HRCT features between lepidic-predominant type and other pathological subtypes in early-stage invasive pulmonary adenocarcinoma appearing as a ground-glass nodule

With the development and popularization of high-resolution computed tomography (HRCT) lung cancer screening, the detection rate of ground-glass nodules (GGNs) has significantly increased [1, 2]. Numerous studies have confirmed that most long-term existed GGNs in the lung are mostly early lung adenocarcinoma or their precancerous lesions [3]. According to whether or not it contained a solid component, a GGN can be classified as pure GGN (pGGN) and mixed GGN (mGGN), a mGGN is divided into ground glass-predominant mGGN (0 < CTR ≤ 0.5) and solid-predominant mGGN (0.5 < CTR < 1) according to a consolidation-to-tumor ratio (CTR) on HRCT [4]. The 2015 World Health Organization (WHO) Classification of Lung Tumors [5] classified invasive pulmonary adenocarcinoma (IPA) into lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA) according to the main growth patterns. Among them, LPA has the best prognosis, followed by the APA and PPA, whereas SPA and MPA have the worst [6, 7]. Different pathological subtypes of early-stage IPA may have different surgical methods, LPA may be treated with partial lobectomy (segmentectomy or wedge resection) and no lymph node dissection, whereas other subtypes can be treated with standard therapy for anatomical lobectomy and systemic lymph node dissection [7‐9]. Preoperative puncture pathology and intraoperative freezing pathology are helpful for the diagnosis of pathological subtypes of lung adenocarcinoma, but both are limited by materials, and the risk of lung adenocarcinoma subtypes is underestimated [10]. HRCT can reflect the overall aggressiveness of nodules, and can help to improve the accuracy of pathological subtype diagnosis. Previous studies [11‐13] have shown that HRCT features of GGN have high diagnostic value in differentiating early IPA from preinvasive lesions (PIL) and minimally invasive adenocarcinoma (MIA), but there are few studies on the correlation of HRCT features among subtypes of IPAs. Therefore, it is essential that HRCT features should be used to identify LPA from other subtypes in IPAs with GGN.

In this study, the HRCT features of IPAs appearing as pGGN and mGGN (CTR ≤ 0.5) were retrospectively analyzed to determine imaging differences between the LPA and other pathological subtypes to provide imaging help for clinical surgical decision-making.

This study was approved by the Ethics Committee of Fourth Medical Center of Chinese PLA General Hospital (approval No. 2019YL002-HS001). All participants and/or their family members provided the informed consent.

The clinical findings of the patients were summarized in Table 1. Among 589 patients, 203 were men and 386 were women; the average age was 55 years (range, 23–78 years); 122 were smokers, 462 were nonsmokers, and five had an unknown smoking history. Of these patients, 260 patients underwent one-lobe lobectomy, 269 underwent single-wedge resection or segmental resection, one underwent two-lobe lobectomy (right upper lobe + middle lobe), 25 underwent one-lobe lobectomy combined with one-segmental or wedge resections, and 31 with two lesions and three with three lesions underwent multiple segmental or wedge resections. Of all GGNs, one GGN was detected in 553 patients, two GGNs in 32 patients, three in 3 patients and four in 1 patient.

To our knowledge, LPA has the best prognosis without lymph node dissection or only lymph node sampling, whereas n-LPA requires systematic lymph node dissection [8], so we performed a retrospective analysis of 630 GGNs that were identified pathologically after resection as early-stage IPA with invasive foci more than 5 mm. Previous studies [11‐13] has confirmed that HRCT features had good diagnostic value in differentiating IPA from PIL-MIA, therefore, we excluded PIL and MIA cases and focused on differences in the HRCT features of IPA subtypes. Our previous studies also showed that even with pGGN, 39% were various subtypes of IPAs [15]. In this cohort, we included pGGNs and mGGNs with CTR ≤ 0.5, and pGGNs accounted for 65.2%. The number of LPA was greater than that of n-LPA (367/263), and the proportion of pGGNs in the LPA group was significantly higher than that in the n-LPA group (P <  0.001). This was consistent with the previous report that the ground-glass opacity on HRCT was positively correlated with the lepidic growth pattern of the tumor pathologically [7]. In GGNs, the emergence of various IPA subtypes may be related to the following aspects, APA and PPA appeared as GGN for air-filled sparse hypertrophic areas [13]; This study included three SPAs, which were composed of a mixture of solid-predominant growth pattern and other growth patterns, of which lepidic growth patterns accounts for 40%, 30%, 30%, and their diameters were all less than 10 mm; MPA is usually manifested as solid nodules, and the micropapillary type in our study was other subtypes containing a small number of micropapillary structures, so it can be manifested as GGN; And beyond that, This discrepancy between radiological and pathological findings could be explained by a partial volume effect, detection of small nonaerated components may be difficult because of inadequate spatial resolution [13]. Although, our all CT images were acquired by using HRCT at 1 mm or 1.25mm slice thickness, a much higher resolution may be needed to detect small nonaerated invasion.

This was the larger study of GGNs for the purpose of differentiating LPA from n-LPA group. We observed that the ratio of IPA was significantly higher in women (65.5%) and no smokers (79.1%). The Fleischner Society Guidelines [2] also referred to the incidence of adenocarcinoma in nonsmokers was increasing, with female nonsmokers being affected significantly more often than male nonsmokers. However, the relationship to nodule type was not reported. In our study, there were no significant differences between LPA and n-LPA groups in both sex and smoking history.

In univariate and multivariate analysis showed that deep lobulation, spiculation, vascular change and bronchial change were more common in the n-LPA group than in the LPA group. (P <  0.05). Several studies have examined marginal lobulation and spiculation related to “tumor development or invasion” in adenocarcinoma [2, 5, 12]. Zhang et al. [16] showed bronchial change was a predictor of invasiveness. Gao et al. [17] found III and IV vascular changes were more prone to invasive behavior, where type III vessels within lesions are tortuous or rigid without an increase in amount and type IV vessels are more complex vascular changes than the other types, such as irregular expansion and convergence of multiple blood vessels. Liang et al. [18] also demonstrated that the number of blood vessels entering GGN (vascular aggregation) was a risk factor for predicting invasiveness. These morphologic features were associated with active fibroblast proliferation in adenocarcinoma and caused by the contraction of fibrous tissues [19]. Noguchi et al. [20] suggested that active fibroblast proliferation in adenocarcinoma was related to the invasive growth of tumors.

Previous studies [13, 14] comparing IPA with PIL-MIA had shown that the CT value of GGN was confirmed to be associated with invasiveness. For example, Zhou et al. [11] showed that the lesion with CT values in pGGN and mGGN greater than − 583.6HU and − 571.6HU, respectively, was more likely to be IPA. Lee et al. [12] showed that GGNs with CT values of > − 472HU were more likely to be IPAs. This result was similar to the mean CT value (> − 472.5HU) we predicted for the n-LPA, theoretically, however, the mean CT value threshold of IPA subtypes should be greater than that of IPA and MIA-PIL. This may be due to the fact that we used the Freehand ROI but not Circle ROI to draw along the edge of the GGN as large as possible on the maximum transverse axis on the lung window, but Lee used the circular ROI outline causing the loss of the edge part with large gas content for irregular nodules, thus raising the CT value. However, considering the influence of CT scanning parameters on the CT value of GGN, it was limited to make a diagnosis only by CT value. In this study, CTR > 27.4% was more likely to be n-LPA with poor prognosis, which was consistent with the conclusion by Tsutani et al. [21] that showed GGN with CTR > 25% had a high postoperative recurrence rate. Ko et al. [22] studied 138 cases of stage I lung adenocarcinoma with GGN, and the CTR of LPA and n-LPA were 14.5 and 35.4% (P = 0.002), which were higher than the CTR of LPA (13.9%) and n-LPA (27.8%) in this study. Considerations were first related to the exclusion of mGGNs with CTR > 0.5, which reduced the proportion of solid predominant GGNs in the n-LPA group, however, LPA was rare in mGGNs with CTR > 0.5, so it was less affected in LPA, and secondly, the measurement methods of the two studies were inconsistent.

In univariate analysis, there were statistically significant differences in the mean diameter and tumor–lung interface (P = 0.021, < 0.001), but not in multivariate analysis. Some studies [12, 13] showed the size of the nodule was related to the malignancy of the tumor, however the pathological subtypes of IPA were determined by the proportion of invasive component which was more common in the central region of the GGN [19], while the size of the nodule was determined by the peripheral lepidic growth pattern progressing slowly. In this study, the mean diameter of GGN in the LPA group and the n-LPA group overlapped greatly (14.49 ± 5.22 mm:15.43 ± 4.79 mm), so it could not be used as an independent predictor. Hwang et al. [23] also showed that in patients with early pulmonary adenocarcinoma measuring < 3 cm, disease-free survival was remarkably correlated with the size of the solid part of the tumor, but not with the whole tumor. A fuzzy tumor–lung interface was more likely to occur in the LPA group than in the n-LPA group. The lepidic growth pattern part of LPA was more common than that of n-LPA. the lepidic growth pattern was that the tumor cells growing along thickened alveolar walls and air filled in the alveolar cavity [12], when the air content of the peripheral part was close to that of adjacent normal lung tissue and the CT spatial resolution was limited, the tumor–lung interface of GGN on CT was fuzzy. However, the frequency of clear tumor–lung interface was higher in both groups and was not statistically significant in multivariate analysis. No significant differences were observed in pleural indentation sign and bubble-like lucency. Masahiro et al. [24] found that the incidence of pleural indentation increased with increased tumor invasiveness, the volume ratio of solid components in GGN was > 63% and that the incidence of pleural indentation sign increased. Nevertheless, we investigated GGNs with CTR of < 50% and did not consider the distance between the nodules and pleura. The incidence of bubble-like lucency in both groups was low, which was related to the observation of multi-directional reconstruction images, excluding the air space connected with the bronchus.

Our study also found that AUC values of the logistic regression model, the mean CT values and CTR were 0.840 (sensitivity, 76.4%, specificity, 78.7%), 0.781 (sensitivity, 60.5%, specificity, 83.1%), and 0.593 (sensitivity, 38.4%, specificity, 83.9%), respectively. The logistic regression model, which obtained by combining deep lobulation, spiculation, vascular change, and bronchial change, the mean CT values and CTR, can improve the sensitivity more than using mean CT value or CTR alone in distinguishing LPA from n-LPA. Differentiating LPA and n-LPA was very important for the preoperative planning of surgical procedures and simultaneously as a reference value for GGN management. For GGN in patients with deep lobulation and vascular and bronchial changes, the follow-up should be terminated and surgical treatment should be considered.

This study has certain limitations. First, this was a retrospective analysis, mainly based on pathological diagnosis. The assessment of IPA subtypes may be inconsistent, especially when multiple subtype components coexisted. Second, this study only focused on lepidic and nonlepidic types of IPA and did not further analyze imaging differences among other pulmonary adenocarcinomas.

The HRCT features, including deep lobulation, spiculation, vascular change, and bronchial change, may indicate nonlepidic IPA in GGNs, and the diagnosis of nonlepidic IPA is supported when the mean CT value is > − 472.5 HU or CTR is > 27.4%. Simultaneously, the combined application of mean CT value, CTR, and HRCT features can effectively improve the diagnosis of nonlepidic.