According to Yusef et al. who did a study in 204 patients, the tumor location was the main factor for lymph node metastases in univariate and multivariate analysis (11). In an analysis of 566 patients, Shafazand et al. identified age less than 65 years, tumor location, histological type (adenocarcinoma and large cell) as predictive factors for metastatic lymph nodes (12). Another retrospective study of 379 patients by Suzuki et al. also found that the histopathological type (adenocarcinoma) was a predictive factor for mediastinal lymph node metastases (31). In our study for NSCLCs with pulmonary nodule, in accordance with previous studies, we found that histological type (adenocarcinoma) and poor histologic differentiation are related to lymph node metastases. However, we could not identify age or tumor location as predictive factors for any lymph node metastases. The reason for this discrepancy may be due to the natural or manual differences such as the sampling process, the number of cases and statistic methods used.
During the past several years, the relationship between GTD and lymph node metastases has been heavily studied. Yang et al. divided 198 patients into 3 GTD subgroups using 3.0 cm and 7.0 cm cutoff points. They suggested that a large GTD was related to lymph node metastases (20). Besides, Min et al. and Moulla et al. concluded that GTD > 3.0 cm was a predictive factor for any lymphatic metastasis (10, 11). Furthermore, Flieder et al. found that the incidence of node metastases in patients with GTD > 2.0 cm was twice that of those with GTD ≤ 2.0 cm, suggesting that the larger tumors were accompanied with advanced disease (19). Therefore, for NSCLC patients, tumor size is closely related to lymph node metastases.
With the advanced imaging technologies, more and more pulmonary nodules have been detected in NSCLC patients (23). Bao. et al. suggested that pathological positive lymph nodes were common in small size NSCLC patients who were diagnosed with clinical negative lymph nodes (24). Therefore, precise preoperative diagnosis and appropriate medical methods are increasingly important for NSCLC patients. However, comparing with large tumor size, the characteristics of lymph node metastases in small size tumors are still in debate. In a study for pT1a NSCLC cases, Yu et al classified 2268 patients into three subgroups: GTD ≤ 1.0 cm, 1.0 cm > GTD ≤ 2.0 cm; and 2.0 cm > GTD ≤ 3.0 cm. They concluded that the higher risk of lymph node involvement was accompanied with larger tumor size, which proved that tumor size is a significant predictor of lymphatic metastasis (15). Nevertheless, according to the analysis of 185 NSCLC patients with tumors less than 2.0 cm, Shi et al. revealed that there was no lymph node metastasis in tumors <1.0 cm and no obvious difference was observed in the lymphatic metastatic rate between 1.6-2.0 cm and 1.0-1.5 cm tumors (13). Moreover, Zhang et al. found that tumor size was not a reliable factor to predict lymphatic status of NSCLCs (16, 18). In our study, our results showed that there is no significance difference for GTD with the presence or absence of lymph node metastases and there exist no obvious differences of positive metastasis rates between the three GTD groups, which indicated that GTD may not be a sensitive factor to predict positive lymph nodes.
Our study found that the TV of patients with positive lymph nodes is obviously larger than that of negative lymph node cases. This may suggest that the larger TV is associated with a higher probability of lymphatic metastasis. Besides, according to analysis by groups, we found obvious differences in metastases rates in the three groups. Several previous studies demonstrated that TV is an independent prognostic factor for NSCLC patients who underwent complete resection (21, 27, 29, 30). Tsai et al. suggested that the TV is a more accurate indicator to evaluate tumor size as well as survival of patients with stage Ia NSCLC (32). Furthermore, it has been proven that TV may reflect the true tumor burden better than GTD (21). Therefore, combining with previous studies and our results, we concluded that TV is a more reliable indicator to predict if there are positive lymph nodes for tumors ≤ 3.0 cm.
According to the equation of TV and GTD mentioned above, the two TV cutoff points corresponded to 1.43 cm3 and 2.43 cm3 of GTD respectively, which were not 1.0 cm3 and 2.0 cm3 by the standard classification. In our study, the relationship between GTD and TV proved to be an exponential growth model, which means that the distribution of TV was discrete even with the same GTD category. In other words, a minor increase in GTD will lead to doubling of the TV (21). Therefore, TV may describe the true tumor burden more accurately than GTD, especially for pulmonary nodules.
The necessary extent of lymph node dissection in the surgical treatment of NSCLC patients remains controversial (33). Therefore, the precise preoperative staging plays a significant role in making a treatment plan. To the best of our knowledge, most previous studies mainly focused on the prediction of whether or not there are metastatic lymph nodes using GTD or TV. However, previous researches have proven that the treatment and prognosis varied a lot between N1 and N2 NSCLC patients, which means that, only identifying positive lymph nodes is not enough to meet clinical needs (8). Therefore, we evaluated the correlation between GTD and N categories to verify if there was a relationship between these two factors. The significant relationship between GTD and N stages was not observed in all the cases or in any of the groups. However, TV and N stages had a clear correlation and accord with growth models, which indicated that the larger TV may indicate higher lymph nodes stages. Therefore, we suggested that TV is a more sensitive marker for predicting the specific N stages in pulmonary nodule tumor masses.
According to our analysis by groups, for TV>0.9-14.2 cm3, the correlation between TV and N stages is significantly obvious. Though the correlation between TV and N stage is in accordance with the growth model for all cases, we did not find any correlation when TV ≤ 0.9 cm3, which may due to the limited case number of this group. According to the classification of T stage from the TNM staging system, with the larger tumor mass, the characteristics of T2, T3 and T4 have obvious differences from those of T1 since confounding factors are compromised in higher stages (8). Several previous studies have suggested that lymph node metastases is affected by some other factors besides the tumor itself (11–13). Therefore, we believe that the differences of characteristics in each TV interval may account for this result. Overall, based on the equation of TV and GTD mentioned before, these results revealed that TV may be an especially sensitive lymphatic predictive marker when tumor mass had a GTD>2.0-3.0 cm. Nevertheless, for GTD ≤ 2.0 cm, both GTD and TV are not reliable factors to predict specific N stages and further studies with larger sample sizes are needed.
With the wide use of three-dimensional reconstruction of CT and PET-CT, TV has become the other important indicator besides GTD to estimate the preoperative condition for NSCLC patients (34, 35). Furthermore, its significant prognostic value has been proven for patients treated by nonsurgical means such as radiotherapy (36, 37). Therefore, considering current limited studies of the relationship between TV and lymph nodes, our study may provide additional reference for predicting metastatic lymph nodes and choosing proper treatment plans to improve the prognosis for pulmonary nodule NSCLC patients.
Several limitations of this study should be mentioned. First, this is a retrospective observational study comprised of potential biases. Second, semi-automatic volumetric measurement of solid masses surrounded by lung parenchyma was demonstrated to be reproducible with standardized protocols. Nevertheless, TV could not be calculated precisely if the tumor was accompanied with atelectasis or obstructive pneumonia. Third, since this study was carried out in a single medical center research, a larger number of cases from multiple medical centers may be needed to further evaluate our conclusion.