Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments

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Abstract

Background

Chromogranin A (CgA) is the most important tumour marker for well-differentiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differentiated neuroendocrine carcinoma (NEC). This study investigated whether the markers progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and CK19 (MonoTotal®) can be of additional value to the histological classification and help predict survival in these patients.

Methods

CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET (G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteristics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox regression analyses.

Results

The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively) when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivariate survival analysis, only CKfr was associated with survival (P < 0.0001) for patients with well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC, both CKfr and NSE were associated with survival (P < 0.0001 and P = 0.003, respectively).

Conclusion

Within all histological groups a combination of tumour markers proved to be more informative as diagnostic and prognostic marker than each marker alone. In patients with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in patients with SCNEC, proGRP and CKfr are preferred.

Introduction

Classification of neuroendocrine tumours (NET) is an area of ongoing debate.32, 33, 39 In 2010, the WHO released a new classification scheme for the digestive system based on histological grade.4 This classification divides NETs into well-differentiated NET, including grade 1 and 2 (G1NET and G2NET) and poorly differentiated (grade 3) neuroendocrine carcinoma (NEC), including large and small cell neuroendocrine carcinoma (LCNEC and SCNEC). Meanwhilst, the classification for lung tumours has not changed since 1994 and was already based on grade of differentiation.39 These tumours are divided into typical (comparable to grade 1) and atypical (comparable to grade 2) carcinoid, based on the number of mitoses per high-power field in combination with the presence of necrosis.

Currently, chromogranin A (CgA) is the most frequently used marker, especially in the management of patients with well-differentiated NET, but has some limitations, as various assays are available and an international standardisation is lacking. In addition, elevated CgA levels may be caused by renal or liver failure, and the use of proton pump inhibitors.13, 22 For poorly differentiated NEC, neuron-specific enolase (NSE) is the marker of choice.8, 9, 29 NSE is present in neurons and neuroendocrine cells and can therefore serve as biomarker. Progastrin-releasing peptide (proGRP) is a promising tumour marker for small cell lung cancer (SCLC).23, 25 ProGRP is the precursor of the neuropeptide gastrin-releasing peptide (GRP) and its production is increased in SCLCs.23, 25 Molina et al. described elevated levels in patients with NET, but the histological characteristics of these tumours were not mentioned. Cytokeratin fragments (CKfr) are sensitive indicators of tumour cell turnover and thus especially useful in the management of patients with malignancies of epithelial origin.3 MonoTotal® is an assay used to determine cytokeratin 8, 18 and 19 (CK8, CK18 and CK19) fragments in serum. Moreover, CKfr is associated with angiogenesis factors which may play a role in NET; however, CKfr has not yet been investigated in NET.5, 10

Therefore, this study evaluates the role of CgA, NSE, proGRP and CKfr in the diagnosis and prognosis of NET.

Section snippets

Patients

Serum samples of all consecutive patients diagnosed with NETs from 1994 until 2009 were used for the present study with their consent. From each patient one blood sample was taken at the time of initial presentation to our institute. After centrifuging, serum was stored at −30 °C until measurement.

Patients were divided into two main groups according to the WHO classification4, 16, 38: well-differentiated NET (G1NET and G2NET); and poorly differentiated NEC (grade 3) with LCNEC and SCNEC. In

Results

For this study a total of 855 serum samples were collected: 282 healthy persons, 280 well-differentiated NET and 293 poorly differentiated NEC (Table 1). Almost half of the patients (264/573 = 46%), were pretreated before referral to our institute. In patients with G1NET, most tumours originated in the gastro-intestinal tract (n = 129, 53%). In 81 patients with metastatic disease (33%), the primary tumour site was unknown. The lung was the predominant site in G2NET and SCNEC: 50% and 80%,

Discussion

This is the first study in which the tumour markers progastrin-releasing peptide (proGRP) and cytokeratin fragments CK8, CK18 and CK19 (CKfr) in addition to the established markers CgA and NSE were investigated in patients with NET. Recently published studies demonstrated the relevance of classifying the NET according to improved histopathological grading.21, 30, 34 Therefore, this grading system (from G1 to G3) was also applied in our study group.

In recent years CgA showed the highest

Role of the funding source

Novartis Pharma B.V. and Abbott Diagnostics had no role in the study design or in the collection, analysis and interpretation of data.

Conflict of interest statement

None declared.

Acknowledgements

The authors would like to thank Abbott Diagnostics and Novartis Pharma B.V. for their funding.

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