Tumor angiogenesis and regional lymph node metastasis of NSCLC
Tumor angiogenesis is an important factor affecting tumor growth, invasion, metastasis and prognosis [12-14]. The lymph node metastasis of tumor cells has three common ways: (i) Tumor cells directly invade the lymphatic vessels; (ii) Tumor cells directly invade into the micro vessels, and then through the incomplete basement membrane into the tumor stroma, and then enter the lymphatic vessels leading to lymph node metastasis; (iii) Tumor cells that entered into the blood circulation may also enter into the stroma of tumor or tissue with blood flow and cause lymph node metastasis. Obviously, in the process, the value of tumor angiogenesis is significant [14,15]. It was reported that lymph node metastasis of cervical cancer was closely related to tumor angiogenesis . This study also showed that regional lymph node metastasis of NSCLC was related to the luminal vascular parameters, and the luminal vascular parameter LVA in group A are lower than group B, while no correlation with MVD. We believe that regional lymph node metastasis of NSCLC is more closely associated with the luminal vascular, and because of MVD including the vessels with and without lumen , the different proportion of them may cause the relationship between MVD and lymph node metastasis different too. Besides, the microvascular wall is mostly thin-walled and fissured, and even if some of the lumen is formed, it is also no function. Therefore, although MVD is considered to be a reliable indicator of tumor angiogenesis [17,18], luminal vascular parameters may be a better indicator for the evaluation of tumor biological behavior. But the results of this study show that there were no significant difference in LVN and LVP, we found that no matter in group A or group B, the morphology of vascular lumen was inconsistent. In group A, the lumen was mostly oval, while in group B, the blood vessels tended to be more round. Our analysis may be due to two reasons. First, because of the high density of tumor cells in group A, the interstitial space is small. The second reason is that the low maturity of vascular smooth muscle lead to the lumen lack of tension.
The current situation of preoperative assessment of NSCLC with lymph node metastasis
At present, CT and PET-CT are the main non-invasive methods for preoperative assessment of NSCLC with lymph node metastasis. The size of lymph nodes is the main basis of CT in judging regional lymph node metastasis of NSCLC. The short diameter of lymph node is usually 10 mm as the threshold for the diagnosis of lymph node metastasis, but it is easy to lead to false positive and false negative [3,4]. Moreover, the metastatic lymph nodes less than 10 mm in short diameter were also easily misdiagnosed in surgical operation and pathological examinations. This study showed that the short diameter of lymph node was less than or equal to 10 mm in 11 cases (25 lymph nodes) of lymph node metastasis group, while greater than 10 mm in 8 cases (12 lymph nodes) of non-lymph node metastasis group. This also shows that it leads easily to false positivity and false negativity, if the size of lymph nodes is used to judge whether the lymph node are metastatic or not. The lymph node greater than 10 mm in short diameter is not necessarily metastasis, but less than 10 mm may also be metastasis.
FDG-PET/CT is currently the most important noninvasive method for diagnosing lymph node metastasis. Maximal standardized uptake value (SUVmax) is a good index marker for the diagnosis of metastatic lymph nodes, but there is no consensus on the optimal threshold of SUVmax, and some non-metastatic lymph nodes can also have high uptake of 18 F-FDG. it may also lead to false positive and false negative [19,20]. In addition, due to the fact that PET/CT equipment and inspection fees are very expensive，it has not been widely used, especially in China.
The value of CT perfusion parameters in diagnosing regional lymph node metastasis of NSCLC in pre-operation
CTPI can provide qualitative and quantitative hemodynamic information, and it can reflect noninvasively the angiogenesis of tumor [9,21,22]. It has important application value in quantitative and qualitative research of tumor. This study showed that CT perfusion parameter BF was correlated with the luminal vascular parameters LVA . All the perfusion parameters were not correlated with MVD. BF refers to the flow rate of blood in unit time and volume. That is to say, the larger the LVA , the larger the blood flow rate and the blood volume of per unit volume and time. This demonstrates that the dual source CT perfusion parameters can indicate the luminal vessels of tumor, but as for MVD is uncertain. This may also be associated with the microvessels including some non-functional vessels.
It was reported that CTPI plays an important role in evaluating lymph node metastasis of cancer in pre-operation [23,24]. This study showed that the dual source CT perfusion parameters are related to the luminal vascular parameters of NSCLC, while the luminal vascular parameters are related to regional lymph node metastasis of NSCLC, which provides a theoretical basis for the evaluation of regional lymph node metastasis of NSCLC by CT perfusion parameters. In this study, CT perfusion parameter BF of NSCLC group with regional lymph node metastasis was lower than that of NSCLC group without regional lymph node metastasis. This showed that the dual source CT perfusion parameter BF have certain value in predicting regional lymph node metastasis of NSCLC. Our analysis may be due to following reasons. First, we found that there were more poorly differentiated tumors in group A than in group B. In group A, the lumen was mostly oval, while in group B, the blood vessels tended to be more round, so BF of group A was lower. The second reason is that the more poorly differentiated tumors, the more obvious the destruction of blood vessels was, which was more favorable for the cancer cells to enter the interstitial tissue to have lymph node metastasis, but because of the serious destruction of blood vessels, caused the low blood flow. In addition, the immature blood vessels in poorly differentiated tumors are relatively more and disordered, which also affects the blood flow rate of the tissues to a certain extent, and the proliferation speed of poorly differentiated tumor cells is fast, and the situation of tissue ischemia and hypoxia is more. In this study, BV, MTT and PS there are no correlation with microvascular parameters. BV there is no difference in between group A and group B, therefore, we speculated that blood volume can only reflect the total amount of blood contained in the lesion, but its value in reflecting its biological behavior is limited. PS is not only related to the integrity of endothelial cells, but also to the pressure balance between plasma and tissue fluid. Poorly differentiated tumors have relatively severe damage to tumor blood vessels, which may increase the permeability of blood vessels. However, the rapid proliferation of poorly differentiated tumor cells will leads to the increase of tissue fluid pressure. Therefore, we believe that PS are uncertain in the evaluation of lymph node metastasis. MTT there is difference in between group A and group B, but there are no correlation with microvascular parameters, therefore, we have no reliable theoretical basis for predicting regional lymph node metastasis of NSCLC by MTT. MTT may be a potential indicator, but we need to deepen our understanding of tumor blood vessels to confirm this conclusion.
ROC curve was used to evaluate the value of the dual source CT perfusion parameter BF in predicting regional lymph node metastasis of NSCLC. The result showed that BF was valuable in predicting regional lymph node metastasis of NSCLC in pre-operation. And the possibility of NSCLC with regional lymph node metastasis may be suggested when BF<85.16 ml/100ml/min. For these patients, the regional lymph node dissection should be performed more carefully, systematically and extensively to avoid missing the small metastatic lymph nodes.