Prognostic stratification of T1 lung adenocarcinoma with micropapillary or solid patterns: a cohort study

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide. According to GLOBOCAN 2022, it accounted for 2.5 million new cases and 1.8 million deaths, representing 12.4% of all cancer cases and 18.7% of cancer deaths (1). Furthermore, adenocarcinoma is the most common histologic subtype of non-small cell lung cancer (NSCLC), comprising over half of all lung cancer cases (2). Recently, advances in low-dose computed tomography (LDCT) screening have increased detection rates of early (stage I) lung adenocarcinoma (3). However, even among stage I patients who undergo curative resection, about 10–25% still experience recurrence or death during follow-up (4,5). Notably, studies indicated that patients with T1a–b tumors have superior 5-year recurrence-free survival (RFS) compared to those with T1c tumors (6,7). In addition, Li et al. found that patients with T1c tumors have markedly worse prognosis than those with T1a–b tumors (8).

Tumor heterogeneity is a determinant factor of the recurrence of early-stage lung adenocarcinoma. In the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification, five subtypes that differ significantly in prognosis have been defined (9). Although micropapillary and solid patterns represent distinct histologic architectures, they are commonly grouped as high-grade patterns in prognostic analyses due to their shared biological aggressiveness and similar clinical behavior. Moreover, high-grade patterns predict high risk of recurrence, independent of tumor size (10). Furthermore, numerous studies have demonstrated that early invasive lung adenocarcinomas containing even minimal micropapillary and/or solid (MP/S) patterns exhibit negative prognostic factors including higher rates of lymphovascular invasion (LVI), more frequent nodal metastasis, earlier recurrence, and poorer RFS or overall survival (OS) (11).

Additionally, Bertoglio et al. demonstrated that even within pathological stage IA, patients with the MP/S subtype exhibited a significantly worse prognosis compared to other subtypes, approaching the outcomes of stage IB patients (12). Moreover, Choi et al. reported that the presence or absence of the MP/S patterns was able to stratify stage I patients into prognostically distinct subgroups. And this stratification demonstrated a superior prognostic value than IA/IB classification (13). These results indicate that the MP/S subtype may serve as a more significant prognostic determinant than tumor size in stage I.

However, to date, the 9th edition of the tumor, node and metastasis (TNM) staging system [2024] does not consider the prognostic impact of MP/S pattern (14). Furthermore, previous studies mainly focused on the heterogeneous T1 stages, lacking of research in the specific high-risk T1c subgroup. Therefore, we consecutively recruited a cohort of 586 patients with stage I lung adenocarcinoma. This study aimed to evaluate the potential differences in OS and RFS of adenocarcinoma with the same T category stratified by the presence of MP/S patterns. Besides, subgroup analysis was conducted to specifically evaluate the prognostic value of MP/S patterns in T1c patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2351/rc).

Methods

Participants

This single-center retrospective cohort study included 586 consecutive patients who underwent curative surgical resection in our thoracic surgery department between January 2018 and December 2019. All patients had pathologically confirmed stage I invasive lung adenocarcinoma [American Joint Committee on Cancer (AJCC), 8th Edition] on postoperative pathology (15). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Institutional Review Board of The First People’s Hospital of Changzhou City approved The study (approval No. 2024 Technology CL263) and waived the requirement for informed consent due to the study’s retrospective design.

The flowchart (Figure 1) illustrates the selection process. The initial cohort comprised 787 patients with pathologically confirmed stage I lung adenocarcinoma. The inclusion criteria were: (I) radical surgical resection (lobectomy or sublobar resection) with systematic mediastinal lymph node dissection or sampling; (II) postoperative pathological diagnosis of stage IA or IB invasive non-mucinous lung adenocarcinoma; specifically, invasive adenocarcinomas with an invasive size ≤5 mm that did not meet the criteria for MIA were included; (III) availability of complete clinical, pathological, and follow-up data. The exclusion criteria were: (I) postoperative diagnosis of adenocarcinoma in situ, minimally invasive adenocarcinoma, or mucinous adenocarcinoma; (II) visceral pleural invasion on pathology; (III) positive surgical margins (R1 or R2 resection); (IV) history of multiple primary lung cancers or other systemic malignancies; (V) incomplete clinicopathological or follow-up information. Ultimately, 586 patients were included in the analysis.

Figure 1 Flowchart of patient selection. ADC, adenocarcinoma.

Histological classification

Tissue specimens were fixed in 10% formalin, paraffin-embedded, sectioned and stained with hematoxylin and eosin (H&E). Two pathologists, blinded to patients’ clinical characteristics and outcomes, independently evaluated the H&E-stained slides. Histological subtyping was performed based on the 2011 IASLC/ATS/ERS classification (9). For each tumor, the lepidic, acinar, papillary, micropapillary, and solid growth patterns were recorded in 5% increments (total 100%). Any component ≥5% was considered present. Discrepancies were resolved through consensus discussion. Tumors were classified as micropapillary and/or solid positive (MP/S⁺) if any MP/S component accounted for ≥5% of the tumor; tumors without micropapillary or solid components were classified as micropapillary and/or solid negative (MP/S⁻).

Follow-up of recurrence and survival

Patients underwent surveillance with thoracic-abdominal computed tomography with or without ultrasonography, physical examination, and history review every 6 months for the first 2 years, then annually for up to 5 years. Positron emission tomography/computed tomography (PET/CT) or biopsies were performed when recurrence was suspected. The primary endpoints were RFS and OS. RFS was defined as the time from surgery to the first documented recurrence or any cause of death. OS was calculated from surgery until death from any cause. Follow-up data were obtained from outpatient, inpatient records, and telephone interviews. The dates of the surgery, the first recurrence diagnosis, and death were recorded to calculate RFS and OS.

Statistical analysis

All analyses were conducted using R software (version 4.2.1). Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared by independent samples t-test, while non-normally distributed data were expressed as median (interquartile range) and compared by Mann-Whitney U test. Categorical variables were presented as frequency (%) [n] and compared by χ² or Fisher’s exact test. Survival curves for RFS and OS were estimated by the Kaplan-Meier method and compared by log-rank test. Potential prognostic variables were first screened by univariate Cox proportional hazards regression models. Clinically relevant variables and those with P<0.05 in univariate analysis were included into multivariate Cox models to identify independent. All tests were two-sided, with P<0.05 considered statistically significant.

Results

Clinicopathologic features

Regarding T category (Table 1), the cohort comprised 345 (58.9%) T1a–b, 155 (26.5%) T1c, and 86 (14.7%) T2a, respectively. Among the 586 patients, 59 experienced recurrence (10.1%). Meanwhile, 40 individuals exhibited death (6.8%). The median follow-up times for MP/S⁻ and MP/S⁺ were 57 and 51 months respectively. Of 586 patients, 402 (68.6%) were MP/S⁻ and 184 (31.4%) were MP/S⁺. Compared to MP/S⁻ patients, the MP/S⁺ group had a higher proportion of males (48.4% vs. 35.6%; P=0.003) and ever-smokers (28.3% vs. 20.1%; P=0.03). The MP/S⁺ group underwent lobectomy more frequently than MP/S⁻ patients (79.9% vs. 70.1%, P=0.01). Histologically, MP/S⁺ tumors were less likely to be associated with lepidic component (present 17.4% vs. 35.3%; P<0.001) and more often associated with papillary features (51.1% vs. 42.3%; P=0.047). The MP/S⁺ group also had higher rates of LVI (14.7% vs. 6.0%; P<0.001) and adjuvant therapy (16.3% vs. 3.7%; P<0.001). Tumor stage distribution also differed: MP/S⁺ was enriched for T1c and T2a tumors and depleted for T1a–b (P<0.001). Other variables, including age, tumor location, acinar pattern and spread through air spaces (STAS), showed no significant differences. Overall, MP/S⁺ patients had a higher proportion of high-risk pathologic features and were more likely to receive adjuvant therapy.

Survival analysis of T1a–b stratified by MP/S

As shown in Figure 2, the Kaplan–Meier curve indicates that the T1a–b MP/S⁺ group had a significantly higher risk of recurrence than T1a–b MP/S⁻ group [hazard ratio (HR) =4.29, 95% confidence interval (CI): 1.69–10.88, P=0.002]. Similarly, T1a–b MP/S⁺ group has a worse OS (HR =7.96, 95% CI: 2.06–30.80, P=0.003). Interestingly, when we compare the T1a–b MP/S + group with the T1c MP/S⁻ group, there is no significant difference in RFS (HR =0.89, 95% CI: 0.37–2.13, P=0.79), nor in OS (HR =0.74, 95% CI: 0.25–2.21, P=0.60). These results suggest that MP/S⁺ confers poor outcomes even in small tumors; patients with T1a–b MP/S⁺ have outcomes similar to those with T1c MP/S⁻ patients. And as shown in Tables 2,3, the T1 stratified by MP/S is an independent prognostic factor, supporting the prognostic role of MP/S patterns in T1a-b.

Figure 2 Kaplan-Meier plots for recurrence-free survival (A) and overall survival (B) in T1a-b patients stratified by MP/S and T1c MP/S⁻ patients. P values by log-rank test and HR and 95% CI estimated by univariate Cox model. CI, confidence interval; HR, hazard ratio; MP/S, micropapillary and/or solid; MP/S⁺, micropapillary and/or solid positive; MP/S⁻, micropapillary and/or solid negative.

Survival analysis of T1c stratified by MP/S

Figure 3 shows that among T1c tumors, the MP/S⁺ group had higher recurrence risk (HR=2.70, 95% CI: 1.24–5.90, P=0.01) and OS (HR=2.08, 95% CI: 1.03–7.57, P=0.04) than MP/S⁻. For RFS, there was no significant difference between T2a and T1c MP/S⁺ (HR=1.01, 95% CI: 0.54–1.88, P=0.98). For OS, T2a was still not significantly different from T1c MP/S⁺ (HR=0.87, 95% CI: 0.39–1.94, P=0.73). Tables 4,5 confirmed no significant difference between T2a and T1c MP/S⁺ in RFS and OS in univariate regression analysis. These findings suggest that T1c MP/S⁺ patients have a poorer prognosis like T2a patients. Notably, LVI and age exhibited strong associations with recurrence and death both in univariate and multivariable models.

Figure 3 Kaplan-Meier plots for recurrence-free survival (A) and overall survival (B) in T1c patients stratified by MP/S and T2a patients. P values by log-rank test and HR and 95% CI estimated by univariate Cox model. CI, confidence interval; HR, hazard ratio; MP/S, micropapillary and/or solid; MP/S⁺, micropapillary and/or solid positive; MP/S⁻, micropapillary and/or solid negative.

Multivariate analysis of RFS and OS in T1 stratified by MP/S

In multivariable Cox regression (Tables 2,3), the composite ‘T1 stratified by MP/S’ variable was an independent predictor of RFS and OS. Each one-category increase in the variable was associated with a significantly higher risk of recurrence (adjusted HR 1.69, 95% CI: 1.29–2.21; P<0.001) and death (adjusted HR 1.96, 95% CI: 1.39–2.75; P<0.001). Male sex and age were also independent adverse factors: male sex increased hazards for RFS (adjusted HR 2.30; P=0.02) and OS (adjusted HR 2.62; P=0.04), while each additional year of age modestly increased risk (RFS: adjusted HR 1.05; P=0.01; OS: adjusted HR 1.06; P=0.03). Notably, LVI and STAS exhibited strong univariate associations but did not retain significance in multivariable models. These findings confirmed the T1 stratified by MP/S as significantly prognostic factors for both RFS and OS.

Discussion

In this study, we aimed to examine the prognostic stratification of T1 lung adenocarcinoma according to T category and MP/S patterns. The presence of MP/S patterns was significantly related to poorer RFS and OS in T1 subgroups. Specifically, T1a–b MP/S⁺ exhibited outcomes close to those of T1c MP/S⁻, whereas T1c MP/S⁺ demonstrated outcomes comparable to those of pathologic T2a. Multivariable Cox models confirmed the stratification as an independent prognostic factor. Overall, these results indicate that MP/S is a critical determinant affecting prognosis in stage I.

Several studies have already shown that MP/S patterns are negative indicators for early-stage lung adenocarcinoma (10). For example, in a cohort of 422 stage IA patients, Peng et al. reported that any MP/S component (even non-predominant) dramatically reduced 5-year RFS (91% vs. 70%) and independently increased recurrence risk (15). Li et al. also found that minimal MP/S (≥5% of the tumor) in stage I adenocarcinomas with ground-glass components was independently correlated with shorter RFS (16). Our research demonstrated analogous correlations. Specifically, MP/S⁺ tumors exhibited a higher prevalence of aggressive clinical characteristics (more frequently associated with smoking and LVI) and demonstrated significantly poorer outcomes. Furthermore, a multicenter European study conducted by Bertoglio et al. indicated that T1 tumors with high-grade components exhibited survival rates indistinguishable from those of pathologic T2a cases (12). Our findings indicate that stratification by MP/S in T1 lung adenocarcinoma serves as an independent risk factor for early lung cancer, with T1c MP/S⁺ patients exhibiting a prognosis comparable to T2a cases. Nevertheless, we did not observe this phenomenon in T1a–b MP/S⁺ patients.

This risk stratification might have practical clinical implications. The optimal candidate for postoperative adjuvant therapy remains unclear, particularly for stage IA patients (17). Currently, the National Comprehensive Cancer Network Clinical Practice Guidelines for NSCLC did not regularly recommend giving adjuvant therapy to patients at stage IA (18). Nonetheless, numerous studies have indicated that MP/S predominant or poorly differentiated tumors in early-stage lung adenocarcinoma post-surgery may benefit from adjuvant therapy (19-22). Thus, Li et al. reported it is essential to identify patients with high-risk pathological factors for adjuvant therapy (23). Research from Japan also suggests that T1c patients could benefit from adjuvant therapy (24). In our current study, patients with T1c MP/S⁺ have a poor prognosis and may benefit from postoperative therapy and the application of adjuvant therapy in this group of patients can reduce the probability of postoperative metastatic recurrence. However, the Cox regression analysis did not identify a correlation with improved survival outcomes, which may be attributed to the limited sample size.

The JCOG0802/WJOG4607L and CALGB 140503 trials demonstrated that lobectomy and segmental lung resection are comparable for small (≤2 cm) adenocarcinomas (25,26). Our results showed that lobectomy, compared to other resections, was not a significant prognostic factor in the T1 patients. Notably, some reports suggest that MP/S patterns are associated with higher rates of local recurrence after sublobar resection (27,28). Given the high recurrence risk and unfavorable biological behaviors of MP/S, limited resection may compromise oncological radicality. Therefore, lobectomy with systematic lymph node dissection, as a standard radical surgical approach, should be prioritized to ensure complete tumor clearance, maximize local control, and improve long-term prognosis and quality of life.

There are some limitations in this study. First, this is a retrospective, single-center study and may introduce a potential selection bias and limits external generalizability. Second, the thresholds of the presence of MP/S⁺ that we used may differ from the other cohort. Thirdly, in the 2011 IASLC/ATS/ERS classification, the cribriform and complex glandular components were integrated into the acinar percentage and could not be retrospectively isolated for separate analysis. This limitation may have introduced a bias, as some high-risk tumors with these patterns were likely categorized into our MP/S⁻ group. However, the fact that significant survival disparities were still observed between the MP/S⁺ and MP/S⁻ cohorts underscores the dominant biological aggressiveness of the MP/S. Finally, the relatively small sample sizes of certain subgroups (especially T1a–b MP/S⁺) may have had an impact on the analysis.

Conclusions

In conclusion, our study showed that the presence of MP/S patterns affected the prognosis for stage T1 lung adenocarcinomas. T1c MP/S⁺ tumors exhibited recurrence and survival outcomes similar to those of stage T2a, while T1a–b MP/S⁺ tumors performed as poorly as T1c MP/S⁻. These findings underscore the importance of integrating MP/S status into clinical decision-making for postoperative risk assessment.

Acknowledgments

Thanks for the guidance and help of Professor Qianyun Wang from Soochow University.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2351/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2351/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2351/prf

Funding: This research was supported by the Changzhou Science and Technology Bureau (No. CJ20241104).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2351/coif). 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 and its subsequent amendments. The Institutional Review Board of The First People’s Hospital of Changzhou City approved the study (approval No. 2024 Technology CL263) and waived the requirement for informed consent due to the study’s retrospective design.

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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