Differential expression of forkhead box M1 and its downstream cyclin-dependent kinase inhibitors p27kip1 and p21waf1/cip1 in the diagnosis of pulmonary neuroendocrine tumours

Abstract

Aims: Pulmonary neuroendocrine (NE) tumours represent a spectrum of phenotypically distinct entities with different biological behaviours. Difficulties in classifying these tumours are frequently encountered in clinical practice. Forkhead box M1 (FoxM1) is essential for the development of various cancers and is a proliferationspecific transcription factor that regulates transcription of cell cycle genes, including cyclin-dependent kinase inhibitors p27(kip1) and p21(waf1/cip1). This study was performed to determine the utility of FoxM1, p27(kip1) and p(21waf1/cip1) as immunomarkers for subtyping pulmonary NE tumours. Methods and results: FoxM1, p27(kip1) and p21(waf1/cip1) expression was evaluated by immunohistochemistry in 60 pulmonary NE tumours [19 typical carcinoids TCs), six atypical carcinoids (ACs), 17 large cell neuroendocrine carcinomas (LCNECs) and 18 small cell lung cancers (SCLCs)]. The frequencies of FoxM1 and p21 waf1/cip1 expression were significantly different between TCs and ACs (each P = 0.009), and those of FoxM1 and p27 kip1 expression were significantly different between LCNECs and SCLCs (P = 0.012 and P = 0.002, respectively). The combined FoxM1 ())/ p21 waf1/cip1()) and FoxM1 (+)/p27 kip1(high) phenotypes had the best diagnostic accuracy for distinguishing TCs from ACs, and SCLCs from LCNECs, respectively. Conclusions: FoxM1, p27 kip1 and p21 waf1/cip1 showed distinct immunoreactivity according to histological subtype, which may be of value as an ancillary test in the differential diagnosis of pulmonary NE tumours.