INTRODUCTION
Lymph node metastasis is confirmed by lymph node dissection during operation. However, anatomical lobectomy combined with systematic lymph node dissection remains controversial for early lung cancer treatment.[1–4] Moreover, in situ and microinvasive adenocarcinomas of the lung barely have lymph node metastasis.[5,6] The risk of lymph node metastasis in IA1 and IA2 lung cancers is relatively low.[7] Currently, the research results of clinical stage IA3 in JCOG1211 in Japan have not been published yet.[8] Therefore, it is necessary to identify the risk factors for lymph node metastasis in clinical stage IA3 lung adenocarcinoma.
MATERIAL AND METHODS
Patients
The ethics committee of Wenzhou Central Hospital (xmsq2021-0131) approved the retrospective study. As the study was retrospective, written informed consent from patients was not needed. Three hundred and thirty-four patients diagnosed with clinical stage IA3 lung adenocarcinoma between January 2017 and January 2022 were included in the study. Inclusion criteria were preoperative clinical staging based ontumor, node, and metastasis (TNM) staging (IASLC eighth edition), single tumor with diameter (>2–3 cm), performance status of zero or one, sufficient organ function, invasive adenocarcinoma, and absence of distant organ metastasis. Exclusion criteria were incomplete case records, severe emphysema, pulmonary fibrosis, interstitial pneumonia, history of severe heart failure, myocardial infarction, heart disease within the past six months, pleural dissemination, short axis of mediastinal lymph nodes greater than 1 cm, lymph node metastasis confirmed on positron emission tomography-computer tomography (PET-CT), or preoperative neoadjuvant radiotherapy or chemotherapy.
Methods
All patients had completed preoperative tests, including contrast-enhanced thoracic CT, PET-CT, echocardiography, pulmonary function evaluation, and carcinoembryonic antigen (CEA) measurement. Before the operation, no puncture biopsy was conducted. Lobectomy combined with systemic lymph node dissection was conducted. The systematic lymph node dissection for right-side tumors contained 2R, 4R, and 7–12 stations, while 4–12 stations were required for left-side tumors. The lymph node classification complied with the IASLC (eighth edition). Information on age, sex, smoking history, preoperative serum CEA levels, CTR, tumor location, SUVmax, and pleural retraction was obtained from medical records.
Statistical analysis
Univariate analysis and multivariate logistic regression analyses were conducted using SPSS (version 23.0, Inc, Chicago, IL, USA) to identify the risk factors of lymph node metastasis. Univariate analysis was determined using Fisher’s exact test or X2 test. The categorical variables (p < 0.1 with univariate analysis) were included in the multivariate regression analysis. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were calculated to evaluate the prediction values of CTR and CEA. P < 0.05 was statistically significant.
RESULTS
The 334 patients eligible for the study included 190 males and 144 females. Fifty-one (15.3%) patients had mediastinal lymph node metastasis according to the postoperative pathological diagnosis. Of them, 45 patients exhibited N1 positive lymph nodes, 11 showed N2 positive lymph nodes, and five showed both N1 and N2 positive lymph nodes. The lymph node metastasis rate was 57.9% in patients with >5 ng/mL CEA, 18.1% in those with >0.75 CTR, 18.0% in those with >5 SUVmax, and 20.3% in those with pleural traction on CT images.
Figure 1 shows lymph node status according to postoperative histological analysis. N1 lymph node metastasis occurred in five cases (3.8%) of lepidic-predominant lung adenocarcinoma, six cases (6.2%) of acinar predominant, five cases (13.9%) of papillary predominant, 15 cases (53.6%) of micropapillary predominant, and 14 cases (31.7%) of solid predominant. N2 lymph node metastasis was detected in all cases except those with the lepidic predominant subtype.
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Figure 1: Distribution of lymph node status is shown according to pathologic subtypes of clinical stage IA3 lung adenocarcinoma. Green: pN2; orange: pN1; blue: pN0
According to univariate analysis, the following factors were identified as important predictors of mediastinal lymph node metastasis, i.e., age (p = 0.03), CTR (p < 0.001), SUVmax (p = 0.013), CEA level (p < 0.001), and pleural traction (p = 0.016). Gender, tumor location, and smoking history were not identified as significant predictors [Table 1]. The five significant predictive factors from univariate analysis were included in the multivariate analysis. The results showed that the preoperative CEA level (OR: 3.05, 95%CI: 1.226–7.586, P = 0.016) and CTR (OR: 2.75, 95%CI: 1.482–6.346, P = 0.025) were two independent predictive factors for mediastinal lymph node metastasis [Table 2].
Figure 2 shows ROC curves generated following distributions of each important variable of mediastinal lymph node metastasis. The AUC values for CTR and CEA levels were 0.790 (95%CI: 0.727–0.853) and 0.682 (95%CI: 0.591–0.773), respectively.
Table 1: Clinical characteristics and univariate analysis of lymph node metastasis for patients
Table 2: Independent predictors of lymph node metastasis using multivariate analysis
Figure 2: ROC curves show the predictability of lymph node metastasis based on CTR (a) and CEA (b). CTR: Consolidation tumor ratio; CEA: carcinoembryonic antigen; ROC: receiver operating characteristic; AUC: area under the curve; CI: confidence interval
DISCUSSION
According to many studies, mediastinal lymph node metastasis may even occur in early nonsmall cell lung cancer.[9,10] If lymph node metastasis can be identified before surgery, these affected patients will benefit from surgical resection after neoadjuvant therapy.[11–13] However, it is difficult to evaluate mediastinal lymph node metastasis by enhanced CT or PET-CT before operation. This study excluded patients with mediastinal lymph node metastasis by preoperative PET-CT. Nevertheless, 15.3% (51/334) of patients with mediastinal lymph node metastasis were not found by PET-CT before the operation, which explained the limitations of PET-CT in evaluating mediastinal lymph node metastasis.
Mediastinal lymph node metastasis occurred in all the clinical stage IA3 lung invasive adenocarcinomas according to postoperative pathology in this study. But Ye et al. suggested that no mediastinal lymph node metastasis was observed in patients with stage IA lepidic predominant lung adenocarcinoma,[14] which may be due to the small sample size. According to our results, the total rate of mediastinal lymph node metastasis in IIA3-stage lung adenocarcinomas was 15.3%. Koike et al. reported that the overall mediastinal lymph node metastasis rate in patients with stage IA nonsmall cell lung cancer was only 7.5%.[15] The overall mediastinal lymph node metastasis rate in patients with stage IA lung adenocarcinoma was 10.6%, according to Ye et al.[14] Only 8.5% of patients with stage IA had mediastinal lymph node metastasis according to Ding et al.[16] The latest research results in Japan reported that the lymph node metastasis rate for stage IA lung adenocarcinomas is 4.9%.[17] These studies suggest that the rate of mediastinal lymph node metastasis in IA3 stage lung adenocarcinomas was significantly higher than that in IA stage lung adenocarcinomas. The size of the tumors might affect the occurrence of mediastinal lymph node metastasis. Given the differences in the mediastinal lymph node metastasis rates between IA3 and IA1/IA2 stage lung adenocarcinomas, further refinement of clinical staging may help optimize mediastinal lymph node dissection.
Lee et al. showed that the abnormal CEA level is closely related to the distant metastasis of nonsmall cell lung cancer.[18] Our results showed that the mediastinal lymph node metastasis rate in patients with CEA (>5 ng/mL) was 57.9%. Wang et al. reported that CEA (>5 ng/mL) is a risk factor for lymph node metastasis (OR = 1.574, P = 0.001) in patients with early-stage peripheral lung adenocarcinoma.[19] Ye et al. also showed that CEA (>5 ng/mL) is associated with an increased risk of lymph node metastasis in stage IA lung adenocarcinomas (OR = 3.923, P < 0.001).[14] In patients with clinical stage IA nonsmall cell lung cancer, Koike et al. revealed that preoperative CEA (>3.5 ng/mL) is a risk factor for mediastinal lymph node metastasis.[15] All results mentioned above are consistent with our study. An important risk factor for mediastinal lymph node metastasis of lung cancer is preoperative CEA abnormality. The systemic lymph node dissection should be preferably applied to stage IA3 lung adenocarcinoma patients with >5 ng/mL CEA.
Previous JCOG series studies have shown that CTR will affect the long-term survival of lung cancer patients.[4,20] The results of JCOG0201 suggest that patients with <0.25 CTR and small tumors (<2 cm) should be diagnosed with noninvasive adenocarcinoma.[20] The JCOG0804 study suggests that it is not necessary to perform systematic lymph node dissection in most lung adenocarcinoma patients with <0.25 CTR.[2] The 5-year disease-free survival reached 99.7% (95% CI: 98.3–99.9%). In this study, the rate of lymph node metastasis in patients with tumor size (<2–3 cm) and CTR (<0.75) was only 5.6% (5/90). Although long-term follow-up is lacking, our results still suggest that lung adenocarcinoma patients with <0.75 CTR may be less prone to develop mediastinal lymph node metastasis. The probability of mediastinal lymph node metastasis remarkably increased in lung adenocarcinoma patients with >0.75 CTR. Additionally, Koike et al. showed that CTR (>0.75) is an important risk factor for mediastinal lymph node metastasis (OR = 1.126, P < 0.001).[15] Another study by Chen et al. suggested that CTR (>0.62) is a risk factor for mediastinal lymph node metastasis (OR = 12.723, P = 0.002).[21] Consistently, our results demonstrate that the value of CTR (>0.75) is a high-risk factor for mediastinal lymph node metastasis in patients with clinical stage IA3 lung adenocarcinoma.
Lu et al. have shown that the pathological subtype of lung adenocarcinoma is an indicator of long-term survival of lung cancer patients.[22] Kim et al. reported that the 5-year disease-free recurrence risk of papillary predominant (OR = 2.49, P < 0.001) and solid predominant (OR = 1.99, P = 0.003) is higher than that of other types of lung adenocarcinoma.[23] According to other research groups, pathological subtype is a significant risk factor for mediastinal lymph node metastasis of stage IA lung adenocarcinoma.[14,19] Although pathological subtypes were excluded from the multivariate analysis, our results indicate that the lymph node metastasis rates of micropapillary adenocarcinoma and solid adenocarcinoma attained 60.7 and 39.0%, respectively. The systematic lymph node dissection should be the primary choice for the two unique types of lung adenocarcinomas. Unfortunately, no patient in this study underwent systematic lymph node dissection due to a lack of pathological analysis before surgery.
A retrospective study showed that patients with lymph node metastasis have a significantly higher SUVmax value than patients without lymph node metastasis.[24] Lv et al. reported that the mean SUVmax (9.2) was an independent risk factor for lymph node metastasis in patients with nonsmall cell lung cancer (OR, 1.126; 95% CI, 1.040–1.220; P = 0.004).[25] Univariate analysis indicated that SUVmax had a significant effect on the risk of lymph node metastasis in patients with lung adenocarcinoma in this study. In multivariate analysis, SUVmax was not an independent risk factor for lymph node metastasis, which may be explained by the fact that the cutoff value of SUVmax was different from the previous research.
Wang et al. discovered that pleural traction was an independent risk factor for lymph node metastasis in lung adenocarcinoma (OR, 2.099; 95% CI, 1.513–2.911; P < 0.001).[19] However, it was not an independent risk factor for lymph node metastasis in patients with lung adenocarcinoma in our study. Ongoing studies are conducted to confirm the relationship between pleural retraction and lymph node metastasis in patients with lung adenocarcinoma.
Our study has some limitations. First, it is a retrospective study and single center with a relatively small number of cases; therefore, patient-selection bias may have existed. Prospective multi-institutional trials are required for a definitive conclusion. Second, the long-term follow-up outcome is not known, but since lobectomy and mediastinal lymph node dissection are conducted in all cases, our results will help identify the mediastinal lymph node dissection of IA3 lung adenocarcinoma.
According to our results, CEA (>5 ng/mL) and CTR (>0.75) are independent risk factors for lymph node metastasis in patients with clinical stage IA3 lung adenocarcinoma. The systematic lymph node dissection may be recommended for IA3 lung adenocarcinoma patients, especially in the settings of CTR >0.75 and CEA >5 ng/mL.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was supported by the Natural Science Foundation of Zhejiang Province, China (LQ22H160024), and the Program from Wenzhou Municipal Science and Technology Bureau of China (2022Y1136).
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Ye X, Fan W, Wang Z, Wang J, Wang H, Niu L, et al. Clinical practice guidelines on image-guided thermal ablation of primary and metastatic lung tumors (2022 edition). J Cancer Res Ther 2022;18:1213–30.
2. Cui Y, Wang W, Yao S, Qiu Z, Cong L. Relationship between circulating lung-specific X protein messenger ribonucleic acid expression and micrometastasis and prognosis in patients with early-stage nonsmall cell lung cancer. J Cancer Res Ther 2020;16:1641–7.
3. Huang X, Wang J, Chen Q, Jiang J. Mediastinal lymph node dissection versus mediastinal lymph node sampling for early stage non-small cell lung cancer:A systematic review and meta-analysis. PLoS one 2014;9:e109979.
4. Suzuki K, Watanabe SI, Wakabayashi M, Saji H, Aokage K, Moriya Y, et al. A single-arm study of sublobar resection for ground-glass opacity dominant peripheral lung cancer. J Thorac Cardiovasc Surg 2022;163:289–301.
5. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, et al. The IASLC lung cancer
staging project:Proposals for Coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer. J Thorac Oncol 2016;11:1204–23.
6. Behera M, Owonikoko TK, Gal AA, Steuer CE, Kim S, Pillai RN, et al. Lung adenocarcinoma
staging using the 2011 IASLC/ATS/ERS classification:A pooled analysis of adenocarcinoma
in situ and minimally invasive adenocarcinoma. Clin Lung Cancer 2016;17:e57–64.
7. Moon Y, Park JK, Lee KY, Kim ES. Prognosis after wedge resection in patients with 8(th) edition TNM stage IA1 and IA2 non-small cell lung cancer. J Thorac Dis 2019;11:2361–72.
8. Aokage K, Saji H, Suzuki K, Mizutani T, Katayama H, Shibata T, et al. A non-randomized confirmatory trial of segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-section computed tomography (JCOG1211). Gen Thorac Cardiovasc Surg 2017;65:267–72.
9. Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, et al. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma:Results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 2011;141:662–70.
10. Pan L, Mo R, Zhu L, Yu W, Lv W, Hu J. Time trend of mediastinal lymph node dissection in stage IA non-small cell lung cancer patient who undergo lobectomy:A retrospective study of surveillance, epidemiology, and end results (SEER) database. J Cardiothorac Surg 2020;15:207.
11. Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J Clin Oncol 2012;30:172–8.
12. Wang Y, Song J, Li W, Zeng H, Liu N, Zhu S, et al. Effectivity of involved-field radiotherapy for recurrent brain metastasis in patients with small-cell lung cancer. J Cancer Res Ther 2022;18:1276–85.
13. Xu S, Cao S, Yu Y. High systemic immune-inflammation index is a predictor of poor prognosis in patients with nonsmall cell lung cancer and bone metastasis. J Cancer Res Ther 2021;17:1636–42.
14. Ye B, Cheng M, Li W, Ge XX, Geng JF, Feng J, et al. Predictive factors for lymph node metastasis in clinical stage IA lung adenocarcinoma. Ann Thorac Surg 2014;98:217–23.
15. Koike T, Koike T, Yamato Y, Yoshiya K, Toyabe S. Predictive risk factors for mediastinal lymph node metastasis in clinical stage IA non-small-cell lung cancer patients. J Thorac Oncol 2012;7:1246–51.
16. Ding N, Mao Y, Gao S, Xue Q, Wang D, Zhao J, et al. Predictors of lymph node metastasis and possible selective lymph node dissection in clinical stage IA non-small cell lung cancer. J Thorac Dis 2018;10:4061–8.
17. Aokage K, Suzuki K, Wakabayashi M, Mizutani T, Hattori A, Fukuda H, et al. Predicting pathological lymph node status in clinical stage IA peripheral lung adenocarcinoma. Eur J Cardiothorac Surg 2021;60:64–71.
18. Lee DS, Kim YS, Jung SL, Lee KY, Kang JH, Park S, et al. The relevance of serum carcinoembryonic antigen as an indicator of brain metastasis detection in advanced non-small cell lung cancer. Tumour Biol 2012;33:1065–73.
19. Wang Y, Jing L, Wang G. Risk factors for lymph node metastasis and surgical methods in patients with early-stage peripheral lung adenocarcinoma presenting as ground glass opacity. J Cardiothorac Surg 2020;15:121.
20. Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751–6.
21. Chen YC, Lin YH, Chien HC, Hsu PK, Hung JJ, Huang CS, et al. Preoperative consolidation-to-tumor ratio is effective in the prediction of lymph node metastasis in patients with pulmonary ground-glass component nodules. Thorac Cancer 2021;12:1203–9.
22. Lu D, Yang J, Liu X, Feng S, Dong X, Shi X, et al. Clinicopathological features, survival outcomes, and appropriate surgical approaches for stage I acinar and papillary predominant lung adenocarcinoma. Cancer Med 2020;9:3455–62.
23. Kim M, Chung YS, Kim KA, Shim HS. Prognostic factors of acinar- or papillary-predominant adenocarcinoma of the lung. Lung Cancer 2019;137:129–35.
24. Mattes MD, Moshchinsky AB, Ahsanuddin S, Rizk NP, Foster A, Wu AJ, et al. Ratio of lymph node to primary tumor SUV on PET/CT accurately predicts nodal malignancy in non-small-cell lung cancer. Clin Lung Cancer 2015;16:e253–8.
25. Lv X, Wu Z, Cao J, Hu Y, Liu K, Dai X, et al. A nomogram for predicting the risk of lymph node metastasis in T1-2 non-small-cell lung cancer based on PET/CT and clinical characteristics. Transl Lung Cancer Res 2021;10:430–8.
