Background: Increased levels of chromogranin A (CgA), a protein secreted by many neuroendocrine cells, have been detected in sera of patients with neuroendocrine tumors or renal, hepatic, or heart failure. In patients with heart failure, serum CgA correlates with tumor necrosis factor-alpha (TNF) and soluble TNF receptors (sTNF-Rs), with important prognostic implications. The prognostic value of CgA and sTNF-Rs was investigated in advanced nonsmall cell lung cancer (NSCLC), a histologically heterogeneous group of tumors that may undergo neuroendocrine differentiation.
Methods: CgA and sTNF-Rs were analyzed in the sera of 88 patients with NSCLC before chemotherapy by enzyme-linked immunoadsorbent assay (ELISA) and in tumors by immunohistochemistry.
Results: Thirteen percent of patients had CgA values greater than the highest value observed in normal subjects (distribution range, 9-724 ng/mL and 28-196 ng/mL, respectively). Immunohistochemical studies showed no correlation between CgA expression in tumors and serum levels. Conversely, circulating CgA was associated with worse Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P = .0005), more advanced stage (P = .042), and survival, with CgA being an independent prognostic factor of poor outcome (hazards ratio [HR] 1.31 for 100 ng/mL increase; 95% confidence interval [95% CI], 1.08-1.60 [P = .0071]). sTNF-R1 and sTNF-R2 were also associated with ECOG PS (P = .0001 and P = .02, respectively). sTNF-Rs was weakly correlated with circulating CgA (r = 0.39 for TNF-R1 and r = 0.40 for TNF-R2), suggesting a regulatory link between sTNF-Rs and CgA secretion.
Conclusions: Increased serum levels of CgA in NSCLC are independent from protein expression in tumors and more likely related to neuroendocrine response associated with worsening of patient condition. In addition to ECOG PS and stage, CgA is an independent indicator of poor prognosis.