Pulmonary Metastases in Urogenital Cancers; Surgical Treatment and Outcomes

Background Metastasis is remaining one of the major problems in cancer treatment. Like many other malignancies, urogenital tumors originating from kidney, prostate, testes, and bladder tend to metastasize to the lungs. The aim of this retrospective study is to evaluate the results of pulmonary metastasectomy in patients with primary urogenital tumors. Methods This study was approved by the local ethical committee. This study retrospectively analyses the patients who underwent lung resections for metastases in our department between 2002 and 2018. 22 out of 126 patients referred for pulmonary metastasectomy to our department had metastases from urogenital tumors. Demographic data and clinicopathological features were extracted from the medical records. Disease-free interval (DFI) was dened as the time between the rst curative surgery and the detection of pulmonary metastasis. Results Among 22 patients who underwent lung metastasectomy consisted of 17 males and ve females. Their metastasis originated from renal cell carcinoma (RCC; n = 9), bladder tumor (n = 7), testis tumors (n = 4), and prostate cancer (n = 2). There was no intraoperative complication. Postoperative complications were seen in 2 patients. Conclusions data role the limitations of this study, we aim to document our promising results of pulmonary metastasectomy in patients with primary urogenital tumors.

Demographic data and clinicopathological features were extracted from the medical records. Diseasefree interval (DFI) was de ned as the time between the rst curative surgery and the detection of pulmonary metastasis.
Conclusions Although pulmonary metastases and its surgical management in various types of tumors is well known and documented, the data is limited to the role of the surgery for metastases of urogenital cancers on literature. Despite the limitations of this study, we aim to document our promising results of pulmonary metastasectomy in patients with primary urogenital tumors.

Background
Metastasis remains one of the major problems in cancer treatment. Like many other malignancies, urogenital tumors originating from kidney, prostate, testes, and bladder tend to metastasize to the lungs [1,2]. Unfortunately, the presence of metastases is usually associated with a poor prognosis. Although there is no consensus on this issue, metastasectomy may be the part of the treatment especially in cases in which the primary disease is under control [1][2][3]. In many cases sublobar non-anatomic resections su cient to ensure complete excision and care should be taken to sparing the lung tissue during metastasectomy.
There is no prospective, randomized study in this issue therefore the information on long-term survival in patients surgically treated for urogenital cancers' lung metastases is limited. Besides, studies in the literature are usually focused on subtypes of urogenital cancers, and collective publications are extremely rare.
This retrospective study and literature review aim to evaluate the results of pulmonary metastasectomy in patients with primary urogenital tumors and make a contribution to the literature by clarifying the role of surgery in treatment.

Methods
This study was approved by the local ethical committee. We retrospectively analyzed 126 patients who underwent lung resections for metastases in our department between January 2002 and December 2018.
The patients included in the study consisted of who had received curative treatment for one of the urogenital malignancies and were in routine follow-up. Ovarian and uterine malignancies were excluded.
During the study period, synchronous metastases are also observed, but all these cases had disseminated disease, and lung resections (wedge resections) only performed for diagnostic purposes.
Therefore, synchronous metastases are excluded. Inclusion and exclusion criteria for the study are shown in Table 1. Twenty-two patients who met the inclusion criteria were eligible for participation in the study. Statistical analysis was performed using SPSS 25.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were analyzed using Chi-square tests. Continuous variables were analyzed using the Mann-Whitney U test. Survivals were estimated using the Kaplan-Meier method.

Results
Among 22 patients who underwent surgery consisted of 17 males and ve females. Their metastasis originated from renal cell carcinoma (RCC; n = 9), bladder tumor (n = 7), testis tumors (n = 4), and prostate cancer (n = 2). Their mean age was 57,11 years (range, 21-75). The mean age of the patients with RCC and bladder tumor at the time of diagnosing metastasis was 57,6 and 59,33 years, respectively. The mean age of patients with testis tumors is 27 ( Table 2).
The majority of patients had no symptoms, and their metastasis was detected incidentally in their routine follow-up. Two patients with centrally localized tumors were presented with severe cough and mild hemoptysis.
The site of metastasis was left lung in fteen, right lung in six patients. One patient had bilateral lung metastases.
Wedge resection applied in seventeen cases with negative surgical margins. Lobectomy, instead of wedge resection, was applied in three patients because of the multiple metastases located in only one lobe. Due to the central localization of the metastasis and the presence of hemoptysis and destroyed lung, we had to applied pneumonectomy in two cases. These two patients were in good performance status and tolerated the pneumonectomy well. In 13 patients, the operation was started with VATS but was converted to thoracotomy because the metastatic nodules were not detected. Muscle-sparing lateral thoracotomy applied in seven patients. In patients operated on by VATS had shorter hospitalization and drainage time and better postoperative pain status than thoracotomy (Table 3).
Re-operation was needed, and wedge resection was applied in one case due to the recurrent lung metastasis one year after the rst surgery.
No major complications occurred during surgery. Postoperative complications were observed in 2 patients in total. Postoperative hemorrhage was seen in one patient in the early postoperative period, and re-operation was applied.
Prolonged air leakage was observed in one patient and we managed this complication using the Heimlich valve system. In this patient, the chest tube was removed at the end of the rst postoperative month. No major complication occurred in other patients on postoperative follow-up.

Discussion
Although lung metastasis excision in various types of tumors is well known and documented, the data is limited to the role of the surgery for metastases of urogenital cancers on literature (Table 5).
In literature, studies have demonstrated 5-years survival rates between 15,9%-%33 from urothelial carcinoma, after pulmonary metastasectomy [9][10][11][12][13][14]. It was also shown that patients who had shown great response to chemotherapy and had no evidence of early or rapid progression elsewhere had been shown to bene t more from metastasectomy. In our experience, we had four cases of metastatic urothelial carcinoma with a 57.1% 2-years survival rate. Adjuvant therapy was not administered after the pulmonary metastasectomy. There is limited data in the literature regarding the bene t of giving adjuvant treatment after complete metastasectomy in renal cell carcinoma. In these studies, there was no signi cant difference in survival in the group with and without systemic adjuvant therapy [15]. However, pulmonary metastasectomy combined with systemic targeted therapy and/or immunotherapy could be an optimal treatment approach in the future, but it needs to be supported by clinical trials.
The lung is the most common site of metastases in patients with testicular germ cell tumors. Studies demonstrated that resection of the pulmonary metastases has a positive effect on survival rates, especially patients with lesions limited to one site. In literature, 5-years survival rates were reported between 45%-65% after metastasectomy [16][17][18][19][20][21][22]. McGuire MS et al. have reviewed 105 patients with NSGCTs who undergone thoracotomy because of pulmonary metastasis and the viable nonteratomatous disease in the chest or retroperitoneum was described as a poor prognostic factor [18]. In another study, Pfannschmidt J et al. have reviewed 52 cases of NSGCT who undergone pulmonary metastasectomy, and 5-year survival was reported as 75.8%. The authors described incomplete resection and elevated tumor marker levels, AFP and/or hCG as poor prognostic factors [19]. In our study, we had 4 cases of testicular tumors which histological types were embryonal carcinoma. These patients underwent radical inguinal orchiectomy, retroperitoneal lymph node dissection, and adjuvant chemotherapy.
However, because of metachronous pulmonary metastases, surgical resection was needed, and adjuvant chemotherapy was administered. The 2-years survival was detected as 50% after pulmonary metastasectomy.
Isolated solitary pulmonary metastases are extremely rare in prostate carcinomas. In prostate carcinoma, lung metastases usually present diffuse interstitial or multinodular patterns, and there is no clue about the survival bene t of pulmonary metastasectomy [23,24]. Therefore, pulmonary metastasectomy should be performed only if the patient has solitary pulmonary metastasis resistant to hormone therapy or has severe respiratory symptoms refractory to conservative management. In our experience, we had only two patient of prostate carcinoma who underwent wedge resection. These two patients died in the rst six postoperative month due to disease progression.
It is also important to choose the appropriate surgical method in patients with pulmonary metastases. Video-assisted thoracoscopic surgery (VATS) has well-documented bene ts over open thoracotomy like less pain, less in ammatory response, shorter hospitalization and fast recovery after surgery [25][26][27].
The main concern regarding the use of VATS for metastasectomy is the risk of inability to performing complete resection. There isn't any information in the literature to con rm these concerns. Several studies even reported no relation between VATS and open thoracotomy in recurrence in the ipsilateral lung [28,29]. Therefore, VATS is routinely used in our clinic for pulmonary metastasectomy. Sometimes it would be di cult to localize metastatic nodules or ground-glass opacities (GGO) intraoperatively during the VATS procedure. Thankfully, various methods that make it possible to localize these kinds of lesions with the VATS technique have been described. The most commonly used methods for this purpose are methylene blue and hook wire marking [30]. We routinely use CT-guided methylene blue staining techniques in patients with small nodules and GGOs (Fig. 1). Although the lesion is localized with almost complete accuracy by these marking methods, the con rmation should be performed with a frozen section.
In highly selected patients, resection of pulmonary metastases present minimal risk and prolong survival in urogenital tumors. Previous studies described the presence of prolonged DFI, unilateral metastases, surgically resectable tumors, and less than 3 radioimagistic detectable metastases, as a positive predictive factor. With this study, we aim to evaluate the results of pulmonary metastasectomy in patients with primary urogenital tumors in our clinic.

Conclusion
Nowadays, with the increasing use of minimally invasive methods, operation and hospitalization times have been shortened, and second, third, or even fourth operations in the same patient have become more possible and easier for both patient and surgeon. Although there is no consensus in the management of these patients in the literature, we suggest pulmonary metastasectomy in urogenital cancers especially for patients with good respiratory conditions. We also recommend the usage of video-thoracoscopic surgery instead of thoracotomy. Small nodules and ground-glass opacities can cause problems for VATS, but as we have mentioned, this problem can be overcome by marking techniques.

Consent for publication
Not applicable.
Availability of data and materials Data are not publicly available. Data are however available from the authors upon reasonable request and with permission.

Competing interests
The authors declare that they have no competing interests.

Funding
The authors received no speci c funding/support for this study.
Authors' contributions KCC and SOK analyzed and interpreted the patient data regarding the pulmonary metastasis. GB performed the statistical analyses and was a major contributor in writing the manuscript. All authors read and approved the nal manuscript. Tables   Table I. Inclusion and exclusion