|Year : 2016 | Volume
| Issue : 5 | Page : 120-125
Distribution and prognosis of mediastinal lymph node metastases of nonsmall cell lung cancer
Dawei Guo1, Yiming Ni2, Xiayi Lv2, Zhihao Zhang3, Peng Ye2
1 Department of Cardiothoracic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou; Department of Cardiothoracic Surgery, Chinese People's Armed Police Force, Zhejiang Corps Hospital, Jiaxing 314000, China
2 Department of Cardiothoracic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou, China
3 Department of Cardiothoracic Surgery, Chinese People's Armed Police Force, Zhejiang Corps Hospital, Jiaxing 314000, China
|Date of Web Publication||7-Oct-2016|
Department of Cardiothoracic Surgery, First Affiliated Hospital of Zhejiang University, Hangzhou 310000
Source of Support: None, Conflict of Interest: None
Background and Objective: With the popularity of minimally invasive techniques, preoperatively determining whether mediastinal lymph node dissection (MLD) is necessary for patients with cN1/2 nonsmall cell lung cancer (NSCLC) has sparked controversy once again. This study aims to analyze whether different primary sites are associated with the distribution of mediastinal lymph node metastases and to investigate the necessity of lymph node dissection and the factors influencing prognosis.
Materials and Methods: One hundred and thirteen patients with pathologically confirmed NSCLC with N2 lymph node metastases were included in the study and were grouped according to the lung lobes, in which primary lesions were located for statistically analyzing the metastatic rates of different mediastinal lymph node stations. Through a 3-year follow-up survey, risk factors influencing the 3-year postoperative survival were analyzed.
Results: N2 stations with the highest metastasis rate for different pulmonary lobes were Station 2/4 of the right upper lobe (100%), Station 7 of the right middle/lower lobes (80.0%/88.9%), Station 5 of the left upper lobe (84.4%), and Station 7 of the left lower lobe (78.6%). Three-year survival rate of the cross-regional N2 group was lower than the total N2 group (47.8% vs. 75.3%), P = 0.009 (<0.01). Three-year survival rates for preoperative stages T1 and T2 were superior to stages T3 and T4, showing significant differences (P < 0.05).
Conclusion: Station 7 is likely the most frequently metastases sites in all mediastinal lymph node stations. Cross-regional metastasis of N2 and staging of T3 and T4 were the risk factors for 3-year survival rate, whereas poor differentiation was not the risk factor. Due to the presence of micrometastases and skip metastases, MLD was first recommended for patients with preoperative stage cN1/2.
Keywords: Lung neoplasms, mediastinal lymph node, metastasis, prognosis
|How to cite this article:|
Guo D, Ni Y, Lv X, Zhang Z, Ye P. Distribution and prognosis of mediastinal lymph node metastases of nonsmall cell lung cancer. J Can Res Ther 2016;12:120-5
| > Introduction|| |
At present, lung cancer has become the malignancy with the highest mortality worldwide. From the pathological point of view, nonsmall cell lung cancer (NSCLC) is the most common type, accounting for about 80%–85%. Surgery is the first-choice treatment for NSCLC. Mediastinal lymph node status is the most important influencing factor for the treatment and prognosis of lung cancer. For NSCLC patients preoperatively diagnosed as cN1/2, conventional surgical approach is mediastinal lymph node dissection (MLD) (i.e., Groups 1, 2, 3, 4, 7, 8, and 9 in the right; Groups 1, 2, 4, 5, 6, 7, 8, and 9 in the left) at present. However, with the deepening of the concept of minimal invasion, whether MLD is suitable for all cN1/2 patients once again aroused controversy due to reasons such as large wounds from thorough dissection, long operative time, and many postoperative complications. The purpose of this study is to explore whether there is a correlation between primary sites and mediastinal lymph node metastatic stations, the necessity of MLD as well as the prognostic risk factors by analyzing the clinical data of lung cancer patients with different primary sites and the distribution of mediastinal lymph node metastases at different lung segments and lobes.
| > Materials and Methods|| |
A total of 113 patients from August 2010 to August 2012 were selected for retrospective study, all of whom underwent radical resection of lung cancer and were pathologically confirmed as NSCLC. Scope of MLD exceeded three stations, and postoperative paraffin sections all confirmed the presence of N2 lymph node metastases. Mediastinal lymph node stations included groups 2/4, 3, 5, 6, 7, 8, and 9 (Group 1 was excluded due to low clearance rate).
Exclusion criteria included postoperative confirmation of small cell lung cancer; no N2 metastasis; <3 MLD groups or <3 mediastinal lymph nodes; died from surgical complications within 1 month postoperatively.
The study comprised 76 males and 37 females aged ranging between 35 and 79 years, with a mean of 54 years. There were 68 cases of central lung cancer (preoperative bronchoscopic neoplasms and positive biopsy); 45 cases of peripheral lung cancer; 95 cases who underwent thoracotomy; 18 cases of video-assisted thoracoscopic surgery; 15 cases of total pneumonectomy; 98 cases of pulmonary lobectomy; 11 cases of left total pneumonectomy; and 4 cases of right total pneumonectomy; no deaths within 1 month postoperatively.
Distribution of primary lesion location
right upper lobe (21 cases) comprised apical segment (RS1) group (4 cases), posterior segment (RS2) group (6 cases), apicoposterior segment (RS1 + 2) group (6 cases), and anterior segment (RS3) group (5 cases). Right middle lobe (5 cases) comprised outer segment (RS4) group (3 cases) and inner segment (RS5) group (2 cases). Right lower lobe (27 cases) comprised dorsal segment (RS6) group (6 cases), basal segment (RS7–10) group (16 cases), and cross segment group (5 cases). Left upper lobe (32 cases) comprised apicoposterior segment (LS1 + 2) group (15 cases), anterior segment (LS3) group (6 cases), intralingual segment (LS4) group (4 cases), and extralingual segment (LS5) group (7 cases). Left lower lobe (28 cases) comprised dorsal segment (LS6) group (5 cases), basal segment (LS7–10) group (17 cases), and cross segment group (6 cases).
All patients received radical surgery, i.e., pulmonary lobectomy or total pneumonectomy plus hilar lymph node dissection and MLD. Intraoperatively, ipsilateral hilar lymph node dissection, interlobar lymph node dissection, and MLD were performed, following pneumonectomy based on Naruke's distribution diagram of lung cancer lymph nodes. Staging was done according to the International Association for the Study of Lung Cancer 2009 7th edition. Chi-square test was employed for statistical analysis.
| > Results|| |
There were 113 cases of N2, of which 77 cases of N1 + N2 and 36 cases of skip metastases. Of 1181 N2 lymph nodes dissected, 442 were positive with a positive rate of 37.4%. In terms of pathological classification, there were 66 cases of adenocarcinoma, 40 cases of squamous carcinoma, 5 cases of adenosquamous carcinoma, 1 case of mucoepidermoid carcinoma, and 1 case of sarcomatoid carcinoma. From the perspective of differentiation classification, 58 cases were poorly differentiated, 40 cases were moderately differentiated, and 15 cases were well differentiated.
There were a total of 21 right upper lobe cases, of which metastasis rate was 100% (21/21) for Group 2/4, 61.9% (13/21) for Group 3, 28.6% (6/21) for Group 7, and 0 for Groups 8 and 9. There were a total of five right middle lobe cases, of which metastasis rate was 40.0% (2/5) for Group 2/4, 10.0% (1/5) for Group 3, 80.0% (4/5) for Group 7, and 0 for Groups 8 and 9. There were a total of 27 right lower lobe cases, of which metastasis rate was 11.1% (3/27) for Group 2/4, 11.1% (3/27) for Group 3, 88.9% (24/27) for Group 7 which was the highest, and 22.2% (6/27) for Groups 8 and 9. Among a total of 32 left upper lobe cases, metastasis rate was 84.4% (27/32) for Group 5 which was the highest, 21.9% (7/32) for Group 6, 21.9% (7/32) for Group 7, and 6.3% (2/32) for Groups 8 and 9. Among a total of 28 left lower lobe cases, metastasis rate was 21.4% (6/28) for Group 5, 12.5% (4/32) for Group 6, 78.6% (22/28) for Group 7 which was the highest, and 46.4% (13/32) for Groups 8 and 9 [Table 1]. No metastasis was seen in Station 9 lymph node of right upper lobe lesions and Station 6 lymph node of left lower lobe lesions.
|Table 1: Primary tumor sites and metastasis rates of different mediastinal lymph node stations|
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Patients underwent surgeries from August 2010 to August 2012 were collected, who had a postoperative follow-up time of 3 years. Some adenocarcinoma patients (12 patients) experienced epidermal growth factor receptor mutations, who were successfully given targeted therapy and had significantly prolonged survival, and thus they were excluded from the study. Among 101 cases, 72 patients were in the N1 + N2 group, 23 patients were in the cross-regional N2 group (N2 was divided into superior and inferior mediastinal lymph nodes, with the superior zone consisting of 1–6 groups and inferior zone consisting of 7–9 groups; metastasis of superior and middle lobe lesions to the inferior zone or metastasis of lower lobe lesions to superior zone was precisely cross-regional N2), while 34 patients constituted the skip metastasis group (no N1 metastasis but with N2 metastasis). Three-year survival rates were 75.3%, 56.9%, 47.8%, and 61.8%, respectively. Cross-regional N2 group had a prognosis poorer than the N2 group, P = 0.009 (<0.01), presenting significant differences. No significant difference was found in the prognosis between the N1 + N2 group and the skip metastasis group, P > 0.05. The results are shown in [Table 2].
|Table 2: The 3-year survival rates of different N2 groups in nonsmall cell lung cancer patients|
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Correlation between preoperative T staging and prognosis is shown in [Table 3]. Prognosis of NSCLC worsened with increasing T stages, with 3-year survival rates for stages T1–T4 being 75.0%, 64.4%, 36.8%, and 27.3%, respectively. According to Chi-square test, statistical differences existed between T2 and T3, P = 0.02 (<0.05). No significant difference was found between T1 and T2 and between T3 and T4, indicating poor prognosis of stages T3, T4 patients with N2 metastasis.
|Table 3: The 3-year survival rates of different T stages in nonsmall cell lung cancer patients|
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Correlation between differentiation degree and prognosis is shown in [Table 4]. With decreasing degree of tumor differentiation, 3-year survival rates also dropped. Three-year survival rates for well-, moderately- and poorly-differentiated NSCLC were 63.6%, 53.8%, and 43.1%, respectively. Comparison of P values of the poorly-differentiation group to the well- and moderately-differentiated groups was 0.217 and 0.314, respectively, showing significant differences.
|Table 4: The 3-year survival rates of different differentiation degree groups in nonsmall cell lung cancer patients|
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| > Discussion|| |
Degree of mediastinal lymph node metastasis is one of the most important prognostic factors for NSCLC. According to statistics, mediastinal lymph node metastatic rate of NSCLC was between 20% and 40%. There remains a huge controversy on the scope of MLD. Especially for patients unclear of preoperative N1 or N2, the scope and extent of dissection were closely linked to the prognosis. Therefore, grasping the drainage path of pulmonary lymph and investigating the distribution regularity of N2 are very necessary.
According to the lymphatic anatomical features of the lungs, the return path was usually as follows: Lymph fluid from pulmonary tissues first arrived at the segmental hili and then entered the lobar and pulmonary hili. Afterward, one part was injected into the mediastinal lymph node and another part was injected upward to the jugular venous angle along the ipsilateral vascular and tracheal space. In addition, a part of return at lower pulmonary lobe was still partially injected into the celiac lymph nodes through diaphragm while lymph fluid in the upper lobe can be returned to the subcarinal lymph nodes or directly skipped metastasized to the inferior mediastinal region. Lymphatic drainage within some pulmonary segments can be directly injected into the subclavian veins and thoracic ducts, which may be the reason for skip N2 or N0 but hematogenous metastasis. In this study, the left and right upper lobe metastasis rates for Group 7 were 21.9% and 28.6%, respectively. Primary lesions were located in the left upper lingual segments in seven patients, and metastasis rates were 14.2% and 28.4%, respectively, for Groups 8 and 9, thus confirming that the lymph fluid in the left upper lingual segments can be returned to the Groups 8 and 9 lymph nodes. Right middle, lower, and left lower lobe metastasis rates for Group 7 were all higher than other stations, which were 80.0%, 88.9%, and 78.6%, respectively. Right and left lower lobe metastasis rates for Group 9 were 22.2% and 46.4%, respectively, indicating that the lymphatic drainage of lower lobe lung cancer mainly took Group 7 as the main channel, which can be returned to Group 8 or 9 and then injected upward to Group 7.
Through analysis, the right upper lobe metastasis rate for Group 2/4 was 100% in this study; right lower lobe metastasis rate for Group 7 was 88.9%; left upper lobe metastasis rate for Group 5 was 84.4%; and left lower lobe metastasis rate for Group 7 was 78.6%; hence, we believed that the right upper lobe lung cancer was metastasized mainly to the right pretracheal or paratracheal lymph nodes (Group 2/4). Right medium and lower lobe lung cancer were metastasized mainly to subcarinal lymph nodes (Group 7) and possessed high metastatic rate to upper mediastinal lymph nodes. Lung cancer in the left upper lobe apicoposterior and anterior segments were most common in Group 5 while left lingual segment and left lower lobe lung cancer were metastasized mainly to the subcarinal lymph nodes (Group 7). This was similar to the conclusions of the retrospective study by Asamura et al. on 166 patients with NSCLC. Cerfolio and Bryant retrospectively analyzed 954 NSCLC patients and found that the right upper lobe lung cancer was metastasized mainly to the lymph nodes on the right side of Group 4; right medium and lower lobe lung cancer were metastasized mainly to lymph nodes on the right side of Groups 4 and 7; left upper lobe lung cancer was metastasized mainly to the lymph nodes in Group 6; left lower lobe lung cancer were metastasized mainly to the lymph nodes in Group 7. Among viewpoints aforementioned, the main metastatic sites of the left upper lobe lung cancer were inconsistent with the conclusions of our center, and the reasons were unclear yet.
Bulk data analysis on the relationship between primary lung segments and mediastinal lymph node metastases is still lacking. Due to the relatively small number of cases statistically analyzed in our center, precise data were unable to be obtained. Topol and Maslon found the presence of direct lymphatic drainage channels between the pulmonary segments and the mediastinal lymph nodes by autopsy, whose incidence was 13.2% in the right lung, 7.2% in the left lung, and the highest in the right upper lung and its anterior segments. In our center, lung cancer in anterior right upper lobes was found in five cases, of which N1 were positive but N2 were negative in three cases. This may be associated with the direct lymphatic channels. In addition, lower lung basal segments can also reach the upper lobe paratracheal lymph nodes via direct lymphatic drainage pathways, and lymphatic drainages in some lung segments have even exceeded the scope of mediastinal lymph nodes, which were directly injected into the subclavian veins and thoracic ducts. Because of the compression of tumors, the lymphatic obstruction of tumor thrombi, and the presence of intrapulmonary and intermediastinal direct lymphatic return channels, the cross-regional, cross-mediastinal lymph node metastases may occur. This set of data demonstrated that the metastasis rate was 11.1% for primary lung cancer in the right lower lobes in Groups 3 and 2/4; 6.3% for those in the left upper lobe in Group 9; and 21.4% for those in the left lower lobe in Group 5, which were in line with the cross-regional, cross-transfer characteristics.
Although the channel of pulmonary lymphatic drainage began from lung, passed through pulmonary hili, mediastinum, and then to thoracic cavity, the lymphatic metastatic channels of malignancies were not fully in accordance with such linear model. Lymphatic drainage network of lung cancer can be extensive and varied. Skip metastasis, that is, mediastinal lymph node metastasis without intrapulmonary or hilar lymph node metastasis, is one of them. Bonner et al. reported that the overall proportion of mediastinal lymph node skip metastasis was 17%–41%. In this study, N2 patients totaled 113, of whom 77 patients were complicated by N1 and 36 patients were skipped metastasis patients (including 21 adenocarcinoma patients, 11 squamous carcinoma patients, and 4 other patients), with a skip proportion of 31.9%. Possible reasons for analyzing skip were as follows: (1) After pulmonary lobectomy, surgeons and pathologists failed to carefully dissect the isolated pulmonary segments and hilar lymph nodes, resulting in artificial N1 loss. (2) Cases with skip metastases cannot be ruled out for N1 lymph node micrometastases, that is, due to the different testing methods, the submitted segmental or hilar lymph nodes had a certain degree of micrometastatic loss rate, which was about 20% according to Prenzel et al.'s report. (3) Drainage of partial lung segments may not pass through hili but are directly sent to mediastinal lymph nodes. Riquet et al. once reported that the incidence of such case was about 24%. According to substantial literature reports, patients with pathological types of adenocarcinoma and primary lesions in the right lower lung were more prone to skip lymph node metastasis, which was consistent with the present study.,,, However, there were still different views indicating that squamous carcinoma was more prone to skip metastasis. Such argument may suggest that the major factor influencing skip metastasis was the biogenetic characteristics of tumor itself, rather than pathological classification. Due to the presence of skip metastasis, MLD was superior to sampling as the former can reduce misdiagnosis. According to a report, enlarged lymph nodes had a benign rate of 40% and malignant rate of morphologically normal lymph nodes was about 25%. About 20% of clinical third phase patients were erroneously divided into clinical first phase or second phase as they cannot determine the presence of N2. Postoperatively, the ratio of clinical stage shifting due to skip metastasis of lymph nodes was about 33%. Statistical data of Dr. Zhang et al. suggested that the skip metastatic incidence of upper lobar tumors was 57.0%, which was higher than 43.0% of the lower lobe. Skips of the right upper lobes most commonly occurred in Groups 2, 3, and 4; right medium and lower lobes in Group 7; left upper lobe in Groups 5 and 6; and left lower lobes in Groups 7 and 9. Five-year survival rate was 22.1% in the skip group, which was higher than 13.6% in the N1 + N2 group.
Prognostic study of cross-regional mediastinal lymph node metastasis remains controversial. Cross-regional N2 group consisted of 23 patients, and its 3-year survival rate decreased compared to the total group (47.8% vs. 75.3%). Among them, 13 patients had subcarinal lymph node metastases of upper lobe tumors; 6 patients constituted the upper right group; and 7 patients constituted the upper left group. Three-year survival rate was 15.4%, which was similar to the conclusions of Dr. Aokage et al. They analyzed twenty patients complicated by subcarinal lymph node metastasis, whose primary lesions were located in the upper lobes. Five-year survival rate was 9.0%, which was significantly lower than 32.0%, the rate for patients complicated by subcarinal lymph node metastasis only, indicating that the patients with subcarinal lymph node metastasis had poor prognosis. For a more detailed understanding of the factors influencing the prognosis, through follow-up study, we divided 101 N2 patients into the single-station N2 group and multi-station N2 group. Numbers of cases were 73 versus 29, while 3-year survival rates were 58.9% versus 31.1%, indicating poorer prognosis for the multi-station N2 group than the single-station N2 group. According to literature reports, 5-year survival rate for multi-station N2 was 9%–23%, while it for single-station N2 can reach 25%–60%. In addition, intrapulmonary metastasis classified as T4 was also seen as a poor prognostic risk factor, whose probability of occurrence among NSCLC patients receiving surgical resection was about 8%–9%., According to the classification of lymph node status, intrapulmonary metastasis rates corresponding to N0, N1, and N2 were 3.7%, 7.6%, and 14.8%, respectively.
In brief, because of the anatomical features, tumor compression, lymphatic obstruction, and skip metastasis characteristics of lymphatic return, we recommended systemic MLD for cT3-4N1/2 patients, and the reasons were as follows: (1) More comprehensive, accurate grasp of lymph node status, and provide help for postoperative treatment; (2) improve the prognosis; literature show that compared to the systematic mediastinal lymph node sampling and simple random lymph node sampling techniques, the systematic MLD had a 5-year survival rate significantly higher than the latter two procedures;, (3) do not increase the incidence of postoperative complications. We analyzed that T3/T4 and cross-regional lymph node metastasis were the risk factors for poor prognosis. Poor tumor differentiation was not an independent risk factor. It was worth mentioning that there were still 12 patients whose well-differentiated tumors metastasized to the mediastinal lymph nodes in this group, but the prognosis was good comparatively. In addition, due to the relatively small number of cases, we cannot make a detailed exposition of the correlation between different primary lung segments and mediastinal lymph node metastases.
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[Table 1], [Table 2], [Table 3], [Table 4]