Lung Nodules in Pediatric Osteosarcoma: Calcification as the Unique Radiological Criterion to Confirm Metastasis

Lung Nodules in Pediatric Osteosarcoma: Calcification as the Unique Radiological Criterion to Confirm Metastasis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Lung Nodules in Pediatric Osteosarcoma: Calcification as the Unique Radiological Criterion to Confirm Metastasis Helena Martínez Sánchez, Adela Cañete Nieto, Daniel Sánchez Mateos, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7146838/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Sep, 2025 Read the published version in Pediatric Radiology → Version 1 posted 8 You are reading this latest preprint version Abstract PURPOSE: Osteosarcoma is the most common bone pediatric cancer with the lung being the primary site of metastasis. Chest CT is used to assess metastatic disease at diagnosis, classifying patients as localized or metastatic. Although there are radiological characteristics that suggest whether a lung nodule is metastatic, in daily practice nonspecific lesions on CT may complicate classification. Our objective is to compare radiological findings with the histology of lung nodules deemed malignant by CT and to review current radiological criteria. METHODS: A retrospective review was conducted of lung nodules in patients under 18 years old, diagnosed with osteosarcoma between 2014-2024 in a tertiary hospital. Radiological features, including calcification, size, shape, and location, were analyzed for their correlation with histological confirmation of metastasis. RESULTS: 116 nodules were identified as malignant by radiology in 33 osteosarcoma patients. 69% of patients had pulmonary nodules that met radiological criteria for malignancy during follow-up. All underwent surgical resection, and histology confirmed metastasis in 49%. Only calcification showed a significant correlation with histological confirmation of metastasis. CONCLUSIONS: CT imaging has an optimal sensitivity but low specificity for detecting lung metastases in osteosarcoma. However, we demonstrate that calcification is significantly correlated with histological confirmation of metastasis and may aid in confirming lung metastasis in osteosarcoma patients. Still furtherstudies are needed to refine radiological criteria to improve accuracy and reduce false positive rates. Osteosarcoma Radiotherapy Magnetic Resonance Imaging Pulmonary Nodules Computed Tomography Scan [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)-CT Figures Figure 1 Figure 2 INTRODUCTION Osteosarcoma (OS) is the most common bone sarcoma, with an incidence rate of about 0.3 per 100,000 cases per year [1-3]. The incidence is significantly higher in adolescents (15-19 years), with rates ranging from 0.8 to 1.1 per 100,000 persons per year. Several risk factors are associated with the development of osteosarcoma, [1,4] including previous radiotherapy (RT), bone Paget's disease and germline genetic abnormalities associated with Li-Fraumeni syndrome, hereditary retinoblastoma and others. Advanced imaging techniques, such as magnetic resonance imaging (MRI) and [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)-CT, are used to determine the extent of the tumor and assess the involvement of surrounding soft tissues and other distant sites. A chest computed tomography scan (CT) scan is performed for monitoring the presence of lung metastases, which are prevalent in osteosarcoma patients [1,5]. The likelihood of these metastases is increased in males, in cases where the primary tumour is larger and in cases where the tumour is located in the femur or tibia [5,6]. The presence of pulmonary metastases remains a significant challenge in the management of osteosarcoma, influencing prognosis and treatment outcomes. Patients with metastatic osteosarcoma have an extremely poor prognosis, with a five-year survival rate of only 20% to 40%, compared to 40% to 70% for those with localised OS [5-7]. Its resection has been demonstrated to be directly associated with increased survival. [7,8]. However, there is no global consensus regarding the radiological criteria for the indication of pulmonary metastasectomy [8]. On the other hand, in routine clinical practice, non-specific lesions frequently appear on CT scans, prompting uncertainty about their classification and the subsequent therapeutic and prognostic implications. Studies have demonstrated that although lung CT has a high sensitivity for detecting pulmonary nodules (PN), with values reaching 84% in the literature [9], its specificity is low, with false positive rates after biopsy ranging from 32% to 65% [10,11]. In this context, the divergences in criteria and recommendations call for further studies to establish standardised guidelines. Identifying the nature of the PN is essential for proper staging, selecting the appropriate treatment protocol and determining prognosis. [12] The objective of this study is to compare the radiological findings from CT scans with the histological findings of surgically resected tumors in patients diagnosed with osteosarcoma-associated lung metastases. In addition, the study will evaluate the efficacy of current radiological criteria in diagnosing and characterising pulmonary metastases in osteosarcoma. METHODS Study design This observational retrospective cohort study was conducted employing a tertiary hospital database. Retrospective longitudinal data were collected from electronic clinical information including patient demographics, radiological features of PN in imaging test (lung CT), treatment, prognosis and histopathology. The radiological criteria indicated in the current guidelines were applied [8,13]. According to them a patient with pulmonary metastasis is defined as having three or more lesions greater than 5 mm in maximum diameter or any lesion greater than or equal to 1 centimetre. It was also taken into account other features such as peripheral location, rounded shape with well-defined margins, bilaterality or calcification to consider malignant a PN. The imaging test analyzed was a high-resolution lung CT, attempting to obtain the images at maximum inspiration. It is programmed to be performed with thin cuts of lung tissue (1mm) with an overlap for reconstruction between 0.5mm cuts and helical acquisition. Subsequently, the lung parenchyma was reviewed, extending the section thickness to 6-8 mm and using the MIP (maximum intensity projection) post-processing option to facilitate the rapid and accurate identification of lung nodules. Tomography scans have been systematically performed without contrast, unless there was a specific reason that requires it, such as involvement of the pleura, chest wall, or hilar or mediastinal lymphadenopathy. Participants All patients under 18 years of age at the time of diagnosis with OS during a 10-year period (2013-2023) treated in our Pediatric Oncology Unit were selected. We excluded those patients with confirmed histological lung metastases detected by palpation during thoracotomy due to the absence of correlation by imaging. Study Outcomes The study aimed to compare the radiological features from CT lung scans (calcification, size, location and shape) with the histological findings of surgically resected tumors in patients diagnosed with osteosarcoma-associated lung metastases. It will evaluate the efficacy of current radiological criteria in diagnosing and characterising pulmonary metastases in osteosarcoma. Statistical analysis Initially, the statistical significance of each variable's effect on the outcome was assessed. Fisher test was applied to analyse the frequency distribution of metastasis occurrence in relation to calcification (levels: No, Yes and Non-specific), size (levels: ≤0.5cm, 0.5-1cm and ≥1cm), location (levels: Peripheral, Central and Non-specific), and shape (levels: Non-specific, Round, Polygonal and Cissural). If significant differences were found, a post-hoc analysis was conducted using pairwise comparisons with Bonferroni correction. This approach enabled the determination of the association between these categorical variables and the outcome. Next, a multivariate logistic regression was used to study the likelihood of metastasis occurrence, using calcification (reference level: No), size (reference level: ≤0.5 cm), location (reference level: Non-specific), and shape of tumor (reference level: Non-specific) as predictors. The Odds Ratio (OR), confidence intervals, and p-values associated with each coefficient (Wald test) were calculated. The most parsimonious model was chosen, by selecting as model predictors those variables that achieved a significance level of p<0.1 (marginally significant or significant) when all variables were used in the model. All statistical analyses were performed using the statistical software R (version 4.2.3). A level of significance of p<0.05 was chosen as a significance threshold. RESULTS A total of 116 nodules were identified by radiology as malignant and 33 patients with osteosarcoma were included in the study. At the time of diagnosis, 48% (16/33) of patients exhibited PN suggestive of malignancy on initial lung CT, while 52% (17/33) were considered as localised. Of those who initially had a CT lung scan without malignant PNs, 41% (7/17) had new lesions suggestive of malignancy during subsequent treatment and follow-up. Therefore, 69% (23/33) of all patients had PNs that met radiological criteria for malignancy at some point during follow-up period. The mean number of nodules per patient was 5.2, with a range of 1 to 18. Figure 1 shows a CT scan with a PN suggestive of metastasis. The radiological characteristics of the PNs considered malignant by lung CT are shown in Table 1. Calcification was present in 59% (69/116). 84% (97/116) were less than or equal to 0.5 cm in size, 13% (15/116) were of medium size (0.5-1cm) and only 3% (4/116) were greater than or equal to 1 cm. 78% (90/116) were located peripherally, 6% (7/116) centrally and 16% (19/116) could not be adequately specified. In terms of shape, 23% (26/116) were rounded with well-defined borders, 11% (13/116) were cissural, 12% (14/116) were polygonal and 54% (63/116) could not be optimally determined due to their small size. All PNs that met radiological criteria for malignancy underwent resection surgery and histological study of the removed specimen. Pathology results showed that metastasis was confirmed by histology in only 49% (57/116) of the samples analysed (Table 2). In the remaining patients that did not show metastasis, histology showed lymphoid tissue, granulomas, intrapulmonary lymph nodes and hamartomas. Univariate analysis was performed to study the correlation of each of the radiological characteristics with the confirmation of metastasis by histology. Regarding calcification, Fisher test revealed a significant association between the frequency of metastasis and calcification. (p = 0.00004). Post-hoc analysis indicated that significant differences were found between the groups with and without calcification (p = 0.00009, Bonferroni correction for multiple comparisons). Regarding the size of the nodules, metastasis was confirmed in 58% of those smaller than 0.5 cm, in 53% of those of medium size (0.5-1 cm) and in 50% of those larger than or equal to 1 cm. Fisher test did not reveal a significant association between the size of the nodule and metastasis. Regarding the location of the nodule, metastasis was confirmed in 52% of those at the peripheral level. No significant association between location and metastasis was found (Fisher test, p 0.38). With regard to the shape, Fisher's test showed statistical significance (p = 0.011). However, post-hoc pairwise analysis correcting for multiple comparisons using the Bonferroni correction did not reach significance level for any pair of shapes. These results of the univariate analysis are shown in table 3. A multivariate logistic regression model was fitted to explain the occurrence of metastasis using the following categorical variables calcification, size, location, and shape. Significant differences were observed only for the variable calcification (Wald test, p = 0.0008, comparing Yes to No as the reference level). To achieve a more parsimonious model, a logistic regression analysis was subsequently conducted using only the two variables that exhibited the most relevance (p < 0.1): calcification and shape. The results are shown in table 4 . The OR for calcification (Yes) is 5.70, showing that the odds of metastasis are 5.70 times higher for tumors with calcification compared to those without, with statistical significance (p = 0.0004). The OR for shape (Cissural) is 0.26, indicating a 74% reduction in the odds of metastasis for cissural shapes compared to Non-specific shapes, with marginal significance (p = 0.0703). The nomogram corresponding to this model is shown in Figure 2. Likelihood ratio test of the model was significant (p < 0.001). 26% (6/23) patients who had presented synchronous or metachronous PN suggestive of malignancy presented a pulmonary relapse that required a surgical reintervention. Of the total number of patients with OS (33), 54.5% (18/33) are currently alive without disease and 15.15% (5/33) are alive with disease. The percentage of deaths to date has been 30.3% (10/33). Of the total number of patients who did not survive, 70% had synchronous or metachronous pulmonary metastasis. DISCUSSION The detection of lung metastases in osteosarcoma is one of the predictive factors that most influence patient's prognosis. Therefore, having sensitive and specific radiological criteria is essential. According to the most recent European guidelines [13], a patient with pulmonary metastasis is defined as having three or more lesions greater than 5 mm in maximum diameter or any lesion greater than or equal to 1 centimetre. In addition, other guidelines such as the Spanish Society of Paediatric Haematology and Oncology (SEHOP) 2011 metastatic guidelines also describe that there are features that may suggest its malignant nature, such as peripheral location, rounded shape with well-defined margins, bilaterality or calcification [8]. Furthermore, the guidelines also state that preoperative biopsies are not indicated if there is radiological suspicion of malignancy. [8,13]. Based on the literature, 10-20% of patients diagnosed with OS will have synchronous lung metastases (at diagnosis) and 40-55% will have metachronous lung metastases. In our cohort, the incidence of PN suggestive of malignancy on imaging was slightly higher (69%). This may be justified by the inevitable interobserver variability that may exist in detecting and interpreting smaller PNs. Furthermore, reducing the CT slice thickness to 1 mm increases the detection of lung nodules <5mm but also increases the number of false positives, which may also explain the highest incidence of PN suggestive of malignancy on imaging. This can lead to an increase in the rate of unnecessary surgical interventions (thoracotomies and thoracoscopies) with its associated comorbidities that may involve. Therefore, despite the great advantages of high-precision CT scans, it is advisable to take into account their possible associated drawbacks due to they can over-detect non-specific nodules that make us take unnecessary measures for the patient. Furthermore, another fact that must be taken into account is the presence of PN in children without oncological pathology. Samim et al conducted a study to evaluate the frequency and characteristics of pulmonary nodules on CT in healthy children, revealing that the presence of small pulmonary nodules is a common incidental finding in children without malignancy, with a prevalence of 38% [11]. These data are in line with those carried out by Renne et al who in a pediatric trauma setting reported a prevalence of 33%. [14]. These findings are important to appropriately interpret the presence of pulmonary nodules in children with malignant tumors as osteosarcoma. In fact, the most recent European guidelines for the treatment of osteosarcoma [13] advocate performing fewer lung CT scans during patient follow-up if the patient has not previously had lung metastases and there is no clinical or radiographic suspicion of them, with the aim of reducing the detection of small non-specific nodules and lowering the rate of false positives. However, in our study the positive predictive value was very low, with malignancy confirmed by pathological anatomy in only 49% of them. This result is similar than the results previously obtained in literature, with false positive rates ranging between 32 and 65% in children. [10,12,15-17] The choice of approach for the resection of the PN must be individualized. The advantages of thoracoscopy are smaller incisions, better pain control, and faster postoperative recovery. However, open thoracotomy has the advantage of being able to perform direct palpation of the lung and detect PNs that are not visible on imaging. Therefore, it is generally the gold standard in patients with OS. [18]. In our cohort the decision of approach was individualised according to the characteristics of the patient and the number and location of the PN. In all cases surgery was performed between primary tumour intervention and three weeks later. In our study we excluded those patients with confirmed histological lung metastases detected by palpation during thoracotomy due to the absence of correlation by imaging. In our cohort, in neither group did size show a significant correlation with confirmation of malignancy by histology. In other studies, such as Kaliff et al and Brader et al , size did show a significant correlation although in each study the cut-off points differed, ranging from 5 mm to 12.5 mm [12,19]. The lack of significance in our work may be due to the few PNs present in our sample larger than 5 mm. Of all the radiological criteria suggestive of malignancy, in our study only calcification presented a significant correlation with the confirmation of metastasis by histology. These results are contrary to those obtained in patients with primary tumours of other origin, where calcification has been considered a protective factor for the presence of metastasis [11,20]. This may be because the osteoid matrix produced by osteosarcoma may lead to calcification of these nodules. [12] To our knowledge, very few studies in the literature have previously presented PN calcification as an independent factor for malignancy [9,12] and only one study has been performed exclusively in the paediatric population [12]. Our results support the results obtained by Brader et al and Cicarese et al . Regarding the shape of the nodules, our cohort suggests that those with a cissural shape could have a certain protective tendency for the confirmation of metastasis, which is in line with what was previously described in the literature. Despite this, the results are not conclusive, so more studies should be done in this regard to confirm this fact. CONCLUSIONS We present the most extensive pediatric cohort of lung nodules in osteosarcoma. In our review, calcification is shown as the only radiological criterion that has a significant correlation with histological confirmation of metastasis. To our knowledge, only two previous studies had identified this finding as an independent predictor of malignancy [9,12], and only one had been conducted exclusively in a pediatric population [12]. Our study not only confirms this association in pediatric patients but also represents the largest cohort analyzed to date in this population. The significance of this finding lies in its potential to refine current diagnostic protocols, offering a more reliable tool for differentiating between benign and malignant pulmonary nodules in pediatric patients, ultimately leading to more tailored and less invasive treatment strategies. While CT imaging is a highly sensitive tool for detecting pulmonary metastases, its specificity and positive predictive value remain limited. Despite the importance of using sensitive tests for identifying pulmonary metastases, given the impact of their resection on survival, the high false-positive rate observed in our cohort and in previously described studies suggests the need for refinement of radiological criteria. Misclassifying pulmonary nodules as malignant based solely on imaging studies may lead to more aggressive treatments, including higher-intensity chemotherapy protocols and invasive surgeries with associated risks, as well as significant psychological impact on the patient and their family. Therefore, optimizing radiological criteria is essential to improve diagnostic accuracy and reduce the false-positive rate. Declarations DATA AVAILABILITY STATEMENT The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest: The authors declare no conflict of interest. ETHICAL STATEMENT An independent Ethics Committee granted ethical approval in accordance with the Helsinki declaration and the Good Clinical Practice guidelines (CPMP/ICH/135/95) for the whole research. Since this study was retrospective and consisted in clinical charts revisions, the ethics committee approved an informed consent exemption in its approval. REFERENCES Strauss, S. J., Frezza, A. M., Abecassis, N., Bajpai, J., Bauer, S., Biagini, R. et al. ESMO Guidelines Committee, EURACAN, GENTURIS and ERN PaedCan. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology, 32(12), 1520–1536. https://doi.org/10.1016/j.annonc.2021.08.1995 Gatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E et al. Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol. 2017; 18: 1022-1039 De Pinieux G, Karanian M, Le Loarer F, Le Guellec S, Chabaud S, Terrier P et al. 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Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner society. Radiology 2015. 237:395–400 Tables Table 1. Descriptive summary of radiological variables. CT FEATURE RESULTS Calcification Yes 69 (59,48%) No 42 (36,21%) Non-specific 5 (4,31%) Size Size ≤ 0.5 cm 97 (83,62%) Size 0,5-1 cm 15 (12,93%) Size ≥ 1 cm 4 (3,45%) Location Peripheral 90 (77,59%) Central 7 (6,03%) Non-specific 19 (16,38%) Shape Round 26 (22,41%) Cissural 13 (11,21%) Polygonal 14 (12,07%) Non-specific 63 (54,31%) Table 2. Pathological anatomy results of PNs suggestive of malignancy by CT. Histology confirms metastasis Yes 57 (49,14%) No 59 (50,86%) Table 3. Results of univariate analysis relating each of the radiological characteristics to confirmation of metastasis by histology. Feature Confirmation of metastasis P value Calcification Yes 46/69 (67%) 0.00004 No 20/42 (48%) Non-specific 2/5 (40%) Size ≤0.5 cm 47/97 (58%) 0.9185 0.5-1cm 8/15 (52%) ≥ 1 cm 2/4 (50%) Location Peripheral 47/97 (52%) 0.3809 Central 2/7 (28%) Non-specific 8/27 (42%) Shape Round 13/26 (50%) 0.01156 Cissural 3/14 (21%) Polygonal 3/13 (23%) Non-specific 38/63 (60%) Table 4. Results of the final logistic regression model fitted to explain the occurrence of metastasis, including the coefficients, 95% confidence intervals (C.I.), OR, and p-values for each predictor in the model. p-values < 0.1 are indicated in bold. Predictor Coeficient C.I. (95%) OR p-value (intercept) -0.639 [-1.5, 0.16] - 0.1269 Calcification: Yes 1.740 [0.80, 2.74] 5.70 0.0004 Calcification: Non-specific 0.461 [-1.72, 2.47] 1.59 0.6509 Shape: Round -0.930 [-1.97, 0.08] 0.39 0.0737 Shape: Polygonal -1.098 [-2.76, 0.35] 0.33 0.1539 Shape: Cissural -1.357 [-2.99, 0.03] 0.26 0.0703 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7146838","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":489122763,"identity":"01774d4a-371c-498a-8de4-6ef512d7ffb7","order_by":0,"name":"Helena Martínez 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Fe","correspondingAuthor":false,"prefix":"","firstName":"Jesús","middleName":"García","lastName":"Vázquez","suffix":""},{"id":489122771,"identity":"41d3ecec-4fa1-48a6-8ce9-e39eee27de88","order_by":8,"name":"Marta Salom Taverner","email":"","orcid":"","institution":"Hospital Universitari i Politècnic La Fe","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"Salom","lastName":"Taverner","suffix":""},{"id":489122772,"identity":"5f6833b8-7a04-420d-aafe-142e180fe020","order_by":9,"name":"Alfredo Marco Macián","email":"","orcid":"","institution":"Hospital Universitari i Politècnic La Fe","correspondingAuthor":false,"prefix":"","firstName":"Alfredo","middleName":"Marco","lastName":"Macián","suffix":""},{"id":489122773,"identity":"6f6ff07d-f360-4e32-b599-e8c3c96fbb01","order_by":10,"name":"Antonio Juan Ribelles","email":"","orcid":"","institution":"Hospital Universitari i Politècnic La Fe","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Juan","lastName":"Ribelles","suffix":""}],"badges":[],"createdAt":"2025-07-17 08:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7146838/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7146838/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00247-025-06410-3","type":"published","date":"2025-09-29T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87527993,"identity":"4be2c706-03fe-4a7d-8fe5-0ffad1324aec","added_by":"auto","created_at":"2025-07-24 20:13:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":253808,"visible":true,"origin":"","legend":"\u003cp\u003eLung CT of patient with OS showing single pulmonary nodule in the left lower lobe. Resection by thoracoscopy after harpoon marking. Pathology confirmed the diagnosis of subpleural metastasis of osteoblastic osteosarcoma.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7146838/v1/eac4784035513f83a8e7fd19.png"},{"id":87527656,"identity":"1e8b1e7b-8791-4655-b803-18a0883fb695","added_by":"auto","created_at":"2025-07-24 20:05:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43853,"visible":true,"origin":"","legend":"\u003cp\u003eNomogram illustrating the predicted probability (Pr) of Metastasis based on the levels of Calcification and Shape. The total score corresponds to the probability of metastasis occurring, shown on the bottom scale (*** p\u0026lt;0.0001).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7146838/v1/ec9f54b9a750640aa842b474.png"},{"id":92883978,"identity":"aedc2e9d-9c03-4e18-937d-081151db5270","added_by":"auto","created_at":"2025-10-06 16:11:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":990867,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7146838/v1/dc64531a-f2dc-449f-95f3-0a43682fdc4d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLung Nodules in Pediatric Osteosarcoma: Calcification as the Unique Radiological Criterion to Confirm Metastasis\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eOsteosarcoma (OS) is the most common bone sarcoma, with an incidence rate of about 0.3 per 100,000 cases per year [1-3]. The incidence is significantly higher in adolescents (15-19 years), with rates ranging from 0.8 to 1.1 per 100,000 persons per year. Several risk factors are associated with the development of osteosarcoma, [1,4] including previous radiotherapy (RT), bone Paget's disease and germline genetic abnormalities associated with Li-Fraumeni syndrome, hereditary retinoblastoma and others.\u003c/p\u003e\n\u003cp\u003eAdvanced imaging techniques, such as magnetic resonance imaging (MRI) and [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)-CT, are used to determine the extent of the tumor and assess the involvement of surrounding soft tissues and other distant sites. A chest computed tomography scan (CT) scan is performed for monitoring the presence of lung metastases, which are prevalent in osteosarcoma patients [1,5]. The likelihood of these metastases is increased in males, in cases where the primary tumour is larger and in cases where the tumour is located in the femur or tibia [5,6]. The presence of pulmonary metastases remains a significant challenge in the management of osteosarcoma, influencing prognosis and treatment outcomes. Patients with metastatic osteosarcoma have an extremely poor prognosis, with a five-year survival rate of only 20% to 40%, compared to 40% to 70% for those with localised OS [5-7]. Its resection has been demonstrated to be directly associated with increased survival. [7,8]. However, there is no global consensus regarding the radiological criteria for the indication of pulmonary metastasectomy [8].\u003c/p\u003e\n\u003cp\u003eOn the other hand, in routine clinical practice, non-specific lesions frequently appear on CT scans, prompting uncertainty about their classification and the subsequent therapeutic and prognostic implications. Studies have demonstrated that although lung CT has a high sensitivity for detecting pulmonary nodules (PN), with values reaching 84% in the literature [9], its specificity is low, with false positive rates after biopsy ranging from 32% to 65% [10,11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this context, the divergences in criteria and recommendations call for further studies to establish standardised guidelines. Identifying the nature of the PN is essential for proper staging, selecting the appropriate treatment protocol and determining prognosis. [12]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe objective of this study is to compare the radiological findings from CT scans with the histological findings of surgically resected tumors in patients diagnosed with osteosarcoma-associated lung metastases. In addition, the study will evaluate the efficacy of current radiological criteria in diagnosing and characterising pulmonary metastases in osteosarcoma.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis observational retrospective cohort study was conducted employing a tertiary hospital database. Retrospective longitudinal data were collected from electronic clinical information including patient demographics, radiological features of PN in imaging test (lung CT), treatment, prognosis and histopathology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe radiological criteria indicated in the current guidelines were applied [8,13]. According to them a patient with pulmonary metastasis is defined as having three or more lesions greater than 5 mm in maximum diameter or any lesion greater than or equal to 1 centimetre. It was also taken into account other features such as peripheral location, rounded shape with well-defined margins, bilaterality or calcification to consider malignant a PN.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe imaging test analyzed was a high-resolution lung CT, attempting to obtain the images at maximum inspiration. It is programmed to be performed with thin cuts of lung tissue (1mm) with an overlap for reconstruction between 0.5mm cuts and helical acquisition. Subsequently, the lung parenchyma was reviewed, extending the section thickness to 6-8 mm and using the MIP (maximum intensity projection) post-processing option to facilitate the rapid and accurate identification of lung nodules. Tomography scans have been systematically performed without contrast, unless there was a specific reason that requires it, such as involvement of the pleura, chest wall, or hilar or mediastinal lymphadenopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients under 18 years of age at the time of diagnosis with OS during a 10-year period (2013-2023) treated in our Pediatric Oncology Unit were selected. We excluded those patients with confirmed histological lung metastases detected by palpation during thoracotomy due to the absence of correlation by imaging.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study aimed to compare the radiological features from CT lung scans (calcification, size, location and shape) with the histological findings of surgically resected tumors in patients diagnosed with osteosarcoma-associated lung metastases. It will evaluate the efficacy of current radiological criteria in diagnosing and characterising pulmonary metastases in osteosarcoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInitially, the statistical significance of each variable's effect on the outcome was assessed. Fisher test was applied to analyse the frequency distribution of metastasis occurrence in relation to calcification (levels: No, Yes and Non-specific), size (levels: ≤0.5cm, 0.5-1cm and ≥1cm), location (levels: Peripheral, Central and Non-specific), and shape (levels: Non-specific, Round, Polygonal and Cissural). If significant differences were found, a post-hoc analysis was conducted using pairwise comparisons with Bonferroni correction. This approach enabled the determination of the association between these categorical variables and the outcome.\u003c/p\u003e\n\u003cp\u003eNext, a multivariate logistic regression was used to study the likelihood of metastasis occurrence, using calcification (reference level: No), size (reference level: ≤0.5 cm), location (reference level: Non-specific), and shape of tumor (reference level: Non-specific) as predictors. The Odds Ratio (OR), confidence intervals, and p-values associated with each coefficient (Wald test) were calculated. The most parsimonious model was chosen, by selecting as model predictors those variables that achieved a significance level of p\u0026lt;0.1 (marginally significant or significant) when all variables were used in the model.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using the statistical software R (version 4.2.3). A level of significance of p\u0026lt;0.05 was chosen as a significance threshold.\u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 116 nodules were identified by radiology as malignant and 33 patients with osteosarcoma were included in the study. At the time of diagnosis, 48% (16/33) of patients exhibited PN suggestive of malignancy on initial lung CT, while 52% (17/33) were considered as localised. Of those who initially had a CT lung scan without malignant PNs, 41% (7/17) had new lesions suggestive of malignancy during subsequent treatment and follow-up. Therefore, 69% (23/33) of all patients had PNs that met radiological criteria for malignancy at some point during follow-up period. The mean number of nodules per patient was 5.2, with a range of 1 to 18.\u0026nbsp;\u003cem\u003eFigure 1\u003c/em\u003e shows a CT scan with a PN suggestive of metastasis.\u003c/p\u003e\n\u003cp\u003eThe radiological characteristics of the PNs considered malignant by lung CT are shown in Table 1. Calcification was present in 59% (69/116). 84% (97/116) were less than or equal to 0.5 cm in size, 13% (15/116) were of medium size (0.5-1cm) and only 3% (4/116) were greater than or equal to 1 cm. 78% (90/116) were located peripherally, 6% (7/116) centrally and 16% (19/116) could not be adequately specified. In terms of shape, 23% (26/116) were rounded with well-defined borders, 11% (13/116) were cissural, 12% (14/116) were polygonal and 54% (63/116) could not be optimally determined due to their small size.\u003c/p\u003e\n\u003cp\u003eAll PNs that met radiological criteria for malignancy underwent resection surgery and histological study of the removed specimen. Pathology results showed that metastasis was confirmed by histology in only 49% (57/116) of the samples analysed (Table 2). In the remaining patients that did not show metastasis, histology showed lymphoid tissue, granulomas, intrapulmonary lymph nodes and hamartomas.\u003c/p\u003e\n\u003cp\u003eUnivariate analysis was performed to study the correlation of each of the radiological characteristics with the confirmation of metastasis by histology. Regarding calcification, Fisher test revealed a significant association between the frequency of metastasis and calcification. (p = 0.00004). Post-hoc analysis indicated that significant differences were found between the groups with and without calcification (p = 0.00009, Bonferroni correction for multiple comparisons).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the size of the nodules, metastasis was confirmed in 58% of those smaller than 0.5 cm, in 53% of those of medium size (0.5-1 cm) and in 50% of those larger than or equal to 1 cm. Fisher test did not reveal a significant association between the size of the nodule and metastasis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the location of the nodule, metastasis was confirmed in 52% of those at the peripheral level. No significant association between location and metastasis was found (Fisher test, p 0.38). With regard to the shape, Fisher's test showed statistical significance (p = 0.011). However, post-hoc pairwise analysis correcting for multiple comparisons using the Bonferroni correction did not reach significance level for any pair of shapes. These results of the univariate analysis are shown in \u003cem\u003etable 3.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA multivariate logistic regression model was fitted to explain the occurrence of metastasis using the following categorical variables calcification, size, location, and shape. Significant differences were observed only for the variable calcification (Wald test, p = 0.0008, comparing Yes to No as the reference level). To achieve a more parsimonious model, a logistic regression analysis was subsequently conducted using only the two variables that exhibited the most relevance (p \u0026lt; 0.1): calcification and shape. The results are shown in \u003cem\u003etable 4\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eThe OR for calcification (Yes) is 5.70, showing that the odds of metastasis are 5.70 times higher for tumors with calcification compared to those without, with statistical significance (p = 0.0004).\u0026nbsp;The OR for shape (Cissural) is 0.26, indicating a 74% reduction in the odds of metastasis for cissural shapes compared to Non-specific shapes, with marginal significance (p = 0.0703).\u003c/p\u003e\n\u003cp\u003eThe nomogram corresponding to this model is shown in Figure 2. Likelihood ratio test of the model was significant (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e26% (6/23) patients who had presented synchronous or metachronous PN suggestive of malignancy presented a pulmonary relapse that required a surgical reintervention. Of the total number of patients with OS (33), 54.5% (18/33) are currently alive without disease and 15.15% (5/33) are alive with disease. The percentage of deaths to date has been 30.3% (10/33). Of the total number of patients who did not survive, 70% had synchronous or metachronous pulmonary metastasis.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe detection of lung metastases in osteosarcoma is one of the predictive factors that most influence patient's prognosis. Therefore, having sensitive and specific radiological criteria is essential. According to the most recent European guidelines [13], a patient with pulmonary metastasis is defined as having three or more lesions greater than 5 mm in maximum diameter or any lesion greater than or equal to 1 centimetre. In addition, other guidelines such as the \u003cem\u003eSpanish Society of Paediatric Haematology and Oncology (SEHOP) 2011 metastatic guidelines\u003c/em\u003e also describe that there are features that may suggest its malignant nature, such as peripheral location, rounded shape with well-defined margins, bilaterality or calcification [8]. Furthermore, the guidelines also state that preoperative biopsies are not indicated if there is radiological suspicion of malignancy. [8,13].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on the literature, 10-20% of patients diagnosed with OS will have synchronous lung metastases (at diagnosis) and 40-55% will have metachronous lung metastases. In our cohort, the incidence of PN suggestive of malignancy on imaging was slightly higher (69%). This may be justified by the inevitable interobserver variability that may exist in detecting and interpreting smaller PNs. Furthermore, reducing the CT slice thickness to 1 mm increases the detection of lung nodules \u0026lt;5mm but also increases the number of false positives, which may also explain the highest incidence of PN suggestive of malignancy on imaging. This can lead to an increase in the rate of unnecessary surgical interventions (thoracotomies and thoracoscopies) with its associated comorbidities that may involve. Therefore, despite the great advantages of high-precision CT scans, it is advisable to take into account their possible associated drawbacks due to they can over-detect non-specific nodules that make us take unnecessary measures for the patient.\u003c/p\u003e\n\u003cp\u003eFurthermore, another fact that must be taken into account is the presence of PN in children without oncological pathology. \u003cem\u003eSamim et al\u0026nbsp;\u003c/em\u003econducted a study to evaluate the frequency and characteristics of pulmonary nodules on CT in healthy children, revealing that the presence of small pulmonary nodules is a common incidental finding in children without malignancy, with a prevalence of 38% [11]. These data are in line with those carried out by \u003cem\u003eRenne et al\u003c/em\u003e who in a pediatric trauma setting reported a prevalence of 33%. [14]. These findings are important to appropriately interpret the presence of pulmonary nodules in children with malignant tumors as osteosarcoma. In fact, the most recent European guidelines for the treatment of osteosarcoma [13] advocate performing fewer lung CT scans during patient follow-up if the patient has not previously had lung metastases and there is no clinical or radiographic suspicion of them, with the aim of reducing the detection of small non-specific nodules and lowering the rate of false positives.\u003c/p\u003e\n\u003cp\u003eHowever, in our study the positive predictive value was very low, with malignancy confirmed by pathological anatomy in only 49% of them. This result is similar than the results previously obtained in literature, with false positive rates ranging between 32 and 65% in children. [10,12,15-17]\u003c/p\u003e\n\u003cp\u003eThe choice of approach for the resection of the PN must be individualized. The advantages of thoracoscopy are smaller incisions, better pain control, and faster postoperative recovery. However, open thoracotomy has the advantage of being able to perform direct palpation of the lung and detect PNs that are not visible on imaging. Therefore, it is generally the gold standard in patients with OS. [18]. In our cohort the decision of approach was individualised according to the characteristics of the patient and the number and location of the PN. In all cases surgery was performed between primary tumour intervention and three weeks later. In our study we excluded those patients with confirmed histological lung metastases detected by palpation during thoracotomy due to the absence of correlation by imaging.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our cohort, in neither group did size show a significant correlation with confirmation of malignancy by histology. In other studies, such as \u003cem\u003eKaliff et al\u003c/em\u003e and \u003cem\u003eBrader et al\u003c/em\u003e, size did show a significant correlation although in each study the cut-off points differed, ranging from 5 mm to 12.5 mm [12,19]. The lack of significance in our work may be due to the few PNs present in our sample larger than 5 mm.\u003c/p\u003e\n\u003cp\u003eOf all the radiological criteria suggestive of malignancy, in our study only calcification presented a significant correlation with the confirmation of metastasis by histology. These results are contrary to those obtained in patients with primary tumours of other origin, where calcification has been considered a protective factor for the presence of metastasis [11,20]. This may be because the osteoid matrix produced by osteosarcoma may lead to calcification of these nodules. [12] To our knowledge, very few studies in the literature have previously presented PN calcification as an independent factor for malignancy [9,12] and only one study has been performed exclusively in the paediatric population [12]. Our results support the results obtained by \u003cem\u003eBrader et al\u003c/em\u003e and \u003cem\u003eCicarese et al\u003c/em\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the shape of the nodules, our cohort suggests that those with a cissural shape could have a certain protective tendency for the confirmation of metastasis, which is in line with what was previously described in the literature. Despite this, the results are not conclusive, so more studies should be done in this regard to confirm this fact.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eWe present the most extensive pediatric cohort of lung nodules in osteosarcoma. In our review, calcification is shown as the only radiological criterion that has a significant correlation with histological confirmation of metastasis. To our knowledge, only two previous studies had identified this finding as an independent predictor of malignancy [9,12], and only one had been conducted exclusively in a pediatric population [12]. Our study not only confirms this association in pediatric patients but also represents the largest cohort analyzed to date in this population. The significance of this finding lies in its potential to refine current diagnostic protocols, offering a more reliable tool for differentiating between benign and malignant pulmonary nodules in pediatric patients, ultimately leading to more tailored and less invasive treatment strategies.\u003c/p\u003e\n\u003cp\u003eWhile CT imaging is a highly sensitive tool for detecting pulmonary metastases, its specificity and positive predictive value remain limited. Despite the importance of using sensitive tests for identifying pulmonary metastases, given the impact of their resection on survival, the high false-positive rate observed in our cohort and in previously described studies suggests the need for refinement of radiological criteria. Misclassifying pulmonary nodules as malignant based solely on imaging studies may lead to more aggressive treatments, including higher-intensity chemotherapy protocols and invasive surgeries with associated risks, as well as significant psychological impact on the patient and their family. Therefore, optimizing radiological criteria is essential to improve diagnostic accuracy and reduce the false-positive rate.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eConflict of interest: The authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICAL STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn independent Ethics Committee granted ethical approval in accordance with the Helsinki declaration and the Good Clinical Practice guidelines (CPMP/ICH/135/95) for the whole research. Since this study was retrospective and consisted in clinical charts revisions, the ethics committee approved an informed consent exemption in its approval.\u0026nbsp;\u003c/p\u003e"},{"header":"REFERENCES","content":"\u003col\u003e\n\u003cli\u003eStrauss, S. J., Frezza, A. M., Abecassis, N., Bajpai, J., Bauer, S., Biagini, R. et al. ESMO Guidelines Committee, EURACAN, GENTURIS and ERN PaedCan. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology, 32(12), 1520\u0026ndash;1536. https://doi.org/10.1016/j.annonc.2021.08.1995\u003c/li\u003e\n\u003cli\u003eGatta G, Capocaccia R, Botta L, Mallone S, De Angelis R, Ardanaz E et al. Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol. 2017; 18: 1022-1039\u003c/li\u003e\n\u003cli\u003eDe Pinieux G, Karanian M, Le Loarer F, Le Guellec S, Chabaud S, Terrier P et al. Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network. PLoS One. 2021; 16 (e0246958)\u003c/li\u003e\n\u003cli\u003eFuchs B, Pritchard D. Etiology of osteosarcoma. Clin Orthop Relat es. 2002; 397: 40-52\u003c/li\u003e\n\u003cli\u003eAlburquerque J, Silva M, Marchiori E, Brandao V, Menna M. CT features of osteosarcoma lung metastasis: a retrospective study of 127 patients. J Bras Pneumol. 2023;49(2):e20220433 https://dx.doi.org/10.36416/1806-3756/e20220433\u003c/li\u003e\n\u003cli\u003eZhang C, Guo X, Xu Y, Han X, Cai J, Wang X, et al. Lung metastases at the initial diagnosis of high-grade osteosarcoma: prevalence, risk factors and prognostic factors. A large population-based cohort study. Sao Paulo Med J. 2019;137(5):423-429. https://doi. org/10.1590/1516-3180.2018.0381120619 \u003c/li\u003e\n\u003cli\u003eScanagatta P, Girelli L. Metastasectomy in pediatric patients: indications, technical tips and outcomes. J Thorac Dis 2017;9(Suppl 12):S1299-S1304 \u003c/li\u003e\n\u003cli\u003eEscobosa O, Gros L, Lassaleta A, M\u0026aacute;rquez C, Mata C, Pardo N et al. Protocolo de tratamiento del sarcoma osteog\u0026eacute;nico metast\u0026aacute;sico en ni\u0026ntilde;os y adolescentes. Sociedad Espa\u0026ntilde;ola de Hematolog\u0026iacute;a y Oncolog\u0026iacute;a Pedi\u0026aacute;tricas. 2011\u003c/li\u003e\n\u003cli\u003eCiccaresse F, Bazzocchib A, Ciminarib R, Righic A, Roccad M, Rimondib E et al. The many faces of pulmonary metastases of osteosarcoma: Retrospective study on 283 lesions submitted to surgery Eur J Radiol (2015), http://dx.doi.org/10.1016/j.ejrad.2015.09.022\u003c/li\u003e\n\u003cli\u003eCruz-Conde M; Gallego Herrero C, Rasero Ponferrada M, Alonso S\u0026aacute;nchez J, P\u0026eacute;rez Alonso V. Manejo pr\u0026aacute;ctico de los n\u0026oacute;dulos pulmonares en las neoplasias pedi\u0026aacute;tricas m\u0026aacute;s frecuentes. Radiol 63, 2021, 245-251c\u003c/li\u003e\n\u003cli\u003eSamim A, Littooij AS, van den Heuvel-Eibrink MM, Wessels FJ, Nievelstein RAJ, de Jong PA. Frequency and characteristics of pulmonary nodules in children at computed tomography. Pediatr Radiol. 2017;47, http://dx.doi.org/10.1007/s00247-017-3946-2, 1751.8. \u003c/li\u003e\n\u003cli\u003eBrader P, Abramson SJ, Price AP, Ishill NM, Zabor EC, Moskowitz CS, et al. Do characteristics of pulmonary nodules on computed tomography in children with known osteosarcoma help distinguish whether the nodules are malignant or benign? J Pediatr Surg. 2011;46(4):729-35. Erratum in: J Pediatr Surg. 2011;46(8):1685.\u003c/li\u003e\n\u003cli\u003eR van Ewijk, Dr. Nikolas Herold. European standard clinical practice recommendations for children and adolescents with primary and relapsed osteosarcoma. European standard-of-care guidelines for osteosarcoma. Version 1 2023-04-26.\u003c/li\u003e\n\u003cli\u003eRenne J, Linderkamp C, Wacker F, Berthold L, Weidemann J. Prevalence and configuration of pulmonary nodules on multi-row CT in children without malignant diseases. 2015. Eur Radiol 25:2651\u0026ndash;2656\u003c/li\u003e\n\u003cli\u003eMcCarville MB, Lederman HM, Santana VM, Daw N, Shochat S, Li CS et al. Distinguishing benign from malignant pulmonary nodules with helical chest CT in children with malignant solid tumors. 2006. Radiology 239:514\u0026ndash;520 6. \u003c/li\u003e\n\u003cli\u003eSilva CT, Amaral JG, Moineddin R, Moineddin R, Doda W, Babyn P. CT characteristics of lung nodules present at diagnosis of extrapulmonary malignancy in children. 2010. AJR Am J Roentgenol 194:772\u0026ndash;778 7. \u003c/li\u003e\n\u003cli\u003eAbsalon MJ, McCarville MB, Liu T, Santana V, Daw N, Navid F. Pulmonary nodules discovered during the initial evaluation of pediatric patients with bone and soft-tissue sarcoma. 2008. Pediatr Blood Cancer 50:1147\u0026ndash;1153 8. \u003c/li\u003e\n\u003cli\u003eHeaton TE, Hammond W, Farber B, Pallos V, Meyers P, Chou A et al. A 20-year retrospective analysis of CT-based pre-operative identification of pulmonary metastases in patients with osteosarcoma: J Pediatr Surg 2017 Jan;52(1):115-119.\u003c/li\u003e\n\u003cli\u003eKaliff A, Mendes F, Miranda M, De Sa Rodrigues K, Almeida B, Custodio P, et al. Pulmonary metastases in children: are we operating unnecessarily? Rev Col Bras Cir. 2018;45(3):e1129\u003c/li\u003e\n\u003cli\u003eMacMahon H, Austin JHM, Gamsu G, Herold C, Jett J, Naidich D et al. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner society. Radiology 2015. 237:395\u0026ndash;400\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Descriptive summary of radiological variables.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 401px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCT FEATURE\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRESULTS\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCalcification\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e69 (59,48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e42 (36,21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e5 (4,31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSize\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSize \u0026le; 0.5 cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e97 (83,62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSize 0,5-1 cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e15 (12,93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSize \u0026ge; 1 cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e4 (3,45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eLocation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePeripheral\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e90 (77,59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCentral\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e7 (6,03%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e19 (16,38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eShape\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRound\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e26 (22,41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCissural\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e13 (11,21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePolygonal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e14 (12,07%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 201px;\"\u003e\n \u003cp\u003e63 (54,31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. Pathological anatomy results of PNs suggestive of malignancy by CT.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 602px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eHistology confirms metastasis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e57 (49,14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e59 (50,86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Table 3. Results of univariate analysis relating each of the radiological characteristics to confirmation of metastasis by histology.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eFeature\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eConfirmation of metastasis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP value\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCalcification\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;46/69 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.00004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;20/42 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;2/5 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSize\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026le;0.5 cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;47/97 (58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.9185\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.5-1cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;8/15 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026ge; 1 cm\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;2/4 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eLocation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePeripheral\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;47/97 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.3809\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCentral\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;2/7 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;8/27 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eShape\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eRound\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;13/26 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.01156\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eCissural\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;3/14 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePolygonal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;3/13 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNon-specific\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;38/63 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4. Results of the final logistic regression model fitted to explain the occurrence of metastasis, including the coefficients, 95% confidence intervals (C.I.), OR, and p-values for each predictor in the model. p-values \u0026lt; 0.1 are indicated in bold.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003ePredictor\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eCoeficient\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;C.I. (95%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eOR\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e(intercept)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e-0.639\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[-1.5, 0.16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e-\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.1269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eCalcification: Yes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[0.80, 2.74]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e5.70\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0004\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eCalcification: Non-specific\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.461\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[-1.72, 2.47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e1.59\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.6509 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eShape: Round\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e-0.930\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[-1.97, 0.08]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.39\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0737\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eShape: Polygonal\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e-1.098\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[-2.76, 0.35]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.33\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.1539 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cem\u003eShape: Cissural\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e-1.357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e[-2.99, 0.03]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0703\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-radiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prad","sideBox":"Learn more about [Pediatric Radiology](http://link.springer.com/journal/247)","snPcode":"247","submissionUrl":"https://submission.nature.com/new-submission/247/3","title":"Pediatric Radiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Osteosarcoma, Radiotherapy, Magnetic Resonance Imaging, Pulmonary Nodules, Computed Tomography Scan, [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)-CT","lastPublishedDoi":"10.21203/rs.3.rs-7146838/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7146838/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePURPOSE: Osteosarcoma is the most common bone pediatric cancer with the lung being the primary site of metastasis. Chest CT is used to assess metastatic disease at diagnosis, classifying patients as localized or metastatic. Although there are radiological characteristics that suggest whether a lung nodule is metastatic, in daily practice nonspecific lesions on CT may complicate classification. Our objective is to compare radiological findings with the histology of lung nodules deemed malignant by CT and to review current radiological criteria.\u003c/p\u003e\n\u003cp\u003eMETHODS: A retrospective review was conducted of lung nodules in patients under 18 years old, diagnosed with osteosarcoma between 2014-2024 in a tertiary hospital. Radiological features, including calcification, size, shape, and location, were analyzed for their correlation with histological confirmation of metastasis.\u003c/p\u003e\n\u003cp\u003eRESULTS: 116 nodules were identified as malignant by radiology in 33 osteosarcoma patients. 69% of patients had pulmonary nodules that met radiological criteria for malignancy during follow-up. All underwent surgical resection, and histology confirmed metastasis in 49%. Only calcification showed a significant correlation with histological confirmation of metastasis.\u003c/p\u003e\n\u003cp\u003eCONCLUSIONS: CT imaging has an optimal sensitivity but low specificity for detecting lung metastases in osteosarcoma. However, we demonstrate that calcification is significantly correlated with histological confirmation of metastasis and may aid in confirming lung metastasis in osteosarcoma patients. Still furtherstudies are needed to refine radiological criteria to improve accuracy and reduce false positive rates.\u003c/p\u003e","manuscriptTitle":"Lung Nodules in Pediatric Osteosarcoma: Calcification as the Unique Radiological Criterion to Confirm Metastasis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-24 19:57:12","doi":"10.21203/rs.3.rs-7146838/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-29T06:28:11+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"85163073130009280468033451377010590680","date":"2025-07-28T15:03:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-24T09:03:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65723385391528644012022206810950745351","date":"2025-07-24T06:41:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-22T06:16:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-22T00:31:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-22T00:30:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Radiology","date":"2025-07-17T08:37:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-radiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prad","sideBox":"Learn more about [Pediatric Radiology](http://link.springer.com/journal/247)","snPcode":"247","submissionUrl":"https://submission.nature.com/new-submission/247/3","title":"Pediatric Radiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a1eea539-19d6-4c78-afae-4396e2046c8c","owner":[],"postedDate":"July 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:06:52+00:00","versionOfRecord":{"articleIdentity":"rs-7146838","link":"https://doi.org/10.1007/s00247-025-06410-3","journal":{"identity":"pediatric-radiology","isVorOnly":false,"title":"Pediatric Radiology"},"publishedOn":"2025-09-29 15:57:42","publishedOnDateReadable":"September 29th, 2025"},"versionCreatedAt":"2025-07-24 19:57:12","video":"","vorDoi":"10.1007/s00247-025-06410-3","vorDoiUrl":"https://doi.org/10.1007/s00247-025-06410-3","workflowStages":[]},"version":"v1","identity":"rs-7146838","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7146838","identity":"rs-7146838","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}