiedenmann, Department of
Peter Knigge, Department of Surgery, Rigshospitalet, Copenha- Internal Medicine, Division of Hepatology and Gastroenterolo-
gen (Denmark); Paul Komminoth, Institute for Pathology, Stadt- gy, Campus Virchow-Klinikum, Charité-Universitätsmedizin
spital Triemli, Zürich (Switzerland); Beata Kos-Kudła, Slaska Berlin, Berlin (Germany).
Akademia Medyczna Klinika Endokrynologii, Zabrze (Poland);

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