A comprehensive algorithm to distinguish between MPLC and IPM in multiple lung tumors patients

Introduction

In recent years, the mortality of lung cancer has been significantly reduced through screening with low-dose helical computed tomography (CT) (1,2). However, the identification of multiple lung nodules has emerged as an increasingly common clinical problem (3-5). One previous study suggested that more than 15% of lung cancer patients had multiple lesions (6). Relative to the general population, patients with lung cancer had a 3.5-fold increased risk of all second cancer (7). To better individualize treatment, it is crucial for clinicians to be able to differentiate between intrapulmonary metastasis (IPM) and multiple primary lung cancer (MPLC). In the latest TNM classification system, lung cancer is classified as: T3 if more than one nodule is found in one lobe, T4 if a different ipsilateral lobe is involved, and M1a if the contralateral side is affected (8,9). However, this criteria defaulted to patients with multiple nodules as IPM. Neglecting cases of MPLC and confusing two types of multifocal lung cancer patients, this classification might lead to clinical errors. Moreover, patients with independent primary tumors tend to have a better prognosis than those with IPM (10-12). A meta-analysis indicated that the overall survival (OS) of patients with MPLC was superior to that of patients with IPM (HR =2.66, 95% CI: 1.30–5.44; P=0.007) (12).

Unfortunately, despite the issue being widely discussed, no golden standard for distinguishing multiple primary tumors from metastatic lung carcinomas exists. As early as 1975, Martini and Melamed (MM) proposed criteria to distinguish separate primary lesions from metastasis, and this has been broadly accepted (13). Their criteria were empirically derived and considered the major histologic type, interval time for metachronous tumors, and tumor location, and the clinical application of MM criteria still needed further scientific discussions and updates. Then criteria introduced by the American College of Chest Physicians (ACCP) combined the comprehensive histologic assessment of the MM criteria with the evaluation of morphology, immunohistochemistry, and molecular features (14-16). Girard et al. further proposed the comprehensive histologic assessment (CHA) that appeared to be a promising way to determine whether multiple lung carcinomas were metastatic or multiple primaries (17). CHA included a semi-quantitative grading system assessing growth patterns and cytologic features for the first time. After that, the International Association for the Study of Lung Cancer Staging (IASLC) developed clinical and pathological recommendations for identifying solely second primary lung cancers (10). Nevertheless, there was no accurate method to identify which lesions have arisen from one another. The actual process of metastasis was too complex to found biomarkers, which was influenced not only by the intrinsic and epigenetic determinants of tumor cells, but also by a series of complex tumor host interactions between the primary and the metastatic sites (18,19).

Recently, a growing number of studies have validated genomic testing can be used to confirm the consistency of the tumor lineage (20-23). Genomic profiling of single genes or a subset of genes and DNA rearrangement profiles had been shown to be efficient (22,24-26). Then the implementation of next-generation sequencing (NGS) further enhance the accuracy of molecular testing (27-29). However, these detection technologies carry the disadvantages of having limited sensitivity and high costs of clinical implementation. Another potential technique is radiology, because CT has become more widely used. Suh et al. suggested IPM should be considered if both of two suspected malignant lesions appear as solid predominant lesions without spiculation or air-bronchogram on CT (30). Moreover, none of method has clear guidelines for rare histological subtyping of lung cancer or more than two nodules, which may result in defects in clinical practice. Here, we report a comprehensive proposal for distinguishing IPM from MPLC in lung cancer, and retrospectively investigate the prognosis after surgical treatment in 576 patients with multiple lung tumors. We present the following article in accordance with the MDAR reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5505).

Methods

Patients and tumor selection

All patients who had undergone resection of lung carcinoma at West China Hospital of Sichuan University in Chengdu, China, between April, 2009, and December, 2017, were retrospectively reviewed. A total of 576 individuals with pathologically confirmed multiple lung carcinomas who had sufficient data available including clinical, histological, molecular characteristics and imaging analysis were enrolled. The following information was also collected for each patient: age (at the time of surgery), sex, smoking history, number of lesions, tumor location, tumor histology, adjuvant therapy, node invasion, pleural invasion, and epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) mutation status. Patients with an interval of less than 6 months between tumors were defined as synchronous, while the remainders were defined as metachronous. All of the patients were followed up until July 8, 2019 to obtain OS. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and the ethics committee of West China Hospital has approved this study (Project No. 2019-195). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Histologic assessment

The researchers extracted the histologic information from the patients’ pathological records. All tumor slides had been reviewed by experienced pathologists. The 2015 WHO classification reclassified lung cancer into adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma and other malignant types (31). According to CHA, the predominant histologic pattern was defined according to the histologic component with the greatest percentage (17). In our study, adenocarcinoma subtypes were atypical adenocarcinoma hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). IA was further subdivided into lepidic, acinar, papillary, micropapillary, and solid adenocarcinoma. The overall method of detailed histological evaluation also covered cytological and stromal characteristics, including the cell morphology, degree of keratosis, stroma, and necrosis of squamous cell carcinoma. Meanwhile, the status of mediastinal lymph nodes dissected, including N2 and N3 nodes, was also recorded.

Molecular analysis

Mutational and genomic profiling techniques were performed to assess the clonal relationships between multiple tumors from individual patients, covering 9 genes [EGFR, ALK receptor tyrosine kinase gene (ALK), erb-b2 receptor tyrosine kinase 2 gene (ERBB2), v-raf murine sarcoma viral oncogene homologue B1 (BRAF), MNNG HOS transforming gene (MET), c-ros oncogene 1 receptor tyrosine kinase (ROS1), rearranged during transfection proto-oncogene (RET), kirsten rat sarcoma viral oncogene homolog (KRAS), and tumor protein p53 gene (TP53)]. More than 50 hotspot mutations were diagnosed in tumor pairs.

Imaging analysis

The preoperative CT images were reviewed and nodule information was extracted from the imaging reports. Lesions were classified into four types: pure ground-glass nodule (GGN), ground-glass opacity (GGO)-predominant part-solid nodule (PSN), solid-predominant PSN, and pure solid nodule (32). In addition, the malignant features of the nodules were evaluated for spiculation and lobulation. Simultaneously, systemic metastasis was confirmed by PACS (picture archiving and communication system) reports. Extrapulmonary metastases, such as brain or bone metastases, were considered to be distant metastases.

Algorithm for multiple lung tumors

The algorithm, which was based on multidisciplinary criteria (Figure 1), classified multiple nodules as IPM or MPLC. First, metachronous nodules were defined as MPLCs if the time period between nodules was above the threshold of 5 years. Second, each nodule was fully evaluated by histology. Tumors of different histological types or with tumors in situ were considered to be MPLC. If all tumors were unusual histologic types, such as neuroendocrine carcinoma, the patient was classified as IPM. Adenocarcinomas with different or rare predominant architectural patterns were also defined as metastasis in the lung. Lymph node metastases and distant metastases also indicated IPM. Thirdly, the molecular results determined whether tumors pairs were IPM or MPLC. Tumors which shared at least two gene mutations or one rare mutation in common were classified as IPM. Finally, the lesion features on preoperative imaging was used to obtain the final classification. When a nodule was pure GGN/GGO-dominant or harbored spiculation/lobulation, it was defined as MPLC. Furthermore, patients who had three or more lung cancer nodules with any two nodules presenting a metastatic relationship were considered to be IPM.

Figure 1 The comprehensive algorithm for patients with multiple lung tumors. Tumor in situ are defined as atypical carcinoma hyperplasia, and lung cancer in situ. Unusual histologic types are defined as other types of lung cancer apart from adenocarcinoma and squamous cell carcinoma. The rare predominant pattern of adenocarcinoma is defined as midpapillary. The rare mutation is defined as TP53. MPLC, multiple primary lung cancer; IPM, intrapulmonary metastasis; GGN, pure ground-glass nodule; GGO, ground-glass opacity.

Previous criteria

According to the MM criteria, IPM was classified when: tumor pairs, with synchronous tumors of a similar histological subtype which were located in same segment and/or without adenocarcinoma in situ, or with presence of carcinoma in the shared lymphatics of the two paired tumors (Table S1) (13). Metachronous tumors were defined as MPLCs when the tumor interval was >2 years. In cases where the time interval between tumors was <2 years, if the two tumors were located in the same lobe, or nodal involvement or systemic metastasis, these tumor pairs would be defined as IPMs.

Table S1 Commonly cited criteria to distinguish separate primary lung cancer from metastasis
Full table

According to the ACCP criteria, tumors with the same histological subtypes were seen as MPLCs if they were located in different lobes with no nodal involvement or systemic metastases, and the time period between tumors in a pair were less than 4 years; as IPM with the presence of lymphatic or systemic metastases and/or a short interval of less than 2 years. In addition, tumors of different histological subtypes, tumors with the same histological subtype but exhibiting different molecular genetic characteristics and carcinomas in situ were defined as MPLAs as well (Table S1) (14-16).

Statistical analyses

The clinical, histological, and molecular characteristics, and imaging features of the patients were collected from the Hospital Information System. To compare the clinical characteristics of patients with IPM and MPLC, continuous and categorical variables were analyzed by Student’s t-test and chi-square test, respectively. The consistency of different classification methods was assessed using Cohen κ score (33). OS was measured from the first surgical resection to death or the last follow-up. The OS rate was estimated using the Kaplan-Meier method. The log-rank test and Cox hazards regression analysis were performed to identify the effect of factors on survival in univariate analysis. The Cox model was used in multivariate analysis for variables that were significantly associated with OS. Analyses were performed with IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. A P value of <0.05 was considered to be statistically significant.

Results

Patients and histological characteristics

The 576 patients with multiple lung cancers included in this study were predominantly male (301 of 576, 52%) and non-smokers (340 of 576, 59%) (Table 1). Of the patients, 330 had synchronous tumors, while 246 patients had metachronous tumors with multiple tumors more than 6 months after resection. Over half of the patients were found to have malignant tumors located in different ipsilateral lobes (325 of 576, 56%), followed by contralateral lesions (196 of 576, 34%).

Table 1 The clinical and histological characteristics of 576 patients with multiple lung tumors
Full table

Of 1,295 tumors, the predominant carcinoma type was adenocarcinoma (1,041 of 1,295, 80%), among which, acinar (228 of 1,041, 22%), lepidic, and papillary adenocarcinoma were the three most frequent architectural patterns. In all cases of lung nodules, 44% of all patients had undergone lobectomy (575 of 1,295, 44%), and wedge resection was also common (336 of 1,295, 26%). Overall, the tumors were more likely to occur on the right side (791 of 1,295, 61%), and most were ≤3 cm in size when detected or resected (927 of 1,295, 72%).

Patients with IPM or MPLC

The comprehensive criteria identified 171 patients with IPM and 405 cases of MPLC. Compared with the MM classification, we found discordance for 84 patients (κ=0.65) (Figure 2). Among the patients, 42 had MPLC according to the MM criteria but were classified as IPM according to our final classification based on a time to relapse of >2 years (n=37) and the presence of more than two nodules (n=5). Meanwhile, 42 patients had IPM according to MM criteria but were reclassified as MPLC according to our final classification based on nodules being located in the same lobe or segment (n=36) and different predominant patterns of adenocarcinoma (n=6). At the same time, the κ consistency between our method and the ACCP criteria was 0.72 with 73 different patients (Figure 2). Of the patients, 15 had MPLC according to the ACCP criteria but were reclassified as IPM according to the final classification based on them having a rare histological type (n=3), more than two nodules (n=3), and a time to relapse of >2 years (n=9). Meanwhile, 58 patients had IPM according to ACCP criteria but were reclassified as MPLC according to the final classification based on nodules being located in the same lobe or segment (n=47) and a time to relapse of <2 years (n=11).

Figure 2 A comparison of the final classification with MM and ACCP classification. MM, Martini and Melamed; ACCP, American College of Chest Physicians; MPLC, multiple primary lung cancer; IPM, intrapulmonary metastasis.

In our final classification, more than half of the men (106 of 171) were placed in the IPM group, with less than half of the men (195 of 405) being placed in the MPLC group (Table 2). The median age at first resection of the IPM group was 57.69 years old, and that of the MPLC group was 59.56 years old. The proportion of smokers in the two groups was 48% (82 of 171) and 64% (258 of 405), respectively. There were significant differences between patients with IPM and MPLC in terms of gender (P<0.001), age at first resection (P=0.028), and smoking history (P<0.001). There were also statistically significant differences between the groups in relation to tumor chronology (P=0.010), tumor side (P=0.016), nodal involvement (P<0.001), pleural invasion (P=0.001), chemotherapy (P<0.001), radiotherapy (P<0.001), and PD-L1 mutational status (P=0.001).

Table 2 The clinical, histological, and molecular characteristics of the IPM and MPLC patients
Full table

Follow-up and survival

In the univariate analysis, OS for all 576 patients who harbored multiple lung tumors was associated with gender (P<0.001), smoking history (P<0.001), nodal involvement (P<0.001), pleural invasion (P=0.002), chemotherapy (P=0.006), radiotherapy (P<0.001), and the mutational status of EGFR (P<0.001) and PD-L1 (P<0.001) (Table 3). In the multivariate analysis, nodal involvement (P=0.04) and radiotherapy (P=0.04) were independent prognostic factors of OS.

Table 3 Univariate and multivariate analyses of overall survival
Full table

Notably, no matter which method was used to classify multifocal lung cancer, patients with independent primary tumors had a significantly better prognosis than patients with IPM (Table 3, Figure 3) (MM classification: HR =3.28, 95% CI: 2.35–4.58; P<0.001; ACCP classification: HR =4.02, 95% CI: 2.85–5.67; P<0.001; final classification: HR =3.99, 95% CI: 2.86–5.57; P<0.001). In patients with MPLC, the multivariate analysis showed that never smoking (P=0.004) was associated with survival (Table S2). In patients with IPM, most of the variables had no correlation with survival except tumor number (Table S3).

Figure 3 The survival curves of the IPM and MPLC patients after the final classification. MPLC, multiple primary lung cancer; IPM, intrapulmonary metastasis.

Table S2 Univariate and multivariate analyses of overall survival in 405 patients with MPLC
Full table

Table S3 Univariate and multivariate analyses of overall survival in 171 patients with IPM
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Discussion

With the diffusion of high-resolution CT screening, the detection rate of lung nodules has improved. However, the correct diagnosis of patients with multinodular lung cancer has become a concern (34,35). In this study, we have presented a comprehensive algorithm for multiple lung carcinomas which combines histologic, molecular, and imaging information. The algorithm divided the types of lung cancer in detail and made recommendations for more than two tumors. To explore the predictors of survival outcomes in patients with multiple lung tumors after surgical treatment, we performed an analysis of clinical characteristics and OS to compare IPM and MPLC. Notably, our results showed that the clinical characteristics of patients with IPM were clearly different from those with MPLC. Also, the OS of the IPM group was significantly higher than that of the MPLC group. Survival analysis underlined the survival benefit of being node-negative and not receiving radiotherapy in patients with multiple lung cancers.

Although the TNM staging system is based on the best available current evidence, there is conflict between cTNM (clinical TNM) and pTNM (pathological TNM) in patients with multiple lesions. According to the eighth TNM classification system, whenever two or more lung nodules are present, they are classified as T3, T4, or M1 depending on the location of the tumors (36). These multinodular patients, who are upgraded to stage III or stage IV, are usually treated with chemotherapy or radiation, and have a poor prognosis. However, our study confirmed that the IPM and MPLC groups not only had completely different clinical characteristics, but also held significantly different survival rates. Patients with intra-pulmonary metastasis had significantly worse OS than patients with primary lung tumors (HR =3.99, 95% CI: 2.86–5.57; P<0.001). The 5-year survival rate in the patients with MPLC was 81.8%, whereas the survival rate in patients with IPM was 40.2% (11). IPM represents the advanced stage of lung cancer. This is the biggest difference between IPM and MPLC, and the reason why doctors need to distinguish between the two for precise treatment. These results are consistent with those of previous studies (Table S4) (5,11,26,37,38).

Table S4 Overall survival of patients with multiple lung cancers in previous studies
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Recently, IASLC proposed the Criteria to Distinguish Synchronous Second Primary Lung and Related Pulmonary Tumor, taking imaging, biopsy, and clinical features into account (10). However, the process of tumor metastasis has remained ambiguous (39,40). Table 4 summarized several main criteria and latest methods for multiple lung cancer. Here, we presented a clinical classification method for defining multiple lung carcinomas, which is an improvement on the existing methods and technology. Compared with previous criteria, our comprehensive algorithm combined multidisciplinary criteria including histologic assessment, molecular analysis and imaging analysis. The distinguishing process was verified in the large population, based on the latest evidence of evidence-based medicine. In addition, we considered the rare subtypes of lung cancer and patients with more than two pulmonary nodules for the first time. In general, our algorithm was more scientific and more suitable for clinical work.

Table 4 Main criteria and latest methods for multiple lung cancer
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Previous studies have confirmed that metachronous cancers may be IPM even if relapse occurs after 2 years, but no IPM occurs later than five years (10). For this reason, a threshold of five years was chosen in our research for defining metachronous nodules as MPLC, rather than the two-year threshold used by the previous criteria. Histological assessment has always been an important part of defining multiple lesions. The subtypes of cancers that do not occur very often are considered ‘rare’; these included adenosquamous carcinoma and carcinoids (41). Meanwhile, lung cancers other than adenocarcinoma and squamous cell carcinoma with a low incidence were defined as “unusual”. For adenocarcinoma, morphological assessment of architectural patterns was mostly effective when the predominant patterns were rare midpapillary. Molecular analysis has emerged as a rising technology in recent years. With the help of powerful biological analysis tools, we have developed an understanding of the mechanism of various genes involved in tumorigenesis. We chose these 9 genes that were associated with evolution of lung cancer (25,42,43). Herein the common drivers of tumor were considered as markers of the similar origin, and vice versa. For example, the mutational status of the TP53 gene was discordant in multiple lung cancer patients, suggesting a different clonal origin despite the fact that most of them had almost identical histologic features (44). What’s more important, eight genes except TP53 were recommended by National Comprehensive Cancer Network (NCCN), which played an important role in the subsequent selection of targeted drugs (45). Furthermore, imaging is able to reveal the characteristics of preoperative nodules. It has been confirmed that the higher the number of nodular ground-glass components, the higher the number of malignant features, and the more likely the nodules are to be primary nodules (30).

In this study, we included a large number of multiple lung cancer patients who had undergone resections. Non-smokers accounted for the majority of patients. Previous research has suggested that lung cancer in individuals have never smoked is the seventh leading cause of cancer-related mortality (46). Several factors contributing to the increased risk of lung cancer in non-smokers included secondhand smoking, occupational exposure, indoor air pollution, and genetic susceptibility. In a study of such non-smoking patients, adenocarcinoma was the mainly pathological type, followed by squamous cell carcinoma, which is the same as previous studies (47).

Nodal involvement and radiotherapy were both risk factors for survival in multiple lung cancer. Lymph node involvement represents metastasis of tumors and affects patient staging and treatment options (48,49). Radiation therapy destroys lung cancer cells by using high-energy beams called X-rays to damage their DNA. However, this treatment may damage patients’ lungs, causing a cough, breathing problems, and shortness of breath. The side effects of long-term application of radiotherapy have been clearly demonstrated to reduce patients’ quality of life (50,51). In the MPLC patients, smoking history was significantly associated with a poor prognosis. Tobacco smoking is the major cause of all major histological types of lung cancer (52,53). Numerous studies have confirmed that tobacco is a risk factor for lung cancer, with the relative risk for smokers being 1.8 times higher than that for non-smokers (RR =1.8, 95% CI: 1.4–2.2) (54). In the IPM patients, the prognosis of patients with two nodules was worse than that of patients with three or more nodules, which is probably due to timely treatment after nodule detection. Otherwise, this may be an inaccurate result caused by the uneven inclusion of patients in each group.

In this large-scale study of 576 patients with multiple lung cancers, we proposed a comprehensive algorithm for differentiating patients with multiple lung tumors and validated the poor survival rate of IPM. However, this study also had some limitations. First, it was a retrospective analysis with inherent selection bias: only operated patients were considered because detailed pathological information could only be observed after surgical removal of the lesion. According to our literature review, the number of eligible patients with multiple lung tumors ranged from 20 to 357. Our sample size is relatively large including 576 patients with 1,295 tumors in the current study. Also, prospective validation is still required to implement this classification on a large scale of multicenter. In the future, it may be possible to achieve the non-invasive judgment of preoperative nodules by using artificial intelligence, and there have been some reports that CT imaging analysis can predict the degree of histologic tissue invasion or subcentimeter pulmonary adenocarcinomas (55,56). Another limitation was that the actual process of metastasis was too complex to be judged based on several indicators. Traditionally, it was believed that there was a physical channel for malignant cell transfer from one site to another; it was for this reason that nodal and systemic metastasis were used as important criteria for IPM in this study. However, this speculative hypothesis has been called into question in recent years. Scientific evidence has demonstrated that the spread of tumors does not depend on physical metastases but on other determinants (18,19). All factors need larger prospective studies from multiple centers to verify their causality and underlying mechanisms.

In conclusion, our results indicated that the comprehensive algorithm was a relevant tool for classifying multifocal lung cancers, which could guide treatment decisions. Patients with IPM clearly differed from patients with MPLC in terms of clinical features and survival status. No nodal involvement and not receiving radiotherapy were associated with superior OS in patients with multiple lung tumors.

Acknowledgments

Funding: This work was supported by grants 81871890 and 91859203 from National Natural Science Foundation of China, grant 2017-CY02–00030-GX from the Science and Technology Project of Chengdu.

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5505

Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-5505

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5505). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013), and the ethics committee of West China Hospital has approved this study (Project No. 2019-195). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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