How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma?

Abstract

Background Pulmonary metastases are a poor prognostic factor in patients with osteosarcoma; however, the clinical significance of subcentimeter lung nodules and whether they represent a tumor is not fully known. Because the clinician is faced with decisions regarding biopsy, resection, or observation of lung nodules and the potential impact they have on decisions about resection of the primary tumor, this remains an area of uncertainty in patient treatment. Surgical management of the primary tumor is tailored to prognosis, and it is unclear how aggressively patients with indeterminate pulmonary nodules (IPNs), defined as nodules smaller than 1 cm at presentation, should be treated. There is a clear need to better understand the clinical importance of these nodules. Questions/purposes (1) What percentage of patients with high-grade osteosarcoma and spindle cell sarcoma of bone have IPNs at diagnosis? (2) Are IPNs at diagnosis associated with worse metastasis-free and overall survival? (3) Are there any clinical or radiologic factors associated with worse overall survival in patients with IPN? Methods Between 2008 and 2016, 484 patients with a first presentation of osteosarcoma or spindle cell sarcoma of bone were retrospectively identified from an institutional database. Patients with the following were excluded: treatment at another institution (6%, 27 of 484), death related to complications of neoadjuvant chemotherapy (1%, 3 of 484), Grade 1 or 2 on final pathology (4%, 21 of 484) and lack of staging chest CT available for review (0.4%, 2 of 484). All patients with abnormalities on their staging chest CT underwent imaging re-review by a senior radiology consultant and were divided into three groups for comparison: no metastases (70%, 302 of 431), IPN (16%, 68 of 431), and metastases (14%, 61 of 431) at the time of diagnosis. A random subset of CT scans was reviewed by a senior radiology registrar and there was very good agreement between the two reviewers (κ = 0.88). Demographic and oncologic variables as well as treatment details and clinical course were gleaned from a longitudinally maintained institutional database. The three groups did not differ with regard to age, gender, subtype, presence of pathological fracture, tumor site, or chemotherapy-induced necrosis. They differed according to local control strategy and tumor size, with a larger proportion of patients in the metastases group presenting with larger tumor size and undergoing nonoperative treatment. There was no differential loss to follow-up among the three groups. Two percent (6 of 302) of patients with no metastases, no patients with IPN, and 2% (1 of 61) of patients with metastases were lost to follow-up at 1 year postdiagnosis but were not known to have died. Individual treatment decisions were determined as part of a multidisciplinary conference, but in general, patients without obvious metastases received (neo)adjuvant chemotherapy and surgical resection for local control. Patients in the no metastases and IPN groups did not differ in local control strategy. For patients in the IPN group, staging CT images were inspected for IPN characteristics including number, distribution, size, location, presence of mineralization, and shape. Subsequent chest CT images were examined by the same radiologist to reevaluate known nodules for interval change in size and to identify the presence of new nodules. A random subset of chest CT scans were re-reviewed by a senior radiology resident (κ = 0.62). The association of demographic and oncologic variables with metastasis-free and overall survival was first explored using the Kaplan-Meier method (log-rank test) in univariable analyses. All variables that were statistically significant (p < 0.05) in univariable analyses were entered into Cox regression multivariable analyses. Results Following re-review of staging chest CTs, IPNs were found in 16% (68 of 431) of patients, while an additional 14% (61 of 431) of patients had lung metastases (parenchymal nodules 10 mm or larger). After controlling for potential confounding variables like local control strategy, tumor size, and chemotherapy-induced necrosis, we found that the presence of an IPN was associated with worse overall survival and a higher incidence of metastases (hazard ratio 1.9 [95% CI 1.3 to 2.8]; p = 0.001 and HR 3.6 [95% CI 2.5 to 5.2]; p < 0.001, respectively). Two-year overall survival for patients with no metastases, IPN, or metastases was 83% [95% CI 78 to 87], 65% [95% CI 52 to 75] and 45% [95% CI 32 to 57], respectively (p = 0.001). In 74% (50 of 68) of patients with IPNs, it became apparent that they were true metastatic lesions at a median of 5.3 months. Eighty-six percent (43 of 50) of these patients had disease progression by 2 years after diagnosis. In multivariable analysis, local control strategy and tumor subtype correlated with overall survival for patients with IPNs. Patients who were treated nonoperatively and who had a secondary sarcoma had worse outcomes (HR 3.6 [95% CI 1.5 to 8.3]; p = 0.003 and HR 3.4 [95% CI 1.1 to 10.0]; p = 0.03). The presence of nodule mineralization was associated with improved overall survival in the univariable analysis (87% [95% CI 39 to 98] versus 57% [95% CI 43 to 69]; p = 0.008), however, because we could not control for other factors in a multivariable analysis, the relationship between mineralization and survival could not be determined. We were unable to detect an association between any other nodule radiologic features and survival. Conclusion The findings show that the presence of IPNs at diagnosis is associated with poorer survival of affected patients compared with those with normal staging chest CTs. IPNs noted at presentation in patients with high-grade osteosarcoma and spindle cell sarcoma of bone should be discussed with the patient and be considered when making treatment decisions. Further work is required to elucidate how the nodules should be managed. Level of Evidence Level III, prognostic study.

Indeterminate pulmonary nodules are not associated with worse overall survival in Ewing Sarcoma

“…First, as was noted by Raciborska et al, the presence of multiple bilateral IPN greater than 3 mm in diameter is suggestive of malignancy. Second, as opposed to findings in our prior study on osteosarcoma, 18 metastatic disease is just as likely to develop in extra-pulmonary as in pulmonary sites. Finally, also in contrast to findings in osteosarcoma where IPN growth following neoadjuvant chemotherapy is a poor prognostic factor, this study suggests that in Ewing sarcoma, IPN improvement on chemotherapy reflects a malignant nodule.…”

“…17 This approach was utilized during our previous study on osteosarcoma. 18 First, thin (1 mm) and thick (5 mm) slices in the lung window were screened to identify suspicious nodules. Second, if the nodule was absent on the maximum intensity projection (MIP), it was removed from consideration.…”

“…We recently demonstrated that 16% of patients with highgrade osteosarcoma and spindle cell sarcoma of bone have IPN on diagnosis and that their overall survival is worse than those with negative staging chest CTs. 8 The rate and prognostic significant of IPN in Ewing sarcoma is unknown but has important treatment implications. Ewing sarcoma is typically treated with neoadjuvant chemotherapy, en-bloc surgical excision of the tumour followed by adjuvant chemotherapy.…”

Clinical significance of indeterminate pulmonary nodules on the survival of 364 patients with nonmetastatic, high‐grade, localized osteosarcoma: A 12‐year retrospective cohort study

“…Studies have reported improved outcomes in patients with osteosarcoma with a lower number of resectable pulmonary metastases 5,20 . However, Kim et al 21 observed that patients with IPNs at the time of diagnosis had poorer survival rates than those without chest CT abnormalities. We categorized patients into two groups based on age (<18 years and ≥18 years) and observed no significant differences in survival rates of adults without nodules and with IPNs.…”

Incidence, Survival, And Associated Factors Estimation In Osteosarcoma Patients With Lung Metastasis: A Single-Center Experience of 11 Years In Tianjin, China

“…Similarly, the latest study showed that around 14% osteosarcoma patients were with lung metastasis at diagnosis and the indeterminate nodules in lung can turn into the metastatic disease at a median time of 5.3 months [7]. Lung metastasis has become the focus in osteosarcoma in recent years.…”