Background
Lung cancer is the leading cause of cancer deaths worldwide, constituting 18 % of all cancer-related deaths. Up to 80–85 % of lung cancers are classified as non–small-cell lung cancer (NSCLC) [
1]. Surgical treatment is an important therapy for early-stage non-small cell lung cancer (NSCLC). The extent of disease in NSCLC is staged according to the TNM classification [
2], and because the stage at diagnosis is the principal prognostic indicator, accurate staging is essential for treatment decisions.
In theory, patients with early-stage non-small cell lung cancer can be cured by surgical resection alone. However, approximately 30 % of patients with pathologic stage 1 NSCLC have a recurrence of the tumor and die, despite complete surgical resection [
3,
4]. This poor prognosis suggests the occurrence of micrometastasis, which often occurs before the primary operation and therefore cannot be assessed by routine clinical examinations and conventional histopathologic methods after the cancer has already spread to the regional lymph nodes. The detection of occult disease could help to identify those patients with lymph nodes micrometastases NSCLC who are at high risk for tumor recurrence and who might benefit from adjuvant therapy. Therefore, for an accurate prediction of prognosis, it is necessary to assess the lymph node status and to characterize micrometastasis.
The prognostic value of molecular tumor cell detection in patients with lymph node micrometastases NSCLC remains uncertain. To clarify this issue, we conducted a systematic review with meta-analyses of studies that evaluated the prognostic significance of molecular tumor cell detection in lymph nodes.
Discussion
This systematic review and meta-analysis showed that the molecular detection of tumor cells in regional lymph nodes is associated with an increased risk of disease recurrence and poor survival in patients with negative pathologic lymph node status NSCLC.
Lung cancer remains the most common cancer in the world, both in terms of new cases (1.8 million cases, 12.9 % of all cancers) and deaths (1.6 million deaths, 19.4 %) because of the high number of fatal cases [
16]. The TNM staging system of lung cancer is widely used as a guide for predicting the prognosis. The presence of lymph node metastases along with T and M status represents the most accurate factor that is currently available for the prediction of prognosis in patients who undergo complete surgical resection. However, a significant proportion of patients with early stage NSCLC who undergo potentially curative resections subsequently relapse and die. This suggests that occult micrometastasis can exist at the time of surgery; the rate is clearly underestimated by current clinical staging examinations and conventional histopathologic methods. A nodal micrometastasis was defined according to the definition of the International Union Against Cancer (UICC; i.e. as a single or small number of tumor cells that are 0.2 mm in dimension [ITCs] and as tumor deposits < 2.0 mm but greater than 0.2 mm in dimension [MMs]) [
17]. If the UICC definition was not applied or mentioned explicitly, single or clustered cells that were detected in molecular analyses were also considered as occult disease. In this study, we identified occult micrometastatic tumor cells in pN0 lymph nodes in half of the patients with completely resected stage 1 NSCLC using an immunohistochemical staining assay. The patients with lymph node micrometastasis had a poorer prognosis than the patients without micrometastasis by univariate or multivariate analyses; the prognostic impact was independent from the TNM staging system [
8].
For this meta-analysis, we attempted to closely follow the recommendations presented by the Cochrane Collaboration. We pre-specified a strict study protocol, and we searched documents from several international conferences, electronic databases and reference research for relevant trials. The language was not restricted. Eight documents, which were published worldwide from 1996 to 2011, were included in the meta-analysis. Despite the number of documents that have been reported and the well-explained risk of patients with LNMM, the prognostic significance of LNMM of patients with NSCLC has remained highly undetermined. Therefore, we pooled the analysis of all documents that indicated a strong evidence of the independent, adverse prognostic impact of LNMM regarding OS and DFS at the time of the initial diagnosis of operable NSCLC.
Micrometastases disease is the significant cause of mortality from solid tumors. Tumor cells that are detected molecularly in the LN of patients with NSCLC are subjected to one of three fates: death, dormancy, or proliferation [
18]. Most metastatic cells die in this hostile microenvironment [
19,
20], or they balance the growth rates with the death rates [
21]. Other cells adapt by responding to stimuli from the microenvironment.
The poor prognostic significance of LNMM regarding OS and DFS likely occurs because the tumor cells that survive in the LN can completely escape dormancy and begin to proliferate as soon as they reach their destination. Alternately, some of the tumor cells begin to proliferate later after an unknown situation that permits them to overcome inhibitory effects at the metastatic site [
18]. Therefore, these tumor cells become viable micrometastases rather than shed tumor cells with a limited life span. Lymph node micrometastasis, as well as overt lymph node metastasis, does not necessarily reflect lymphogenous spread, but it can signal the early phase of hematogenous systemic tumor cell dissemination.
This meta-analysis has shown that the detection of lymph node occult micrometastatic tumor cells is helpful in predicting recurrence and the prognosis of patients with early stage NSCLC. It would also be possible to select patients who might benefit from adjuvant chemotherapy., postoperative adjuvant chemotherapy is not a routine standard therapy for patients with completely resected NSCLC because of its unreliable results for the improvement of prognosis. However, numerous trials, including two randomized trials [
22,
23], of induction chemotherapy for stage 3A NSCLC have shown that it was feasible and indicated higher response rates and a survival advantage. Additionally, LNMM patients with a minimal amount of residual tumor could respond better to chemotherapy.
This study has limitations because of the sample size. Although we contacted each author to supplement the missing data, the number of included studies was insufficient to perform some of the preplanned subgroup analyses, and only 3 subgroup studies were included in our analysis. Consequently, we could not identify the effect modifiers that could be attributable to the low statistical power.
Conclusions
In conclusion, there is evidence that molecular tumor cell detection in regional lymph nodes indicates poor prognosis in node-negative NSCLC. Despite a prognostic impact of tumor cell detection across the applied detection assays, standardized protocols should be used in future studies that use standardized end points and adhere to the UICC definition of tumor cells and micrometastasis. By using such protocols, it should be clarified within prospective randomized trials whether patients with occult lymph node disease benefit from adjuvant chemotherapy. Furthermore, the findings of this study encourage efforts to identify subpopulations of disseminated cells that put patients at a particular risk of disease recurrence and poor survival.
Competing interests
The authors declare that they have no competing interests.
Authors’ contribution
JM and JD contributed substantially to the conception and design of this meta-analysis and gave final approval of the version of the analysis to be published. XD, QL and DZ contributed to the analysis and interpretation of all data and drafted the article. BH critically reviewed and revised the article for important intellectual content. LJ and KC reviewed the article in the final reviewed process. All authors read and approved the final manuscript.