Exploring the Diagnostic Dilemma of Indeterminate Pulmonary Nodules in Patients with Primary Sarcoma of Bone.

To report the incidence of indeterminate pulmonary nodules (IPN) and the rate of progression of IPNs to metastasis in patients with primary bone cancers. We also aimed to evaluate clinical or radiological parameters that may identify IPNs more likely to progress to metastatic disease and their effect on overall or event-free survival in patients with primary bone sarcoma. A systematic search of the electronic databases Medline, Embase, and Cochrane Library was undertaken for eligible articles on IPNs in patients with primary bone sarcomas, published in the English language from inception of the databases to 2023. The Newcastle-Ottawa Quality Assessment Form for Cohort Studies was utilized to evaluate risk of bias in included studies. Six studies, involving 1667 patients, were included in this systematic review. Pooled quantitative analysis found the rate of incidence of IPN to be 18.1% (302 out of 1667) and the rate of progression to metastasis to be 45.0% (136 out of 302). Nodule size (more than 5 mm diameter), number (more than or equal to 4), distribution (bilaterally distributed), incomplete calcification, and lobulated margins were associated with an increased likelihood of IPNs progressing to metastasis, however, their impact on overall or event-free survival remains unclear. The risk of IPNs progressing to metastasis in patients with primary bone sarcoma is non-negligible. Large IPNs have a high risk to be an actual metastasis. We suggest that IPNs in these patients be followed up for a minimum of 2 years with CT imaging at 3, 6, and 12 month intervals, particularly for nodules measuring >5 mm in average diameter. This is the first systematic review on IPNs in patients with primary bone sarcomas only and proposes viable management strategies for such patients.

Baseline staging CT scans are performed on nearly every patient after the diagnosis of a sarcoma to evaluate for the presence of metastatic disease. These scans often identify abnormalities that may or may not be related to the known malignancy. Despite the high frequency of incidental findings, there is little guidance for clinicians faced with assessing these radiographic abnormalities. The interpretation of incidental findings is important because it may influence decisions regarding surveillance frequency, prognostic estimation, and surgical and medical intervention. The purpose of this study was to determine (1) the frequency of abnormal findings and indeterminate nodules on staging CT scans; (2) the natural history of indeterminate nodules identified at the time of sarcoma diagnosis; and (3) the factors associated with indeterminate nodules representing true metastatic disease. Between September 2010 and February 2016 we treated 233 patients with bone and soft tissue sarcomas. Of those, 227 (97%) had a staging CT scan of the chest or chest/abdomen/pelvis performed within 2 months of diagnosis. To be eligible for this retrospective study, a patient had to have a minimum of 6 months of radiographic followup after that initial CT scan. A total of 36 (16%) were lost to followup or did not have radiographic surveillance at least 6 months later, and 48 (21%) were excluded for other prespecified reasons, leaving 149 patients for evaluation. We recorded all abnormal findings listed in the official radiology CT report of the lung, bone, liver, and lymph nodes. We assessed progression of indeterminate nodules by reviewing radiology reports, which listed both size and number of findings, and clinical notes outlining the current assessment of disease status and treatment plan. If indeterminate nodules grew in size or number consistent with metastatic disease or were confirmed histologically, they were considered to represent true metastasis. Bivariate methods were used to investigate an association between various clinical factors, which were obtained from chart review, and progression of indeterminate nodules to clear metastatic disease. One hundred thirty-five of 149 patients (91%) had at least one abnormal finding on a staging CT scan. Forty-nine patients (33%) presented with indeterminate lung nodules, 15 (10%) with indeterminate liver lesions, four (3%) with indeterminate bone lesions, and 57 (38%) with enlarged lymph nodes. Fifteen of the 49 patients with indeterminate lung nodules (31%), one of 15 liver nodules, zero of four bone lesions, four of 13 lymph nodes 1 to 2 cm in size, and two of 44 subcentimeter lymph nodes (4.5%) were clearly metastatic on followup. A primary tumor size ≥ 14 cm in greatest dimension was more suggestive of indeterminate nodules representing true metastatic disease compared with smaller primary tumors in both lung (eight of 10 compared with seven of 36 [19%]; odds ratio, 16.6; 95% confidence interval, 2.9-95.9; p < 0.001) and lymph nodes (six of 18 compared with zero of 36 [0%], p < 0.001). It is extremely common for abnormal findings and incidental nodules to be present at the time of a staging CT scan in patients with sarcoma. Although patients with indeterminate nodules should have continued surveillance, it appears from this study that the majority of these findings do not represent true metastatic disease. Given a minimum followup of 6 months, it is possible the actual proportion of indeterminate lesions representing true metastatic disease may increase over time. Level III, prognostic study.

We prospectively studied 331 sarcoma patients treated between April 1999 and December 2004 to see if small, indeterminate pulmonary nodules are of prognostic significance. Seventy-one (21%) had indeterminate pulmonary nodules on initial spiral CCT. Twenty of 71 (28%) patients with indeterminate nodules progressed with metastatic disease. Metastatic disease developed in 18/20 (90%) in the area of the original indeterminate nodule. The presence of tiny (<5 mm) indeterminate nodules was not a prognostic variable, however, the presence of nodules > or =5 mm was associated with worse 3 year disease-free survival compared to those with no nodules or tiny nodules (81% versus 49%) but better than those with definite metastatic disease at presentation (49% versus 5%). Because patients with pulmonary nodules > or =5 mm are at increased risk for metastatic disease compared to patients with normal CCT or those with <5 mm nodules but better survival than patients with Stage IV disease, we believe a new staging system of these patients should be considered and recommend careful followup.

What is the Significance of Indeterminate Pulmonary Nodules in Patients Undergoing Resection for Pancreatic Adenocarcinoma?

This study aims to investigate radiological and clinical factors which predict malignancy in indeterminate pulmonary nodules in patients with head and neck cancer (HNC). Prospective data were collected in 424 patients who were reviewed in the NHS Lothian HNC multidisciplinary meeting from May 2016 to May 2018. Staging and follow-up CT chest imaging were reviewed to identify and assess pulmonary nodules in all patients. About 61.8% of patients had at least one pulmonary nodule at staging CT. In total, 25 patients developed malignancy in the chest. Metastatic disease in the chest was significantly associated with unknown or negative p16status (p<.0005). Pleural indentation and spiculation were associated with indeterminate nodules, subsequently being shown to represent metastatic disease (p>.0005 and p=.046, respectively). Negative or unknown p16status was associated with an increased propensity to develop metastatic disease in the chest in patients with HNC.

161 Background: Preoperative abdominal imaging often detects indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma. The natural history of IPN in this setting is not well characterized. Methods: Patients with adenocarcinoma of the head of the pancreas who underwent pancreaticoduodenectomy (PD) were queried from a prospectively maintained database. Pre- and postoperative imaging was reviewed and IPN characterized and analyzed for associations with nodule progression and overall survival (OS). Results: 463 patients underwent PD for adenocarcinoma of the head of the pancreas from 2000-2010. Of these, 329 (71%) had reviewable pre-operative imaging. 48 patients (15%) had pre-operative IPN (non-calcified) identified with follow-up imaging available for review. The only pre-operative factor associated with the presence of IPN was increasing age (68 v. 64 years; p=0.003). 8 patients (12%) had new or enlarging nodules, of whom 5 (7%) had confirmed pulmonary metastatic adenocarcinoma. There was no difference in OS between patients with or without pre-operative IPN (2-year OS 41% v. 38%, respectively; p=0.37). Further, no radiographic criteria of IPN (including # of, size of, bilateral, calcified, solid, spiculated, smooth, lobular, or ground-glass nodules) was associated with OS. On follow-up, new or enlarging nodules were not associated with OS. Conclusions: IPN are often found in patients undergoing PD for pancreatic adenocarcinoma. The majority of IPN remain stable on post-operative imaging. Neither the presence of IPN nor nodule characteristics was associated with OS. These data do not support the routine additional workup of pre-operative IPN in patients with resectable adenocarcinoma of the head of the pancreas; however, larger studies are needed to further characterize the significance of IPN in the preoperative evaluation of patients with pancreatic adenocarcinoma.

Subcentimeter Pulmonary Nodules are Not Associated with Disease Progression in Patients with Renal Cell Carcinoma

The clinical significance of radiologically detected silent pulmonary nodules in early breast cancer

Background:Indeterminate pulmonary nodules in patients diagnosed with osteosarcoma present a challenge for accurate staging and prognosis. The aim of this study was to explore the significance of this finding.Methods:A retrospective cohort study of 120 patients with osteosarcoma was performed in the North East of England. Chest computed tomographies (CTs) at presentation were reviewed and the incidence of ‘indeterminate’ nodules recorded. Follow-up scans were reviewed and survival as well as prognostic features were analysed.Results:25% of our cohort presented with indeterminate nodules. Of these, 33% were subsequently confirmed as metastases, the majority within a year. Kaplan–Meier survival analysis showed that patients with indeterminate nodules fared better than those with frank metastatic disease, and similar to those who presented with a normal chest CT. We found no radiographic features that predicted survival.Conclusions:Indeterminate nodules remain a clinical and diagnostic dilemma. Close monitoring of patients is advised during the first year from presentation, and there is potential for indeterminate nodules to develop into frank metastases later than five years from presentation.

The aim of this study was to assess the clinical impact of indeterminate pulmonary nodules (no more than four pulmonary nodules of less than 5mm or one nodule measuring between 5 and less than 10mm by computed tomography [CT]) in children and adolescents with adult-type non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) at diagnosis. Patients with NRSTS treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed. Local radiologists, blinded to clinical information except for patients' age and tumor histotype, reviewed the chest CT at diagnosis and filled out a case report form. Because patients with or without indeterminate nodules in the EpSSG NRSTS 2005 study received the same type of treatment, event-free survival (EFS) and overall survival (OS) between groups by log-rank test were compared. Overall, 206 patients were examined: 109 (52.9%) were without any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases, which were then considered to be misclassified and were excluded from further analyses. Five-year EFS was 78.5% (95% CI, 69.4%-85.1%) for patients without nodules and 69.6% (95% CI, 57.9%-78.7%) for patients with indeterminate nodules (p=.135); 5-year OS was 87.4% (95% CI, 79.3%-92.5%) and 79.0% (95% CI, 67.5%-86.8%), respectively (p=.086). This study suggests that survival does not differ in otherwise nonmetastatic patients with indeterminate pulmonary nodules compared to nonmetastatic patients without pulmonary nodules. Radiologists should be aware of the classification of indeterminate pulmonary nodules in non-rhabdomyosarcoma soft tissue sarcomas and use it in their reports. More than a third of patients with non-rhabdomyosarcoma soft tissue sarcoma can be affected by indeterminate pulmonary nodules. Indeterminate pulmonary nodules do not significantly affect the overall survival of pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma.

Objective: To investigate the frequency and significance of pulmonary nodules in patients with colorectal cancer (CRC). Subjects and Methods: Medical records of 1,344 patients with CRC who underwent thoracic computerized tomography scans between January 2003 and December 2009 were reviewed. Those with any distant metastatic disease or who were already known to have pulmonary malignancies were excluded. Number, size, shape and location of the nodules were evaluated. A multivariate analysis was performed to determine the predictive factors for evidence of metastases. Results: Of the 1,344 patients, 55 (4.09%) had nodules that met the criteria of an indeterminate pulmonary nodule. The mean follow-up time was 25 ± 17.9 months and the mean time to develop pulmonary metastasis was 15.5 ± 6.4 months. The nodules of 17 (30.9%) patients showed progression at follow-up; 8 had metastasized. Multivariate analysis showed multiple indeterminate pulmonary nodules (p = 0.006) of parenchymal localization (p = 0.016) with an irregular border (p = 0.002), which is predictive of metastatic disease. Conclusion: Our study has shown that multiple indeterminate pulmonary nodules with an irregular border in a parenchymal location were more likely to represent metastatic disease. However, the frequency of the occurrence of indeterminate pulmonary metastases of CRC was low.

Incidental visualization of indeterminate pulmonary nodules is considered a clinical dilemma. We identified patients for inclusion in this study by searching for the term "indeterminate nodules" in the radiology database of rectal cancer patients who underwent surgery. Patients with definite metastatic disease were excluded. In total, 224 patients underwent chest computerized tomography (CT) and 59 of these patients had indeterminate pulmonary nodules detected more than twice by CT scan. Six patients (10.2%) were confirmed to have metastatic lesions on follow-up evaluation. Pulmonary nodule size (P=0.028), pathologic N status (P=0.049), positive nodal status (P=0.036) and the number of positive lymph nodes (P=0.033) were significant risk factors for pulmonary metastasis. In the pulmonary metastasis group, the patients who had received adjuvant oxaliplatin-based (FOLFOX4) chemotherapy had longer intervals to developing metastasis compared to patients who had not received it. It is not necessary to perform excessive surveillance routinely for all rectal cancer patients who have indeterminate pulmonary lesions. Intensive follow-up chest CT or other invasive diagnostic modalities should be considered only in patients with pulmonary nodules larger than 5.7 mm or positive nodal status. In addition, patients receiving adjuvant FOLFOX4 chemotherapy should be followed-up for longer periods.

To evaluate the clinical significance of indeterminate pulmonary nodules at diagnosis (defined as ≤ 4 pulmonary nodules < 5 mm or 1 nodule measuring ≥ 5 and < 10 mm) in patients with pediatric rhabdomyosarcoma (RMS). We selected patients with supposed nonmetastatic RMS treated in large pediatric oncology centers in the United Kingdom, France, Italy, and the Netherlands, who were enrolled in the European Soft Tissue Sarcoma Study Group (E pSSG) RMS 2005 study. Patients included in the current study received a diagnosis between September 2005 and December 2013, and had chest computed tomography scans available for review that were done at time of diagnosis. Local radiologists were asked to review the chest computed tomography scans for the presence of pulmonary nodules and to record their findings on a standardized case report form. In the E pSSG RMS 2005 Study, patients with indeterminate pulmonary nodules were treated identically to patients without pulmonary nodules, enabling us to compare event-free survival and overall survival between groups by log-rank test. In total, 316 patients were included; 67 patients (21.2%) had indeterminate pulmonary nodules on imaging and 249 patients (78.8%) had no pulmonary nodules evident at diagnosis. Median follow-up for survivors (n = 258) was 75.1 months; respective 5-year event-free survival and overall survival rates (95% CI) were 77.0% (64.8% to 85.5%) and 82.0% (69.7% to 89.6%) for patients with indeterminate nodules and 73.2% (67.1% to 78.3%) and 80.8% (75.1% to 85.3%) for patients without nodules at diagnosis ( P = .68 and .76, respectively). Our study demonstrated that indeterminate pulmonary nodules at diagnosis do not affect outcome in patients with otherwise localized RMS. There is no need to biopsy or upstage patients with RMS who have indeterminate pulmonary nodules at diagnosis.

617 Background: Increasing numbers of patients with early breast cancer undergo routine staging using computerized tomography (CT). Those in whom indeterminate pulmonary nodules are visualized without the presence of other potentially metastatic lesions represent a clinical dilemma of whether they should be managed as early breast cancer or metastatic disease. This study sought to investigate the incidence, clinical characteristics and outcomes of patients with indeterminate pulmonary nodules in breast cancer, which has important implications for their management and also entry into clinical trials. Methods: Medical records of individual breast cancer patients who underwent thoracic CT scans between the years 2002 to 2007 were analyzed and those with obvious metastatic disease were excluded. Patients were identified via the radiology database by searching for the following terms: suspicious lung metastases, and/ or indeterminate nodules. Results: Out of 2,578 patients scans, we identified 34 cases (1.3%) with indeterminate pulmonary nodules without evidence of disease elsewhere on CT scanning. We categorized these cases to the size of the nodules. At a median follow-up of 13.5 months, there were no changes in lesion size in 86% of the patients with a solitary nodule smaller than 1cm, and 89% with multiple sub-centimeter nodules. In contrast, 100% of cases with pulmonary nodules larger than 1cm had progressed at follow up (χ2, p=0.004). Conclusions: Breast cancer cases with sub-centimeter indeterminate pulmonary lesions and no evidence of metastases elsewhere are unlikely to represent metastatic disease. Treatment with curative intent or entry into clinical trials should not be excluded. No significant financial relationships to disclose.

Contribution of a Blood-Based Protein Biomarker Panel to the Classification of Indeterminate Pulmonary Nodules.