Centonze Giovanni, Maisonneuve Patrick, Simbolo Michele, Lagano Vincenzo, Grillo Federica, Prinzi Natalie, Pusceddu Sara, Missiato Loretta, Colantuono Marilena, Sabella Giovanna, Bercich Luisa, Mangogna Alessandro, Rolli Luigi, Grisanti Salvatore, Benvenuti Mauro Roberto, Pastorino Ugo, Roz Luca, Scarpa Aldo, Berruti Alfredo, Capella Carlo, Milione Massimo
1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Histopathology. 2023 May;82(6):870-884. doi: 10.1111/his.14873. Epub 2023 Feb 21.
According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/2 mm 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.
根据世界卫生组织的指南，非典型类癌（ACs）是分化良好的肺神经内分泌肿瘤，每2毫米有2 - 10个有丝分裂象和/或坏死灶（通常为点状）。除形态学标准外，未提出其他预测AC临床结局的工具。这项工作的目的是确定能够预测AC疾病侵袭性和进展的新因素。方法与结果：收集了370例肺类癌，并由两位专家病理学家进行集中评估。研究了形态学和免疫组化标志物（Ki-67、TTF-1、CD44、OTP、SSTR2A、Ascl1、p53和Rb1），并将其与无病生存期（DFS）和总生存期（OS）相关联。370例肿瘤中有58例被定义为AC。生存分析表明，Ascl1阳性的AC患者和OTP阴性的AC患者的DFS分别显著差于Ascl1阴性的AC患者和OTP阳性的AC患者。结合Ascl1和OTP的表达，形成了反映疾病侵袭性的分组（P = 0.0005）。Ki-67≥10%的患者的DFS显著差于Ki-67<10%的患者。在多变量分析中，Ascl1（存在与否，风险比[HR]=3.42，95%置信区间[CI]1.35 - 8.65，P = 0.009）和OTP（存在与否，HR = 0.26，95%CI 0.10 - 0.68，P = 0.006）与DFS独立相关。Ki-67≥10%的患者的预后往往比Ki-67<10%的患者更差。相反，OTP（存在与否，HR = 0.28，95%CI 0.09 - 0.89，P = 0.03）、肿瘤分期（III - IV期与I - II期，HR = 4.25，95%CI 1.42 - 12.73，P = 0.01）和年龄增加（每增加10岁，HR = 1.67，95%CI 1.04 - 2.68，P = 0.03）与OS独立相关。结论：这项对肺ACs的回顾性分析表明，Ascl1和OTP可能是术后复发的主要预后驱动因素。
