Abstract
BACKGROUND
Approximately 10–20% of nonsmall cell lung carcinomas (NSCLC) show neuroendocrine (NE) differentiation, as evaluated by panendocrine markers or ultrastructural evidence of dense‐core secretory granules. However, little is known regarding the prevalence and clinical implications of NE differentiation in patients with Stage I NSCLC.
METHODS
The authors analyzed 220 consecutive patients with Stage I NSCLC (pT1–T2N0M0) among 2100 patients with primary lung carcinoma who underwent surgical treatment between 1987 and 1993. Using light microscopy and immunohistochemical staining for synaptophysin, chromogranin A, and respiratory tract‐related hormones, 28 NSCLC specimens with NE differentiation (NSCLC‐ND) and 11 large cell neuroendocrine carcinoma (LCNEC) specimens were identified.
RESULTS
The 28 NSCLC‐ND specimens included 15 adenocarcinomas and 13 squamous cell carcinomas. Neoplastic cells with NE features never exceeded 20% in NSCLC‐ND specimens, whereas neoplastic cells amounted to 20–90% in LCNEC specimens. NSCLC‐ND specimens with > 5% NE‐differentiated tumor cells showed increased Ki‐67 labeling index (P = 0.007) and invasive phenotype, as evaluated by fascin immunoreactivity (P = 0.021). Patients with adenocarcinoma, but not with squamous cell carcinoma, who had > 5% NE‐differentiated cells had a worse clinical course compared with patients who had ordinary NSCLC, with reduced overall survival (P = 0.017) and disease free survival (P = 0.049). In multivariate analysis, NE differentiation > 5% neoplastic cells in patients with adenocarcinoma independently predicted a poorer prognosis (hazard ratio, 2.61; 95% confidence interval, 0.99–6.85). Hormone production was restricted to chromogranin positive NSCLC‐ND but did not affect prognosis.
CONCLUSIONS
Stage I adenocarcinomas with ≥ 5% NE tumor cells are clinically aggressive tumors, similar to LCNEC. Hormone production identifies a more fully developed neuroendocrine phenotype but is not relevant to prognosis. The identification of NE‐differentiated cells in patients with NSCLC may have clinical relevance. Cancer 2003;10:2487–97. © 2003 American Cancer Society.
DOI 10.1002/cncr.11376