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Address for reprints: Masaki Anraku, MD, Department of Thoracic and Thyroid Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDepartment of Thoracic and Thyroid Surgery, Kyorin University School of Medicine, Tokyo, Japan
There is little evidence of the outcome of pulmonary metastasectomy for uterine tumors when comparing different histologies. This study aimed to delineate the primary histology that leads to more favorable outcomes after pulmonary metastasectomy.
Methods
The database of the Metastatic Lung Tumor Study Group of Japan for 1984 to 2016 was used to analyze the outcomes of patients with gynecologic malignancies who underwent pulmonary metastasectomy. Prognostic factors and long-term outcomes were compared according to the histology of the primary uterine tumors, specifically adenocarcinoma, squamous cell carcinoma, and sarcoma. The adjusted hazard risks according to disease-free intervals (DFIs) and the number and maximum size of resected tumors were also analyzed to delineate the pattern of risk trends.
Results
A total of 319 patients were included in the analysis (122 with adenocarcinomas, 113 with squamous cell carcinomas, 46 with sarcomas, and 38 with other types). The 5-year survival rate was 66.5% for the entire cohort, 71.6% for the patients with adenocarcinoma, 61.3% for those with squamous cell carcinoma, and 55.4% for those with sarcoma. Multivariate analyses identified the positive prognostic factors as DFI ≥12 months in adenocarcinoma and sarcoma and the primary site (corpus) of uterine tumors in adenocarcinoma. The nonlinear adjusted hazard risks indicated that a shorter DFI was associated with an elevated risk of death in patients with adenocarcinoma and sarcoma.
Conclusions
The survival outcome after pulmonary metastasectomy varies according to primary tumor histology, and the prognostic factors differ among histologic subtypes. Surgical indications should be determined based on the prognostic factors for each histology.
Survival outcomes after pulmonary metastasectomy vary according to the histology of uterine tumors. Surgical indications should be determined based on the prognostic factors for each histology.
Pulmonary metastasis of uterine cancer is rare, and randomized controlled trials are difficult to perform under these conditions. Surgical resection should be considered for highly selected patients because of the favorable survival outcomes after pulmonary metastasectomy. Individualized preoperative risk stratification may allow for treatment optimization.
In a survey of clinical practice among members of the European Society of Thoracic Surgeons, approximately two-thirds of the responders answered positively to performing pulmonary metastasectomy for cancers of the endometrium and cervix.
ESTS Pulmonary Metastasectomy Working Group Pulmonary metastasectomy: a survey of current practice amongst members of the European Society of Thoracic Surgeons.
Most thoracic surgeons assume that pulmonary metastasectomy may prolong patient survival as long as the surgery can be performed safely and metastatic lesions are at least macroscopically removed with a tumor-free primary site, all of which are based on the hope that the nodules are the last remnant disease. Repetitive resections of metastatic pulmonary lesions and aggressive resections for both pulmonary and extrapulmonary metastatic disease have been reported in metastatic sarcomas, including uterine leiomyosarcoma, owing to the development of less invasive surgical techniques.
Given that all previous series included no comparison groups (ie, patients with pulmonary metastasis treated with therapies other than surgery) in a prospective randomized fashion, the true benefit and potential disadvantage of pulmonary metastasectomy on the overall outcome, pulmonary function, and quality of life are yet to be clarified.
Despite the issues in the field of metastasectomy, we have reported the outcome of pulmonary metastasectomy in 133 cases of uterine malignancies from the Japanese metastatic tumor registry because of their rarity compared with other primary tumors, such as colorectal cancer, soft-tissue sarcoma, and kidney cancer.
At that time, we could not compare the potential differences in prognostic factors by primary tumor histology because of the relatively small number of subjects with each histologic type. In this study, with an accumulated number of cases from the same registry database, we specifically investigated the differences in prognosis and prognostic factors according to the major histologic types of malignant uterine tumors.
Methods
The Metastatic Lung Tumor Group database of Japan was used for our analyses. Approval for conducting the study was obtained from the institutional Research Ethics Boards of the affiliated hospitals, and individual consent was waived (approval 2020366NI; approved on February 19, 2021). Although the clinical decision for surgical intervention was made on an individual case basis by each institution, in general, metastasectomy was intended to perform a macroscopically complete removal of all pulmonary lesions in patients without any radiographic evidence of extrathoracic metastasis or a sign of uncontrolled primary tumors. Patients who underwent lung biopsy for diagnostic purposes were excluded from the study. The follow-up was performed at each institution. The following data were collected for analysis: age, tumor histology, number of pulmonary metastases, date of recurrence detection, date of primary site treatment, date of pulmonary metastasectomy, site of primary cancer (cervix or corpus), laterality of the resection (unilateral or bilateral), size and number of tumors resected, type of metastasectomy (wedge resection, segmentectomy, lobectomy, and pneumonectomy), whether lymph node (LN) dissection was performed and its extent (mediastinal, hilar dissection, or sampling), and mortality and morbidity of the surgery.
Disease-free intervals (DFIs) were defined from the date of treatment of the primary tumor to the date of pulmonary recurrence detection. The study period was divided into two parts—the early period from 1984 to 2000 and the later period from 2001 to 2016—to compare the trends in surgical approaches, mode of resection, and overall survival. Operative mortality was defined as death within the first 30 days after surgery or during hospitalization.
Statistical analyses were conducted using JMP version 16.0 and SAS version 9.4 (SAS Institute). Differences between groups of continuous variables were analyzed using the Student t test, ANOVA, or the Wilcoxon/Kruskal–Wallis test, depending on the normality of data distribution. Comparisons between groups of categorical variables were conducted using the chi-square test. Overall survival was defined as the time between pulmonary metastasectomy and death or the date of last follow-up. Patients who were alive at the date of the last follow-up were censored. Survival curves according to clinicopathologic factors were depicted using the Kaplan–Meier method, and comparisons between the curves were performed using the log-rank test. Cox proportional models were used for univariate and multivariate analyses to assess the relationship between clinicopathologic features and survival after pulmonary metastasectomy. For the multivariate analysis of all study cases or those with adenocarcinoma, age (<60 vs ≥60 years), anatomic site of the primary tumor (cervix vs corpus), study period (early vs late), DFI (<12 months vs ≥12 months), number of tumors resected (<4 vs ≥4), maximum tumor size (<3 vs ≥3 cm), nonsurgical treatment for primary tumors (yes vs no), and mode of pulmonary resection (wedge/segmentectomy vs lobectomy) were used. For cases with squamous cell carcinoma or sarcoma, the anatomic site of the primary tumor was not used as a covariate for multivariate analysis, because most of the tumors were located in the cervix with squamous cell carcinoma and in the corpus with sarcoma. We also examined the nonlinear relationships between DFI, the number of resected tumors, and the maximum size of resected tumors and overall survival, adjusting for the foregoing variables using a cubic spline multivariable Cox proportional model. Statistical significance was set at P < .05.
Results
We identified 371 patients who underwent pulmonary metastasectomy for uterine malignancy between 1984 and 2016. Of these, 319 patients with complete survival data were included in this study (Figure 1). The median follow-up period was 41 months (range, 0-429 months). The completeness of the follow-up (death or follow-up at ≥24 months after metastasectomy) was 80.0%. No operative deaths occurred in this study cohort. The patient characteristics are shown in Table 1. The most common types of primary tumor histology were adenocarcinoma (n = 122), squamous cell carcinoma (n = 113), and sarcoma (n = 46), which together composed approximately 90% of the study cohort. The sarcoma subtypes were leiomyosarcoma (n = 36), carcinosarcoma (n = 7), and stromal sarcoma (n = 3), and the other types included choriocarcinoma (n = 15; 4.7%), adenosquamous cell carcinoma (n = 9; 2.8%), myoma (n = 4; 1.3%), and others (n = 10; 3.1%). The average age of the 319 cases was 57.1 years (range, 24-88 years). Regarding the site of the primary tumor, all but 2 cases of squamous cell carcinoma originated in the cervix, whereas more than 90% of sarcoma cases originated in the corpus. Regarding the treatment of primary tumors, surgery was included in the treatment approach for most cases of adenocarcinoma (95.9%) and sarcoma (100%), but only 66.4% of squamous cell carcinomas were treated surgically to control the primary tumor. Other types of therapy, such as radiotherapy, chemotherapy, and chemoradiotherapy, were combined to treat primary tumors (Table 1). Among the 117 patients with adenocarcinoma who underwent surgery for the primary tumors, 67 underwent combined treatment, of whom 54 received chemotherapy, 8 received radiotherapy, and 5 received chemoradiotherapy. Similarly, among the 24 of 46 sarcoma patients, 22 underwent combined chemotherapy and one each underwent radiotherapy and chemoradiotherapy. Among the 62 of 75 squamous cell carcinoma patients, 26 underwent chemotherapy, 22 underwent radiotherapy, and 14 underwent chemoradiotherapy along with surgical resection.
Figure 1Flow diagram of the study. Of the 371 patients who underwent surgical resection for pulmonary metastasis from uterine malignancies, 52 were excluded due to a lack of data. A total of 319 patients were included in this study.
A summary of the pulmonary metastasectomies is presented in Table 2. Bilateral pulmonary metastasectomy was performed in approximately 20% of the cases, regardless of the primary histology. Among those with bilateral lung resections (n = 56), 22 underwent one-stage simultaneous lung resection and 34 underwent two-stage metastasectomy. In terms of the surgical approach, 122 of the 319 patients (38.2%) underwent open thoracotomy for tumor resection and 174 (54.5%) underwent video-assisted thoracoscopic surgery (VATS). Unsurprisingly, VATS was used more frequently in the later study period (170 of 218 cases; 78%) than in the early period (4 of 101 cases; 4%) (P < .001). (Table E1). Regarding the mode of surgical resection, lobectomy rather than sublobar resection was performed more frequently in the early study period than in the later study period (44 of 101 [43.7%] vs 53 of 218 [24.3%]; P = .002). In contrast, the minimally invasive approach (ie, VATS) and sublobar resection (segmentectomy or wedge resection) gained popularity during the latter study period. Both the maximum size and the number of tumors resected in the later period were smaller than those in the early period (later vs early; size [cm]: 1.86 ± 1.35 vs 2.91 ± 1.78, P < .0001; number: 1.48 ± 1.02 vs 2.30 ± 2.34, P < .0001).
Table 2Summary of pulmonary metastasectomy: Laterality, mode of resection, approach, and lymphadenectomy
Mediastinal or hilar LN dissection or sampling was performed in approximately 40% of the cases. Among the cases with LN resection (n = 134; 42.0%), 61 patients underwent mediastinal LN resection, 37 underwent hilar LN resection, and 20 underwent only sampling (16 cases were unknown regarding the field of LN resection). Among those who underwent LN resection, 92 (68.7%) had single-lung metastasis and 33 (24.6%) had LN metastasis. When comparing cases with adenocarcinoma, squamous cell carcinoma, and sarcoma, the number of resected pulmonary metastatic tumors showed no statistical difference. The maximum tumor size was larger (P < .001) and the DFI was shorter in squamous cell carcinoma than in adenocarcinoma or sarcoma (P = .01).
The overall survival of all 319 patients was 66.5% at 5 years after pulmonary metastasectomy. The 5-year survival rate for each histology was 71.6% (95% CI, 62.0%-81.2%) for adenocarcinoma, 61.3% (95% CI, 51.2%-71.4%) for squamous cell carcinoma, and 55.4% (95% CI, 41.0%-72.9%) for sarcoma (P = .0238) (Figure 2, A). The 5-year survival rates for each anatomic site of the primary tumors were 72.0% (95% CI, 65.9%-81.7%) in the corpus group and 61.3% (95% CI, 53.6%-70.1%) in the cervix group (P = .0070) (Figure 2, B). The 5-year survival rates for each period were 51.8% (95% CI, 40.7%-62.9%) in the early period and 72.1% (95% CI, 64.5%-79.6%) in the later period (P = .0159) (Figure 2, C). There was no difference in prognosis between patients with and without LN dissection (P = .8192) (Figure E1, A). However, there was a trend toward a worse prognosis in the group of patients with metastatic LNs compared to those without LN resection (P = .0799) (Figure E1, B). Among those with LN resection (n = 134), there was a different trend in postsurgical outcomes when comparing cases with and without LN metastasis (P = .0524) (Figure E1, C).
Figure 2Overall survival after pulmonary metastasectomy of uterine malignancies. A, Poorer overall survival for squamous cell carcinoma and sarcoma compared with adenocarcinoma. B, Worse overall survival in pulmonary metastases from cervical uterine cancer than those from endometrial cancer. C, Better outcomes in the later period group compared with the early period group. CI, Confidence interval.
In the univariate analysis of all 319 study patients, the anatomic site of the primary tumor (cervix), date of surgery (1984-2000), DFIs <12 months, a larger number of tumors resected, and surgical approach (thoracotomy) were identified as unfavorable prognostic factors (Table 3). Multivariate analysis of all cases identified the anatomic site of the primary tumor (cervix) and the number of tumors resected as significant prognostic factors (Table 4). As for the differences in each histologic subtype, multivariate analyses detected primary tumors in the corpus and DFI of ≥12 months in adenocarcinoma (hazard ratio [HR], 0.38 [95% CI, 0.17-0.82; P = .014], and 0.20 [95% CI, 0.07-0.71; P = .0149], respectively), the later study period (2001-2016) in squamous cell carcinoma (HR, 0.48; 95% CI, 0.23-0.97; P = .0417), and DFI of ≥12 months in sarcoma (HR, 0.34; 95% CI, 0.12-0.97; P = .0443) as favorable prognostic factors (Table 4). The study period (early vs late study period) and surgical approach (open vs VATS) affected the postsurgical outcomes in the univariate analysis of all subjects (P = .0183 and .0145, respectively) and subjects with squamous cell carcinoma (P = .0015 and .0028, respectively) (Table 3); however, only the multivariate analysis of the study period for squamous cell carcinoma showed a significant difference. The mode of surgical resection did not influence survival after metastasectomy in univariate analyses in any histologic group (all, P = .19; adenocarcinoma, P = .17; squamous cell carcinoma, P = .18; sarcoma, P = .70).
Table 3Univariate analyses for overall survival with a Cox proportional hazards model
The nonlinear relationship between the selected parameters and death for each histology is shown in Figure 3. As shown in Figure 3, A, the risk of death in adenocarcinoma was higher with a DFI <12 months; however, the risk ratio gradually declined as the DFI increased. No detectable change in risk was observed in squamous cell carcinoma (Figure 3, B), but a similar trend as in adenocarcinoma was observed in sarcoma (Figure 3, C). For each histology, the adjusted risk of death increased as the number of resected tumors increased (Figure 3, D-F). The maximal resected tumor size was not associated with an increased risk of death in adenocarcinoma (Figure 3, G) or squamous cell carcinoma (Figure 3, H); however, a linear correlation was observed in sarcoma (Figure 3, I).
Figure 3Risk-adjusted hazard function analysis depicting spline curves for each histology. A-C, Disease-free intervals (months) in adenocarcinoma (A), squamous cell carcinoma (B), and sarcoma (C). D-F, Total number of resected tumors in adenocarcinoma (D), squamous cell carcinoma (E), and sarcoma (F). G-I, Maximum tumor size in adenocarcinoma (G), squamous cell carcinoma (H), and sarcoma (I).
Uterine malignant tumors include various histologic types; however, little evidence is available regarding the distinctions among the histologic types on survival outcome or prognostic factors of pulmonary metastasectomy. A survey conducted among members of the European Society of Thoracic Surgeons revealed that 65% to 70% of surgeons considered uterine malignancies a surgical indication for pulmonary metastasectomy.
ESTS Pulmonary Metastasectomy Working Group Pulmonary metastasectomy: a survey of current practice amongst members of the European Society of Thoracic Surgeons.
The results of this study may aid the decision making process for metastasectomy in uterine malignancies and guide the referral of patients to thoracic surgeons. Marked differences in several factors associated with postresection outcomes were demonstrated among adenocarcinoma, squamous cell carcinoma, and sarcoma as the primary histology of uterine malignant tumors (Video 1). Figure 4 provides a graphical abstract of the study. The adjusted hazard risks of each histology showed distinct trends; for adenocarcinoma, pulmonary metastasectomy may benefit patients if their primary site of uterine cancer is the corpus and their DFI is >12 months; however, the size and number of tumors might not affect the outcome after metastasectomy. On the other hand, in squamous cell carcinoma, one can be liberal in terms of DFI or maximal tumor size as surgically indicative factors, although the real prognostic benefit of metastasectomy remains unknown. Regarding sarcoma, both the number and size of tumors need to be carefully evaluated if metastasectomy is considered because the risk of death increases as the number or size of the tumors increases, suggesting a more aggressive tumor behavior of sarcoma compared with the other histologic types.
Figure 4Graphical abstract of the study. Risk-adjusted hazard analyses were conducted on 319 cases of metastatic uterine cancer after pulmonary metastasectomy. CI, Confidence interval.
Regarding the difference in survival rate by study period, the results may have improved in the later period because of advances in the diagnosis and treatment of both uterine cancers and metastatic lesions. In terms of diagnosis, smaller metastatic lesions could be detected owing to the advancements in computed tomography scanning.
This trend can be seen in our data, with smaller and less metastatic tumors resected in the later period. Lead time bias could have occurred when a smaller metastatic lesion might have led to earlier surgical resection. In addition, fluoro-2-deoxy-D-glucose positron emission tomography is an effective imaging tool for evaluating LN and distant organ metastatic lesions.
These advances and tools were not available in the early period and could have contributed to more accurate oncologic evaluations for optimal treatment in the later period, which might have excluded patients with extrapulmonary distant metastasis from pulmonary metastasectomy. As for the treatment, modern advances in chemotherapy have been linked to improved survival of patients with uterine cancers.
Recent clinical studies of uterine cancer also have shown promising results of targeted therapy with an immune checkpoint inhibitor (pembrolizumab), a tyrosine kinase inhibitor (lenvatinib), and a human epidermal growth factor receptor 2 targeting monoclonal antibody (trastuzumab).
; however, in metachronous metastases, the reported rate of recurrent pulmonary metastases after radical hysterectomy for cervical cancers is 2.1% to 6.1% in the literature,
indicating a relatively rare condition. It is challenging to compare the surgical outcomes observed in this study with those of other studies on metastasectomy owing to the rarity of the disease and the wide variety of factors that affect prognosis, including differences in patient background (eg, different primary tumor stages, various treatment protocols of the primary tumors, synchronous or metachronous diseases), in surgical indications for lung metastasis, in treatment combinations, and in timing (ie, combined chemotherapy before or after metastasectomy).
Moreover, published case series have reported different findings: pulmonary metastasectomy for different histologic subtypes of primary tumors, owing mainly to the relatively small study size (23-133 patients),
In our study, we analyzed the data on a relatively large number of patients with 3 major histologic subtypes—adenocarcinoma, squamous cell carcinoma, and sarcoma of the uterus metastasizing to the lung—which were deemed to have only pulmonary metastasis treated for an intent-to-cure purpose. Therefore, survival outcome reflects a relatively benign part of the spectrum in a heterogeneous prognostic group of patients with hematogenous metastasis in each histology.
LN dissection in pulmonary metastasectomy remains controversial. Some studies have reported that mediastinal LN involvement is a negative prognostic factor for metastatic colorectal cancer.
Based on our present findings, it can be said that although the outcomes of those with LN involvement were poor, the significance of the therapeutic effect of LN dissection remains unknown owing to selection bias, the lack of uniform indications for LN dissection, and the lack of an appropriate control group. Nonetheless, LN dissection or sampling could have some value in terms of confirming local tumor spread. In addition, one may say that LN dissection should be part of the procedure in cases of single lung tumors, which can be primary lung cancer.
This study has some limitations. First, this was a retrospective study with a long study period, but collecting such a large number of cases with pulmonary metastasectomy from only uterine malignancies would be very difficult within a short period, as a recent review has summarized the previous series of pulmonary metastasectomies in uterine malignancies.
Second, because this study used multicenter registry data, there were no uniform or standardized criteria for metastasectomy, although the registered centers followed the general indications for metastasectomy.
Third, there is selection bias in the database. All of the registered cases were surgically treated patients, and thus this study could not prove the survival benefit of metastasectomy because of a lack of appropriate control cases for those treated without pulmonary metastasectomy.
It is unlikely that a randomized controlled trial for this rare disease entity with various disease conditions will be conducted. Despite the foregoing limitations, collating the patients and the clinical factors with differing tumor histologies of the uterus in association with postresection outcomes would aid clinical decision making, because the results could reflect the oncologic aggressiveness of each histology.
Conclusions
Surgical indications for pulmonary metastasectomy for uterine malignancies should be determined based on the prognostic factors for each histologic type. Highly selected patients with pulmonary metastasis from uterine malignancies will continue to be candidates for pulmonary metastasectomy, although the lack of randomized controlled trials has left the real benefits of metastasectomy uncertain.
Conflict of Interest Statement
The authors report no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Figure E1Overall survival after pulmonary metastasectomy of uterine malignancies regarding lymph node (LN) dissection. A, No difference was observed between the groups with or without LN dissection. B, A poorer prognostic trend was observed in the group of LN metastases. C, Among patients with LN dissection, a better prognostic trend was observed in the group with negative LN metastases. CI, Confidence interval.
Institutional Review Board approval: This study was approved by the Ethics Committee of the University of Tokyo Hospital on February 19th, 2021 (no. 2020366NI).
Informed consent statement: The Ethics Committees of the affiliated hospitals waived the need for informed consent as long as the patient data remained anonymous.
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