The Effect Of Cribriform Pattern On Survival Prognosis Of Patients With Acinar Predominant Lung Adenocarcinoma

Background and ObjectiveLung cancer is the most common type of cancer worldwide,with pulmonary adenocarcinoma(ADC)being the most common histological type.Morphologically,pulmonary ADC is heterogeneous and defined as a predominant subtype.Invasive ADC can be divided into lepidic(Lep)predominant,papillary(Pap)predominant,acinar(Aci)predominant,solid(Sol)predominant and micropapillary(Mip)predominant ADC,as established by the International Association for the Study of Lung Cancer(IASLC),American Thoracic Society(ATS)and the European Respiratory Society(ERS).The cribriform(Cri)pattern is not a subtype in lung ADC,but one of the types of Aci predominant.In recent years,several studies have demonstrated that patients with Cri pattern have poor prognosis.This study was performed to examine the effect of Cri pattern for the clinicopathology and prognosis in patients with Aci predominant ADC,meanwhile,we proposed the conception of Cri predominant ADC of the lung and further explored the relevant clinicopathological characteristics,molecular characteristics and survival prognosis of Cri predominant ADC.MethodsHistological subtypes were evaluated in 279 patients who underwent complete resection for ADC of the lung.Firstly,patients of the Aci predominant were divided into two subgroups according to the percentage of Cri pattern(?5%vs.<5%),and clinicopathological characteristics,overall survival(OS)and disease-free survival(DFS)were compared.Secondly,when the percentage of Cri pattern was the largest,we proposed the conception of Cri predominant lung ADC,and divided the original Aci predominant lung ADC into Cri predominant and pure Aci predominant ADC.Both clinicopathological characteristics and survival prognosis were compared between patients with Cri predominant and pure Aci predominant ADC.Finally,we restricted study to the patients with pure Aci predominant tumours.In this cohort,the cases were further divided into two groups based on Cri percentage(?5%vs.<5%)to analyze the clinical pathological characteristics.Results(1)Cri pattern,ranged from 5%to 100%of the total tumour volume(mean±SEM,30%±2%),was found in 111(39.8%)cases of 279 patients.The Cri pattern was most found in Aci predominant(79/117,67.5%),followed by Sol predominant(21/76,27.6%),Mip predominant(4/19,21.1%)and Pap predominant(6/45,13.3%),lowest in Lep predominant ADC(1/22,4.5%).Cri pattern was associated with aggressive pathological behaviour,including advanced TNM(Tumour,node,metastases)stages of cancer,obvious nuclear atypia,more mitoses,lymph node invasion,metastasis and larger tumour size.(2)The subgroup with Cri pattern?5%in the Aci predominant ADC(n=117)had significantly poorer survival prognosis(OS,P<0.001;DFS,P=0.005)compared to the Cri pattern<5%subgroup.Moreover,Cox multivariate analyses revealed that the Cri pattern ? 5%was an independent negative predictor for OS(HR,2.768;95%CI,1.079-6.695;P=0.034)but not DFS(HR,1.632;95%CI,0.807-3.301;P=0.173).(3)There were 33 Cri predominant patients and 84 pure Cri predominant patients in 117 Aci predominance patients.OS(P=0.035)was significantly lower in the Cri predominant group(n=33)than in the pure Aci predominant group(n=84),and similar to those of patient with Sol predominant(P=0.268)and Mip predominant(P=0.514).(4)In 84 pure Cri predominant cohort,patients in the?5%group showed unfavourable clinical outcomes compared to their counterparts(OS,P=0.001;DFS,P=0.006).Multivariate survival analyses showed that Cri pattern were still independent poor predictors for OS(HR,2.883;95%CI,1.102-7.546;P=0.031).(5)The Cri predominant tumour expressed Ki67 more diffusely,,and there was no significant difference in Epidermal growth factor receptor(EGFR)mutation between the Cri predominant and the Aci predominant ADC.Conclusions(1)The Cri pattern(? 5%)is associated with aggressive pathological behaviour in ADC of the lung,such as obvious nuclear atypia,more mitoses,lymph node invasion,metastasis,larger tumour size and advanced stages of cancer.(2)The Cri pattern(? 5%)is an independent poor prognostic indicator for patients with Aci predominant ADC;(3)The survival of patients with Cri predominant ADC poorer than patients with pure Aci predominant ADC.With these results taken into account,we proposed that the Cri predominant should be considered a new histologic subtype of lung ADC.