As early as 1958, Brewer recognized that VPI in lung cancer was an important prognostic factor (18), especially in early stage NSCLC. In the mid-1970s, VPI was used as a specific description in the TNM Classification of Malignant Tumors (TMN) set forth by the Union for International Cancer Control, which is now in its 8th edition (17). In the 7th edition, NSCLC with a diameter ≤ 3cm and VPI was upgraded from Tla or Tlb stage to T2a stage, and the degree of VPI was classified (1). VPI was defined as tumor invasion beyond the pleural elastic layer of the visceral layer (PL1) and invasion of the pleural surface of the visceral layer (PL2). The VPI classification changes the clinician's assessment of staging and prognosis, thus affecting the treatment strategy.
According to the TNM criteria, local invasion of a tumor in the pleura without one in the visceral layer should be classified as T2 (18). It has also been suggested that intrapulmonary pleural invasion in the interlobar region should be classified as T3 (19). Most literature reports are of T2 and T3 lung cancer, and there are few studies on T1 cases. No taxonomic study has been conducted on T1 GGN. When the tumor is in contact with the pleura, VPI is more likely to exist. As an important method to predict VPI, measuring and calculating the indicators on the corresponding CT images is highly valuable (20). Considering the radiation dose, conventional CT and U-HRCT were not performed simultaneously, only underwent U-HRCT scan were enrolled.
Based on previous research findings, compared the accuracies of U-HRCT and conventional CT for detecting morphological features on CT in the evaluation of GGN, The result shown that the detection rate was higher for U-HRCT target scanning than for conventional CT target reconstruction, and this improvement significantly enhanced the diagnostic accuracy of early lung adenocarcinoma (21). In U-HRCT scans, a large matrix size maintained the spatial resolution and improved the image quality and assessment of lung diseases, despite an increase in image noise, when compared to a 512 matrix size, which can provide more detailed lung anatomy and pathology information for the evaluation of lung diseases(22, 23). Compared with the surgical pathological findings, U-HRCT had a relative higher diagnostic accuracy of early lung adenocarcinoma than conventional CT. the U-HRCT prototype scanner provides a better image quality of subsolid nodules and contributes significantly to reduce the patients' follow-up period (24). So, in this study, we adopted U-HRCT to obtain submillimeter images. Through three-dimensional orthogonal post-processing, the morphology, integrity, and features of the interlobar fissure can be displayed from different perspectives, and this information can be obtained accurately before surgery, which is more advantageous than a conventional CT scan; Total scanning dose of U-HRCT is about 180 mGy.cm, it was lower than that of conventional CT scan. So, we believe that HRCT will be a routine scan for further accurate diagnosis.
In this study, 17 patients (13.5%) presented incomplete interlobar fissures, but no cases of interlobular fissures invading adjacent lobes with VPI were observed, which may be related to the low invasiveness of T1 GGN. none of the 55 pGGN contacting the pleural surface of the interlobar fissure showed VPI. The results were consistent with Hattori et al. (25), who reported that in NSCLCs with pGGN resection of less than 3cm, there was no VPI. Ahn et al. (9) also did not find VPI in the pGGN group. But some studies (26) show that VPI was often seen in pGGN adenocarcinoma. In our study, 4 cases of infiltrating adenocarcinoma were acini subtype, 3 had pleural thickening, 1 had pleural indentation, and 2 were cases of pathological spread through airway spaces. Pathological HE staining and elastic fiber dyeing did not reveal VPI, whereas pleural thickening and inflammatory cell infiltration was revealed in the elastic fiber layer, with no tumor cells beyond the elastic layer. All above support the fact that pGGNs are less pathologically invasive (27, 28) and cannot penetrate the thick elastic layer in early lung adenocarcinoma.
As for mGGN contacting the pleural surface, this study showed that there were significant differences between the cases with and without VPI in terms of density, contacting solid, solid diameter, and solid ratio. Some studies have confirmed the correlation between CT findings and pathological results (29), with the degree of solid component being an important invasive factor that was related to poor prognosis (30). In this study, all the positive VPI groups had solid contact with the pleura, which suggested that the solid part was an important invasive component of GGN for lung adenocarcinoma, but there was no significant difference in the interface length (P > 0.05). Partial solid nodules with a solid ratio greater than 0.5 were more likely to invade the visceral pleura. Ohde et al. (31) reported that in T1 NSCLC, a solid ratio greater than 50% was related to invasion, which was consistent with our study. In our study, solid diameter > 6mm and solid ratio > 38% were revealed to be independent predictors of VPI (P < 0.05). The AUC of the two factors for VPI diagnosis reached 0.8, and the sensitivity for both was 80%, which could provide an important reference value for preoperative diagnosis of visceral pleural infiltration. In contrast to the study by Ahn et al. (13), there was no significant difference in nodule size, interface length, interface length ratio, and contacting solid in our study (P > 0.05), which may be related to differences in nodule types and sample size.
Previous studies on CT findings of pleural invasion have shown that pleural thickening is a useful diagnostic feature (32). Gallagher et al. (33) pointed out that there were three types of changes in the visceral pleural elastic layer: (a) no secondary changes; (b) obvious elastic overlap and inflammatory infiltration; and (c) fibroblast proliferation and thickening. The pleura is affected by inflammation and fibrosis. Even without VPI, subpleural tumors often cause anatomical changes in the pleura (1), which can manifest as pleural thickening on CT. In our study, among the 56 patients with mGGN without VPI, 36 (64%) had pleural thickening and 38 (67%) had pleural indentation. Fourteen (32%) of 44 patients with preinvasive lesions had pleural thickening, and 19 (43%) had pleural indentation. The pathology showed overlap of elastic fibers, inflammatory infiltration, and fibrosis. In our study, there was no significant difference in pleural thickening and pleural indentation in patients with mGGN with and without VPI (P values were 0.398 and 0.099, respectively,). The results showed that pleural changes such as pleural thickening and pleural indentation were not important factors affecting VPI in NSCLC with interlobar pleural contact.
Our study has several limitations. First, our study is a retrospective study, which limits our analytical validity. Second, our study had a small sample size. Similar and larger multi-center studies are needed to confirm our current conclusions. Third, we did not evaluate inter- and intra-observer reproducibility, which may influence the CT features evaluation. The relationship between VPI and long-term outcomes such as survival, recurrence, and metastasis were not analyzed in this study. However, this study is still in progress, and relevant data, such as progression-free survival and overall survival, are in further follow-up.
In conclusion, U-HRCT and three-dimensional orthogonal post-processing technology were used to improve the spatial resolution and contrast resolution of CT images and to more accurately evaluate GGN and its relationship with interlobar fissure. This was helpful in predicting VPI. When GGN with a diameter of ≤ 3cm was in contact with the interlobar fissure, the ground glass nodule component was less invasive. There was no VPI in patients with pGGN. Regarding mGGN, a solid diameter > 6mm and a solid ratio > 38% observed in CT evaluation could be used as an independent predictor of VPI in early stage NSCLC.