Elsevier

European Journal of Cancer

Volume 48, Issue 12, August 2012, Pages 1766-1773
European Journal of Cancer

Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours?

https://doi.org/10.1016/j.ejca.2011.11.005Get rights and content

Abstract

Introduction

Chromogranin A (CgA) is the principal tumour marker for gastroenteropancreatic neuroendocrine tumours (GEPNET). Combining serum CgA and pancreatic polypeptide (PP) levels may increase the sensitivity of tumour markers in the diagnosis of GEPNET.

Objectives

(1) To evaluate the sensitivity of PP and CgA in GEPNET. (2) To compare changes in serum CgA and PP levels with the morphological evolution of the tumours.

Patients and methods

Sixty-six pancreatic and 49 gastrointestinal NET, with at least one serum determination of CgA and PP at the same time were retrieved from an institutional data base. Secondly, the variations in serum CgA or PP at successive determinations were compared to Response Evaluation Criteria in Solid Tumours (RECIST) criteria in 57 patients (112 follow-up visits) with high serum CgA levels and in 21 patients (37 follow-up visits) with high serum PP levels.

Results

Among the 115 patients included in the study group, an increase in serum CgA (normal <98 μg/L) or PP (normal <100 pmol/L) was found in respectively 79 (69%) and 36 (31%) cases. Seven patients had normal CgA and elevated PP levels. Both markers were significantly more elevated in metastatic disease (74% versus 51% for CgA and 37% versus 18% for PP). The concordance rates between serum markers and RECIST criteria were 51% for CgA and 54% for PP.

Conclusions

Serum PP determination identify few false-negative results of serum CgA determination in GEPNET. Our study does not validate the use of CgA or PP as surrogate markers for detecting changes in tumour burden.

Introduction

Well-differentiated gastroenteropancreatic neuroendocrine tumours (GEPNET) are heterogeneous tumours sharing some common features such as the capacity for hormone secretion and the expression of characteristic differentiation markers. Tumour growth rate is one of the major prognostic factors. It is usually evaluated through the evaluation of clinical symptoms and regular imaging studies (every 3–12 months), allowing decision-making ranging from close surveillance, through liver directed treatment in case of predominant liver metastases, to systemic therapy. Therefore, assessment of tumour burden changes is essential for the management of patients with GEPNET. However, repeating imaging studies is a cumbersome and expensive practice, especially in view of the long course of the disease. Therefore, a serum marker that correlates with disease progression would be clinically very useful.

Chromogranin A (CgA) is the most useful tumour marker in patients with GEPNET.1, 2 CgA is a 49-kilodalton (kD) acidic glycoprotein, specifically expressed by peptidergic endocrine cells. CgA plays major roles in the storage and secretion of hormones within the large dense core vesicles typical of peptidergic endocrine cells. It is physiologically released by exocytosis and may be detected in blood. Immunocytochemical detection of CgA is the gold standard to confirm the ‘neuroendocrine’ character of tumour cells. CgA is also used as a serum marker. In patients with GEPNET, previous studies have shown different ranges of sensitivity and specificity according to the stage, secretory activity, primary tumour, somatostatin analogues, and differentiation.2, 3, 4, 5, 6, 7 CgA seems to provide a more sensitive assessment as compared to other biomarkers.8, 9 Korse et al. recently reported its use for the diagnosis of carcinoid heart disease in combination with BNP.10 Some studies, but not all, have suggested a linear correlation between serum CgA levels and tumour burden,6, 11 and that serum CgA levels could be an independent prognosis factor of overall survival.10, 12 In addition, early CgA response to some treatments may correlate with improved progression-free survival.12, 13 Lastly, the sensitivity and specificity of concordance between CgA and morphological change is 71–100% and 22–100%, respectively.8, 14, 15, 16, 17, 18, 19 However, false positive results are possible: CgA levels may be elevated in a number of other cancers and in other non-neoplastic conditions.2, 19 In addition, no standardisation exists for its measurement: different techniques, based on enzyme-linked immunosorbent assay (ELISA) or immunoradiometric assay (IRMA) assays, have been developed.2, 20

Pancreatic polypeptide (PP), whose physiological role remains to be fully elucidated, has also been proposed as a potential NET marker.21, 22 PP is composed of 36 amino acids produced by a distinct type of endocrine cell located primarily in the islets of Langerhans of the pancreatic head, by pancreatic NET, and sometimes by gastrointestinal (GI) NET.23 Panzuto et al. reported increased PP levels in 63% of pancreatic NET and in 53% of patients with primary GI NET.24 The combined assessment of PP and CgA may lead to a significant increase in sensitivity in the diagnosis of GEPNET, particularly for pancreatic NET.24 However, to date, no clear data exist about its use in the follow-up of patients with GEPNET.

Therefore, the purposes of this retrospective study were: (1) to determine whether combining serum determinations of PP and CgA could improve the sensitivity of serum determinations of CgA alone for the assessment of tumour burden in patients with GEPNET; (2) to compare changes in serum CgA and PP levels with the evolution of RECIST morphological criteria in patients with high CgA levels or high PP levels.

Section snippets

Patients

From June 2004 to March 2008, we retrospectively studied all patients with GEPNET referred to our institution with at least one blood sample for simultaneous CgA and PP serum measurements in our laboratory. Bronchial or other primitives of NET were excluded from the study. The tumours were diagnosed, classified, and graded according to the classifications.25, 26 Characteristics of the 115 patients enroled are described in Table 1. The median follow-up since the diagnosis was 2.1 (0–41.2) years.

Results of CgA and PP measurements at baseline

Serum levels of CgA and PP at baseline (median and range) were 168 (24–61024) μg/L and 32 (20–64317) pmol/L, respectively (Fig. 1). Out of the 115 patients included, 79 (69%) and 36 (31%) had serum CgA and PP levels above the reference range; 62 (54%) and 18 (16%) patients had serum CgA and PP levels above two normal ranges, respectively; the distribution of measurements is given in Fig. 1. Seven patients had normal CgA and elevated PP levels.

A multiple endocrine neoplasia type 1 (MEN1) was

Discussion

The present study deals with the practical interest of the determination of serum PP levels in combination with that of CgA for the diagnosis and follow-up of GEPNET. Our study was prompted by the report from Panzuto et al. that, in 68 patients, the combined assessment of PP and CgA increased the sensitivity of the diagnosis of GEPNET, particularly in pancreatic NET.24 However, to date, no clear data are available about the interest of this approach for the follow-up of patients with GEPNET.

PP

Conflict of interest statement

None declared.

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