An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Systematic Review and Meta-Analysis

Abstract

Background: Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors. Objectives: To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence. Methods: A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology. Results: Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1–200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 ± 2.7% with a specificity of 93.8 ± 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 × ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5–251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 ± 6.8% and specificity 79.4 ± 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 ± 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified. Conclusion: The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.

Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors: An ENETS Center of Excellence Experience

“…Of the 43 BPNEN patients, all were NETest-positive; however, only 11 (26%) were CgA-positive. Our results confirm previous observations that CgA measurements are ineffective in lung NENs [5, 17] and that the NETest is significantly more effective than CgA positivity as a diagnostic for lung NENs [37].…”

“…Finally, although CgA is considered ineffective as a biomarker in BPNENs [5] and recent studies and meta-analyses [17] have confirmed its lack of utility, we had the opportunity to evaluate whether it was as effective as the NETest. Of the 43 BPNEN patients, all were NETest-positive; however, only 11 (26%) were CgA-positive.…”

Utility of a ready-to-use PCR system for neuroendocrine tumor diagnosis

“…The positive NETest findings in IPMN and colon adenocarcinoma are consistent with observations from an earlier publication that identified minor overlap [35]. Similarly, positive NETest scores in lung neoplasia have recently been reported based upon the existence of neuroendocrine elements in lung cancer [36]. A histopathologically verified colon NEC and a G3 gastric NEC were both NETest-positive (score: 87 and 80, respectively) as would be predicted in tumors that have a neuroendocrine genotype and phenotype.…”

The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors

“…Some reports consider it to correlate with tumor biology and size and to provide information in respect of outcome [ 29 , 30 ]. More recently, the enthusiasm for the clinical use of CgA is much diminished as rigorous studies have demonstrated low utility [ 31 – 35 ]. Of particular concern has been the inability of the different assays to produce comparable data [ 36 – 41 ].…”