Long-term results of middle lobectomy patients operated for non-small cell lung cancer

Abstract

Objectives

Lobectomy is the most frequently performed surgical treatment for lung cancer; isolated middle lobectomy (IML) is the least frequently performed lobectomy. Until recently, IML performed for Non-Small Cell Lung Cancer (NSCLC) located in the middle lobe of the lung was considered insufficient in oncologic surgery, and upper bilobectomy (Upper lobe + Middle lobe) or lower bilobectomy (Lower lobe + Middle lobe) was performed for isolated middle lobe tumors. Since postoperative morbidity and mortality rates are worse in bilobectomy compared to lobectomy, IMLs have become frequently performed. In this study, patients who underwent IML for NSCLC were compared with upper or lower lobectomies (ULL), and the oncologic results of patients who underwent IML were evaluated.

Materials and methods

In this study, 45 patients who underwent IML at our institution between 2012 and 2022 and 45 patients, who underwent right upper or lower lobectomy and were similar in terms of gender and age, were retrospectively analyzed. Oncological outcomes between these two groups were evaluated.

Results

The mean age of 45 patients, 34 (75.6%) male and 11 (24.5%) female, who underwent IML was found to be 62.5 ± 8.4 years. According to the type of surgery, 27 (60%) patients underwent thoracotomy and 18 (40%) patients underwent Video-Assisted Thoracoscopic Surgery (VATS). When tumor histopathologies were examined in all lobectomy patients, it was seen that squamous cell carcinoma was statistically significantly more dominant in IML patients than in the other two lobectomy groups (p = 0.014). In addition, it was seen that the tumor size was smaller in IML patients than in the other groups (p = 0.005). When the survival characteristics between these two groups were evaluated, the overall survival time (OS) of patients who underwent IML was 118.0 (59.0–124.0) months, while the overall survival time of patients who underwent ULL was 71.0 (66.0–74.0) months, and no statistically significant difference was found between the groups. No statistically significant difference was observed between the groups in terms of 30-day and 90-day mortality rates and 5-year survival rates.

Conclusion

There was no significant difference in survival between patients who underwent IML for NSCLC and those who underwent same-sided ULL. Based on these results, IML can be considered as an oncologically appropriate treatment option for masses confined to the middle lobe without the need for bilobectomy.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s12055-024-01886-4.

Introduction

Lung cancer is the most common type of cancer worldwide and is the leading cause of cancer-related deaths. The surgical intervention represents the gold standard therapeutic modality for the curative management of non-small cell lung cancer (NSCLC), with lobectomy being the most commonly preferred surgical method. Lung cancer located in the right middle lobe is a less common location than other lobes and accounts for approximately 5% of all lung cancers [1–3]. Isolated middle lobectomy (IML) is the least common type of lobectomy. The optimal surgical procedure for isolated middle lobe tumors remains uncertain, given the limited studies comparing patients undergoing IML with those undergoing same-sided upper-lower lobectomy (ULL).

The middle lobe is the smallest lobe of the lung and is surrounded by two large lobes. Lymphatic drainage of the middle lobe is provided by the right peribronchial, right para-tracheal, pretracheal, periesophageal, subcarinal and, in half of the cases, left peribronchial lymph nodes (LNs) [4]. Therefore, high rates of metastases to both superior and inferior mediastinal LNs have been reported in middle lobe tumors. Superior and inferior mediastinal LNs metastases have been identified as significant unfavorable prognostic indicators in individuals diagnosed with middle lobe cancer and are associated with one another [5]. Based on these features, the prognosis associated with tumors situated in the middle lobe remains incompletely understood, although there are studies suggesting that the prognosis of the tumor is worse due to the diversity of lymphatic drainage [6–8].

Within the scope of this study, patients who underwent IML for NSCLC were compared with patients who underwent ULL, and the oncological outcomes of patients who underwent middle lobectomy were evaluated.

Patients and methods

Study design

In this study, data of 72 patients who underwent IML in our institution between 2012 and 2022 were retrospectively analyzed. Individuals between the ages of 18 and 99 years were evaluated in the study. 27 patients diagnosed with small cell lung carcinoma, carcinoid tumor, metastatic disease, and bilobectomy were excluded from the study. A total of 90 patients were evaluated, including 45 patients who underwent IML and 45 patients who were similar in terms of gender and age and who underwent ULL. The mean age of the patients was 63 ± 9.2 years (35–87), 73 (81.1%) were male and 17 (18.9%) were female. No statistically significant difference was found between the treatment groups. When other demographic and clinical findings were examined according to the treatment groups, no statistically significant difference was observed between the treatment groups in all variables. The distribution of demographic and clinical findings of the patients according to the treatment groups is shown in Table 1.

Table 1.

The comparison of patients in terms of lobectomy operation (upper, lower and isolated middle lobectomy)

Variables	Total (N = 90)	Upper-Lower Lobectomy (n = 45)	Middle Lobectomy (n = 45)	p-value
Gender, n (%)				0.281
Male	73 (81.1)	39 (86.7)	34 (75.6)
Female	17 (18.9)	6 (13.3)	11 (24.4)
Age (years)				0.955
Mean ± (SD)	63 ± 9.2	63 ± 9.5	63 ± 9.1
≤ 60 years	35 (38.9)	19 (42.2)	16 (35.6)	0.665
> 60 years	55 (61.1)	26 (57.8)	29 (64.4)
Incision, n (%)				0.397
VATS	41 (45.6)	23 (51.1)	18 (40)
Thoracotomy	49 (54.4)	22 (48.9)	27 (60)
Chest wall resection, n (%)	1 (1.1)	0 (0)	1 (2.3)	0.494
Neoadjuvant treatment, n (%)	2 (2.2)	1 (2.2)	1 (2.2)	1.000
Histology
Squamous cell carsinoma Adenocarsinoma Large cell carsinoma	54 (60) 30 (33.3) 6 (6.7)	31 (68.9) 12 (26.7) 2 (4.4)	23 (51.1) 18 (40) 4 (8.9)	0.159
Tumor size mean ± sd	3.1 ± 1.7	3.4 ± 1.9	2.9 ± 1.5
< 3 cm 3–7 cm 7 cm <	62 (68.9) 25 (27.8) 3 (3.3)	29 (64.4) 14 (31.1) 2 (4.4)	33 (73.3) 11 (24.4) 1 (2.2)	0.156
N stage
N0 N1 and N2	75 (83.3) 15 (16.7)	37 (82.2) 8 (17.8)	38 (84.4) 7 (15.6)	0.679
Stage
I II and III	65 (72.2) 25 (27.8)	30 (66.7) 15 (33.3)	35 (77.8) 10 (22.2)	0.733

Abbreviation: Standard Deviation (SD)

Surgical technique

During the surgery, anesthetists performed double lumen intubation, arterial and central venous pressure monitoring, and epidural analgesia as standard procedures. After the necessary liberalizations, the disease was evaluated and a resection plan was made. In patients with incomplete fissure and tumor located in the middle lobe, the fissure was completed with a stapler, taking into account the middle lobe artery, bronchus and vein. In patients with a limited level of fissure, IML was performed in patients who could undergo complete resection by creating a fissure against the lower or upper lobe. Bilobectomy was performed in patients where the tumor had clearly crossed the fissure and invaded the lower or upper lobe. In doubtful cases, the LNs in the hilar region, especially around the bronchus and artery, were examined with frozen section, and if there was a suspicion that complete resection could not be achieved, the resection was extended. Resection was not extended only due to the presence of an incomplete fissure or hilar lymph node (LN) metastasis (provided that it did not prevent complete resection).

Complete mediastinal LN dissection was performed in all patients. Especially in thoracotomy, all LNs were dissected, starting from the upper lobe bronchus and artery to the separation of the lower lobe basal and superior segments.

All procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national) and the Helsinki Declaration of 1975, which was renewed in 2008. The ethics committee of our hospital (2020-CREC-139/ 28.09.2022 2022/54) approved the protocol for the current study. All patients gave written informed consent for surgical treatment and were aware that all information could be used anonymously for scientific purposes only.

Statistical analysis

Analyses were performed using SPSS Version 23.0 (IBM Corp. Released 2015, IBM SPSS Statistics for Windows, Version 23.0, Armonk, NY) and MedCalc statistical software version 12.7.0.0 (MedCalc Software, Ostend, Belgium). A two-tailed Kolmogorov–Smirnov test was applied to examine for whether the continuous quantitative variables follow a Gaussian distribution. Nominal variables were reported as percentages and compared using a two-tailed Chi-square or Fisher test, when applicable. Continuous quantitative variables were reported as mean ± standard deviation (SD) if they followed a Gaussian distribution. Mann Whitney U-test was used to compare the median of two dependent groups. If means were used, the independent samples t-test was used. Kaplan–Meier method was used for survival calculations and survival rates were compared with log-rank analysis. The P value was set at < 0.05 for statistical significance.

Results

Two groups were formed as 45 patients who underwent IML, and 45 patients who underwent ULL, who were similar in terms of gender and age. These two groups were evaluated in terms of age, gender, type of surgery, histopathology, tumor size, LN, stage, neoadjuvant-adjuvant therapy and survival. The evaluation of demographic and clinical characteristics of the IML and ULL groups is presented in Table 1.

In the IML group, there were 34 (75.6%) male and 11 (24.4%) female patients, and the mean age was 63 ± 9.1 years. According to the type of surgery, 27 (60%) patients were operated on via thoracotomy and 18 (40%) patients were operated on via Video-assisted thoracoscopic surgery (VATS). Histopathological examination revealed squamous histology in 23 (51.1%) patients, adenocarcinoma in 18 (40%) patients, and large cell carcinoma histology in 4 (8.9%) patients. When tumor sizes were evaluated, there were 33 (73.3%) patients under 3 cm and 12 (26.7%) patients over 3 cm. When N stage subtypes were examined, it was seen that 38 (84.4%) patients were N0, 3 (6.7%) patients were N1 and 4 (8.9%) patients were N2, and of these 35 (77.8%) patients were Stage I, 10 (22.2%) patients were Stage II and III. The two patients with the largest tumor size (7–9 cm) had squamous cell carcinoma that did not exceed the tumor fissure, and neither patient had LN involvement. Neoadjuvant treatment was applied to 1 (2.2%) patient, and adjuvant treatment was applied to 11 (24.4%) patients. Thirty-day mortality was seen in 1 (2.2%) patient, 90-day mortality was seen in 2 (4.4%) patients. The mean follow-up period of the patients was 64.2 + 39.6 months and 5-year overall survival was 64%. When the patients who underwent ULL were evaluated, 39 (86.7%) were male, 6 (13.3%) were female and the age group was 63 ± 9.5 years. Twenty three (51.1%) patients were operated with VATS and 22 (48.9%) patients were operated with thoracotomy. When the tumor histologies were examined, it was determined that 31 (68.9%) patients had squamous cell type, 12 (26.7%) patients had adenocarcinoma cell type and 2 (%4.4) patients had large cell carcinoma cell type. According to tumor sizes, there were 29 (64.4%) patients under 3 cm and 16 (35.6%) patients over 3 cm. When N subtypes were examined; 37 (82.2%) of the patients had N0, 5 (11.1%) had N1, 3 (6.7%) had N2; and according to stages, a total of 15 (33.3%) patients were Stage I, 30 (66.7%), and Stage II and III. Neoadjuvant treatment was given to 1 (2.2%) patient, and adjuvant treatment was given to 13 (66.7%) patients. No 30-day mortality was observed in any patient, while 90-day mortality was observed in 1 (2.2%) patient. The mean follow-up period of the patients was 69.7 + 11.2 months, and 5-year overall survival was 80.0%. Mortality, mean follow-up period and survival findings according to Kaplan Meier test results are listed in Table 2. While the median overall survival (OS) in the ULL group was 71 months, the median OS in the IML group was 118 months, and no statistically significant difference was found between the treatment groups (p = 0.899) (Table 2) (Fig. 1).

Table 2.

Follow-up and survival data of patients

VARIABLES	TOTAL (N = 90)	UPPER-LOWER LOBECTOMY (N = 45)	MIDDLE LOBECTOMY (N = 45)	P value
Mean follow-up (Months)	67 ± 29.1	69.7 ± 11.2	64.2 ± 39.6	0.374
Mortality				1.000
30 Days	1 (1.1)	0 (0)	1 (2.2)
90 Days	3 (3.3)	1 (2.2)	2 (4.4)
Median Overall survival (95% CL), (Months)		71.0 (66.0–74.0)	118.0 (59.0–124.0)	0.899

Abbreviation: Condidence level (CL)

Fig. 1.

Comparison of IML and ULL Survival. Abbreviation: Isolated middle lobectomy: (IML) Upper or lower lobetomy: (ULL)

Discussion

The therapeutic approach for curative NSCLC predominantly involves surgical resection in eligible patients subsequent to thorough preoperative assessment and staging procedures. Lobectomy is typically the most common surgical procedure in patients with early stage NSCLC. Except for a few studies on the prognosis of NSCLC arising from the middle lobe, there are limited studies comparing the prognosis of IML and survival with same side lobectomies. Our study included 45 patients who underwent IML, representing 5.96% of all right-sided anatomic resections performed in our institution for NSCLC during the study period. This rate is similar to the literature which was reported between 4.3% and 7.3% [1].

Moon and colleagues reported that adenocarcinomas exhibited a poorer prognosis among patients undergoing IML, a significant difference in 3-year disease-free survival rates at all stages (63.2% vs. 82.5%, p = 0.024) and a significant difference in survival between central and peripheral tumors in stage I (70.4% vs. 91.0%, p = 0.023) [9]. Similarly, Funai et al. and Saijo et al. documented that the prognosis of squamous cell carcinoma differed according to its location in the lung and that centrally located tumors were correlated with a worse prognosis [10, 11]. In our study, squamous cell carcinoma was more predominant and statistically significant when histology was analyzed between the groups.

Whether extended lymphadenectomy leads to improved prognosis in IML patients remains unclear. In a study by Sato et al. investigating the prognostic impact of nodal metastatic spread patterns in 45 middle lobe pN_1–2 NSCLCs resected by different surgical procedures up to pneumonectomy, it was reported that LNs adjacent to the middle lobe bronchus were the most frequently involved; however, LNs of the lower lobe bronchus affected the prognosis [12]. Although the most common metastatic mediastinal site was subcarinal LNs, metastases to the upper mediastinal LNs had a negative prognostic effect on survival. In our study, when we evaluated N₀, N₁ and N₂ patients, there was no statistically significant difference between those who underwent IML and ULL (p = 0.679).

Mazza et al. argued that the lower survival rate in patients who underwent middle lobectomy stemmed from factors such as reduced LN dissection and earlier infiltration of the visceral pleura leading to faster metastasis compared to upper or lower right lobectomy [2]. Additionally, it has been argued that patients who underwent IML had smaller tumor size. In our study, when the tumor sizes were examined, the tumor size in patients who underwent IML was significantly smaller than those who underwent ULL. In our study, OS was found to be lower in patients with IMLgroups compared to ULL groups, but no statistically significant difference was found.

Puri and colleagues argued that tumor location did not affect survival in a retrospective single-center analysis of 841 patients with stage I and II tumors, including middle lobe tumors, at the University of Washington [13].

Miura et al. reported 31 NSCLCs located in the middle lobe and found no difference in survival between tumors originating from the middle lobe and tumors located in other lobes on the same side [1]. However, they reported an increased rate of thoracotomy in patients undergoing IML groups due to greater complexity of lymphatic drainage and pleural dissemination. Similarly, in our study, the number of thoracotomies was higher in patients with IML groups.

Whitson et al. investigated the prognostic value of tumor location in a retrospective study of 13650 T1-2 NSCLC patients undergoing resection [14]. Although multivariate analysis revealed that cancer-related mortality was higher in patients who underwent IML, there was no difference in median survival (Hazard Ratio—HR—1.22; 95% Confidence Interval – CI—1.01–1.46). Vincent et al. reported that none of the 19 patients whose tumors were resected survived after 5 years and the mean survival time was only 9.6 months, whereas the survival time of patients with tumors located in other lobes ranged from 14.6 to 25.6 months [15]. Freise et al. reported a 5-year survival rate of 18% in patients who underwent middle lobectomy and 26.4% to 34.3% in patients with tumors located in other lobes [8]. They argued that this was attributed to the fact that the middle lobe has many lymphatic drainage network extending to the upper and lower mediastinal regions.

Handa et al. found that patients with segment 4 tumors did not show a significant difference in prognosis when compared with tumors located in other lobes, whereas patients with tumors located in segment 5 showed a significantly worse prognosis than patients with tumors located in other lobes; arguing that the possibility of metastasis was higher due to the proximity of segment 5 to the mediastinum [3]. In our study, the 5-year survival rate was 64% after IML and 80% after ULL, but it was not statistically significant.

Li et al. emphasized that bilobectomy is associated with higher morbidity and mortality compared to lobectomy and therefore adding middle lobectomy to upper or lower lobectomy poses risks [16].

So far, the prognosis of patients with middle lobe lung cancer has not been definitively elucidated. After multivariate analysis adjusted for all prognostic factors or baseline differences between groups, histopathology and tumor size were defined as prognostic factors in our study.

Limitations

Our study is one of the rare studies focusing on the therapeutic role of the IML, the number of middle lobectomies is in parallel with previously reported series. Nevertheless, the limitations of the study include retrospective analysis and small group size.

Conclusion

Based on these results, it can be concluded that IML is an oncologically appropriate treatment option for masses limited to the middle lobe. There was no significant difference in survival between patients who underwent IML and patients who underwent ULL for NSCLC. Doubts remain about the role of middle lobectomies in the surgical treatment of large tumors and patients with LN involvement. Larger studies on middle lobectomies are needed to evaluate the efficacy of such a surgical procedure in these patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Authors' contributions

B.A.S and S.Y made substantial contributions to the design of the work.

Y.T and E.Y.S made the analysis of data.

B.A.S and S.Y. made the creation of new software used in the work.

E.Y.S and B.A.S have drafted the work.

A.U and B.A.S revised it.

Funding

There is no specific funding related to this research.

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Declarations

Ethics committee approval

The ethics committee of our hospital (2020-CREC-139/ 28.09.2022 2022/54) approved the protocol for the current study.

Informed consent

All patients gave written informed consent for surgical treatment and were aware that all information could be used anonymously for scientific purposes only.

Competing interests

The authors declare that they have no competing interests.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. This article does not contain any studies with animals performed by any of the authors.