Association of CT characteristics of osteosarcoma lung metastases with spontaneous pneumothorax: a retrospective analysis

Introduction

Osteosarcoma is the most common primary malignant bone tumor in children and young adults, and the most common site of metastasis is the lungs (1,2). Osteosarcoma lung metastases present diverse manifestations on chest computed tomography (CT), including solitary or multiple nodules or masses, occasionally with calcification, cavitation, and hemorrhagic halos surrounding the nodules (3). Spontaneous pneumothorax (SP) is a rare yet recognized complication of osteosarcoma lung metastasis (4-6). Pneumothorax has a detrimental impact on respiratory function and poses a threat to a patient’s life by potentially impeding osteosarcoma treatment.

While documented cases of SP associated with osteosarcoma lung metastases exist (7,8), the CT characteristics of lung metastases in patients with pneumothorax have not been comprehensively described in large series. This study focused on the radiographic characteristics of lung metastases associated with pneumothorax on chest CT images in patients with osteosarcoma. Additionally, we explored chest CT features that may increase the risk of SP. This manuscript is written following the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1015/rc).

Methods

A retrospective analysis of chest CT images of 123 patients diagnosed with osteosarcoma between January 2016 and December 2021 at our hospital was conducted (Figure 1). Inclusion criteria comprised: (I) histologically proven osteosarcoma; (II) presence of metastatic lung lesion(s); and (III) comprehensive and analyzable clinical data. Cases with incomplete clinical and imaging data were excluded. The age, sex, body weight, and height of each participant were recorded. Body mass index (BMI) was calculated as the ratio of weight (kg) to height squared (m²). The size and site of osteosarcoma were also recorded. The primary outcome of the study was the first incidence of pneumothorax, excluding those caused by trauma or lung metastasis resection. The absence of pneumothorax was defined as no pneumothorax until the last chest CT examination available in the Picture Archiving and Communication System at our hospital. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of The First Affiliated Hospital of Sun Yat-sen University (approval No. [2024]-256). Individual consent for this retrospective analysis was waived.

Figure 1 Study flowchart shows patient inclusion and exclusion criteria.

Chest CT images were obtained using a General Electric medical system Lightspeed 64-slice CT spiral CT scanner, covering a scan range from the lung apices to the diaphragm while the patients lay supine and at the end of deep inhalation. The images were acquired using the following parameters: 120 kV tube voltage, automatic exposure control for tube current, a gantry rotation of 280 ms, and a slice thickness of 1 mm. The international guidelines have established standards for the management and follow-up of patients with bone sarcomas (9,10). Patients who underwent surgical interventions for osteosarcoma were scheduled for chest radiography and CT scans every 3 months during the first 2 years. In the third to fifth years of follow-up, the patients underwent chest radiography and CT scans every 6 months. Beyond 5 years postoperatively, annual CT scans were performed for ongoing monitoring.

Two radiologists (with 4 and 7 years of clinical experience, respectively) assessed the chest CT imaging findings. In cases of inconsistencies, both radiologists discussed and resolved the discrepancies. Lung metastases were identified as pulmonary lesions exhibiting characteristics indicative of malignancy, such as a progressive increase in number and/or dimensions on successive CT scans, as well as those observed in patients who have undergone metastasectomy. Our definition of SP encompassed naturally occurring cases but excluded those that were complications resulting from metastasectomy, video-assisted thoracoscopic surgery (VATS) biopsy, bronchoscopy, or trauma. The following variables were coded: number of lesions—solitary = single lesion, multiple ≥ two lesions; pleural involvement—lung metastases extending by contiguous growth into the pleural cavity, chest wall, diaphragm, or mediastinum (Figure 2).

Figure 2 A patient presenting with bilateral spontaneous pneumothorax, primarily focusing on the progression of the left-sided pneumothorax. Upon examination, it was determined that he was afflicted with osteosarcoma in the proximal region of the right tibia (blue arrow) (A). Furthermore, multiple metastases were observed in the left lung, specifically affecting the pleura (red arrow) (B). These metastases exhibit characteristics such as cavity appearance (C), enlargement (D), rupture, and disappear (red arrows), leading to the development of a left-sided pneumothorax (yellow arrow) (E). Additionally, the lung metastases have been found to be enlarged (red arrow) (F).

Statistical analysis

Statistical analyses were performed using the Statistical Package for Social Sciences for Windows version 26.0 (SPSS, Chicago, IL, USA). Dependent variables were analyzed to determine whether they were normally distributed using the Kolmogorov-Smirnov test. Means and standard deviations were calculated for the continuous variables. Parametric data are presented as means with standard deviations, medians with interquartile ranges, or frequencies with percentages. Differences between patients with and without pneumothorax were tested using Student’s t-test for continuous variables and chi-square analysis for categorical variables. Variables demonstrating significant prognostic value in the univariate analysis and CT features were included in the binary logistic regression analysis to determine the factors relevant to pneumothorax. Statistical significance was set at P<0.05.

Results

Table 1 shows the baseline characteristics of 123 patients with osteosarcoma lung metastases, divided into those with and without pneumothorax. Of the 123 eligible patients, 92 (75%, mean age 19±11 years, 57% males) were without pneumothorax and 31 (25%, mean age 16±9 years, 61% males) were with pneumothorax at initial diagnosis. Among those with pneumothorax, 20 had unilateral pneumothorax and 11 had bilateral pneumothorax. Of these, 19 were hospitalized and underwent chest drain insertion as part of their treatment regimen. The median follow-up duration post-primary osteosarcoma diagnosis was 26.1 months. Osteosarcoma primarily occurred in the distal femur (in 55 patients, 45%), proximal tibia (in 37, patients, 30%), proximal humerus (in 15 patients, 12%), and others (e.g., pelvis and sacrum) (in 16 patients, 13%). The distal femur emerged as the most common site. In addition, 36% of primary tumors were found to be <8 cm and 64% were ≥8 cm. A total of 39 patients received treatment with an anti-tumor agent, comprising 37 patients who received apatinib, one patient who received pazopanib, and one patient who underwent anlotinib therapy. Although there was an increased incidence of pneumothorax associated with the administration of the anti-tumor agent, no significant difference was observed (35% vs. 30%, P=0.60). No significant differences were observed in age, sex, BMI, primary tumor size, or site between patients with and without pneumothorax. The median time between discovery of osteosarcoma and lung metastases in patients with pneumothorax was shorter than that in patients without pneumothorax (P=0.039).

Table 2 shows the CT characteristics of lung metastases, both with and without pneumothorax. No evidence of pulmonary bulla or emphysema was observed on chest CT in any of the patients included in the study. Among the 246 unilateral lungs examined, 26 exhibited no metastases, 58 exhibited solitary lesions, and 162 exhibited multiple lesions. Lung metastases manifest as nodules or irregularly shaped masses, which are larger in size in the lungs with pneumothorax (not depicted). Multiple lesions were more likely to occur in the lungs with pneumothorax (39/42 vs. 123/178, P<0.001), have a higher rate of pleural involvement (38/42 vs. 63/178, P<0.001), and have a higher rate of cavitation (23/42 vs. 19/178, P<0.001). A considerable prevalence of calcification (123/220) was observed in lung metastases. However, no statistically significant difference was found between patients with and without pneumothorax.

Pneumothorax was observed at a median of 9 months (10±7.4 months) after the diagnosis of lung metastases. Binary logistic regression analysis results are shown in Figure 3. The median time to the detection of lung metastases, number of lung metastases, and presence of calcification showed no significant differences in the multivariate models. Cavitation in lung metastases and pleural involvement were significantly associated with pneumothorax, with odds ratios of 12.430 [95% confidence interval (CI): 3.011–51.320; P<0.001] and 15.480 (95% CI: 4.038–59.348; P<0.001), respectively.

Figure 3 A binary logistic regression analysis in patients with spontaneous pneumothorax. ^a, time interval between the discovery of osteosarcoma to lung metastases; ^b, number of pulmonary metastases. Significance is set at P<0.05. LL, lower limit; CI, confidence interval; UL, upper limit; SE, standard error; β (beta), standardized beta coefficient.

Discussion

This retrospective study analyzed patients diagnosed with osteosarcoma lung metastases specifically focusing on the radiographic characteristics associated with SP. To the best of our knowledge, no large-scale studies have comprehensively documented the CT characteristics of lung metastases in patients with pneumothorax. Our findings revealed several noteworthy observations. First, we determined that the time between osteosarcoma onset and occurrence of lung metastases was significantly shorter in patients with pneumothorax. Second, the incidence of pneumothorax was notably increased in patients with metastatic lung lesions, particularly in those demonstrating cavitation and pleural involvement. Finally, there was a probable positive correlation between pneumothorax and larger and more metastatic lesions with unfavorable prognosis, although further investigation is warranted to ascertain long-term outcomes.

In our study, we observed a significant association between the presence of cavitation in lung metastases and pleural involvement, as indicated by both univariate and multivariate analyses, with a substantial risk ratio. Metastases under the pleura, along with the development and enlargement of the bullae, are critical factors contributing to this occurrence (11). Metastatic nodules adjacent to the bronchial lumen can lead to air entrapment within the alveoli via the ball-valve mechanism. Subsequent enlargement of the alveoli can cause the fragile alveolar wall to rupture, resulting in the leakage of air into the pleura. Consequently, subpleural blebs may form, possessing the potential to rupture and give rise to an SP (12).

Despite the considerable calcification rate (55.9%) observed in lung metastases, no statistically significant differences were observed between patients with and without pneumothorax. Our findings also revealed a similar prevalence of calcification in patients with osteosarcoma, consistent with the findings of a previous study (13). This observation appears to contradict the hypothesis that metastases include bone constituents, compromising lung and pleural elasticity and rendering them susceptible to rupture. However, further research is required to confirm this hypothesis.

In our study, patients diagnosed with pneumothorax exhibited a shorter median duration to the development of lung metastases and a higher prevalence of bilateral and multiple lesions. The prognosis of osteosarcoma depends on various factors, such as tumor size and site, patient age, presence or absence of metastasis, chemotherapy response, and surgical incision type (14). These findings suggest a potential association between malignancy and tumor aggressiveness. Correspondingly, Chen et al. (15) discovered that a greater number of lung metastases, particularly those detected during chemotherapy, were associated with a poorer prognosis. Similarly, Kempf-Bielack et al. (16) identified both the number of lesions and laterality of pulmonary disease as statistically significant prognostic indicators of the overall tumor burden. Additionally, the timing of pulmonary metastasis is an important prognostic factor in patients with metastatic lung osteosarcoma (17). Pneumothorax complicated by sarcoma is associated with increased mortality compared to patients without this complication (18). However, there is some debate regarding the prognosis of patients with synchronous lung metastasis. Apatinib therapy often accompanies pneumothorax and cavitation of lung metastases (19). This condition can be managed through patient monitoring and supportive care, which can predict an effective prognosis (20,21). Unfortunately, we did not follow up the outcomes of the two groups in our study.

This study had certain limitations. First, this study was conducted retrospectively, and comprehensive clinical and disease progression data were not available for all patients. In addition, conclusive prognostic inferences regarding SP were unattainable due to insufficient follow-up data. The potential independent influence of pneumothorax as a risk factor for 5-year survival in patients with osteosarcoma requires further elucidation.

Conclusions

Patients with metastatic pulmonary lesions, particularly those with cavitation and pleural involvement are susceptible to SP. Regular follow-up of these patients has the potential to ensure early detection and treatment of pneumothorax.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1015/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1015/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1015/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1015/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of the First Affiliated Hospital of Sun Yat-sen University (approval No. [2024]-256). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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