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  • In a previous study Xu et


    In a previous study, Xu et al. [15] demonstrated that the cribriform component could have a high rate of Mocetinostat (MGCD0103, MG0103) node metastasis. Kadota and colleagues [10] reported that the presence (≥10%) of the cribriform component correlated with smoking history, higher stage disease, and pleural invasion. Moreover, the authors revealed that the cribriform component (≥10%) can stratify acinar-predominant tumors with respect to recurrence and may be an independent risk factor for recurrence in stage I LUADs. Warth et al. [11] confirmed that patients with cribriform predominant tumors had the least favorable outcomes for disease-free survival after reviewing 674 resected LUADs with stage I-IV disease. However, such studies have seldom investigated the likely pathological mechanism of the association between LUAD with a cribriform component and poor outcome. Along with the publication relating to the WHO classification of lung cancer in 2015 [9], several new morphological features have been proposed that might be prognostically significant. Besides the cribriform component, spread through air spaces (STAS) is one such feature [16], and has captured attention in recent studies. Warth et al. [17] declared that the presence of STAS was identified in nearly half of 569 LUAD patients with surgical resections. Kadota et al. [16] found that patients with positive STAS who accepted limited resection had higher risks of recurrence than those with negative STAS. Our previous study has shown that the STAS-positive status was significantly associated with poor survival in patients irrespective of surgical procedures [18], which was consistent with other studies [[19], [20], [21], [22]].
    Materials and methods
    Discussion The presence of a cribriform component was associated with poor survival in patients with LUADs, as has been reported previously [[10], [11], [12], [13], [14]]. In addition, STAS, as a new recently proposed concept, has been found to be a significant predictor of inferior survival rates for LUAD patients [[19], [20], [21], [22],[24], [25], [26], [27]]. Studies have shown that the two histological features were associated with some similar clinicopathological factors, such as higher tumor stage [10,17], smoking [14,22], and especially the presence of a solid-predominant subtype [12,19,25]. To date, there has been no study assessing the relationship between the cribriform component and STAS in pathological stage I-III LUAD. Therefore, we investigated the underlying association between the cribriform component and STAS, and focused further on their joint influence on patient prognosis. The design idea of this study has been shown in the Graphical Abstract. Ultimately this will enable us to find potential pathological mechanisms for the poor outcomes in patients presenting with a cribriform component in LUADs. Previous studies of various carcinomas including prostate cancer [28] and colonic adenocarcinoma [29] have found that the cribriform component represents an adverse prognostic factor. Therefore, the cribriform component is not only a novel morphological finding but also a risk factor for an inferior prognosis. As observed by Kuang et al. [12], the cribriform component was associated with EGFR mutation (p = 0.016), AKT1 mutation (p = 0.038), and ALK rearrangement (p < 0.001). Another study characterized that the highest rate of somatic KRAS mutation was found in the cribriform component among all components [11]. In addition, the cribriform component appeared frequently in elderly patients along with the expression of TTF-1 and CK7 [30]. However, the clinicopathologcal characteristics of LUAD with a cribriform component has not been well characterized. Because nearly 80% of LUADs contain two or more components in a single tumor [4,9], semi-quantitative pattern analysis was an effective predictor of patient prognosis, regardless of whether the growth pattern was an independent subtype. With a rate of 32.2% for the cribriform component (≥5%) found in all cases, our results are in agreement with the data from a previous study by Warth et al. [11] who observed that the cribriform-predominant adenocarcinoma accounted for 4.2% among all of the subtypes, and the cribriform-minor accounted for 28.6%. Meanwhile, our findings are also in coincidence with the results presented by Qu et al. [14] who reported that the cribriform component was found in 33% of the 395 LUADs. In addition, it was in line with previous studies demonstrating that the highest frequency of a cribriform component was observed in LUADs with a solid pattern (46 of 76; 60.5%) [10,12]. Our statistical data indicated that patients with a cribriform component had significantly inferior RFS (5-year rate: 12% vs. 71%, p < 0.001) and OS (5-year rate: 8% vs. 56%, p < 0.001) compared with those with no cribriform component. Besides, our analyses revealed that patients with a cribriform component had a significantly increased risk of developing both locoregional recurrences (5-year CIR, 57% vs. 20%, p < 0.001) and distant recurrences (5-year CIR, 31% vs. 9%, p < 0.001) when compared with those with no cribriform pattern. These results suggested that the cribriform component (≥5%) may be used to stratify patients with LUAD into more detailed prognostic groups.