Prognostic significance of CD44 and orthopedia homeobox protein (OTP) expression in pulmonary carcinoid tumours.

Abstract

CD44 and orthopedia homeobox protein (OTP) expressions have shown to be predictive of overall survival in pulmonary carcinoid (PC) tumours. The scope of the present study was to validate their role in PC patients and investigate potential application in clinical practice. Data was collected from patients presenting to a tertiary cancer centre diagnosed with PC between 2003 and 2015. Diagnosis was confirmed by central pathology review. Formalin-fixed paraffin-embedded (FFPE) tissue samples collected at diagnosis were scored using immunohistochemistry (H score) for standard CD44 and nuclear and cytoplasmic OTP protein expression. The study included 108 patients. High CD44/nuclear OTP (nOTP) expression was strongly associated with typical carcinoid (TC) histology (p < 0.001). Eighty-six patients, who underwent radical surgical resection, were selected to assess the impact of patient and tumour parameters on relapse-free survival (RFS). Sixty-nine (80 %) had TC and 17 (20 %) had atypical carcinoid tumours. On multivariate analysis, high CD44 and nOTP expression, TC histology and non-infiltrative tumour growth were associated with superior RFS. Early stage TC (stage pT1aN0) patients (N = 32; 46 %) had excellent prognosis irrespective of CD44/nOTP status. Importantly, TC patients with locally advanced disease (defined as >pT1aN0) and high CD44/nOTP expression (N = 26; 38 %) had excellent RFS (p = 0.005) compared to those with the same stage but low CD44 and/or nOTP (N = 11; 16 %). Additionally, the combination of CD44/nOTP expression and tumour growth pattern led to a more accurate prognostic system compared to the established WHO classification of PC tumours (concordance index = 0.902 vs 0.811, respectively, p < 0.001). Assessment of CD44/nOTP expression combined with tumour growth pattern identifies clear groups with largely different prognosis. These findings provide important information on how patients with these resected cancers should be followed up.