Digestion 2000;62(suppl 1):33–38

Tumor Markers in NeuroendocrineTumors

Barbro Erikssona Kjell Öberga Mats Stridsbergb

aSection for Endocrine Oncology, Department of Medical Sciences, and bDepartment of Clinical Chemistry,

University Hospital, Uppsala, Sweden

Barbro Eriksson, MD, PhDSection for Endocrine Oncology, Department of Medical SciencesUniversity HospitalS–751 85 Uppsala (Sweden)E-Mail barbro.eriksson@medsci.uu.se

ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com

© 2000 S. Karger AG, Basel0012–2823/00/0625–0033$17.50/0

Accessible online at:www.karger.com/journals/dig

Key WordsSpecific tumor markers W General tumor markers W

Chromogranin A W Neuropeptide K W Neuron-specific

enolase W Urinary 5-HIAA

AbstractMost neuroendocrine tumors produce and secrete a

multitude of peptide hormones and amines. Some of

these substances cause a specific clinical syndrome: car-

cinoid, Zollinger-Ellison, hyperglycemic, glucagonoma

and WDHA syndrome. Specific markers for these syn-

dromes are basal and/or stimulated levels of urinary 5-

HIAA, serum or plasma gastrin, insulin, glucagon and

vasoactive intestinal polypeptide, respectively. Some

carcinoid tumors and about one third of endocrine pan-

creatic tumors do not present any clinical symptoms and

are called ‘nonfunctioning’ tumors. Therefore, general

tumor markers such as chromogranin A, pancreatic poly-

peptide, serum neuron-specific enolase and subunits of

glycoprotein hormones have been used for screening

purposes in patients without distinct clinical hormone-

related symptoms. Among these general tumor markers

chromogranin A, although its precise function is not yet

established, has been shown to be a very sensitive and

specific serum marker for various types of neuroendo-

crine tumors. This is because it may also be elevated in

many cases of less well-differentiated tumors of neu-

roendocrine origin that do not secrete known hormones.

At the moment, chromogranin A is considered the best

general neuroendocrine serum or plasma marker avail-

able both for diagnosis and therapeutic evaluation and is

increased in 50–100% of patients with various neuroen-

docrine tumors. Chromogranin A serum or plasma levels

reflect tumor load, and it may be an independent marker

of prognosis in patients with midgut carcinoids.Copyright © 2000 S. Karger AG, Basel

Introduction

The biochemical diagnosis of neuroendocrine tumorsis very important in the clinical workup of patients. Theintroduction of radioimmunoassays for various peptidehormones in the middle of the 1960s increased the clinicalawareness of and the ability to diagnose neuroendocrinegastrointestinal tumors. During the following decadesspecific radioimmunoassays were developed for varioushormones and every laboratory made panels of differentassays. The peptides and amines secreted by neuroendo-crine tumors may serve as tumor markers not only fordiagnosis but also for follow-up of treatment of thesepatients, and there are indications that some markers mayalso have prognostic implications.

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34 Digestion 2000;62(suppl 1):33–38 Eriksson/Öberg/Stridsberg

Specific and General Tumor Markers

Neuroendocrine tumors are known to produce andsecrete a large number of peptide hormones and amines[1, 2]. These substances give rise to various clinical syn-dromes related to the hormone production. These well-known clinical syndromes include the carcinoid syn-drome, Zollinger-Ellison syndrome, hyperoglycemic syn-drome, glucagonoma syndrome, WDHA syndrome, andsomatostatinoma syndrome. Biochemical tumor markerscan be divided into specific and general markers. Specificmarkers for carcinoid tumors are urinary 5-HIAA, neuro-peptide K, substance P or other tachykinins causing thecarcinoid syndrome. Similarly, specific markers for endo-crine pancreatic tumors (EPTs) include gastrin, insulin,c-peptide, pro-insulin, vasoactive intestinal polypeptide,glucagon and somatostatin. General tumor markers forboth tumor types include chromogranins (Cgs), pancreat-ic polypeptide, HCG subunits. Already in a publicationfrom our group in 1990, we could demonstrate that thecirculating marker elevated in most cases of EPTs wasCgA (94%) followed by pancreatic polypeptide (74%) [2].Also, multiple hormone production was evident by thefact that as many as 62% had elevation of serum gastrinsometime during the clinical course of the disease consid-ering that only 30% presented the gastrinoma syndromeinitially. In a relatively recent publication from our group,different tumor markers in carcinoid tumors were lookedat [3]. Urinary 5-HIAA and neuropeptide K showed quitehigh sensitivity in midgut carcinoid tumors, whereas inforegut and hindgut carcinoid the sensitivity of thesemarkers was rather low. Plasma CgA on the other handwas elevated in 70–100% independent of tumor type.

Sometimes patients are encountered in whom a carci-noid syndrome is strongly suspected but measurements ofbasal fasting levels of hormones are normal. In such casesthe pentagastrin test with measurement of plasma tachy-kinins is quite sensitive [4], whereas in patients withrecurrent ulcer disease the secretin test measuring gastrincan detect a gastrinoma in 180% of cases [5].

Chromogranins

Neuroendocrine cells contain typical secretory gran-ules, called large dense-core vesicles based on their char-acteristic appearance on electron microscopy. In additionto the specific peptide hormones or neuropeptides, thesegranules also contain one or more Cg/secretogranin pro-teins [6, 7]. These belong to a unique family of secretory

proteins which share many biochemical properties as wellas an exclusive presence in neuronal and neuroendocrinesecretory granules [8, 9]. The first member of this familyto be identified was CgA. Its name derives from its origi-nal discovery in the catecholamine-containing chromaffingranules of the adrenal medulla [10]. Other well-charac-terized members of the family are CgB and secretograninII [9]. CgA is the best studied granin in humans. It showsthe widest distribution and is present in some cells that donot express CgB or secretogranin II [6, 7]. The physiologi-cal functions of CgA has gradually been elucidated,although many questions still remain. Its ubiquitous pres-ence in neuroendocrine tissues and its cosecretion withpeptide hormones and neuropeptides makes it a suitabletissue and serum marker of neoplasms of neuroendocrineorigin [11–14]. The gene encoding for CgA is located onchromosome 14 [5]. CgA is very hydrophilic with anabundance of charged, mostly acidic amino acids. It con-tains multiple sites with two or more adjacent basic aminoacids, far exceeding the number observed in other pro-teins [16]. CgA may be processed at its dibasic amino acidresidues into tissue-specific biologically active peptides.All members of the granin family contain multiple dibasicresidues and calcium-binding sites suggesting analogousfunctions. CgA is most closely related to CgB [17]. Bothcontain a disulfide-bonded loop structure near their ami-no termini with a highly homologous amino acid se-quence. This structure, which might have a role in direct-ing the Cgs to the right secretory vesicles, is not present inthe secretogranins [18]. The high degree of structuralhomology among Cgs in different mammalian speciessuggests conservation during evolution and this in turnimplicates important biological functions [11].

Pancreastatin is one of the cleavage products of CgAcorresponding to residues 248–303 of the CgA molecule[19]. Pancreastatin is a peptide which inhibits insulin andglucagon secretion from the endocrine pancreas [20, 21].It also suppresses parathyroid hormone secretion fromparathyroid cells [22]. In addition it has a regulatory effecton the secretion from non-endocrine cells including pari-etal cells and exocrine pancreas [23, 24]. During the lastyears several other peptide fragments of CgA have beendescribed. Vasostatin is a peptide derived from the N-terminal part of CgA. In some tissues it is present as a76-amino acid chain and in others as a 113-amino acidchain (called vasostatin I and II, respectively) [25, 26]. Ithas been shown to inhibit vasoconstriction of humanveins [27], to inhibit PTH secretion by bovine parathy-roid tissue [28], and most interesingly to stimulate celladhesion via interaction with integrins [29]. Another

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Tumor Markers in Neuroendocrine Tumors Digestion 2000;62(suppl 1):33–38 35

cleavage product, parastatin, inhibits PTH secretion [30].Chromostatin, another fragment of CgA, has been shownto be able to inhibit the release of catecholamines by adre-nal medulla cells [31]. A receptor for chromostatin hasbeen described on chromaffin cells that binds to the pep-tide with high affinity [32].

The proteolytic processing of CgA probably occursduring its stay in the dense-core vesicles [8]. Dependingon the type and amount of proteases present, the type andamount of the cleavage products may vary in differentneuroendocrine tissues [8, 33]. The present data supportthat peptides derived from intragranular processing ofCgA are coreleased with resident peptide hormones/amines and exert an immediate auto- and paracrine mo-dulatory effect on the secretory activity on neuroendo-crine cells. A classical endocrine effect on distant tissuesmay also be possible as these fragments of CgA are alsoreleased into the circulation [11]. Quite recently it hasbeen suggested that CgA and its fragment could play a rolein the regulation of cell adhesion due to storage and rapidrelease from neuroendocrine cells and neurons [29].

Immunohistochemistry

CgA is found throughout the neuronal and neuroendo-crine system. The endocrine cells are expressing the pro-tein in the endocrine cells of the anterior pituitary, para-follicular C cells of the thyroid, chief cells of the parathy-roids, islets cells of the pancreas and chromaffin cells ofthe adrenal medulla [34]. It is also present in the widespread neuroendocrine system of the bronchial and gas-trointestinal tract and of the skin (Merckel cells). CgA-positive cells have also been found in the prostate. Cellsthat are not of neuroendocrine origin lack CgA such asfollicular cells of the thyroid gland and steroid hormone-secreting cells of the adrenal cortex and the gonads.

Immunohistochemical techniques to detect the pres-ence of CgA in tumor tissues are widely used in clinicalpractice. A list of tumors for which CgA can serve as atissue marker is presented in table 1. In addition to typicalneuroendocrine neoplasms, tumors derived from the ner-vous system, such as ganglioneuroblastomas, ganglioneu-roma and neuroblastoma also show immunostaining forCgA [6]. Also neuroendocrine tumors that have lost theirability to produce peptide hormones (e.g. null-cell pitu-itary adenomas) contain CgA-positive immunostaining.Not only tumors but also neuroendocrine cell hyperplasia,such as gastric enterochromaffin-like (ECL) cells inchronic atrophic gastritis stain positively with CgA [34].

Table 1. CgA-positive neuroendocrine tumors by immunocyto-chemistry

Anterior pituitary tumorsACTH (Cushing)LH/FSHGH (acromegaly)TSHProlactinoma (CgB positive!)Null cell adenoma

Parathyroid tumorsMedullary thyroid carcinomaMerkel cell tumorNeuroendocrine GEP tumors

Carcinoids (foregut, midgut, hindgut)ECL-omaGastrinomaGlucagonomaInsulinoma (CgB positive!)SomatostatinomaVIP-omaNonfunctioning tumors

Ectopic ACTH-producing tumors(Bronchial carcinoids, endocrine pancreatic tumors)

Ganglioneuroma, neuroblastomaPheocromocytomaSmall cell lung cancerProstate cancer

In a study performed by Borch et al. [35], plasma CgAlevels correlated strongly with the endocrine cell densityin the fundic mucosa (p ! 0.001) and it was suggested thatthe elevated CgA was derived from the ECL cells ratherthan gastrin-producing cells.

The prolactin-producing cells of the pituitary lack CgAexpression but show positive staining with CgB anti-bodies. The same is also true for the ß cells of the pan-creas, which are sometimes negative with CgA. In agree-ment with this, some benign insulinomas are CgA-nega-tive but show positive CgB staining. It should also bepointed out that several non-endocrine tumors may showpositive immunoreaction for CgA in a limited number ofcells, e.g. in colorectal cancer and exocrine pancreatic can-cer.

Plasma and Serum Measurements

Since CgA is stored in a majority of different neuroen-docrine tumors, the release to the circulation can be usedas a ‘general’ marker for various neuroendocrine tumors.This is of particular interest in ‘nonfunctioning’ tumors,

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36 Digestion 2000;62(suppl 1):33–38 Eriksson/Öberg/Stridsberg

which may lack other suitable markers. It is also of valueto be analyzed when existing markers are either unstableor rapidly fluctuating, such as serotonin and catechol-amine levels in plasma.

The first radioimmunoassay for measurement of CgAwas reported by O’Connor et al. [12] in 1983, where it wasshown that most patients with established neuroendo-crine tumors had elevated levels of CgA. Since then sever-al radioimmunoassays have been developed. The prob-lem with many of these assays is that they are not actuallymeasuring CgA but possibly splice products such as pan-creastatin, and then the results will be very different. Pub-lished results and circulating levels of CgA from differentcenters may vary depending on what assay they have beenusing.

The plasma levels of CgA are elevated in various pep-tide-producing neuroendocrine tumors and the highestlevels are noted in patients with metastatic carcinoidtumors, particularly midgut carcinoids [3]. In malignantEPT plasma CgA varies from slightly elevated to extremelevels. Plasma CgB is usually a better marker for benigninsulin-producing tumors than CgA.

In an earlier study, involving 44 patients with malig-nant carcinoid tumors, 17 patients with sporadic EPT and11 patients with EPT as part of multiple endocrine neo-plasia type 1 (MEN1), plasma level of CgA was increasedin 99%, whereas CgB was increased in 88% and CgC in6% and pancreastatin in 46% of the patients, illustratingthat it is definitely superior to measure CgA compared topancreastatin [13].

In a publication by Janson et al. [3] the relationshipbetween tumor burden and plasma CgA levels was stud-ied and it was shown that among patients with midgutcarcinoids those with multiple liver metastases had signif-icantly higher levels than those with only a few livermetastases or lymph node metastases only. In a previousstudy of midgut carcinoid patients, who had undergonesurgery and after surgery small residual lymph node me-tastases were left, measurement of plasma CgA was com-pared to urinary 5-HIAA [36]. In this group of 25 patientswith limited disease, all had elevated plasma CgA, where-as only 3 had elevations of urinary 5-HIAA. Similarly, in astudy of plasma CgA levels in patients with MEN1, 40%of patients without other biochemical evidence of an EPThad elevation of CgA, whereas 60% of patients with bio-chemically unequivocal evidence of MEN1 and 100% ofradiologically verified EPT had increased levels [37].These results indicate that there is a correlation betweentumor burden and plasma CgA levels in patients withneuroendocrine tumors. In the latter study, a comparison

was made of the sensitivity of measurements of basal plas-ma CgA and the meal stimulation test in detecting earlyinvolvement of the endocrine pancreas in MEN1 and itwas found that the meal stimulation test is still the mostsensitive method, 75 versus 60% for CgA.

In a study by Bajetta et al. [38], CgA measurementsseemed to be superior to urinary 5-HIAA, neuron-specificenolase and carcinoembryonic antigen as tumor markersin a large group of patients with neuroendocrine tumors(n = 127). The specificity was quite high both for urinary5-HIAA and neuron-specific enolase (100%), whereas thesensitivity was rather low (35.1 and 32.9%, respectively).The corresponding figures for CgA were 86 and 68%.Tumor marker modifications were also studied duringfollow-up of patients and it was found that rises in CgAwere associated with progressive disease in 83% of pa-tients.

We have made similar observations in our patientmaterial [36, 37], where plasma CgA levels were followedtogether with other markers; CgA measurements are themost reliable markers in the follow-up of treatment. Fur-thermore, increases in plasma CgA usually precede radio-logical evidence of progression.

Elevated plasma CgA levels are not entirely specific fora neuroendocrine tumor [39]. Slightly elevated levels havebeen identified in patients with non-endocrine tumors.Neuroendocrine cells are multifocally located in smallnests or scattered within these tumors. Prostatic adeno-carcinomas coexpress CgA and prostate-specific antigensuggesting a common malignant precursor cell [40]. Lim-ited data suggest that prostatic adenocarcinoma contain-ing neuroendocrine cells are more resistant to hormonaltreatment. Similarly patients with colorectal adenocarci-noma containing numerous neuroendocrine cells seem tohave a worse prognosis [13]. On the other hand, patientswith pancreatic adenocarcinoma or non-small cell cancerwhose cancer contains many neuroendocrine cells, seemto have a better prognosis [41].

In addition, there are some other pitfalls in the inter-pretation of CgA levels. ‘False-positive’ elevation of CgAcan be seen in patients with renal impairment, liver fail-ure, atrophic gastritis and inflammatory bowel disease[37]. Also patients receiving proton pump inhibitors havea slight increase in CgA due to gastrin-induced ECL cellhyperplasia. Furthermore, physical stress induced by ex-ercise or somatic trauma can produce a slight elevation inCgA (about twofold) [2].

In patients with neuroendocrine tumors such as carci-noid tumors, an analysis of prognostic factors in 301patients showed that plasma CgA is an independent pre-

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Tumor Markers in Neuroendocrine Tumors Digestion 2000;62(suppl 1):33–38 37

dictor of bad prognosis in midgut carcinoid patientstogether with advanced age [3]. Independent observationsthat increased levels of CgA correlate with bad prognosisin different tumor diseases might indicate a role of CgA asa stimulator of growth, either the molecule itself or any ofthe splice products. Therefore ongoing studies analyzingsplice products of CgA in carcinoid patients might reveala correlation between some of the fragments and progno-sis in those patients.

Future Prospects

CgA is for the moment the most sensitive and reliablemarker both for immunohistochemistry and as a circulat-ing marker in patients with neuroendocrine tumors. Theimplications that Cgs may have tumor biological effectsneed to be further explored. Since CgA is present in prac-tically all neuroendocrine tumors one future applicationcould be to use it for in vivo imaging with the PET tech-nique.

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