Long-term outcomes of lobectomy vs. sublobectomy for stage I lung invasive mucinous adenocarcinoma

To the Editor: Lung invasive mucinous adenocarcinoma (LIMA) is regarded as a subtype of invasive lung adenocarcinoma (LUAD). No significant differences exist in the overall survival (OS) or recurrence-free survival (RFS) between lobectomy and sublobectomy in clinical stage IA non small cell lung cancer (NSCLC) ≤2 cm.[1] Besides, the studies on surgical methods in early LIMA are limited. In this study, we reviewed the clinicopathological features of LIMA and compared its prognosis under different surgical methods. We retrospectively analyzed the data of 235 patients diagnosed with pathological I LIMA at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China, between August 2010 and December 2018. The patients were grouped according to the surgical methods (lobectomy or sublobectomy). This study was reviewed and approved by the Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China (No. 22/244–3446) and was conducted following the Declaration of Helsinki, waiving the requirement for written informed consent from patients. Preoperative clinical and postoperative pathological stagings were performed for all patients according to the 8th edition of the TNM staging system. The patients who underwent lobectomy were combined with lymphatic node dissection (LND) routinely, and the decision of whether patients undergoing sublobectomy should receive LND depended on comorbidities. Patients who underwent LND were subdivided into the systematic (N1 station [10–14 zones] + N2 station [2–9 zones] lymph nodes) and lobe-specific (N1 station [10–14 zones] lymph nodes) groups. Based on the pathological results, LIMAs were divided into two subgroups: mucinous adenocarcinoma (MA) characterized by an invasive mucinous pattern comprising more than 90% of the tumor and mixed mucinous/nonmucinous adenocarcinoma (MMNA) consisting of both mucinous and nonmucinous morphology, with each component accounting for more than 10%. All patients were followed up through outpatient visits or telephone. Tumor markers, physical examination, and computed tomography (CT) of the thorax were performed every 3 months for 2 years, postoperatively. Evaluations were then conducted every 6 months after the initial 2-year period, and annually after 5 years. In cases of recurrence, contrast-enhanced CT, brain magnetic resonance imaging (MRI), or positron emission tomography-computed tomography (PET-CT) was performed as indicated. Histological or radiological evidence of recurrence or metastasis was based on a biopsy or surgical excision. Follow-ups were performed until death or June 2023. Local-regional recurrence (LRR) was defined as tumor recurrence at the surgical margins, ipsilateral lobe, or ipsilateral lymph nodes. Distant metastasis (DM) was defined as tumor metastasis to the contralateral lung lobe or lymph nodes, cervical lymph nodes, abdominal lymph nodes, brain, bone, liver, or other organs. The cumulative incidence of recurrence (CIR) was defined as the cumulative incidence of tumor recurrence owing to LIMA, and the cumulative incidence of death (CID) was defined as the cumulative incidence of patient death owing to LIMA. RFS was defined as the time interval between the date of surgery and tumor recurrence or the end of follow-up. OS was defined as the time interval from the date of surgery to death. Classified variables were presented as number (percentage) and analyzed using χ2 test or Fisher’s exact test. Continuous variables were presented as the mean ± standard deviation or median (Q1–Q3) and tested using the t-test or Mann–Whitney U test, as appropriate. Kaplan–Meier method and log-rank tests were used to assess the differences in CIR and CID between the two groups. Life table was used to analyze the annual risk of recurrence and death, which was calculated based on the number of patients with no recurrence or death at the beginning of each interval. Univariable Cox regression analysis and multivariable analysis were used to assess the risk factors for RFS in patients with pathological I LIMA. Data analyses were primarily conducted with the SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). A value of P <0.05 was considered as significantly statistical difference. A total of 235 patients with pathological stage I LIMA were included in this study [Supplementary Figure 1, https://links.lww.com/CM9/C53], comprising 159 (67.7%) female and 76 (32.3%) male. MA was found in 181 (77.0%), and MMNA was identified in 54 (23.0%). In addition, 206 (87.7%) and 29 (12.3%) patients underwent lobectomy and sublobectomy, respectively [Supplementary Table 1, https://links.lww.com/CM9/C53]. At a median follow-up of 55 months (range: 11–111 months), the overall recurrence, distant metastasis (DM), and local-regional recurrence (LRR) rates in the entire cohort were 22 (9.4%), 7 (3.0%), and 15 (6.4%), respectively. In entire cohort, the 5-year CIR and CID rates were 6.4% and 4.3%, respectively [Supplementary Figure 2, https://links.lww.com/CM9/C53]. During the study period, the patients’ risk of recurrence manifested as fluctuations and reached peak twice at 1 and 5 years after surgery, respectively. And, the risk of tumor-related death exhibited a single peak at 1 year after surgery [Supplementary Figure 3, https://links.lww.com/CM9/C53]. Patients who underwent lobectomy had larger pathological tumor size compared with those with sublobectomy (P = 0.006). The number of lymphatic node dissection was significantly higher in the lobectomy than in the sublobectomy group (P <0.05). The ratio of patients who underwent standard lymphatic node dissection (LND) (N1 + N2) in the lobectomy (202/206, 98.1%) was higher than that in the sublobectomy group (14/29, 48.3%, P <0.001). There were no significant differences in age, sex, body mass index (BMI), smoking history, preoperative symptoms, pathological T stage, predominant component, and tumor differentiation between patients with lobectomy or sublobectomy (all P >0.05) [Supplementary Table 2, https://links.lww.com/CM9/C53]. Supplementary Figure 4, https://links.lww.com/CM9/C53, shows that the total recurrence rate in patients with lobectomy was 7.3%, and those with sublobectomy was 24.1%, with a significant difference between two groups (P <0.001). The incidences of LRR were 5.8% and 10.3% in lobectomy and sublobectomy group, respectively, (P = 0.352); the rates of DM were 1.5% and 13.8%, respectively, (P <0.001). The 5-year CIR in lobectomy group was significantly lower than that in sublobectomy group (6.6% vs. 23.4%, P <0.001) [Supplementary Figure 5A, https://links.lww.com/CM9/C53]. The 5-year CID in the lobectomy and sublobectomy groups were 4.3% and 3.4%, respectively, and there were no significant differences between two groups (P >0.05) [Supplementary Figure 5B, https://links.lww.com/CM9/C53]. The risk of recurrence in the lobectomy group manifested as fluctuations and reached its peak at 1 year and 5 years postoperatively. Similarly, in sublobectomy group, there was also a fluctuating risk and reached its peak at 3 years and 5 years postoperatively [Supplementary Figure 6A, https://links.lww.com/CM9/C53]. The tumor-related death risk curve showed that the risk of death in the lobectomy group manifested as fluctuations reached peak at 1 year and 3 years postoperatively. In the sublobectomy group, the risk of death reach highest at 1 year postoperatively [Supplementary Figure 6B, https://links.lww.com/CM9/C53]. Sublobectomy may be technically easier and associated with fewer perioperative complications, while preserving lung capacity and function, as well as facilitating subsequent resections of potential metachronous tumors. For elderly patients with early-stage NSCLC, lobectomy and sublobectomy have similar prognosis.[2] In our study, there were no statistically significant differences in age between two groups (P = 0.056). Among the 19 patients aged ≥60 years in the sublobectomy group, only 3 patients experienced recurrences. Of the 31 patients with moderate-to-severe pulmonary ventilation dysfunction, 7 patients underwent sublobectomy and 24 patients underwent lobectomy. At the end of follow-up, seven patients who underwent sublobectomy with moderate-to-severe pulmonary ventilation dysfunction were no recurrence. The proportion of patients with moderate-to-severe pulmonary ventilation dysfunction was higher in the sublobectomy group (24.1%) than that in the lobectomy group (11.7%). A higher proportion of patients with moderate-to-severe pulmonary ventilation dysfunction received lobectomy, which may be related to our hospital’s routine preoperative multi-disciplinary treatment (MDT) consultation and rich experience in intraoperative airway management. Univariable Cox regression analysis showed that the surgical method and predominant component were risk factors for RFS in patients with pathological I LIMA (P <0.05, Supplementary Table 4, https://links.lww.com/CM9/C53]). However, no clinicopathological characteristics were risk factors for OS (all P >0.05) [Supplementary Table 4, https://links.lww.com/CM9/C53]. Multivariable analysis showed that predominant component (MMNA vs. MA: hazard ratio [HR], 3.11; 95% confidence interval [CI], 1.33–7.29; P = 0.009) and surgical method (sublobectomy vs. lobectomy: HR, 4.34; 95% CI, 1.73–10.88; P = 0.002) were independent prognostic factors affecting RFS [Supplementary Table 3, https://links.lww.com/CM9/C53]. Based on the Cox multivariable analysis, we established individualized prognostic scoring model of RFS for patients with pathological I LIMA. In this model, MA was rated as 0 point and MMNA as 1 point and rated lobectomy and sublobectomy as 0 point and 1 point, respectively [Supplementary Figure 7, https://links.lww.com/CM9/C53]. Based on the surgical method, the predicted 5-year RFS of patients with scores of 0, 1, and 2 were 95.2%, 86.1%, and 50.0%, respectively, with significant differences among the groups (P <0.001) [Supplementary Figure 8, https://links.lww.com/CM9/C53]. Patients with lung cancer undergoing sublobectomy usually have inadequate lymph node examination compared with those undergoing lobectomy.[3] Inadequate LND was found in the sublobectomy group (6.1 ± 8.5) compared with the lobectomy group (16.6 ± 7.6); the difference between the groups was statistically significant (P = 0.004). Patients who underwent surgery and had a pathological diagnosis of node-positive disease were excluded; of these patients, 14 were T1-2aN1-2M0. Inadequate lymph node resection may be a potential risk factor for higher recurrence rates in patients with early stage LIMA who undergo sublobectomy, but this hypothesis remains to be verified in future studies. Patients with I NSCLC undergoing sublobectomy, the standard margin distance >1 cm or margin-to-tumor ratio ≥1 is recommended.[4] Of the 29 patients with sublobectomy, only 7 achieved the standard margin distance, and none experienced recurrence. The mean margin distance in patients who relapsed and with sublobectomy was 0.6 cm. Therefore, adequate margin distance is also necessary in early LIMA. Several previous studies demonstrated that LIMA patients showed a higher incidence of spread through air spaces (STAS) (50–72.3%) compared with patients with non-mucinous adenocarcinoma (14.8–47.6%).[5] In our study, STAS incidence was low, accounting for only five cases. Among six patients with sublobectomy were proved visceral pleura invasion, which is an independent risk factor for poor survival, four had postoperative recurrence and received postoperative chemotherapy. In combination with the unique aggressive pattern of LIMA, visceral pleural invasion or STAS should be investigated further to determine whether adjuvant treatment should be continued after sublobectomy. In this study, there was a statistical difference in RFS between lobectomy and sublobectomy groups, but it was not reflected in OS. This may be related to the fact that all patients included in the study were I LIMA. In the respect of relapse, we find similar situation that existed in JCOG 0802 trial. It showed nearly a twofold higher rate of local recurrence in the segmentectomy arm. However, the 5-year OS for lobectomy 91.1% (95% CI, 88.4−93.2%) was lower than segmentectomy 94.3% (92.1−96.0%) with HR of 0.663 (95% CI, 0.474−0.927; one-sided P <0.0001 for non-inferiority, P = 0.0082 for superiority).[6] This study had some limitations. First, although, this is one of the largest studies for early stage LIMA study, the number of patients with sublobectomy was remain small, besides, propensity score matching was not performed to address the imbalance of partial baseline characteris as the small sample size, resulting that this study need to be interpreted with care. Second, because the enrolled patients were diagnosed as pathological I, whether inadequate lymph node resection is a potential risk factor or LIMA is likely to have lymph node metastases requires further research. Further study is required to evaluate the value of postoperative adjuvant therapy in stage I LIMA patients after sublobectomy. In summary, our study showed that patients with stage I LIMA with lobectomy had better RFS. Patients with MA have a better prognosis than those with MMNA. Further large-scale clinical studies are needed to verify the follow-up clinical treatment plan of early stage LIMA after sublobectomy with MMNA. Funding This work was supported by the National Key R&D Program of China (No. 2022YFC2407404), National High-Level Hospital Clinical Research Funding (Nos. 2022-PUMCH-A-018 and 2022-PUMCH-C-043), Special Research Fund for Central Universities, Peking Union Medical College (No. 2022-I2M-C&T-B-060), Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2021L01), and the Beijing Municipal Science & Technology Commission (No. Z211100002921058). Conflicts of interest None.