Prognostic significance of micropapillary pattern and risk factors in patients with resected stage I lung adenocarcinoma and possible benefit of adjuvant therapy: a real-world multicenter study

Introduction

Lung cancer is the most common malignant cancer and has the highest mortality among all malignancies worldwide, with a morbidity rate of 11.7% and a mortality rate of 18% according to the 2020 latest global cancer statistics (1-4). Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases, and almost 30% of NSCLC patients are initially diagnosed with resectable disease (stage I–IIIA). Complete surgical resection is recognized as the standard-of-care treatment for patients with early-stage disease (5). In addition, adjuvant chemotherapy or targeted therapy may reduce the recurrence rate following surgery, with the greatest benefit being provided for those with stage II–III NSCLC (6). However, several phase III trials have reported that patients with stage I disease fail to receive survival benefit from adjuvant chemotherapy, with the exception of some stage IB patients with high-risk factors such as poorly differentiated tumor (including pulmonary neuroendocrine lung tumor), vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status (6). In patients with stage IB epidermal growth factor receptor (EGFR) mutation-positive NSCLC, disease-free survival (DFS) and OS were significantly longer among those who received osimertinib (7). The prognostic value of histological subtypes on patients with stage I disease remains to be evaluated.

Lung adenocarcinoma is the most common pathological type of NSCLC. In 2021, the World Health Organization (WHO) pathological classification of thoracic tumors categorized lung adenocarcinoma into five major pathological patterns including lepidic, acinar, papillary, micropapillary (MP), and solid (8,9). In general, the lepidic-predominant pattern is often thought to be associated with a better prognosis than acinar or papillary-predominant patterns, while MP and solid-predominant patterns are associated with the worst prognosis among these types. Lung MP carcinoma has a unique growth pattern and particular morphological features characterized by small papillary tufts in alveolar spaces (10). For this reason, it has been proposed that the presence of this morphological feature should be included in the TNM staging system as a supplement (11,12). Although a study indicated that patients with MP component in lung adenocarcinoma, even if not predominant, experience a worse prognosis (11), the relationship between the actual proportion of the MP component and survival outcomes in patients with stage I disease remains to be clarified. Moreover, it is unclear whether MP and solid patterns should be considered as high-risk factors for stage I patients in the consideration of adjuvant therapy.

In this multicenter retrospective study, we evaluated the correlation between MP proportion and clinicopathological characteristics, its prognostic value for survival in patients with stage I lung adenocarcinoma, and the potential benefit of adjuvant chemotherapy for these patients. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-698/rc).

Methods

Patients and study design

Patients with stage I lung adenocarcinoma with an MP component who underwent curative resection at Peking University Cancer Hospital & Institute and Peking University People’s Hospital from January 2010 to December 2019 were enrolled in this study. Disease stage was evaluated according to the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. Forty-seven patients were excluded if they did not undergo radical resection or had incomplete baseline clinical or follow-up data. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital & Institute (No. 2018KT81). Peking University People’s Hospital was informed and agreed with this study. Informed consent was taken from all the patients.

Pathological evaluation

The pathology was reviewed according to the 2015 WHO classification (8). The proportion of MP component was classified as <10%, 10–50%, and >50%. No patient had MP component <5%, which was defined as negative. Patients were then classified into four groups according to the proportion of MP components (with 10% as the threshold) and the status of solid components (presence or absence) as following: those with MP component <10% and solid component <5% were classified as MP <10% and solid negative (group 1), those with MP component <10% and solid component ≥5% were classified as MP <10% and solid positive (group 2), those with MP component ≥10% and solid component <5% were classified as MP ≥10% and solid negative (group 3), and those with MP component ≥10% and a solid component ≥5% were classified as MP ≥10% and solid positive (group 4). The study profile is shown in Figure S1. Spread-through-air-spaces (STAS) status was defined as the presence of tumor cells within airspaces beyond the edge of the main tumor. Epidermal growth factor receptor (EGFR) mutation testing was recommended for all patients; however, whether a patient actually underwent EGFR testing or not depended on the patient’s decision for financial reasons. The main detection methods for EGFR mutation included amplification mutation system (ARMS), super ARMS, microdroplet digital polymerase chain, or next-generation sequencing (NGS). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS).

Statistical analysis

The Fisher exact test or chi-squared test was used to perform statistical comparisons between the groups. RFS and OS were assessed via Kaplan-Meier curves. Relationships between clinical characteristics and RFS were evaluated with the Cox multivariate logistic regression model. The variables with a P value <0.2 were estimated via multivariate analysis. RFS was calculated from the date of surgery to the date of disease recurrence or death from any cause or the last follow-up. OS was calculated from the date of surgery to the date of death from any cause or the last follow-up. Patients who did not relapse at the last follow-up or died were referred to as censored data. R software version 3.3.3 (The R Foundation for Statistical Computing; http://www.r-project.org) was employed for statistical analysis. The statistical significance was set at 0.05, with significance levels being two-sided. The hazard ratio (HR) and 95% confidence interval (CI) were estimated.

Results

Patient characteristics

A total of 412 patients were enrolled and finally analyzed in the study, with 8, 273, and 131 patients with MP component >50%, 10–50%, or <10%, respectively. The baseline clinical and pathological characteristic of the patients are summarized in Table S1. The median age of the included patients was 63 years. 268 patients were stage IA, and 144 patients were stage IB. The surgical methods include lobectomy, segmentectomy, and wedge resection. Most patients had MP component ≥10% (n=281; 68.2%) and negative solid component (n=319; 77.4%). Significant differences were observed between the four groups in terms of male (P=0.01), presence of vascular invasion (P<0.001), STAS status (P=0.002), and EGFR mutation status (P=0.01). Group 2 had largest proportion of males (45.4%, 78.3%, 44.5%, and 55.7% in groups 1–4, respectively; P=0.01), while groups 3 and 4 had significantly more patients with lymphovascular invasion (15.7%, 13.0%, 34.6%, and 55.7% for groups 1–4, respectively; P<0.001) and STAS status (2.8%, 0.0%, 14.9%, and 15.7% for groups 1–4, respectively; P=0.002). Compared with the group with MP component <10%, that with MP component ≥10% had a greater proportion of patients with vascular invasion (39.9% vs. 15.3%; P<0.001) and STAS status (15.1% vs. 2.3%; P<0.001). Of the 234 patients who underwent EGFR mutation testing, 70.1% (164/234) had the EGFR gene mutation. Patients with MP component ≥10% had a higher EGFR mutation rate than did those with MP component <10% (73.4% vs. 63.8%, P=0.17). Among those patients who underwent mutation testing, group 3 demonstrated the highest mutation rate at 87.5% (69.8%, 41.2%, 87.5%, and 62.8% for groups 1–4, respectively, P=0.01).

Survival outcomes

The overall median follow-up was 35.3 months (range, 0.1–129.7 months). A total of 70 patients experienced disease recurrence and 29 patients died. The main recurrence sites include the lungs, pleura, bones, brain, mediastinum, and supraclavicular lymph nodes. We calculate RFS based on the recurrence time. Patients with MP component >50% had shorter OS compared with those with MP components 10–50% (10–50% vs. >50%: HR =0.293, 95% CI: 0.083–1.027; P=0.052) or <10% (<10% vs. >50%: HR =0.214, 95% CI: 0.056–0.816; P=0.02) (Figure 1). Between the patients with MP component ≥10% group and those with component MP <10%, there were no significant differences in RFS (HR =0.939, 95% CI: 0.574–1.536; P=0.80) or OS (HR =1.547, 95% CI: 0.679–3.522; P=0.29) (Figure S2). Similarly, between the patients with or without solid component-positive tumor, there were no significant differences in RFS (HR =0.961, 95% CI: 0.542–1.704; P=0.89) or OS (HR =1.310, 95% CI: 0.551–3.110; P=0.54) (Figure S3). Moreover, no significant difference in RFS or OS was observed between the four groups (Figure S4). However, a significantly worse RFS was observed for patients with STAS status as compared to those without STAS status (40.2 months vs. not reached: HR =2.131, 95% CI: 1.104–4.112; P=0.02) (Figure 2). In the univariate analysis, the adverse prognostic factors for RFS were identified to be male (HR =1.693, 95% CI: 1.048–2.735; P=0.03), smoking history (HR =1.817, 95% CI: 1.126–2.931, P=0.01), and tumor size >2 cm (HR =1.832, 95% CI: 1.138–2.949; P=0.01).

Figure 1 Overall survival by micropapillary proportion. Patients with MP >50% had worse OS than did those with MP components of 10–50% or <10%, with a nearly significant statistical difference (P=0.052). MP, micropapillary; OS, overall survival.

Figure 2 Recurrence-free survival of patients with micropapillary component and with or without STATS status. A significantly inferior RFS was observed for patients with STAS status as compared to those without STAS status (P=0.021). MP, micropapillary; RFS, recurrence-free survival; STAS, spread through air spaces.

We considered each factor in the univariate analysis identified to be significantly predictive of poor prognosis as a risk factor. Patients were divided into five groups based on the four risk factors (STAS status, male, smoking history, and tumor size >2 cm), and significant differences in RFS (HR =1.58; 95% CI: 1.26–1.98; P<0.001) and OS (HR =1.86; 95% CI: 1.30–2.66; P<0.001) outcomes were observed for patients with no, 1, 2, 3, and 4 risk factors. As compared to patients with no risk factors (n=105), those with at least 1 risk factor (N=307) were associated with significantly worse RFS (HR =2.222, 95% CI: 1.138–4.342; P=0.02) and OS (HR =4.758; 95% CI: 1.13–20.02, P=0.02) (Figure S5). However, the association between these factors and RFS failed to achieve statistical significance in multivariate Cox hazard regression analysis (Table 1).

Association of the MP pattern with RFS after adjuvant therapy

We further analyzed the association of adjuvant therapy with RFS and OS. Most patients chose pemetrexed combined with platinum adjuvant chemotherapy. As this is a non-randomized study, a selection bias may be presented. Between patients receiving adjuvant chemotherapy (n=62) and those receiving surgery alone (n=350; Figure S6), there were no significant differences in RFS (HR =1.049, 95% CI: 0.551–1.998, P=0.88) or OS (HR =0.199, 95% CI: 0.027–1.473; P=0.08) for either stage IA disease (n=268; RFS: HR =1.181, 95% CI: 0.417–3.342, P=0.75; OS: HR =0.854, 95% CI: 0.111–6.575, P=0.88; Figure S7) or stage IB disease (n=144; RFS: HR =0.777, 95% CI: 0.337–1.794, P=0.55; Figure S8). Most patients chose icotinib or gefitinib adjuvant therapy. Similar results were observed for the 20 patients with EGFR-mutated tumor who received adjuvant EGFR-tyrosine kinase inhibitor (TKI) therapy, regardless of disease stage (Figures S9,S10). A significant OS benefit from adjuvant chemotherapy was observed for patients with MP component ≥10% (N=44, P=0.049; Figure 3) and for those with at least one risk factor (STAS status, males, smoking history, or tumor size >2 cm; n=50; P=0.09; Figure S11); however, STAS status was not associated with benefit from adjuvant chemotherapy in terms of RFS (P=0.29) or OS (P=0.51) (Figure S12).

Figure 3 OS of patients with micropapillary component ≥10% with and without adjuvant chemotherapy. Adjuvant chemotherapy was associated with a significant OS benefit for patients with MP component ≥10% (P=0.049). MP, micropapillary; OS, overall survival.

Discussion

This multicenter retrospective study, which evaluated the impact of MP component in patients with stage I lung adenocarcinoma, produced several noteworthy findings. The majority of patients with MP component ≥10% had lymphovascular invasion, STAS status, and the EGFR mutation, all of which are considered to be high-risk factors for recurrence (13,14). Another notable finding was that patients with MP component >50% had worse survival outcomes as compared to those with MP component ≤50%, indicating MP burden to be a poor prognostic factor. Interestingly, our study identified a survival benefit from adjuvant chemotherapy in stage I patients with MP component ≥10%.

Lymphovascular invasion and STAS status were more common among patients with MP component ≥10%, which could explain the findings from a previous study that reported MP component to be associated with more aggressive pathological behavior (15). In the 2021 WHO classification, there is a greater emphasis on recognizing the prognostic significance of STAS. We found that patients with MP component and STAS status had a significantly inferior median RFS, which is broadly consistent with the results in other studies indicating STAS to be associated with worse clinical outcomes in those with lung adenocarcinoma after resection (14,16). Given this inferior survival, we suggest that pathologists pay greater attention to the presence of STAS in patients with MP in clinical practice, with a more rigorous follow-up perhaps being necessary for these patients.

It is also worth noting that a majority of patients with MP pattern were positive for EGFR mutations, with this proportion being the highest (73.4%) in patients with MP component ≥10%. This result is consistent with a previous study which showed an increased frequency of EGFR exon 21 L858R mutation in MP-positive patients as compared with MP-negative patients (32.5% vs. 21.5%; P=0.048), indicating that MP patients harboring EGFR L858R may be at a comparatively higher risk of recurrence (17). The presence of MP feature has also been associated with the development of brain metastases in patients with EGFR mutation after surgery (18). Adjuvant EGFR-TKI therapy is recommended for patients with stage IB NSCLC harboring the EGFR mutation by the 2023 National Comprehensive Cancer Network (NCCN) guidelines (5,19). Since EGFR mutation is more frequent in patients with MP pattern, genetic testing might become part of standard care for those with lung adenocarcinoma and MP component.

A previous study reported a higher risk of recurrence in patients with lung adenocarcinoma harboring MP component, even with a small proportion (11). To our knowledge, the proportion of the MP component varies widely, ranging from 5% to 74% (20,21). However, these studies were limited by the lack of quantitative stratification of the MP component in relation to its prognostic value (20-23). A recent study defined tumors with ≥20% solid component, MP pattern, or complex glandular pattern as high-grade patterns and associated with poor prognosis (23). Another study divided patients into MP patterns absent (MP−) group, non-predominant MP patterns (MP+) group, and predominant MS (MP++) group, and the threshold of median MP proportions was 10% and 55%, respectively, with the higher expression of MP indicating the worse prognosis (15). However, no studies have stratified the proportion of MP components separately for patients with stage I disease. In our study, we classified MP patients into MP component <10%, 10–50%, and >50% and found the worst survival in those with MP >50% (P=0.052).

According to the 2021 WHO pathological classification, patients with MP- or solid-predominant pattern experience the worst prognosis (24-26). Qian et al. found that solid or MP patterns in stage IB were associated with a poor prognosis. The median survival in the solid- or MP-predominant (>5% and the most dominant) group (n=140) was 39.6 months as compared with 49.7 months in the solid- or MP-negative (n=719) group. The main histological subtype was identified based on the pattern with the highest percentage (27). Another study reported that after complete resection, patients with stage I–III lung adenocarcinoma without a solid or MP component had significantly lower recurrence rates than did those patients with a solid or MP component (P<0.01) (28). However, the findings regarding stage I patients with MP component are inconclusive. In our study, we found that the presence of solid components was not associated with worse survival, which is inconsistent with a previously published study that reported the prognostic significance for the presence of MP or solid pattern among patients with tumor size ≤3 cm (29). Therefore, in our opinion, the effect of solid components on the prognosis for patients with stage I disease still needs to be clarified in larger prospective studies.

Few studies have examined the potential prognostic factors for patients with stage I lung adenocarcinoma and MP component. In this study, STAS status, male, smoking history, and tumor diameter >2 cm was identified as prognostic risk factors. In a previous study, tumor size >2 cm and an MP- or solid-predominant pattern were identified as risk factors for recurrence among patients with lung adenocarcinoma with node-negative status and a tumor size ≤3 cm (29). This is line with our finding that tumor size >2 cm was a negative prognostic factor for patients MP pattern. Another study found that adjuvant chemotherapy can be considered for patients with high-risk factors such as visceral pleural involvement, even if the tumor diameter is <3 cm (30). Thus, tumor size is likely a key prognostic factor for patients with stage I (even for T1c) lung adenocarcinoma and MP pattern (29).

It has been suggested that histopathological subtype should be included as a prognostic for decision-making in the treatment of patients with lung adenocarcinoma. In a large cohort of 500 resected patients with lung adenocarcinoma (stage I–IV), improved survival was observed after adjuvant chemoradiotherapy in patients with different histomorphologic patterns including lepidic, acinar, solid, papillary, or MP (31). A solid-predominant pattern has been associated with an improved prognosis after adjuvant chemoradiotherapy (31-33). However, the benefit of adjuvant therapy for patients with stage IA or IB lung adenocarcinoma and MP component after resection remains uncertain. The NCCN guidelines recommend observation for stage IA NSCLC patients who have received radical surgery (19). Moreover, for patients with stage IB harboring the EGFR mutation (exon 19 deletion, or L858R), adjuvant osimertinib is recommended, while adjuvant chemotherapy is only recommended for IB patients with high-risk factors for recurrence. In Asian populations, especially in countries like Japan, South Korea, and China, EGFR mutations are more common. The prevalence of EGFR mutations in NSCLC can range from 30% to over 50%, depending on specific demographics and smoking status. In contrast, Caucasian populations tend to have a lower prevalence of EGFR mutations in NSCLC, typically reported to be around 10% to 15%. Although it was previously reported that adjuvant chemotherapy can improve survival for patients with stage IB MP-predominant lung adenocarcinoma (27), the MP pattern is not considered to be a high-risk factor for stage IB in the NCCN guidelines (30). Our study found a survival benefit from adjuvant chemotherapy for patients with stage I disease and MP component ≥10% (P=0.049); however, patients with MP component >50% had the shortest OS (P=0.052), which may be attributed to the small number of patients receiving adjuvant chemotherapy. Besides, wedge or segmentectomy in such high-risk subgroups might have potential limitation in such high-risk subgroups.

Our study has several notable limitations that should be addressed. To begin, because fewer than 50% of patients experienced primary outcome events, the median RFS or OS was not reached in either group. The impact of adjuvant chemotherapy on stage I patients may not be significant enough. The result based on OS is more reliable. Therefore, longer duration of follow-up is required. Nonetheless, Kaplan-Meier analysis and multivariate Cox proportional hazard regression analyses were performed in our study to confirm the results. Besides, we had the pathologists review the pathology again and categorized it based on previous literature reports according to MP components being less than 10%, between 10–50%, and greater than 50%. It is not possible to annotate the MP components for each patient. Second, the small number of patients with MP component >50% could have affected the statistical significance. Moreover, only a small percentage of patients received adjuvant chemotherapy or EGFR-TKI therapy, limiting the interpretation of the benefit of adjuvant therapy. Although adjuvant immunotherapy could bring survival benefit for II–IIIA NSCLC patients with programmed cell death ligand 1 (PD-L1) positive (34), PD-L1 expression testing was not conducted for these patients and no patient received adjuvant immunotherapy. Additionally, pathology review across institutions may pose diagnostic consistency challenges for MP assessment. Central pathology review to ensure quality control will be conducted in future studies. Finally, due to the retrospective design of the study, selection bias could have been present but difficult to detect. However, a large number of patients treated at multiple centers from 2010 to 2019 were included to decrease the effect of any such selection bias. Further prospective multicenter studies are planned to evaluate the influence of adjuvant immunotherapy on these patients and investigate the value of microresidue detection to more accurately guide therapy.

Conclusions

Patients with MP component ≥10% were more likely to have high-risk features of lymphovascular invasion, STAS status, and EGFR mutation. MP component >50% was associated with worse survival as compared to MP component <50%. Patients with stage I disease and MP component ≥10% might benefit from adjuvant chemotherapy to experience prolonged survival. STAS status, male, a history of smoking, and tumor size >2 cm are high-risk factors for patients with stage I lung adenocarcinoma with MP component. These factors might inform the selection of patients most likely to benefit from adjuvant chemotherapy. Patients without high-risk factors might not require adjuvant chemotherapy. However, additional multi-institutional prospective trials are required to validate these findings.

Acknowledgments

We would like to thank all the medical staff involved in treating the patients.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-698/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-698/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-698/prf

Funding: This research was funded by Beijing Hospitals Authority Youth Program (No. QML20231113), Capital Clinical Characteristics and Application Research (No. Z181100001718104), the Science Foundation of Peking University Cancer Hospital (No. 2022-17), the Peking University Cancer Hospital Inner Mongolia Hospital Public Hospital Reform and High-Quality Development Demonstration Project (Gastrointestinal Cancer + Thoracic Cancer) Research Fund (No. 2024YNYB006), the Wu Jieping Medical Foundation Research Special Grant Fund (No. 320.6750.2023-20-7), the Inner Mongolia Autonomous Nature Science Fund General Project (No. 2025MS08102) and the Peking University Cancer Hospital Clinical Research Joint Fund (No. LHJJ2023006).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-698/coif). Jianjun Zhang serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. P.V.S. reports honoraria for lectures and presentations as well as participation in Advisory Boards by AstraZeneca, BMS, MSD, Roche and Janssen; and reports leadership in IASLC (International Association for the Study of Lung Cancer) (president 2023-2025 and past-president 2025-2027). The other 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 and its subsequent amendments. This study was approved by the Medical Ethics Committee of Peking University Cancer Hospital & Institute (No. 2018KT81). Peking University People’s Hospital was informed and agreed with this study. Informed consent was taken from all the patients.

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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