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The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone
Clinical Radiology xxx (xxxx) xxx
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The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone E. McLoughlin, A.M. Davies, A. Iqbal, S.L. James, R. Botchu* Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK
art icl e i nformat ion Article history: Received 13 August 2019 Accepted 13 November 2019
AIM: To provide a diagnostic approach to pulmonary nodules in patients with chondrosarcoma. MATERIALS AND METHODS: A search of the oncology database at a specialist orthopaedic oncology referral centre was performed to identify all patients who were treated surgically for chondrosarcoma between January 2007 and December 2018. Reports from the computed tomography (CT) examinations of the thorax of these patients were reviewed. In patients who had pulmonary nodules/metastases identified on CT, data on the primary chondrosarcoma and pulmonary nodule characteristics were collected. RESULTS: Twenty point two percent of patients had a pulmonary nodule identified on either initial or follow-up staging CT of the thorax, of which 8.1% were pulmonary metastases. Patients with grade 3 and dedifferentiated chondrosarcoma were more likely to have pulmonary metastases than patients with grade 1/2 chondrosarcoma. The time interval to developing metastases was shorter in patients with grade 2/3 and dedifferentiated chondrosarcoma versus patients with grade 1 chondrosarcoma. A low proportion of patients with grade 1 chondrosarcoma developed metastases (12.5%), all of which were identified at the time of a local recurrence. Nodules 10mm, nodules with lobulate margins, nodules containing irregular or subtle calcification, and nodules seen bilaterally or both centrally and peripherally were more likely to represent pulmonary metastases than benign nodules. CONCLUSION: The diagnostic significance of pulmonary nodules (i.e., whether they represent pulmonary metastases or not) can be predicted by taking into account a number of factors, in particular, the histological grade of the patient’s chondrosarcoma, the size and margins of the nodules, and the presence of subtle/irregular calcification. Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Chondrosarcoma is the third commonest primary bone malignancy in adults.1,2 Although metastases are uncommon in chondrosarcoma, the lungs are the most frequent
site and routine staging includes a computed tomography (CT) examination of the thorax to confirm/exclude pulmonary metastases at presentation or at follow-up, if the chest radiograph is abnormal.3 Challenges arise in the staging and treatment planning of chondrosarcoma, as in other malignancies, when
* Guarantor and correspondent: R. Botchu, Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital, Bristol Road South, Northfield, Birmingham, UK. Tel.: 0121 685 4000. E-mail address: [email protected] (R. Botchu). https://doi.org/10.1016/j.crad.2019.11.017 0009-9260/Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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pulmonary nodules of uncertain clinical significance (termed “indeterminate pulmonary nodules” [IPNs]) are detected at CT, which have some risk of metastatic disease.6e10 Although an IPN in a paediatric/young adult patient with bone sarcoma is unlikely to be benign, chondrosarcoma occurs in an older population (typically patients >40 years) where IPNs are more commonly seen and determining the diagnostic significance of IPNs in this cohort is particularly difficult. Surgery is the only treatment option for chondrosarcoma owing to the lack of response of chondrosarcoma to chemotherapy and radiotherapy.1,4,5 In order to determine the most appropriate surgical intervention, a number of factors including the histological grade, location, and size of the chondrosarcoma as well as the presence or absence of metastatic disease need to be considered.1 If an IPN is identified on the initial staging CT, this can have a significant impact on whether curative or palliative surgery is performed, as surgery must be undertaken promptly due to the lack of alternative treatment options. The diagnostic significance of pulmonary nodules in patients with chondrosarcoma and the optimal approach on how to interpret and monitor nodules, specifically IPNs, in this context is uncertain. The aim of this study was to provide a diagnostic approach to pulmonary nodules in patients with chondrosarcoma.
Materials and methods A search of the oncology database at the Royal Orthopaedic Hospital, a specialist orthopaedic oncology referral centre, was performed to identify all patients who were treated surgically for chondrosarcoma at the Royal Orthopaedic Hospital between January 2007 and December 2018. Patients who had their initial chondrosarcoma diagnosis prior to 2007, but had a restaging CT of the thorax after 2007 were also included. Local committee ethical approval was obtained to perform a retrospective review of the records and imaging of patients involved in the present study. Using the radiology information system (RIS), the original CT thorax reports of these patients were searched for two keywords “metastases” and “nodule” in order to identify the cohort of patients who had pulmonary nodules/ metastases identified on their initial staging or any followup CT. The images of these patients were then reviewed retrospectively in consensus by three of the authors. The CT section thickness ranged between 1 and 4 mm, depending on the year the examination was performed. Maximum intensity projection (MIP) lung window CT images were not reviewed in this study. The presence of pulmonary nodules and whether these were identified on initial staging or follow-up imaging was recorded. Follow-up CT was typically performed 3 months after the initial staging CT if any pulmonary nodules had been detected initially. Although the presence of calcification in a pulmonary nodule usually indicates a high probability that the lesion is benign, calcified chondrosarcoma metastases have been
reported previously.11,12 For the purposes of this study, an IPN was defined as a pulmonary nodule measuring <10 mm in long axis diameter, with or without calcification. An IPN was considered a metastatic nodule if there was evidence of progression in size or number on subsequent imaging. An IPN was deemed false positive for metastases if it resolved or remained static on subsequent imaging. Although the present study focused particularly on the diagnostic significance of pulmonary nodules measuring <10 mm (IPNs), all pulmonary nodules irrespective of size identified on CT were reviewed. The characteristics of each pulmonary nodule were analysed and data on parameters including size, number, margin, density, location, and distribution were collected. In patients with multiple pulmonary nodules, only the characteristics of the largest nodule were recorded. Data were also collected on patient demographics including age, sex, and presence of pre-existing conditions predisposing them to chondrosarcoma. The site of primary tumour, location (central versus peripheral) and histological grade of chondrosarcoma (grades 1e3 and dedifferentiated) was noted for each patient. The mean follow-up time was 60.2 months (range 3.6e227.1 months).
Results Four hundred and fifty-four patients were treated surgically for chondrosarcoma at Royal Orthopaedic Hospital between January 2007 and January 2019. Of these patients, ninety-two (20%) were found to have a pulmonary nodule on either initial or follow-up staging CT on retrospective review. Fourteen patients were excluded from the study due to lack of follow-up imaging, incomplete data, or death from another cause during the course of follow-up. Consequently, the imaging and records of 78 chondrosarcoma patients with pulmonary nodules were reviewed (Fig 1).
Patient demographics Sixty men (77%) and eighteen women (23%) were found to have pulmonary nodules. Pulmonary nodules were identified on initial CT of the thorax in 49 patients (63%) and on follow-up CT in 29 patients (37%). The average age of the patients with pulmonary nodules identified on CT was 56.9 years (range 23e83 years). The average age of patients who had pulmonary metastases was 57.1 years. Five patients (6.4%) had an underlying condition predisposing them to chondrosarcoma (four patients had Ollier disease and one patient had hereditary multiple exostoses [HME]).
Chondrosarcoma features Site Fifty-one patients (65%) had a central (medullary) chondrosarcoma whereas eighteen patients (23%) had a peripheral chondrosarcoma (i.e., arising in a pre-existing osteochondroma). The site of the primary chondrosarcoma could not be determined in nine patients (12%)
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 1 Graphic showing the breakdown of chondrosarcoma patients treated at Royal Orthopaedic Hospital between 2007e2017 by the presence or absence of pulmonary nodules on staging CT. Nodules were further categorised by size (<10 or 10 mm) and diagnostic significance (metastatic or non-metastatic).
as preoperative imaging of the bone tumour was not available for review.
Anatomical location Chondrosarcoma was grouped by anatomical location in decreasing order of frequency: Twenty patients (26%) had chondrosarcoma of a long bone of the lower limb (femur/ tibia), 19 patients (24%) had a pelvic chondrosarcoma, 11 patients (14%) had chondrosarcoma of the scapula, eight patients (10%) had chondrosarcoma in a long bone of the upper limb (humerus), seven patients (9%) had chondrosarcoma of the chest wall, seven patients had chondrosarcoma of a metacarpal (9%), five patients (7%) had chondrosarcoma of the spine/sacrum and one patient had a chondrosarcoma of the calcaneus (1%).
Grade The breakdown of patients with pulmonary nodules by the histological grade of their chondrosarcoma at presentation is shown in Fig 2 and Tables 1 and 2.
Pulmonary nodules (Tables 1e3) Size A total of 52 patients had IPNs (nodules <10 mm) of which 40 (77%) resolved or remained static on follow-up imaging and were considered false positives for metastases (benign). Of these false-positive nodules, 83% measured 5mm and 17% measured 6e9 mm. In contrast, 12 IPNs (23%) demonstrated an increase in size or number on subsequent imaging in keeping with pulmonary metastases.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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E. McLoughlin et al. / Clinical Radiology xxx (xxxx) xxx Table 2 Table of nodules 10 mm by histological grade and nodule characteristics. Nodules 10 mm (n¼ 26)
Figure 2 Pie chart demonstrating the breakdown of patients with pulmonary nodules by histological grade of chondrosarcoma at presentation: 24 patients (31%) had grade 1 chondrosarcoma, 30 patients (39%) had grade 2 chondrosarcoma, 15 patients (19%) had grade 3 chondrosarcoma, eight patients (10%) had dedifferentiated chondrosarcoma, and one patient (1%) had clear cell chondrosarcoma.
Table 1 Table of IPNs (nodules <10mm) by histological grade and nodule characteristics. Nodules <10 mm (IPN; n¼ 52)
Histological grade Grade 1 Grade 2 Grade 3 Dedifferentiated Clear cell Density Ground glass Solid Calcified Number Single Multiple Distribution Central Peripheral Both Location Unilateral Bilateral Margin Smooth Irregular Lobulate
Metastatic nodule (n¼12)
Non-metastatic nodule (n¼40)
2a 4 5 1 0
20 18 0 1 1
0 12 0
11 20 9
3 9
21 19
0 7 5
0 38 2
8 4
31 9
5 0 7
29 11 0
a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence with high grade (2/3) or dedifferentiated chondrosarcoma at time of recurrence.
A total of 26 patients had pulmonary nodules measuring 10 mm. Of these, 24 (92%) demonstrated an increase in size or number on subsequent imaging and were considered to be pulmonary metastases. By contrast, two (8%) resolved or remained static on follow-up imaging and were considered false positives for metastases.
Histological grade Grade 1 Grade 2 Grade 3 Dedifferentiated Other Density Ground glass Solid Calcified Number Single Multiple Distribution Central Peripheral Both Location Unilateral Bilateral Margin Smooth Irregular Lobulate
Metastatic nodule (n¼24)
Non-metastatic nodule (n¼2)
1a 8 9 6 0
1 0 1 0 0
1 19 4
1 1 0
6 18
2 0
1 11 12
0 2 0
8 16
2 0
4 1 19
0 2 0
a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence with grade 3 chondrosarcoma at time of recurrence.
Table 3 Breakdown of metastatic nodules by nodule characteristics. Nodule characteristics Number Single Multiple Size <10mm ¼/>10mm Density GG Solid Calcified Margin Smooth Irregular Lobulate Location Central Peripheral Both Distribution Unilateral Bilateral
Metastatic nodule (n ¼ 36) 9 27 12 24 1 31 4 9 1 26 1 18 17 16 20
Number In the 40 patients with IPNs that were false positives for metastases, a single nodule was noted in 52.5% and multiple nodules in 47.5%. In the 12 patients with IPNs that were found to be pulmonary metastases, a single nodule was identified in 25% and multiple nodules in 75% of patients.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Calcification Nine (17%) of the 52 IPNs identified were fully calcified, all of which remained static on follow-up imaging in keeping with benign granulomata. Four (15%) of the 26 nodules >10 mm were calcified and were all found to be pulmonary metastases. Of the 36 patients with pulmonary metastases, four patients (11%) had calcified pulmonary nodules, all of which measured >10 mm and had irregular or subtle calcification (Figs 3 and 4).
Margin
Figure 3 Cropped axial CT image of the thorax of a 61-year-old man demonstrating a lobulate, partially calcified pulmonary nodule in the right lower lobe. The nodule was identified 13 years after the initial diagnosis of grade 2 chondrosarcoma at the time of a local recurrence. Metastectomy was performed and histology confirmed a metastatic chondroid pulmonary nodule.
Similarly, in the 24 patients with nodules 10 mm that were found to be pulmonary metastases, a single nodule was identified in 25% and multiple nodules in 75% of patients. Of the 36 patients with pulmonary metastases, 25% of patients had a single nodule and 75% had multiple nodules.
Of the 40 IPNs that were false positives for metastases, the nodules had either smooth (72.5%) or irregular (27.5%) margins, but no lobulate margins. In contrast, of the 12 patients with IPNs that were subsequently deemed pulmonary metastases, the nodules had either smooth (42%) or lobulate (58%) margins, but no irregular margins. Of the 26 nodules 10 mm, the nodules that were found to be metastatic had lobulate (79%) or smooth margins (17%) predominately, whereas benign nodules had irregular margins (100%) only. Of the 36 patients with pulmonary metastases, 26 patients had nodules with lobulate margins (72%), nine had smooth margins (25%), and one patient had a nodule with irregular margins (3%).
Distribution In the 12 patients with IPNs that were found to be pulmonary metastases, the distribution of nodules was peripheral (42%) or both central and peripheral (58%). The distribution of IPNs that were false positives for metastases was predominately peripheral (95%). Of the 26 nodules 10 mm, the 24 nodules that were found to be metastatic were predominately found peripherally (46%) or both centrally and peripherally (51%), whereas the two benign nodules were found peripherally (100%).
Figure 4 Axial CT images of the thorax in a 72-year-old male with pulmonary metastases identified on CT 9 years after the initial diagnosis of grade 1 chondrosarcoma at the time of a local recurrence (dedifferentiated disease). Images show disease progression on interval CT performed 3 months apart: a new calcified nodule is seen medially in the right upper lobe (b) not previously seen in (a) and increase in size and calcification in the left upper nodule (d) when compared to (c). Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 5 Cropped axial CT images of the thorax, 4 months apart, of a 50-year-old man demonstrating a lobulate, pulmonary nodule (arrow) in the right lower lobe with no interval change. Patient remains disease free 7 years post-diagnosis.
Of the 36 patients with pulmonary metastases, the distribution of nodules was either peripheral (50%), both central and peripheral (47%) or central (3%; Figs 5e8).
Location In the 12 patients with IPNs that were deemed pulmonary metastases, the location of nodules was unilateral in 66% and bilateral in 33% of patients. The distribution of IPNs that were false positive for metastases was unilateral in 86% of patients and bilateral in 14% of patients. In the 24 patients with nodules 10 mm that were metastases, the nodules
were bilateral in 67% and unilateral in 33% whereas the two nodules that were benign were unilateral (100%). Of the 36 patients with pulmonary metastases, the location of nodules was unilateral in 44% of patients and bilateral in 56% of patients.
Grade The breakdown of IPNs and pulmonary nodules 10 mm as either benign or malignant by histological grade of chondrosarcoma is illustrated in Figs 9e11. Of note, 21 of the 24 patients (87.5%) with grade 1 chondrosarcoma had nodules that resolved or remained static on follow-up imaging. Only three patients with grade 1 disease (12.5%) had nodules that were found to be pulmonary metastases on subsequent imaging. In these cases, nodules were identified at the time of a local recurrence and the histological grade of the recurrence was grade 2/3 or dedifferentiated disease. In patients with pulmonary metastases identified on follow-up CT, the time to develop metastases decreased with increasing tumour grade: patients with grade 1 chondrosarcoma developed metastases an average of 82 months after diagnosis (all at the time of local recurrence), patients with grade 2 and 3 chondrosarcoma developed metastases after an average of 42 months, and patients with dedifferentiated chondrosarcomas developed pulmonary metastases after an average of 19 months (Tables 3 and 4).
Discussion
Figure 6 Cropped axial CT image of the thorax in a 54-year-old woman demonstrating a right fissure node (arrow). Patient remains disease free 5 years post-diagnosis.
Significant advances in CT technology in recent years have led to an increase in the number of pulmonary nodules detected at CT.13,14 The prevalence of non-calcified pulmonary nodules has been reported as 33% in a screening population of high-risk smokers in contrast to a prevalence of 13% in a non-screening population where nodules were found incidentally.15 Other studies investigating the prevalence of non-calcified pulmonary nodules in patients with
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 7 Cropped axial CT images of the thorax, 4 months apart, in a 60-year-old man demonstrating a lobulate, subpleural nodule (arrow) in the left lower lobe with no interval change. Patient remains disease free 9 years post-diagnosis.
extra-pulmonary malignancies have reported detection rates ranging from 13% to 75%.16,17 The significant variation in these results reflects the different CT section thickness with earlier studies (1991) using CT with 10 mm section
Figure 8 Cropped axial CT image of the thorax in a 58-year-old woman demonstrating an irregular, peripheral nodule (arrow) in the left lower lobe. Patient remains disease free 7 years post-diagnosis.
thickness and more recent studies (2016) using multidetector CT of 2 mm section thickness.16,17 In the present study, calcified/non-calcified pulmonary nodules were detected in 20.2% of patients with chondrosarcoma treated at Royal Orthopaedic Hospital between 2007e2018 using a CT machine with a section thickness between 1 and 4 mm. Previous studies have reported the incidence of pulmonary metastases in patients with chondrosarcoma to range between 5.3e32%.1,4,17e20 The present study found the incidence of pulmonary metastases to be 8.1%, at the lower range of what has been reported previously. This may reflect incomplete records at Royal Orthopaedic Hospital owing to the fact that patients with advanced disease initially seen at the centre may have had their subsequent follow-up at their local hospital. The present study focused on the diagnostic significance of pulmonary nodules identified on initial or follow-up staging CT in patients with chondrosarcoma. Although all pulmonary nodules were analysed, the particular focus was on IPNs (pulmonary nodules measuring <10 mm) as these nodules are more diagnostically challenging than larger nodules (10 mm). Previous studies have shown that the rate of metastasis in chondrosarcoma is related to histological tumour grade and that patients with high-grade tumours and local recurrence have been reported to be at high risk for metastasis.1,4,5,17,21 The present study yielded similar results: of the 8 patients with dedifferentiated chondrosarcoma who had pulmonary nodules, the nodules were found to be metastatic in 7 of these patients (87.5%). Of the 15 patients with grade 3 who had pulmonary nodules, the nodules were metastatic in 14 patients (93%). Of the 30 patients with grade 2 chondrosarcoma who had pulmonary nodules, the nodules were found to be metastatic in 12
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 9 Graph demonstrating the breakdown of the 52 pulmonary nodules <10 mm (IPNs) as either benign or metastatic by the histological grade of the primary chondrosarcoma.
patients (40%). Of the 24 patients with grade 1 chondrosarcoma at initial presentation, 3 patients had pulmonary nodules (two patients with IPNs and one patient with nodule >10 mm) that were found to be pulmonary metastases on subsequent imaging (12.5%). It is important to note that all of the metastatic pulmonary nodules in the patients with initially grade 1 disease were identified at the time of local recurrence, which was either grade 3 or dedifferentiated chondrosarcoma. The present results also found that in the seven patients with pulmonary metastases at diagnosis, all of these patients had high grade (grade
2/3 or dedifferentiated) chondrosarcoma. In patients who had metastases diagnosed on follow-up imaging, the rate of occurrence of metastases was related to the histological grade of the tumour, with dedifferentiated chondrosarcomas metastasising an average of 19 months after diagnosis, grade 2/3 metastasising 42 months after diagnosis and grade 1 metastasising an average of 82 months after initial diagnosis. In the present study, pulmonary nodule characteristics were found to be useful in predicting the likelihood of a nodule being metastatic or benign. The size of a pulmonary
Figure 10 Graph demonstrating the breakdown of the 26 nodules 10 mm as either benign or metastatic by the histological grade of the primary chondrosarcoma. Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 11 Graph showing breakdown of nature (benign or malignant) nodules by histological grade.
Table 4 Table of metastatic nodules identified on initial staging or follow-up CT by histological grade. Histological grade
Metastatic nodule (n¼36) At diagnosis
At follow-up
Grade 1a Grade 2 Grade 3 Dedifferentiated Other
0 3 2 2 0
3a 9 12 5 0
Average time to metastases (months) 82 (range: 52e123) 42 (range: 10e124) 42 (range 7e151) 19 (range 4.5e35) N/A
The average time to developing pulmonary metastases by histological grade is noted. a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence which was high grade (2/3) chondrosarcoma (two patients) or dedifferentiated chondrosarcoma (one patient) at the time of recurrence.
nodule was found to be useful with larger nodules more likely to be metastatic: of the 26 pulmonary nodules measuring >10 mm, 24 (92%) were found to be metastatic nodules. Of the 52 pulmonary nodules measuring <10 mm (IPNs), 40 (77%) showed no progression or resolved on subsequent imaging and were deemed false positives for metastases, 87% of these measured 5 mm. Therefore, IPNs measuring 5 mm are more likely to be benign than IPNs measuring >5 mm. Nodule margin was found to be useful in determining whether a nodule was significant. Nodules with lobulate margins were only seen in patients with pulmonary nodules that were metastatic. Nodules with irregular margins were seen predominately in the patients with IPNs that were found to be false positive for metastases apart from one patient with an irregular nodule who had metastases. Nodules with smooth margins were seen in patients with both benign and metastatic nodules and could not be used to differentiate between these entities reliably.
Nodule calcification was found useful in determining the diagnostic significance of pulmonary nodules. Calcified nodules were seen in 13 patients. Of these calcified nodules, nine were fully calcified, measured <10 mm, remained static on follow-up CT, and were considered false positives for metastases. Four patients had irregular/subtly calcified nodules measuring >10 mm and were found to be metastases. Therefore, a completely calcified nodule measuring <10 mm is likely to represent a benign granuloma and subtly/partially calcified nodule measuring >10 mm is more likely to represent a calcified metastatic nodule. The distribution of nodules was helpful in determining the significance of pulmonary nodules. Central nodules or nodules seen both centrally and peripherally were more likely to represent metastatic nodules. Peripheral nodules were seen in patients who had metastatic and benign nodules and were not a reliable discriminator. Bilateral pulmonary nodules were more likely to represent metastases than unilateral nodules. This study has a number of limitations including the retrospective nature, small sample size, and short duration of follow-up (minimum 3.2 months) in three patients. The cohort was small because the only treatment for chondrosarcoma is surgery as they do not respond to chemotherapy or radiotherapy. The reason surgery was stressed is that, unlike many of the American centres who provide a confirmatory diagnostic pathology service, Royal Orthopaedic Hospital is a treatment centre, so all the patients were seen for both diagnosis and treatment. In conclusion, as demonstrated in Table 5, the diagnostic significance of IPNs (i.e., whether they represent pulmonary metastases or not) can be predicted by taking into account a number of factors, in particular, the histological grade of the chondrosarcoma, the size and margin of the nodule, and the presence of subtle/irregular calcification. This will allow for appropriate treatment planning and monitoring of
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Table 5 Table summarising the factors that should be considered when determining the diagnostic significance of pulmonary nodules in patients with chondrosarcoma. Grade 1 chondrosarcoma is highly unlikely to the metastatic at diagnosis and the role of initial staging CT thorax in this cohort is questionable In the event of local recurrence of chondrosarcoma, patients are at increased risk of metastases and restaging CT thorax should be performed regardless of the initial grade of the primary tumour The likelihood of a nodule being metastatic in a patient with dedifferentiated or grade 3 chondrosarcoma is high and moderate in patients with grade 2 chondrosarcoma The average time to developing pulmonary metastases decreases with increasing tumour grade Pulmonary nodule Size Nodules 10 mm are more likely to represent pulmonary metastases than nodules <10 mm Nodules 5 mm are likely to be benign Number The presence of multiple nodules is more likely to represent pulmonary metastases than a single nodule Margin Lobulate nodules are more likely to represent metastatic nodules Irregular nodules are more likely to represent benign nodules Smooth margins are seen in both benign and metastatic nodules Calcification A subtly/irregularly calcified nodule 10 mm is most likely to represent a pulmonary metastasis in a patient with chondrosarcoma A fully calcified nodule <10 mm is most likely to represent a benign granuloma Location Bilateral nodules are more likely to represent pulmonary metastases than unilateral nodules Distribution Nodules in a central location or both central and peripheral are more likely to represent metastases Peripheral nodules are seen in both benign and metastatic disease
Chondrosarcoma
Grade
chondrosarcoma patients who have pulmonary nodules identified at staging CT.
Conflict of interest The authors declare no conflict of interest.
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Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone E. McLoughlin, A.M. Davies, A. Iqbal, S.L. James, R. Botchu* Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK
art icl e i nformat ion Article history: Received 13 August 2019 Accepted 13 November 2019
AIM: To provide a diagnostic approach to pulmonary nodules in patients with chondrosarcoma. MATERIALS AND METHODS: A search of the oncology database at a specialist orthopaedic oncology referral centre was performed to identify all patients who were treated surgically for chondrosarcoma between January 2007 and December 2018. Reports from the computed tomography (CT) examinations of the thorax of these patients were reviewed. In patients who had pulmonary nodules/metastases identified on CT, data on the primary chondrosarcoma and pulmonary nodule characteristics were collected. RESULTS: Twenty point two percent of patients had a pulmonary nodule identified on either initial or follow-up staging CT of the thorax, of which 8.1% were pulmonary metastases. Patients with grade 3 and dedifferentiated chondrosarcoma were more likely to have pulmonary metastases than patients with grade 1/2 chondrosarcoma. The time interval to developing metastases was shorter in patients with grade 2/3 and dedifferentiated chondrosarcoma versus patients with grade 1 chondrosarcoma. A low proportion of patients with grade 1 chondrosarcoma developed metastases (12.5%), all of which were identified at the time of a local recurrence. Nodules 10mm, nodules with lobulate margins, nodules containing irregular or subtle calcification, and nodules seen bilaterally or both centrally and peripherally were more likely to represent pulmonary metastases than benign nodules. CONCLUSION: The diagnostic significance of pulmonary nodules (i.e., whether they represent pulmonary metastases or not) can be predicted by taking into account a number of factors, in particular, the histological grade of the patient’s chondrosarcoma, the size and margins of the nodules, and the presence of subtle/irregular calcification. Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Chondrosarcoma is the third commonest primary bone malignancy in adults.1,2 Although metastases are uncommon in chondrosarcoma, the lungs are the most frequent
site and routine staging includes a computed tomography (CT) examination of the thorax to confirm/exclude pulmonary metastases at presentation or at follow-up, if the chest radiograph is abnormal.3 Challenges arise in the staging and treatment planning of chondrosarcoma, as in other malignancies, when
* Guarantor and correspondent: R. Botchu, Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital, Bristol Road South, Northfield, Birmingham, UK. Tel.: 0121 685 4000. E-mail address: [email protected] (R. Botchu). https://doi.org/10.1016/j.crad.2019.11.017 0009-9260/Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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pulmonary nodules of uncertain clinical significance (termed “indeterminate pulmonary nodules” [IPNs]) are detected at CT, which have some risk of metastatic disease.6e10 Although an IPN in a paediatric/young adult patient with bone sarcoma is unlikely to be benign, chondrosarcoma occurs in an older population (typically patients >40 years) where IPNs are more commonly seen and determining the diagnostic significance of IPNs in this cohort is particularly difficult. Surgery is the only treatment option for chondrosarcoma owing to the lack of response of chondrosarcoma to chemotherapy and radiotherapy.1,4,5 In order to determine the most appropriate surgical intervention, a number of factors including the histological grade, location, and size of the chondrosarcoma as well as the presence or absence of metastatic disease need to be considered.1 If an IPN is identified on the initial staging CT, this can have a significant impact on whether curative or palliative surgery is performed, as surgery must be undertaken promptly due to the lack of alternative treatment options. The diagnostic significance of pulmonary nodules in patients with chondrosarcoma and the optimal approach on how to interpret and monitor nodules, specifically IPNs, in this context is uncertain. The aim of this study was to provide a diagnostic approach to pulmonary nodules in patients with chondrosarcoma.
Materials and methods A search of the oncology database at the Royal Orthopaedic Hospital, a specialist orthopaedic oncology referral centre, was performed to identify all patients who were treated surgically for chondrosarcoma at the Royal Orthopaedic Hospital between January 2007 and December 2018. Patients who had their initial chondrosarcoma diagnosis prior to 2007, but had a restaging CT of the thorax after 2007 were also included. Local committee ethical approval was obtained to perform a retrospective review of the records and imaging of patients involved in the present study. Using the radiology information system (RIS), the original CT thorax reports of these patients were searched for two keywords “metastases” and “nodule” in order to identify the cohort of patients who had pulmonary nodules/ metastases identified on their initial staging or any followup CT. The images of these patients were then reviewed retrospectively in consensus by three of the authors. The CT section thickness ranged between 1 and 4 mm, depending on the year the examination was performed. Maximum intensity projection (MIP) lung window CT images were not reviewed in this study. The presence of pulmonary nodules and whether these were identified on initial staging or follow-up imaging was recorded. Follow-up CT was typically performed 3 months after the initial staging CT if any pulmonary nodules had been detected initially. Although the presence of calcification in a pulmonary nodule usually indicates a high probability that the lesion is benign, calcified chondrosarcoma metastases have been
reported previously.11,12 For the purposes of this study, an IPN was defined as a pulmonary nodule measuring <10 mm in long axis diameter, with or without calcification. An IPN was considered a metastatic nodule if there was evidence of progression in size or number on subsequent imaging. An IPN was deemed false positive for metastases if it resolved or remained static on subsequent imaging. Although the present study focused particularly on the diagnostic significance of pulmonary nodules measuring <10 mm (IPNs), all pulmonary nodules irrespective of size identified on CT were reviewed. The characteristics of each pulmonary nodule were analysed and data on parameters including size, number, margin, density, location, and distribution were collected. In patients with multiple pulmonary nodules, only the characteristics of the largest nodule were recorded. Data were also collected on patient demographics including age, sex, and presence of pre-existing conditions predisposing them to chondrosarcoma. The site of primary tumour, location (central versus peripheral) and histological grade of chondrosarcoma (grades 1e3 and dedifferentiated) was noted for each patient. The mean follow-up time was 60.2 months (range 3.6e227.1 months).
Results Four hundred and fifty-four patients were treated surgically for chondrosarcoma at Royal Orthopaedic Hospital between January 2007 and January 2019. Of these patients, ninety-two (20%) were found to have a pulmonary nodule on either initial or follow-up staging CT on retrospective review. Fourteen patients were excluded from the study due to lack of follow-up imaging, incomplete data, or death from another cause during the course of follow-up. Consequently, the imaging and records of 78 chondrosarcoma patients with pulmonary nodules were reviewed (Fig 1).
Patient demographics Sixty men (77%) and eighteen women (23%) were found to have pulmonary nodules. Pulmonary nodules were identified on initial CT of the thorax in 49 patients (63%) and on follow-up CT in 29 patients (37%). The average age of the patients with pulmonary nodules identified on CT was 56.9 years (range 23e83 years). The average age of patients who had pulmonary metastases was 57.1 years. Five patients (6.4%) had an underlying condition predisposing them to chondrosarcoma (four patients had Ollier disease and one patient had hereditary multiple exostoses [HME]).
Chondrosarcoma features Site Fifty-one patients (65%) had a central (medullary) chondrosarcoma whereas eighteen patients (23%) had a peripheral chondrosarcoma (i.e., arising in a pre-existing osteochondroma). The site of the primary chondrosarcoma could not be determined in nine patients (12%)
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 1 Graphic showing the breakdown of chondrosarcoma patients treated at Royal Orthopaedic Hospital between 2007e2017 by the presence or absence of pulmonary nodules on staging CT. Nodules were further categorised by size (<10 or 10 mm) and diagnostic significance (metastatic or non-metastatic).
as preoperative imaging of the bone tumour was not available for review.
Anatomical location Chondrosarcoma was grouped by anatomical location in decreasing order of frequency: Twenty patients (26%) had chondrosarcoma of a long bone of the lower limb (femur/ tibia), 19 patients (24%) had a pelvic chondrosarcoma, 11 patients (14%) had chondrosarcoma of the scapula, eight patients (10%) had chondrosarcoma in a long bone of the upper limb (humerus), seven patients (9%) had chondrosarcoma of the chest wall, seven patients had chondrosarcoma of a metacarpal (9%), five patients (7%) had chondrosarcoma of the spine/sacrum and one patient had a chondrosarcoma of the calcaneus (1%).
Grade The breakdown of patients with pulmonary nodules by the histological grade of their chondrosarcoma at presentation is shown in Fig 2 and Tables 1 and 2.
Pulmonary nodules (Tables 1e3) Size A total of 52 patients had IPNs (nodules <10 mm) of which 40 (77%) resolved or remained static on follow-up imaging and were considered false positives for metastases (benign). Of these false-positive nodules, 83% measured 5mm and 17% measured 6e9 mm. In contrast, 12 IPNs (23%) demonstrated an increase in size or number on subsequent imaging in keeping with pulmonary metastases.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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E. McLoughlin et al. / Clinical Radiology xxx (xxxx) xxx Table 2 Table of nodules 10 mm by histological grade and nodule characteristics. Nodules 10 mm (n¼ 26)
Figure 2 Pie chart demonstrating the breakdown of patients with pulmonary nodules by histological grade of chondrosarcoma at presentation: 24 patients (31%) had grade 1 chondrosarcoma, 30 patients (39%) had grade 2 chondrosarcoma, 15 patients (19%) had grade 3 chondrosarcoma, eight patients (10%) had dedifferentiated chondrosarcoma, and one patient (1%) had clear cell chondrosarcoma.
Table 1 Table of IPNs (nodules <10mm) by histological grade and nodule characteristics. Nodules <10 mm (IPN; n¼ 52)
Histological grade Grade 1 Grade 2 Grade 3 Dedifferentiated Clear cell Density Ground glass Solid Calcified Number Single Multiple Distribution Central Peripheral Both Location Unilateral Bilateral Margin Smooth Irregular Lobulate
Metastatic nodule (n¼12)
Non-metastatic nodule (n¼40)
2a 4 5 1 0
20 18 0 1 1
0 12 0
11 20 9
3 9
21 19
0 7 5
0 38 2
8 4
31 9
5 0 7
29 11 0
a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence with high grade (2/3) or dedifferentiated chondrosarcoma at time of recurrence.
A total of 26 patients had pulmonary nodules measuring 10 mm. Of these, 24 (92%) demonstrated an increase in size or number on subsequent imaging and were considered to be pulmonary metastases. By contrast, two (8%) resolved or remained static on follow-up imaging and were considered false positives for metastases.
Histological grade Grade 1 Grade 2 Grade 3 Dedifferentiated Other Density Ground glass Solid Calcified Number Single Multiple Distribution Central Peripheral Both Location Unilateral Bilateral Margin Smooth Irregular Lobulate
Metastatic nodule (n¼24)
Non-metastatic nodule (n¼2)
1a 8 9 6 0
1 0 1 0 0
1 19 4
1 1 0
6 18
2 0
1 11 12
0 2 0
8 16
2 0
4 1 19
0 2 0
a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence with grade 3 chondrosarcoma at time of recurrence.
Table 3 Breakdown of metastatic nodules by nodule characteristics. Nodule characteristics Number Single Multiple Size <10mm ¼/>10mm Density GG Solid Calcified Margin Smooth Irregular Lobulate Location Central Peripheral Both Distribution Unilateral Bilateral
Metastatic nodule (n ¼ 36) 9 27 12 24 1 31 4 9 1 26 1 18 17 16 20
Number In the 40 patients with IPNs that were false positives for metastases, a single nodule was noted in 52.5% and multiple nodules in 47.5%. In the 12 patients with IPNs that were found to be pulmonary metastases, a single nodule was identified in 25% and multiple nodules in 75% of patients.
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Calcification Nine (17%) of the 52 IPNs identified were fully calcified, all of which remained static on follow-up imaging in keeping with benign granulomata. Four (15%) of the 26 nodules >10 mm were calcified and were all found to be pulmonary metastases. Of the 36 patients with pulmonary metastases, four patients (11%) had calcified pulmonary nodules, all of which measured >10 mm and had irregular or subtle calcification (Figs 3 and 4).
Margin
Figure 3 Cropped axial CT image of the thorax of a 61-year-old man demonstrating a lobulate, partially calcified pulmonary nodule in the right lower lobe. The nodule was identified 13 years after the initial diagnosis of grade 2 chondrosarcoma at the time of a local recurrence. Metastectomy was performed and histology confirmed a metastatic chondroid pulmonary nodule.
Similarly, in the 24 patients with nodules 10 mm that were found to be pulmonary metastases, a single nodule was identified in 25% and multiple nodules in 75% of patients. Of the 36 patients with pulmonary metastases, 25% of patients had a single nodule and 75% had multiple nodules.
Of the 40 IPNs that were false positives for metastases, the nodules had either smooth (72.5%) or irregular (27.5%) margins, but no lobulate margins. In contrast, of the 12 patients with IPNs that were subsequently deemed pulmonary metastases, the nodules had either smooth (42%) or lobulate (58%) margins, but no irregular margins. Of the 26 nodules 10 mm, the nodules that were found to be metastatic had lobulate (79%) or smooth margins (17%) predominately, whereas benign nodules had irregular margins (100%) only. Of the 36 patients with pulmonary metastases, 26 patients had nodules with lobulate margins (72%), nine had smooth margins (25%), and one patient had a nodule with irregular margins (3%).
Distribution In the 12 patients with IPNs that were found to be pulmonary metastases, the distribution of nodules was peripheral (42%) or both central and peripheral (58%). The distribution of IPNs that were false positives for metastases was predominately peripheral (95%). Of the 26 nodules 10 mm, the 24 nodules that were found to be metastatic were predominately found peripherally (46%) or both centrally and peripherally (51%), whereas the two benign nodules were found peripherally (100%).
Figure 4 Axial CT images of the thorax in a 72-year-old male with pulmonary metastases identified on CT 9 years after the initial diagnosis of grade 1 chondrosarcoma at the time of a local recurrence (dedifferentiated disease). Images show disease progression on interval CT performed 3 months apart: a new calcified nodule is seen medially in the right upper lobe (b) not previously seen in (a) and increase in size and calcification in the left upper nodule (d) when compared to (c). Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 5 Cropped axial CT images of the thorax, 4 months apart, of a 50-year-old man demonstrating a lobulate, pulmonary nodule (arrow) in the right lower lobe with no interval change. Patient remains disease free 7 years post-diagnosis.
Of the 36 patients with pulmonary metastases, the distribution of nodules was either peripheral (50%), both central and peripheral (47%) or central (3%; Figs 5e8).
Location In the 12 patients with IPNs that were deemed pulmonary metastases, the location of nodules was unilateral in 66% and bilateral in 33% of patients. The distribution of IPNs that were false positive for metastases was unilateral in 86% of patients and bilateral in 14% of patients. In the 24 patients with nodules 10 mm that were metastases, the nodules
were bilateral in 67% and unilateral in 33% whereas the two nodules that were benign were unilateral (100%). Of the 36 patients with pulmonary metastases, the location of nodules was unilateral in 44% of patients and bilateral in 56% of patients.
Grade The breakdown of IPNs and pulmonary nodules 10 mm as either benign or malignant by histological grade of chondrosarcoma is illustrated in Figs 9e11. Of note, 21 of the 24 patients (87.5%) with grade 1 chondrosarcoma had nodules that resolved or remained static on follow-up imaging. Only three patients with grade 1 disease (12.5%) had nodules that were found to be pulmonary metastases on subsequent imaging. In these cases, nodules were identified at the time of a local recurrence and the histological grade of the recurrence was grade 2/3 or dedifferentiated disease. In patients with pulmonary metastases identified on follow-up CT, the time to develop metastases decreased with increasing tumour grade: patients with grade 1 chondrosarcoma developed metastases an average of 82 months after diagnosis (all at the time of local recurrence), patients with grade 2 and 3 chondrosarcoma developed metastases after an average of 42 months, and patients with dedifferentiated chondrosarcomas developed pulmonary metastases after an average of 19 months (Tables 3 and 4).
Discussion
Figure 6 Cropped axial CT image of the thorax in a 54-year-old woman demonstrating a right fissure node (arrow). Patient remains disease free 5 years post-diagnosis.
Significant advances in CT technology in recent years have led to an increase in the number of pulmonary nodules detected at CT.13,14 The prevalence of non-calcified pulmonary nodules has been reported as 33% in a screening population of high-risk smokers in contrast to a prevalence of 13% in a non-screening population where nodules were found incidentally.15 Other studies investigating the prevalence of non-calcified pulmonary nodules in patients with
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 7 Cropped axial CT images of the thorax, 4 months apart, in a 60-year-old man demonstrating a lobulate, subpleural nodule (arrow) in the left lower lobe with no interval change. Patient remains disease free 9 years post-diagnosis.
extra-pulmonary malignancies have reported detection rates ranging from 13% to 75%.16,17 The significant variation in these results reflects the different CT section thickness with earlier studies (1991) using CT with 10 mm section
Figure 8 Cropped axial CT image of the thorax in a 58-year-old woman demonstrating an irregular, peripheral nodule (arrow) in the left lower lobe. Patient remains disease free 7 years post-diagnosis.
thickness and more recent studies (2016) using multidetector CT of 2 mm section thickness.16,17 In the present study, calcified/non-calcified pulmonary nodules were detected in 20.2% of patients with chondrosarcoma treated at Royal Orthopaedic Hospital between 2007e2018 using a CT machine with a section thickness between 1 and 4 mm. Previous studies have reported the incidence of pulmonary metastases in patients with chondrosarcoma to range between 5.3e32%.1,4,17e20 The present study found the incidence of pulmonary metastases to be 8.1%, at the lower range of what has been reported previously. This may reflect incomplete records at Royal Orthopaedic Hospital owing to the fact that patients with advanced disease initially seen at the centre may have had their subsequent follow-up at their local hospital. The present study focused on the diagnostic significance of pulmonary nodules identified on initial or follow-up staging CT in patients with chondrosarcoma. Although all pulmonary nodules were analysed, the particular focus was on IPNs (pulmonary nodules measuring <10 mm) as these nodules are more diagnostically challenging than larger nodules (10 mm). Previous studies have shown that the rate of metastasis in chondrosarcoma is related to histological tumour grade and that patients with high-grade tumours and local recurrence have been reported to be at high risk for metastasis.1,4,5,17,21 The present study yielded similar results: of the 8 patients with dedifferentiated chondrosarcoma who had pulmonary nodules, the nodules were found to be metastatic in 7 of these patients (87.5%). Of the 15 patients with grade 3 who had pulmonary nodules, the nodules were metastatic in 14 patients (93%). Of the 30 patients with grade 2 chondrosarcoma who had pulmonary nodules, the nodules were found to be metastatic in 12
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 9 Graph demonstrating the breakdown of the 52 pulmonary nodules <10 mm (IPNs) as either benign or metastatic by the histological grade of the primary chondrosarcoma.
patients (40%). Of the 24 patients with grade 1 chondrosarcoma at initial presentation, 3 patients had pulmonary nodules (two patients with IPNs and one patient with nodule >10 mm) that were found to be pulmonary metastases on subsequent imaging (12.5%). It is important to note that all of the metastatic pulmonary nodules in the patients with initially grade 1 disease were identified at the time of local recurrence, which was either grade 3 or dedifferentiated chondrosarcoma. The present results also found that in the seven patients with pulmonary metastases at diagnosis, all of these patients had high grade (grade
2/3 or dedifferentiated) chondrosarcoma. In patients who had metastases diagnosed on follow-up imaging, the rate of occurrence of metastases was related to the histological grade of the tumour, with dedifferentiated chondrosarcomas metastasising an average of 19 months after diagnosis, grade 2/3 metastasising 42 months after diagnosis and grade 1 metastasising an average of 82 months after initial diagnosis. In the present study, pulmonary nodule characteristics were found to be useful in predicting the likelihood of a nodule being metastatic or benign. The size of a pulmonary
Figure 10 Graph demonstrating the breakdown of the 26 nodules 10 mm as either benign or metastatic by the histological grade of the primary chondrosarcoma. Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Figure 11 Graph showing breakdown of nature (benign or malignant) nodules by histological grade.
Table 4 Table of metastatic nodules identified on initial staging or follow-up CT by histological grade. Histological grade
Metastatic nodule (n¼36) At diagnosis
At follow-up
Grade 1a Grade 2 Grade 3 Dedifferentiated Other
0 3 2 2 0
3a 9 12 5 0
Average time to metastases (months) 82 (range: 52e123) 42 (range: 10e124) 42 (range 7e151) 19 (range 4.5e35) N/A
The average time to developing pulmonary metastases by histological grade is noted. a Grade 1 chondrosarcoma at presentation with pulmonary metastases occurring at the time of local recurrence which was high grade (2/3) chondrosarcoma (two patients) or dedifferentiated chondrosarcoma (one patient) at the time of recurrence.
nodule was found to be useful with larger nodules more likely to be metastatic: of the 26 pulmonary nodules measuring >10 mm, 24 (92%) were found to be metastatic nodules. Of the 52 pulmonary nodules measuring <10 mm (IPNs), 40 (77%) showed no progression or resolved on subsequent imaging and were deemed false positives for metastases, 87% of these measured 5 mm. Therefore, IPNs measuring 5 mm are more likely to be benign than IPNs measuring >5 mm. Nodule margin was found to be useful in determining whether a nodule was significant. Nodules with lobulate margins were only seen in patients with pulmonary nodules that were metastatic. Nodules with irregular margins were seen predominately in the patients with IPNs that were found to be false positive for metastases apart from one patient with an irregular nodule who had metastases. Nodules with smooth margins were seen in patients with both benign and metastatic nodules and could not be used to differentiate between these entities reliably.
Nodule calcification was found useful in determining the diagnostic significance of pulmonary nodules. Calcified nodules were seen in 13 patients. Of these calcified nodules, nine were fully calcified, measured <10 mm, remained static on follow-up CT, and were considered false positives for metastases. Four patients had irregular/subtly calcified nodules measuring >10 mm and were found to be metastases. Therefore, a completely calcified nodule measuring <10 mm is likely to represent a benign granuloma and subtly/partially calcified nodule measuring >10 mm is more likely to represent a calcified metastatic nodule. The distribution of nodules was helpful in determining the significance of pulmonary nodules. Central nodules or nodules seen both centrally and peripherally were more likely to represent metastatic nodules. Peripheral nodules were seen in patients who had metastatic and benign nodules and were not a reliable discriminator. Bilateral pulmonary nodules were more likely to represent metastases than unilateral nodules. This study has a number of limitations including the retrospective nature, small sample size, and short duration of follow-up (minimum 3.2 months) in three patients. The cohort was small because the only treatment for chondrosarcoma is surgery as they do not respond to chemotherapy or radiotherapy. The reason surgery was stressed is that, unlike many of the American centres who provide a confirmatory diagnostic pathology service, Royal Orthopaedic Hospital is a treatment centre, so all the patients were seen for both diagnosis and treatment. In conclusion, as demonstrated in Table 5, the diagnostic significance of IPNs (i.e., whether they represent pulmonary metastases or not) can be predicted by taking into account a number of factors, in particular, the histological grade of the chondrosarcoma, the size and margin of the nodule, and the presence of subtle/irregular calcification. This will allow for appropriate treatment planning and monitoring of
Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017
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Table 5 Table summarising the factors that should be considered when determining the diagnostic significance of pulmonary nodules in patients with chondrosarcoma. Grade 1 chondrosarcoma is highly unlikely to the metastatic at diagnosis and the role of initial staging CT thorax in this cohort is questionable In the event of local recurrence of chondrosarcoma, patients are at increased risk of metastases and restaging CT thorax should be performed regardless of the initial grade of the primary tumour The likelihood of a nodule being metastatic in a patient with dedifferentiated or grade 3 chondrosarcoma is high and moderate in patients with grade 2 chondrosarcoma The average time to developing pulmonary metastases decreases with increasing tumour grade Pulmonary nodule Size Nodules 10 mm are more likely to represent pulmonary metastases than nodules <10 mm Nodules 5 mm are likely to be benign Number The presence of multiple nodules is more likely to represent pulmonary metastases than a single nodule Margin Lobulate nodules are more likely to represent metastatic nodules Irregular nodules are more likely to represent benign nodules Smooth margins are seen in both benign and metastatic nodules Calcification A subtly/irregularly calcified nodule 10 mm is most likely to represent a pulmonary metastasis in a patient with chondrosarcoma A fully calcified nodule <10 mm is most likely to represent a benign granuloma Location Bilateral nodules are more likely to represent pulmonary metastases than unilateral nodules Distribution Nodules in a central location or both central and peripheral are more likely to represent metastases Peripheral nodules are seen in both benign and metastatic disease
Chondrosarcoma
Grade
chondrosarcoma patients who have pulmonary nodules identified at staging CT.
Conflict of interest The authors declare no conflict of interest.
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Please cite this article as: McLoughlin E et al., The diagnostic significance of pulmonary nodules on CT thorax in chondrosarcoma of bone, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.017