Ascl1 and OTP identify four prognostic groups among atypical carcinoids

Introduction: Atypical Carcinoids (AC) according to World Health Organization guidelines are well differentiated Lung Neuroendocrine tumor with 2-10 mitoses/2 mm2 and/or with necrosis. Besides morphological differentiation no further tools in predicting AC clinical outcome are proposed. Aim(s): Identify novel factors able to predict AC disease aggressiveness and progression. Materials and methods: 370 lung carcinoids from several hospitals were collected and centrally reviewed by three experienced pathologists. Immunohistochemistry (IHC) was performed for Ki-67, TTF-1, CD44, OTP, Sstr2a, Ascl1, p53 and Rb. Morphologic and IHC data were correlated with Overall Survival (OS) and Disease-free Survival (DFS). Results: Fifty-eight of 370 tumors were defined as ACs. Survival analysis showed that Ascl1- patients had a significantly longer DFS than Ascl1+ patients (p=0.0014). Furthermore, OTP+ patients had longer DFS than those OTP- (p=0.02). Merging Ascl1 and OTP expression, 4 groups were formed reflecting the aggressiveness of disease (p=0.0005). At Multivariate analysis Ascl1 [Present vs absent, HR=2.90, 95% CI 1.26-6.68, p=0.01], OTP [Present vs absent, HR=0.35, 95% CI 0.15-0.82, p=0.01] and Ki-67 [≥10 vs <10, HR=3.11, 95%CI 1.04-9.31, p=0.04] were associated with DFS. OTP [Present vs absent, HR=0.24, 95% CI 0.08-0.73, p=0.02], tumor stage [III-IV vs I-II, HR=3.83, 95% CI 1.39-10.6, p=0.009] and years increase in age [10-year increase, HR 1.60, 95% CI 1.02-2.50, p=0.04] were independently associated with OS. Conclusion: ACs could be further classified in 4 prognostic subgroups driven by Ascl1 and OTP expression. ACs with Ki-67 ≥10 were associated with reduced DFS.