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Distinguishing Benign from Malignant Pulmonary Nodules with Helical Chest CT in Children with Malignant Solid Tumors¹

¹ From the Departments of Radiological Sciences (M.B.M., H.M.L., R.A.K.), Hematology-Oncology (V.M.S., N.C.D.), Surgery (S.J.S.), and Biostatistics (C.S.L.), St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105-2794; Department of Diagnostic Imaging, UNIFESP-Escola Paulista de Medicina, Sao Paulo, Brazil (H.M.L.); and University of Tennessee, College of Medicine, Memphis, Tenn (M.B.M., R.A.K., V.M.S., N.C.D., S.J.S.). Received April 15, 2005; revision requested June 14; revision received July 22; final version accepted August 25. Supported in part by Cancer Center Support grant CA21765 from the U.S. Public Health Service and by the American Lebanese Syrian Associated Charities (ALSAC). Address correspondence to M.B.M. (e-mail: beth.mccarville{at}stjude.org).

	ABSTRACT

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Purpose: To retrospectively assess whether computed tomographic (CT) findings can indicate the benign or malignant nature of pulmonary nodules in pediatric patients with malignant solid primary tumors.

Materials and Methods: With institutional review board approval, waived parental and patient consent, and HIPAA compliance, the authors determined the incidence of malignancy among 81 pulmonary nodules that were sampled at biopsy within 3 weeks after chest CT (January 1999 to September 2003) in 41 young patients with malignant solid tumors. Three radiologists independently and retrospectively reviewed these scans and the available previously obtained scans, classifying nodules as benign, malignant, or indeterminate on the basis of their number, unilateral versus bilateral distribution, size, margins (indistinct vs distinct), calcification, growth, and associated adenopathy. These classifications were compared with nodule histologic type, and interreviewer agreement was assessed.

Results: The median patient age was 14.8 years (mean, 13.7 years; range, 5–21 years). Twenty-four of the 41 patients (58%) had at least one biopsy-proved malignant nodule. Four (10%) patients had both benign and malignant nodules; 17 (42%) had only benign nodules. Reviewer 1 classified 65% (39 of 60) of nodules correctly; reviewer 2, 57% (37 of 65); and reviewer 3, 67% (43 of 64). Interreviewer agreement was slight to moderate ( 0.43, P .03). In contrast to findings in adults, sharply defined nodules in younger individuals were more likely to be malignant (P = .03) and nodule size was not associated with malignancy (P .32).

Conclusion: The frequency of benign nodules and the inconsistency of predictions based on CT features suggest the need for better predictors of pulmonary nodules being malignant or benign, so as to reduce unnecessary thoracotomy in pediatric patients with solid malignancy.

© RSNA, 2006

	INTRODUCTION

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The development of helical computed tomography (CT) and, more recently, multisection helical CT has improved the quality of chest CT images by diminishing the effects of breathing and cardiac motion (1–4). A technology that is increasing in clinical use, the picture archiving and communication system (PACS), also offers improved accuracy of interpretation with its image review and analysis functions, especially the window and level adjustment and magnification tools (5,6). While these advances have improved the sensitivity of detection of pulmonary nodules, imaging findings alone often do not indicate the nature of the nodules (1,7–9).

The CT imaging features of pulmonary nodules have been extensively evaluated in adults but not in children. (Published pediatric reports are cited in references 8–13.) Because children with malignant solid tumors are at risk of pulmonary metastatic disease, they undergo screening chest CT at diagnosis, throughout treatment, and during routine follow-up. When pulmonary nodules are detected by using CT, an invasive procedure, such as CT-guided needle biopsy or thoracotomy, is usually required to direct subsequent management. These procedures carry known risks and may add unnecessarily to the cost of patient care. Moreover, the number of invasive procedures needed to confirm benign disease should be minimized while diagnosis of malignant nodules is ensured. The purpose of our study, therefore, was to retrospectively assess whether CT findings can indicate the benign or malignant nature of pulmonary nodules in pediatric patients with malignant solid primary tumors.

	MATERIALS AND METHODS

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Our retrospective study was approved by the institutional review board of St. Jude Children's Research Hospital. Parental and patient informed consent was waived, and the study was performed in compliance with the Health Insurance Portability and Accountability Act. All young patients with malignant solid tumors who underwent biopsy of pulmonary nodules between January 1999 and September 2003 were identified through our solid-tumor data bank. From their medical records, a departmental data manager recorded demographic characteristics; the primary diagnosis; the mode of biopsy (percutaneous or with thoracotomy); and the number, site, and histologic types of the biopsy-sampled nodules. For percutaneous biopsies, the needle gauge and number of passes were also recorded.

CT Scanning Technique
Only those patients in whom prebiopsy imaging was performed at our institution were included in the study. Between January 1999 and February 2002, patients were scanned with a Siemens Plus helical single-section CT scanner (Siemens, Erlangen, Germany) by using a 1:1 pitch. Section thickness was 5 mm for patients younger than 5 years and 8 mm for older patients. Between February 2002 and September 2003, patients were scanned with a LightSpeed Ultra helical eight-row detector CT scanner (GE Medical Systems, Milwaukee, Wis) by using a 5-mm section thickness and a 1.35:1 pitch. All patients were scanned by using 120 kVp with the milliampere-second setting adjusted for body weight. To reduce radiation exposure, after May 2002 we used the auto-milliampere function, presetting the noise level to 5, with the maximum allowable milliampere-second per section based on body weight. Patients able to follow breath-holding instructions (generally aged 6 years and older) were scanned during suspended inspiration. Fifty-five of the 70 scans included in our review were obtained without intravenous contrast agent.

Image Review
CT scans obtained within 3 weeks before the biopsy and the most recent previously obtained CT scans (when available) were retrospectively and independently reviewed by three pediatric radiologists. Reviewer 1 had 9 years of pediatric CT experience, with the most recent 6 years spent in a predominantly pediatric oncology practice setting. Reviewer 2 had 22 years of pediatric CT experience, including oncology. Reviewer 3 had 24 years of pediatric CT experience, with 1 year before this study spent in a predominantly pediatric oncology practice. Reviewers were provided with only the patients' primary diagnosis. All images were reviewed in both the lung and mediastinal windows on a MagicView 1000 PACS workstation (Siemens). Any scans originally archived in only the mediastinal window setting were retrospectively converted to a lung window by using the PACS edge enhancement function; image quality was similar to that of images originally archived in a lung window. The PACS image review functions (including window and level adjustment and magnification tool) were used at the discretion of each reviewer.

To ensure accurate comparisons, before imaging analysis we informed reviewer 1 of the site of each biopsy-sampled nodule as determined from the medical record. This reviewer then numbered the corresponding nodules on the CT images by using the annotation function in the PACS. This numbering system allowed us to accurately track specific nodules among reviewers and to correlate them with their corresponding histologic type. As is our routine practice, reviewers analyzed the CT scans for the total number of nodules present, unilateral versus bilateral distribution, lobar site, mediastinal or hilar adenopathy, presence of lymph node calcification, and development of new nodules since the previous CT scan. The size, margin distinctness (distinct vs indistinct), growth (where applicable), and presence and pattern (central vs other) of calcification of each biopsy-sampled nodule were assessed. Each reviewer subjectively classified the sampled nodules as benign, malignant, or indeterminate on the basis of these features.

Statistical Analyses
We used a logistic regression model with the GENMOD (SAS Institute, Cary, NC) procedure to study the relation between each reviewer's prediction of nodule histologic type and the actual nodule histologic type and to determine the reviewers' ability to predict benign versus malignant histologic type. We used a univariate logistic regression model with the GENMOD procedure to determine the relation between individual imaging parameters and predicted and actual nodule histologic types. To identify combinations of imaging parameters related to predicted or actual nodule histologic type, we first selected candidate imaging parameters that had a significance level of .2 by using a univariate logistic regression model with the GENMOD procedure. We then tested combinations of the selected parameters by using a multivariate logistic regression model with the GENMOD procedure and with a backward elimination procedure. Patients predicted or found to have both benign and malignant nodules were considered to have malignant disease for the purpose of analysis.

Because we expected increasing nodule size and increasing total number of nodules to be predictive of malignant histologic type, we used the Fisher exact test to determine possible threshold values that distinguished benign from malignant histologic type. We used the Cohen statistic to determine interreviewer agreement. The exact ² test was used to compare the incidences of benign and malignant histologic types in the subgroup of patients who had multiple nodules sampled at biopsy. All analyses were performed with StatXact-5 software (Cytel Software, Cambridge, Mass) that was implemented by using SAS, version 9.1 (SAS Institute). P .05 was considered to indicate a statistically significant difference.

	RESULTS

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Patients
Fifty young patients (20 female) underwent biopsy of 104 pulmonary nodules during the study period. The median age was 14.8 years (mean, 13.7 years; range, 5–21 years). Five patients were older than 18 years at the time of diagnosis of their primary tumor. Primary diagnoses were osteosarcoma (n = 30), Wilms tumor (n = 4), melanoma (n = 3), Ewing sarcoma (n = 2), alveolar soft-part sarcoma (n = 2), synovial sarcoma (n = 2), hepatoblastoma (n = 2), hepatocellular carcinoma (n = 1), and other sarcomas (n = 4). There were 47 patients who underwent excisional biopsies (with thoracotomy) and three who underwent CT-guided percutaneous needle biopsies. The percutaneous biopsies were performed by using a coaxial technique with an ASAP automatic 20-gauge core-needle biopsy system (Meditech, Boston Scientific, Watertown, Mass); three to six passes (mean, 4) were made into each nodule. Twenty-eight patients (of 50 [56%]) had at least one biopsy-proved malignant nodule. In 19 patients, multiple nodules were sampled at biopsy; five of them had both benign and malignant nodules. Twenty-two of 50 (44%) patients had only benign nodules (Table 1).

Characterization of Nodules
Of the 70 scans reviewed, 18 had originally been archived in only the mediastinal window setting and were converted to a lung window by using the PACS edge enhancement function. The total number of nodules per patient (biopsy sampled and not biopsy sampled) ranged from one to 13 (mean, 2.3; median, 1), as observed by reviewer 1. None of the reviewers identified all 81 sampled nodules, some of which were identified only at palpation during thoracotomy. Furthermore, each reviewer identified and characterized a slightly different number of nodules. All three reviewers classified the 60 nodules that had originally been labeled by reviewer 1. Reviewer 2 identified an additional five nodules, and reviewer 3 identified an additional four nodules. Therefore, reviewer 1 classified 60 of the 81 sampled nodules, reviewer 2 classified 65, and reviewer 3 classified 64. Because reviewer 2 classified the most nodules, we summarized nodule size on the basis of this reviewer's measurements and found that the median diameter of sampled nodules was 0.4 cm (mean ± standard deviation, 0.64 cm ± 0.086; range, 0.1–3.9 cm). Because nodule size has been shown to be an important indicator of nodule histologic type in adults, we also report the frequency of nodule size measurements for all three reviewers (Table 2).

Nodule margin distinctness (Table 3) was significantly related to the prediction of malignancy by each of the three reviewers (all P .02), such that nodules having distinct margins were more likely to be considered malignant than were those having indistinct margins. The development of new nodules since the previous CT scan was a significant predictor of malignant classification by reviewer 3 (P = .02). Hilar adenopathy was significantly associated with the predictions of reviewer 1 (P = .04). This reviewer was more likely to classify nodules as benign when adenopathy was present. None of the other imaging parameters, individually or in combination, was related to a reviewer's prediction of histologic type.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure a: Transverse helical CT images of benign and malignant pulmonary nodules in two young patients with solid malignancies. (a) Image from an 18-year-old male patient with melanoma shows an ill-defined nodule (arrow) that was proved at biopsy to be papillary adenoma. (b) Image from a 12-year-old male patient with osteosarcoma shows a 2-mm sharply defined nodule (arrow) that was proved at biopsy to be metastatic.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   Figure b: Transverse helical CT images of benign and malignant pulmonary nodules in two young patients with solid malignancies. (a) Image from an 18-year-old male patient with melanoma shows an ill-defined nodule (arrow) that was proved at biopsy to be papillary adenoma. (b) Image from a 12-year-old male patient with osteosarcoma shows a 2-mm sharply defined nodule (arrow) that was proved at biopsy to be metastatic.

	DISCUSSION

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At our large children's cancer hospital, most biopsies of pulmonary nodules in patients with malignant solid tumors (47 of 50 [94%]) were performed at thoracotomy during the study period. Many patients were found to have only benign nodules (22 of 50 [44%]) or to have both benign and malignant nodules (5 of 50 [10%]). The incidences and causes of benign pulmonary nodules among children with cancer differ with geographic region and institutional referral patterns. At our institution, patients are often referred for treatment of solid malignancies that are advanced or refractory to conventional therapy. Despite this selection bias, benign pulmonary nodules were fairly common. In other practice settings, benign nodules in this patient population may be more prevalent. Because histoplasmosis is endemic in our region, a high percentage of benign nodules were due to this granulomatous disease. Such endemic pathogens are likely to influence radiologists' impressions of pulmonary nodules in children with cancer and may affect the proportion of benign versus malignant nodules. These factors should be considered when the risk of nodule biopsy (usually by thoracotomy) is weighed against control of the underlying malignancy.

We found that three experienced pediatric radiologists were able to correctly predict nodule histologic type on the basis of CT imaging parameters in only 57%–67% of cases. All three radiologists classified a considerable number of nodules (8%–23%) as indeterminate. Furthermore, interreviewer agreement was only slight to moderate; the greatest agreement was seen between two radiologists whose practice is predominantly oncologic. The ability of these two radiologists to predict benign histologic type was somewhat superior to that of a radiologist whose practice is primarily in general pediatrics. This finding, although not surprising, is noteworthy because most radiologists who interpret the chest CT scans of pediatric oncology patients practice in either a general pediatric or a combined adult-pediatric setting.

Of nine imaging parameters evaluated, only the distinctness of nodule margins and the development of new nodules were significantly related to the radiologists' interpretations. All three radiologists were more likely to predict malignancy if nodule margins were sharply defined. In adults, however, nodules with sharply defined margins are more often benign, and those with irregular or spiculated margins are usually malignant (14–18). We speculate that this difference partly reflects the fact that malignant pulmonary nodules in adults are often primary lung cancers, whereas those in children are almost always metastases. It is also possible that the biologic behavior of primary tumors that metastasize to the lungs differs in these age groups. Of note, all three study radiologists relied on this imaging feature to distinguish benign from malignant nodules, despite the lack of scientific rationale and despite reports to the contrary in the adult literature. This finding underscores the importance of the individual radiologist's experience and highlights the need for additional rigorous investigation of pulmonary nodules in children.

We expected the size and number of nodules to be predictive of histologic type. In a large study conducted by Ginsberg et al (19) and involving 315 adults with cancer, nodules 0.5 cm or smaller were significantly more likely to be benign than larger nodules. Very small (<0.5 cm) pulmonary nodules, often referred to as "ditzels," are especially problematic in pediatric oncology because current imaging technologies depict them more easily, yet size has not been found to be predictive of histologic type (1,20,21). Our findings are in agreement with those of Robertson et al (12), who found that in children with cancer, nodules less than 0.5 cm in diameter were as likely to be malignant as larger nodules. In adults, multiple nodules may indicate a greater likelihood of pulmonary metastatic disease (22). We found that for one reviewer, an increased total number of nodules was only marginally associated with malignancy (P = .05). In our subset of 19 patients who underwent biopsy of multiple nodules, we found no significant difference between the number who had only benign nodules (n = 7) and the number who had metastatic disease (n = 12), although these relatively small subsets limited our statistical power. We also did not find a threshold value for either the size or the number of nodules that statistically distinguished those with benign from those with malignant nodules. Therefore, these imaging parameters appear to have limited predictive value in this patient population.

In adults, pulmonary nodules that remain stable in size for 2 years are highly likely to be benign (1,20,22,23). In our study, 29 of 41 patients had previous CT scans that allowed us to assess nodule growth. Although we found no relation between nodule growth and histologic type, we attribute this finding, in part, to the relatively short intervals between the CT scans (mean, 4.8 months). In addition, there may have been a selection bias: Patients who had significant nodule growth may have been presumed to have metastatic disease without biopsy and therefore would not have been included in our cohort. Although the doubling time of a nodule is undoubtedly an accurate indicator of its histologic type, the clinical usefulness of this information is limited. First, because prompt initiation of therapy is important, observation of potentially metastatic pulmonary nodules over an extended period is not a realistic option. Second, when nodules are very small, it may be difficult to detect an increase in size, even on thin-section CT images: Doubling of the volume of a small nodule only minimally increases the unit of measurement, its diameter. This problem is compounded by the effect of volume averaging, differences in section selection and breath holding between CT examinations, breathing motion artifact, and interreader variability in size measurements (20,24).

A limitation of our study was the somewhat small sample size, which limited our statistical power. We chose our 4-year study period to include only imaging that was performed with a helical CT scanner and archived in our PACS. This restriction allowed us to perform the study in a manner that simulated our current work environment. Another potential limitation was that six of the benign nodules were shown at histologic analysis to be a site of hemorrhage (n = 2) or normal lung (n = 4). It is possible that these represented false-negative findings due to sampling error. However, all but one of these biopsies were performed by using wedge resection, and review of the postoperative chest CT scans revealed no residual nodules in the operative sites.

With the advent of widespread CT screening of adults for lung cancer, a growing body of literature addresses the management of pulmonary nodules in adults. Some investigators suggest that, in this population, no more than 10% of pulmonary nodule biopsies should result in a benign diagnosis (25). Prediction of the likelihood that a nodule is malignant depends on individual patient factors and imaging findings (21,26–28). In our cohort, because the likelihood of malignancy was high, a relatively high percentage of patients (44%) underwent biopsy that revealed only benign nodules. Clearly, better methods are needed to discriminate benign from malignant pulmonary nodules in children with malignant solid tumors. We have shown that there are important differences between children and adults regarding the CT imaging features of pulmonary nodules. Specifically, nodules that are sharply defined are more likely to be malignant than benign, and small nodules (0.5 cm) are as likely to be malignant as larger nodules. The significance of nodule multiplicity needs to be clarified. There is a crucial need for additional studies that rigorously evaluate the significance of CT imaging features of pulmonary nodules in children to provide a legitimate basis for practice standards. To reduce the number of invasive procedures performed to confirm benign disease, better methods of assessing pulmonary nodules in children should also be sought through additional prospective clinical trials.

We plan to investigate the value of positron emission tomography (PET)-CT in the work-up of pulmonary nodules identified at screening CT in our pediatric patients with solid malignancies. This fusion modality may allow us to more accurately and noninvasively assess the metabolic activity of even small pulmonary nodules, which can be accurately localized on coregistered PET/CT images.

	ADVANCES IN KNOWLEDGE

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• Benign histologic features are common in pulmonary nodules that are sampled at biopsy in children with solid primary malignancies.
  
• In children with malignant primary solid tumors, pulmonary nodules with well-defined margins are more often malignant than benign, whereas in adults most malignant nodules have poorly defined margins.
  
• In children with malignant primary solid tumors, small (<0.5 cm) pulmonary nodules appear to be as likely to be malignant as larger (>0.5 cm) nodules, whereas in adults small pulmonary nodules are more likely to be benign than malignant.
  

	FOOTNOTES

 

Abbreviations: PACS = picture archiving and communication system

Author contributions: Guarantor of integrity of entire study, M.B.M.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, M.B.M., H.M.L., V.M.S., S.J.S.; clinical studies, M.B.M., H.M.L., V.M.S., N.C.D., S.J.S., R.A.K.; statistical analysis, C.S.L.; and manuscript editing, M.B.M., H.M.L., V.M.S., N.C.D., S.J.S., R.A.K.

Authors stated no financial relationship to disclose.

	References

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This Article Abstract Figures Only Full Text (PDF) Submit a response View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McCarville, M. B. Articles by Kaufman, R. A. Search for Related Content PubMed PubMed Citation Articles by McCarville, M. B. Articles by Kaufman, R. A.