According to World Health Organization guidelines, Atypical Carcinoids (ACs) are well-differentiated lung neuroendocrine tumors with 2-10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria no further tools in predicting AC clinical outcome are proposed. Aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR2A, Ascl1, p53 and Rb1) were studied and correlated with disease free survival (DFS) and overall survival (OS). Fifty-eight of 370 tumors were defined as AC. Survival analysis showed that patients with Ascl1+ACs and those with OTP-ACs had a significantly worse DFS than patients with Ascl1-ACs and OTP+ACs, respectively. Combining Ascl1 and OTP expressions, groups were formed reflecting the aggressiveness of disease (p=0.0005). Ki-67 ≥10% patients had a significantly worse DFS than patients with Ki-67<10%. At multivariable analysis Ascl1 (present vs absent, HR=3.42, 95%CI 1.35-8.65, p=0.009) and OTP (present vs absent, HR=0.26, 95%CI 0.10-0.68, p=0.006) were independently associated with DFS. The prognosis of patients with Ki-67 ≥10% tended to be worse compared to that with Ki-67<10%. On the contrary, OTP (present vs absent, HR=0.28, 95%CI 0.09-0.89, p=0.03), tumor stage (III-IV vs I-II, HR=4.25, 95%CI 1.42-12.73, p=0.01) and increasing age (10-year increase, HR=1.67, 95%CI 1.04-2.68, p=0.03) were independently associated with OS. This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of post-operative recurrence.
