Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms

Abstract

Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN.

Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study.

Material and methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica).

Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression).

Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

Keywords: Biomarker; Bronchopulmonary; Carcinoid; Chromogranin A; Diagnosis; Lung; Prognosis.

Fig. 1.

CgA levels in BPNET/NEN training and test sets. a Training set CgA levels: In BPNET/NEN, mean level was elevated versus controls (* p < 0.01). In the test set, mean BPNET/NEN level was not different to controls (p = 0.2). b The AUC for differentiating BPNET/NEN from controls for the training set was 0.61 (95% CI 0.53–0.69, p = 0.015) and for the test set was 0.58 (95% CI 0.50–0.66, p = 0.076). c CgA levels were elevated in 33% (n = 66) of the 200 BPNET/NEN. The remaining 134 (67%) samples fell within normal levels (≤108 ng/mL). CgA, chromogranin A.

Fig. 2.

CgA levels in benign and malignant lung disease. a Mean CgA level in COPD (n = 27) was elevated (p = 0.0037) compared to controls (n = 140). Mean level in ACC (n = 62) was not elevated (p = 0.55), but the mean level was increased (p = 0.045) in SCC (n = 43). ACC and SCC CgA levels were significantly less than COPD (p < 0.005). IPF (n = 50) had elevated mean level compared to controls (p = 0.038). SCLC (n = 32) also exhibited elevated levels compared to controls (p < 0.0001). b AUC analysis could not differentiate COPD or IPF from BPNET/NEN (AUC 0.52–0.54, p = 0.48–64), and the AUC between ACC and SCC and BPNET/NEN was not statistically significant (AUC 0.61–0.63, p = 0.06). SCLC likewise could not be differentiated from BPNET/NEN (AUC 0.56, p = 0.23). CgA, chromogranin A; ACC, adenocarcinoma cell carcinoma; COPD, chronic obstructive pulmonary disorder; IPF, idiopathic pulmonary fibrosis; SCC, squamous cell carcinoma; BPNET, bronchopulmonary neuroendocrine tumor.

Fig. 3.

CgA measurement in histological variants and grades of BPNET/NEN. a Mean CgA level was significantly elevated (* p < 0.005) for AC (n = 84) but not TC (n = 116), compared with controls (n = 140). Both TC and AC had a similar proportion (30 and 36%, respectively) of elevated levels. b AUC analysis could not differentiate CgA levels between TC and AC (AUC 0.56, 95% CI 0.47–0.64, p = 0.21). c CgA levels between Grade 1 (Ki67 <4%; n = 67) and Grade 2 (Ki67: 5–24%; n = 39) BPC were not statistically significant (p = 0.45). Grade 3 (Ki67 >24%; n = 4) was lower but this was not statistically different (p = 0.56–0.72) compared to Grade 1 and 2. d The relationship between Ki-67 grading and CgA levels was not significant (Pearson r = 0.143, p = 0.136). CgA, chromogranin A; TC, typical; AC, atypical; AUC, area under the curve.

Fig. 4.

Assessment of CgA in stable and PD. a Mean CgA level between SD (n = 145) and PD (n = 55) was not significant (p = 0.47). Mean levels in SD and PD were increased (* p = 0.018–0.048) compared with controls (n = 140). Both SD and PD had a similar proportion (32 and 31%, respectively) of elevated levels. b AUC analysis for differentiating SD from PD was not statistically significant (AUC 0.53, 95% CI 0.44–0.62, p = 0.47). CgA, chromogranin A; PD, progressive disease; AUC, area under the curve.

Fig. 5.

Clinical utility of CgA and BPNET/NEN monitoring. a CgA levels of 22 patients with progressive disease either treated with SSA (n = 16) or not treated (n = 6) over a 12-month period. b Spider plot analysis identified a significant difference (increase, p = 0.0021) of SSA treatment on CgA. c CgA levels of 27 patients with SD either treated with SSA (n = 4) or not treated (n = 23) over a 12-month period. d Spider plot analysis was unable to differentiate an impact of therapy (p = 0.84) over the evaluation period. CgA, chromogranin A.