The incidence of LN metastasis in patients with clinical stage I NSCLC is significantly lower than that in patients with advanced lung cancer. A randomized trial named ACOSOG Z0030 concluded that systematic mediastinal lymph node dissection could not improve the survival for patients with early‑stage NSCLC by confirming that there was no positive lymph node either in mediastinum or in hilum through presection sampling [18]. However, other scholars pointed out that postoperative pathology has shown that even the small-sized lung cancer (< 2 cm) had hilar and mediastinal node metastasis with an incidence of up to 20% [14, 19]. Furthermore, patients with positive MNM exhibited a 20–38% incidence of skip metastasis, a phenomenon in which MNM occurs without the involvement of HNM [20, 21]. Therefore, accurate integration of lymph node staging in patients with clinical stage I NSCLC is important in guiding the choices of surgical treatments.
In this study, we identified six clinical variables as the independent predictors in common for regional lymph node metastases including the hilar-intrapulmonary region and the mediastinal region, which is consistent with the literature [22–24]. However, the visceral pleural invasion was only associated with the MNM. This phenomenon seems to indicate that we should discuss the HNM and MNM separately. We think this is based on the following anatomical structures of LN system in the lung. The lymph nodes associated with the cancer metastasis are widely labelled using a system of numerical levels and assigned names based on their anatomical locations. First, the hilar-intrapulmonary lymph nodes (groups 10–14), and second, the mediastinal lymph nodes (includes group 2R, 3, 4R, 7, 8, 9R, and group 4L, 5, 6, 7, 8, 9L). Generally, the sequence of LN metastasis of central NSCLC should be step by step as follows: along the bronchial tree from the intrapulmonary region to hilar, and then to the mediastinal region. Different from the central NSCLC, the LN metastasis of peripheral NSCLC with the peripheral capsule being invaded may incline to skip to MNM without HNM due to the lymphatic capillaries directly from the peripheral membrane to the mediastinal lymph nodes [25, 26].
The rapid pathological results during operation would help surgeons to select the right procedures for the patients, for instance, wedge resection, segmentectomy, or lobectomy [27]. However, surgeons do not know which pattern to choose for lymph node dissection because of the complicated lymphatic spreading of lung cancer. Therefore, we creatively developed two utilizable prediction models from a logistic equation for regional LN metastases in patients with clinical stage I NSCLC. In terms of clinical relevance, the models provide more precise estimates of regional LN metastasis during operation for individual patients with clinical stage I NSCLC. Especially, the model for MNM is a good supplement for surgeons to improve their decision-making process for systematic LN resection.
There were some published models developed for the assessment of lymph node disease of lung cancer [28–32]. Some either only focused on the outcome of MNM, or only the preoperative variables were included while appropriate candidates for limited LN resection should be with pathological confirmation of negative LNs, both in the hilar and the mediastinal regions. For these reasons, none of these models is commonly employed in clinical practice. In our models, on the other hand, all variables, from the radiographic size of tumour to visceral pleural invasion, are available before or during operation by regular measures in routine clinical practice without consuming any extra resources or time. The models are even easier to use in clinical practice with the associated nomograms guiding surgeons to choose the optimized method for LN dissection rapidly.
In a case of clinical stage I NSCLC, when intraoperative rapid pathological results reveal invasive lung cancer, standard lobectomy will be performed with the following recommendations for LN dissection which are based on the patient’s category of the prediction models (Table 4). (1) When HNM low risk plus MNM low risk, there is no need to dissect the lymph nodes or only regional LN sampling is adequate. (2) When HNM high risk plus MNM low risk, it usually refers to a central tumour involving the bronchial tree. In this case, complete dissection of hilar-intrapulmonary LNs is a requirement but no need to dissect mediastinal lymph nodes or just do regional LN sampling in the mediastinum. (3) When HNM low risk plus MNM high risk, it usually indicates skipping metastasis in peripheral lung cancer invading the lung membrane. In this case, complete mediastinal LN dissection is required but no need for hilar-intrapulmonary LN dissection or just do regional LN sampling in this region. (4) When HNM high risk plus MNM high risk, a systematic LN dissection is required, including the hilar-intrapulmonary region and the mediastinal region.
Given the retrospective nature of this single-institution study, selection bias is inherent in our study population. Although we validated the models, they still need to be validated by patients from comparative centres. The serum status of CEA and CYFRA221 was predictive factors in our models, but the kinds of tumour marker may not be the same at different hospitals which limits the application of the model. Moreover, the interval between blood test of tumour markers and surgery was not uniformly standardized, which may exert an uncertain impact on the serum status. As our study did not include the tumor recurrent status or the survival rate in this patient population, the relationship between survival rate and predictive value is unknown [33]. Last but not least, there occurs inaccuracy to some extent on the rapid pathological results of the risk-predicting variables during operation, such as visceral pleural invasion, bronchial mucosa and cartilage invasion, and vascular invasion. However, it could be improved in the near future with the development of advanced tools for pathological diagnosis.