Lung carcinoid tumours: histology and Ki-67, the eternal rivalry

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj = 0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade

Novel morphological tools in predicting pancreatic neuroendocrine tumors (Pan-Net) clinical outcome

Introduction: Pancreatic Neuroendocrine Tumor (Pan-NET) clinical outcome shows a high variability among patients within the same World Health Organization (WHO) category. To date, there is a lack of markers to predict recurrence after resection, which makes it difficult to identify patients with higher risk of progression. Aim(s): To evaluate morphologic and clinicopathological features of surgically resected Pan-NET. Materials and methods: Surgical specimens of 150 Pan-NET patients were evaluated for the following diagnostic and prognostic tools: Tumor stage, Ki-67, parenchymal infiltration, neural and vascular invasion, tumor necrosis or sclerosis and tumor deposits. These data were correlated with Overall Survival (OS) and stage I-II-III Disease-Free Survival (DFS). Results: Overall, 76 (50.7%) patients showed localized (stage I-II), 22 (14.7%) locally advanced (stage III), and 52 (34.7%) metastatic disease (stage IV). Tumor size >2 cm (p<0.0001), Ki-67 index (p=0.001), parenchymal infiltration (p=0.0002), vascular and neural invasion (p<0.0001 and p=0.0008) and tumor deposits (p=0.001) were correlated with locally advanced-metastatic disease. At univariate analysis parenchymal infiltration, presence of tumor deposits and necrosis were associated with OS (p=0.03, 0.04 and 0.008) and DFS (p=0.001, 0.007 and <0.0001) while vascular and perineural invasion were correlated only with DFS (p=0.003 and 0.001). Multivariate model showed that locally advanced disease (HR=2.56, p=0.02), parenchymal infiltration (HR=3.83, p=0.008) and tumor deposits (HR=2.45, p=0.03) were correlated with lower DFS. Conclusion: Both parenchymal infiltration and presence of tumor deposits represent emerging tools in predicting tumor recurrence

Ascl1 and OTP tumour expressions are associated with disease-free survival in lung atypical carcinoids

According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2–10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. Methods and results: 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 tumours 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 versus absent, hazard ratio [HR] = 3.42, 95% confidence interval [CI] 1.35–8.65, P = 0.009) and OTP (present versus 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 versus absent, HR = 0.28, 95% CI 0.09–0.89, P = 0.03), tumour stage (III-IV versus 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. Conclusion: This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of postoperative recurrence