In this retrospective cohort study, the percentage of patients who developed lung or pleural abnormalities was 8.2 % during a median follow-up of 31.9 months. However, of these patients, only 3.1% had pleural or pulmonary metastases, according to highly suspicious findings in the images or histopathologic confirmation. Most of these patients had lymphangitic carcinomatosis and pleural metastases. Only one patient with multiple lung nodules had metastasis from gastric adenocarcinoma, and none of the patients with solitary nodules had hematogenous metastasis, meaning that only 0.2% of this cohort had metastatic nodules in the lung parenchyma. These results are consistent with the fact that the etiology of new pulmonary nodules in the follow-up of gastric cancer patients with previous curative management is not related to metastatic histology. The latter is the reason why it is important to understand the incidence of pleuro-pulmonary metastases in gastric cancer patients treated with curative intent.
As expected, patients with pleuro-pulmonary progression of the disease had lower overall survival, and among them, there was a tendency towards a lower overall survival in patients with pleural carcinomatosis. The former finding was not statistically significant, probably due to the low incidence, resulting in a lack of statistical power for pleuro-pulmonary compromise. We found no risk factors for the progression of gastric adenocarcinoma to the lung or the pleura.
Gastric cancer was responsible for over 1,000,000 new cancer cases in 2020 and 768,793 deaths, making this cancer the fifth most frequently diagnosed and the fourth leading cause of cancer-related death. Incidence rates are markedly elevated in Eastern Asia, whereas the rates in Northern America and Northern Europe are generally low and are equivalent to those seen across the African regions . After Eastern Asia and Eastern Europe, South America is one of the regions with the highest incidence of gastric cancer. The ASR per 100.000 population is between 18 and 39 for countries in Eastern Asia, such as Korea and Japan [1, 7]. In Latin America, high-risk pockets are reported in the Andes Mountains, with ASR between 13 and 17 for countries located in this zone, such as Chile and Colombia [1, 8]. The incidence rates in Colombia vary with high-incidence areas located at high altitudes in the Andes Mountains and low-incidence areas on the coasts and valleys . In the present cohort study, most patients come from high altitude regions close to Bogotá. This region is at 2,600m above sea level and has ASR similar to Japan and Korea, with values near 32.1 per 100.000 .
Tumor location in gastric cancer patients is different between Western and Eastern countries; tumors located in the proximal third are more frequent in western countries and this is associated with more advanced stage at presentation and worse survival [7, 9]. Although Colombia has a high gastric cancer incidence in some territories, most patients are diagnosed at an advanced stage and their cancer's biological behavior is closer to that of western countries. In this cohort, more than half of our patients were diagnosed with a stage III disease; 25.8% had diffuse histology, and 13.8% were located in the cardias. Considering our findings, we believe that gastric cancer in western countries, including those from Latin America, has different biological behavior and therefore has different metastasis patterns compared to those reported in Eastern countries.
Distant metastasis does not usually reach the lungs and pleura, occurring in 0.3 to 6% of patients treated with curative intent . This proportion was 3.1% in our series, but the proportion of patients with metastatic hematogenous seeding to the lung parenchyma was low, 0.22%.
In United States, a multi-institutional analysis , including 817 patients with gastric cancer treated with curative intent showed that the most common sites of distant recurrence were peritoneum, followed by liver, lung, and bone. The median recurrence-free survival was 10.8 months, and the median time for lung recurrence was 10.1 months. They found several factors related to recurrence, including age, lesion size, histologic type, number of lymph node metastasis, and the presence of lymphovascular invasion or perineural invasion. The median survival after recurrence was five months, and only 2% developed pleuro-pulmonary metastases. In the present study, we did not find any risk factors for the gastric adenocarcinoma progression to the lung or pleura.
Survival after gastric cancer recurrence is low. Even with chemotherapy, the median survival ranges between 6 and 13 months . The Memorial Sloan-Kettering Cancer Center study , representing a western cohort, described three recurrence patterns of adenocarcinoma: locoregional, peritoneal, and distant or systemic. From 1172 patients who underwent R0 resection, 42.3% had a recurrence. Most recurrences (79%) occurred in the first two years, and disease recurrence was rare after four years. Locoregional recurrences were present in 54%, peritoneal recurrence in 29%, and distant recurrences in 51%. Only 39 patients had recurrences to the lung parenchyma, representing 3.3% of the entire cohort, similar to our study. The median time from recurrence to death was six months, 70% were dead within one year, and the specific recurrence pattern had no significant effect on the time to death.
The cohort study reported by Kong et al. in 2012 , representing an eastern cohort, reported the most extensive series to date; they reviewed 20.187 gastric cancer patients and identified 193 (0.96%) as having metastases to the lung parenchyma, pleura, or lymphangitic metastatic lesions. Even though, the incidence of pleuro-pulmonary metastasis was 3.1% in our cohort, higher than that described by Kong et al. they found that the most frequent pattern of lung metastasis was hematogenous metastasis (44.5%) followed by pleural (24.4%), lymphangitic (18.7%) and mixed (12.6%) metastases. In our series, the main pattern of pleuro-pulmonary metastasis was lymphangitic metastasis present in 42.9% of the patients, followed by a mixed pattern in 28.6%, pleural metastasis in 21.4% and only one patient (0.2%) had hematogenous metastasis. They also found that young age was associated with the lymphangitic spread, and the diffuse type was associated with pleural seeding. This cohort is different from ours because it was not restricted to patients treated with curative intent. Finally, Kong et al. described that 80% of the patients with lung metastases of gastric cancer had concomitant metastases of other organs, especially the peritoneum and liver and they found that the median survival after diagnosing pleuro-pulmonary metastases in gastric cancer patients was four months, and 5-year survival was only 2–4%. In our series, we did not describe the presence of concomitant metastases of other organs and the median survival after diagnosis of pleuro-pulmonary metastases was 1.1 months.
Aurello et al.  described that the median time to recurrence was 14 to 29 months after surgery, similar to what we found in our series, where the median time for developing pleuro-pulmonary metastases after gastric surgery was 22.3 months.
Lung metastasectomy has been proposed for several solid tumors, however, little is known about the resection of gastric cancer lung metastasis . There are many series and case reports describing lung metastasectomy, especially in Asian countries [3, 12–14]. In 2010, Kemp et al.  addressed this question with a review of the articles on this subject published from 1975 to 2008. They reported 21 studies, including 43 patients with overall survival or 39 months and five-year survival of 33% after lung metastasectomy and a median survival time of 29 months. Aurello et al.  performed a systematic review in 2016 that included 44 patients who underwent lung resection for gastric cancer metastasis between 1998 and 2013; after lung resection, recurrence occurred in 21 patients, and six patients were disease-free at the last follow-up; median overall survival after gastric resection 45 months, suggesting that lung metastasectomy could improve the survival of patients with lung metastasis from gastric cancer when compared to patients treated with palliative chemotherapy. Shiono et al.  reported a 5-year overall survival of 28% for patients with gastric cancer treated with pulmonary metastasectomy and a median survival time of 29 months. The study by Iijima et al.  reported ten patients who underwent pulmonary metastasectomy for gastric cancer in Japan; their primary disease was controlled, they had no other extrapulmonary metastases, and the pulmonary metastases were limited to one lung; the overall 3-year survival was 30%, and the median survival time following pulmonary resection was 26.8 months. In our study, the only patient who had lung metastasectomy survived for 32 months after gastrectomy and 12 months after pulmonary resection. We cannot make any conclusions with one patient, but the median survival after lung metastasis diagnosis and treatment was higher compared with patients with unresected pleuro-pulmonary compromise. The role of pulmonary metastasectomy in gastric cancer needs further studies, and it may be proposed only for selected cases.
Even though, thoracic staging with CT-scan for gastric adenocarcinoma is still controversial , we believe it is necessary. In patients with pleural or lymphangitic carcinomatosis, CT-scan findings are usually very suggestive of metastatic compromise. However, in the case of lung nodules, the incidence of metastatic lesions was very low and although this study looked at the development of pulmonary metastases after gastric cancer resection, not at diagnosis; these results may be a starting point for further studies in patients with pulmonary nodules at the time of diagnosis that may change the approach during gastric cancer staging and avoid unnecessary lung resections.
There are several limitations in this study. It was a retrospective analysis of a single institution and it did not describe which patients had concomitant metastatic sites other than the lung and pleura. However, this is the first study that describes the patterns of pleuro-pulmonary metastases in gastric cancer patients treated with curative intent in Latin-America.