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doi:10.1378/chest.07-1352
(Chest. 2007; 132:94S-107)
© 2007 American College of Chest Physicians
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Evidence for the Treatment of Patients With Pulmonary Nodules: When Is It Lung Cancer?*

ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

Momen M. Wahidi, MD, FCCP; Joseph A. Govert, MD; Ranjit K. Goudar, MD; Michael K. Gould, MD, FCCP and Douglas C. McCrory, MD

* From the Department of Medicine (Drs. Wahidi, Govert, Goudar, and McCrory) and the Center for Clinical Health Policy Research (Dr. McCrory), Duke University Medical Center, Durham, NC; Veterans Affairs Palo Alto Health Care System, Palo Alto, and Stanford University School of Medicine (Dr. Gould), Stanford, CA; and Center for Health Services Research in Primary Care (Dr. McCrory), Department of Veterans Affairs Medical Center, Durham, NC.

Correspondence to: Momen M. Wahidi, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Box 3683, Durham, NC 27710; e-mail: wahid001{at}mc.duke.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Background: The solitary pulmonary nodule (SPN) is a frequent incidental finding that may represent primary lung cancer or other malignant or benign lesions. The optimal management of the SPN remains unclear.

Methods: We conducted a systematic literature review to address the following questions: (1) the prevalence of SPN; (2) the prevalence of malignancy in nodules with varying characteristics (size, morphology, and type of opacity); (3) the relationships between growth rates, histology, and other nodule characteristics; and (4) the performance characteristics and complication rates of tests for SPN diagnosis. We searched MEDLINE and other databases and used previous systematic reviews and recent primary studies.

Results: Eight large trials of lung cancer screening showed that both the prevalence of at least one nodule (8 to 51%) and the prevalence of malignancy in patients with nodules (1.1 to 12%) varied considerably across studies. The prevalence of malignancy varied by size (0 to 1% for nodules < 5 mm, 6 to 28% for nodules 5 to 10 mm, and 64 to 82% for nodules > 20 mm). Data from six studies of patients with incidental or screening-detected nodules showed that the risk for malignancy was approximately 20 to 30% in nodules with smooth edges; in nodules with irregular, lobulated, or spiculated borders, the rate of malignancy was higher but varied across studies from 33 to 100%. Nodules that were pure ground-glass opacities were more likely to be malignant (59 to 73%) than solid nodules (7 to 9%). The sensitivity of positron emission tomography imaging for identifying a malignant SPN was consistently high (80 to 100%), whereas specificity was lower and more variable across studies (40 to 100%). Dynamic CT with nodule enhancement yielded the most promising sensitivity (sensitivity, 98 to 100%; specificity, 54 to 93%) among imaging tests. In studies of CT-guided needle biopsy, nondiagnostic results were seen approximately 20% of the time, but sensitivity and specificity were excellent when biopsy yielded a specific benign or malignant result.

Conclusions: The prevalence of an SPN and the prevalence of malignancy in patients with an SPN vary widely across studies. The interpretation of these variable prevalence rates should take into consideration not only the nodule characteristics but also the population at risk. Modern imaging tests and CT-guided needle biopsy are highly sensitive for identifying a malignant SPN, but the specificity of imaging tests is variable and often poor.

Key Words: CT imaging • diagnosis • lung cancer • MRI • prevalence • solitary pulmonary nodule


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
The solitary pulmonary nodule (SPN) is defined as a spherical radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by lung tissue. Because of the widespread use of CT in the investigation of respiratory symptoms, the SPN is a frequent incidental finding. The cause of SPN ranges from lung cancer and metastases from an extrathoracic primary malignancy to infections, scar formation, and other benign lesions. As imaging techniques improve and more nodules are detected, the optimal management of SPN remains unclear. Current strategies include radiographic follow-up, tissue sampling, or surgical resection. Although surgical resection for early stage lung cancer offers potentially curative treatment and the best chance of survival, it is not free of complications and may not be necessary in a significant number of patients with benign SPNs. Evidence-based clinical decision making must incorporate data on the prevalence of SPNs and malignancy in a representative patient population, the radiographic characteristics of the nodule, and the demographic and clinical factors of the patient. We conducted a systematic review to address the following questions: (1) what is the prevalence of SPNs; (2) what is the prevalence of malignancy in nodules with varying characteristics (size, morphology, and type of opacity); (3) what are the relationships between growth rates, histology, and other nodule characteristics; and (4) what are the performance characteristics and complication rates of tests for SPN diagnosis?


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
The review methods were defined prospectively in a written protocol. The SPN Guideline Subcommittee, who authored the accompanying guideline, was consulted. Primary outcomes included prevalence of SPNs, stratified by smoking status, age, and other risk factors; prevalence of malignancy associated with specific nodule characteristics; histologic type and growth rates associated with specific nodule characteristics; diagnostic accuracy (sensitivity, specificity) of tests to determine whether a nodule is malignant; and complication rates of those diagnostic procedures. Secondary outcomes included changes in patient treatment or patient outcomes after diagnostic test or intervention.

Electronic database searches of MEDLINE (through August 19, 2005) and the Cochrane Library (through third quarter 2005) were conducted. The search was limited to English-language articles published since 1995. Additional and older citations were sought through consultations with experts and by identifying citations from included articles, review articles,12 and practice guidelines.3

We sought observational studies as well as diagnostic test evaluation studies (question 4) and, when available, experimental studies, such as randomized, controlled trials, that compared the diagnostic interventions of interest. For studies of diagnostic accuracy, we sought single-arm trials that permitted computation of specificity and sensitivity in relation to a reference standard that included histopathologic verification of positive tests and at least clinical follow-up of negative lesions. These studies were required to have at least 10 patients, including at least 5 participants with malignant nodules. We included studies that enrolled patients with pulmonary nodules that measured up to 4 cm in diameter.

A single reviewer screened titles and abstracts for full-text retrieval, and a second reviewer reviewed citations marked as uncertain. Review of full-text articles was conducted in the same manner to determine inclusion in the systematic review. One reviewer performed primary data abstraction, and a second reviewer reviewed the evidence tables for accuracy. All disagreements were resolved by consensus. Findings were reviewed and approved by members of the lung cancer panel, Thoracic Oncology NetWork, Health and Science Policy Committee, and Board of Regents of the American College of Chest Physicians.

What Is the Prevalence of SPNs?
From the literature review, eight large studies456789101112131415161718 of lung cancer screening were identified (Table 1 ). It is important to note that nodules that are detected in screening studies differ in important ways from nodules that are detected in routine clinical practice. In screening studies, the nodules tend to be smaller, the prevalence of malignant nodules is much lower, and the tumor volume doubling times (VDTs) of malignant nodules are generally longer.


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  		Table 1.. Prevalence of SPNs in Studies of Lung Cancer Screening*

 
The included studies enrolled populations that are believed to be at high risk for lung neoplasm, usually as a result of tobacco use. Both the prevalence of SPNs (8 to 51%) and the prevalence of malignancy in participants with SPNs (1.1 to 12%) varied across studies. The results of these studies were reported in varying manners. Whereas some reported only the number of nodules detected, others provided the percentage of patients with SPNs. In addition, patients with multiple nodules were not clearly separated from those with SPNs, further complicating the attempt to pool data. Gohagan et al6 reported a 20.5% "positivity rate" (ie, 20.5% of patients had a CT scan that was concerning for lung cancer), but the SPN prevalence rate was not reported. Li et al78 reported that 7,847 patients underwent 17,892 screening low-dose and follow-up high-resolution CT (HRCT) scans; the number of patients with pulmonary nodules was not reported, but 819 of those CT scan findings were described as abnormal. In some cases, the same nodule could have appeared on several scans, but also a single patient could have had multiple nodules, making it difficult to estimate prevalence.

What Is the Prevalence of Malignancy in Nodules With Varying Characteristics?
We identified three nodule characteristics for analysis: size, morphology, and type of opacity (Tables 234 ). Seven studies591619202122 that assessed nodule size found a proportional increase in the risk for malignancy as the diameter of the nodule increased (Table 2). With the exception of one small retrospective study20 in which two of two nodules < 5 mm in diameter were malignant, the prevalence of malignancy in nodules that measured < 5 mm was exceedingly low (range, 0 to 1%). The risk for malignancy was higher in nodules that measured between 5 and 10 mm (range, 6 to 28%), and it was very high in nodules that measured > 2 cm in diameter (range, 64 to 82%). It is not clear how many of these lesions were > 3 cm and therefore would qualify as pulmonary masses instead of nodules.


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  		Table 2.. Prevalence of Malignancy in Nodules With Varying Size*

 

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  		Table 3.. Prevalence of Malignancy in Nodules With Varying Edge Characteristics

 

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  		Table 4.. Prevalence of Malignancy in Nodules With Varying Morphology*

 
Data from six studies92122232425 of patients with incidental or screening-detected nodules showed that the risk for malignancy was approximately 20 to 30% in nodules with smooth edges, although one study25 reported a prevalence of malignancy of 58% in nodules with smooth borders. In nodules with irregular, lobulated, or spiculated borders, the risk for malignancy was higher but varied across studies from 33 to 100% (Table 3).

SPN morphology may be classified as solid, partially solid, or ground glass. Some investigators use the term nonsolid to describe the traditional ground-glass morphology. Whereas two studies79 found pure ground-glass opacities to be predominantly malignant (59 to 73%), another study18 using different terminology found that partially solid nodules had a higher likelihood of malignancy (63%) as compared with nonsolid nodules (18%; Table 4). When partially solid and nonsolid nodules were pooled,26 the aggregate prevalence of malignancy in such nodules was 32%. The prevalence of malignancy in solid nodules was generally lower (7 to 9%).

What Is the Histologic Type and Natural History (Growth Rate) of Small Pulmonary Nodules With Varying Characteristics?
Nine studies91027282930313233 analyzed the histology of pulmonary nodules with purely or primarily ground-glass attenuation on HRCT (Table 5Go ). Bronchioloalveolar carcinoma (BAC) was the most common histologic subtype in such nodules (range, 70 to 100%).


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  		Table 5.. Histologic Type and Natural History (Growth Rate) of Small Pulmonary Nodules With Varying Characteristics*

 

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  		Table 5A.. Continued

 
Hasegawa et al10 reported the VDT for malignant SPNs on the basis of their morphologic characteristics: 813 ± 375 days for pure ground-glass opacities, 457 ± 260 days for mixed or partial ground-glass opacities, and 149 ± 125 days for solid opacities. The same study10 found the VDT for nodules < 10 mm in diameter to be nearly double that of nodules > 2 cm (536 ± 283 days vs 299 ± 273 days). A second study33 reported VDT by tumor type but not by radiographic appearance.

What Are the Performance Characteristics of Tests for SPN Diagnosis?
An abundant body of evidence exists for the performance of positron emission tomography (PET) in the evaluation of SPN. Except for one study, the sensitivity of PET for identifying malignancy was consistently high (80 to 100%; Table 6Go ).3435363738394041424344454647484950 In contrast, the specificity of PET was lower and highly variable (40 to 100%). The point on the summary receiver operating characteristic curve that corresponded to the median specificity reported in 17 studies of PET had a sensitivity of 87% and a specificity of 82.6%.


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  		Table 6.. Performance Characteristics and Complication Rates of Tests for SPN Diagnosis: PET With 18-Fluorodeoxyglucose*

 

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  		Table 6A.. Continued

 
Other studies used a variety of radiographic techniques to differentiate benign from malignant SPNs, including HRCT and dynamic CT with nodule enhancement. The latter technology yielded the most promising results (sensitivity, 98 to 100%; specificity, 54 to 93%; Table 7 ).25515253545556 The point on the summary receiver operating characteristic curve that corresponded to the median specificity reported in seven studies of dynamic CT with enhancement had a sensitivity of 96% and a specificity of 75%.


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  		Table 7.. Performance Characteristics and Complication Rates of Tests for SPN Diagnosis: Dynamic CT With Nodule Enhancement*

 
In 11 studies3857585960616263646566 of CT-guided needle biopsy, nondiagnostic results were recorded in 4 to 41% of cases (median, 21%). Nondiagnostic biopsy results were seen in approximately 44% of patients with benign nodules (range, 0 to 89%) and 8% of patients with malignant nodules (range, 0 to 22%). In patients with biopsy results that revealed a specific malignant or benign diagnosis, sensitivity ranged from 82 to 100% (median, 97.5%). However, when nondiagnostic biopsy results were included in the false-negative column, sensitivity ranged from 65 to 94% (median, 90%). Although all but one study reported perfect specificity, some studies assumed that all positive biopsy results were true positive (Table 8 ). In the 11 studies,3857585960616263646566 the risk for pneumothorax ranged from 15 to 43% (median, 26.5%), and 4 to 18% (median, 5%) of patients required chest tube placement.


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  		Table 8.. Performance Characteristics and Complication Rates of Tests for SPN Diagnosis: CT-guided Needle Biopsy*

 
In one study67 of 118 patients with nodules that measured up to 4 cm in diameter, a combined strategy of tissue sampling (percutaneous and bronchoscopic) and radiographic observation with repeat sampling as needed yielded a sensitivity and a specificity of 100%. Further studies are needed to reproduce these promising results.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
What Is the Prevalence of SPNs?
The prevalence of SPNs (8 to 51%) and the prevalence of malignancy in patients with SPNs (1.1 to 12%) varied significantly across studies. This variation stems from the inconsistency among studies in method, enrolled population, and reporting of results.

What Is the Prevalence of Malignancy in Nodules With Varying Characteristics (Size, Morphology, and Type of Opacity)?
The prevalence of malignancy in SPNs increased in proportion to size: 0 to 1% for nodules < 5 mm, 6 to 28% for nodules 5 to 10 mm, and 64 to 82% for nodules > 20 mm. Data from six studies92122232425 of patients with incidental or screening-detected nodules showed that the risk for malignancy was approximately 20 to 30% in nodules with smooth edges; in nodules with irregular, lobulated, or spiculated borders, the rate of malignancy was higher but varied across studies from 33 to 100%. Nodules that were pure ground-glass opacities were more likely to be malignant (59 to 73%) than solid nodules (7 to 9%).

What Are the Relationships Between Growth Rates, Histology, and Other Nodule Characteristics?
BAC is the most common histologic subtype in nodules with purely or primarily ground-glass attenuation on HRCT (range, 70 to 100%). Limited data exist on the VDT of malignant SPNs.

What Are the Performance Characteristics and Complication Rates of Tests for SPN Diagnosis?
The sensitivity of PET imaging for identifying malignant SPNs was consistently high (80 to 100%), whereas specificity was lower and more variable across studies (40 to 100%). Dynamic CT with nodule enhancement yielded the most promising sensitivity (sensitivity, 98 to 100%; specificity, 54 to 93%) among imaging tests. In studies of CT-guided needle biopsy, sensitivity and specificity were excellent when biopsy yielded a specific benign or malignant results, but nondiagnostic results were seen approximately 20% of the time.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
In patients with incidentally detected SPNs, treatment goals include prompt identification of malignant nodules to permit timely surgical resection and avoidance of surgery (when possible) in patients with benign nodules. Patients with SPNs and their clinicians confront challenging treatment decisions and must weigh the risks and benefits of various treatment strategies. Our report sought answers to key questions that are frequently posed when an SPN is encountered.

Our first question addressed the prevalence of SPNs. Between-study variation in the prevalence of SPNs (Table 1) may be partially explained by the use of different radiographic techniques (eg, section thickness on CT), the varying percentage of smokers (former, current, and heavy) included in each study population, and the diverse geographic location of the studies (United States, Japan, Germany, and Italy). Other factors that can affect the prevalence of lung nodules include the technical quality of the scan and interobserver variation related to radiologists’ interpretation of the images. On the basis of nodules found on follow-up scans, Swensen et al12 reexamined baseline scans and retrospectively diagnosed new nodules in 26% of patients. Several studies commented on the appearance of new nodules and resolution of previously seen nodules during scheduled follow-up scans, further complicating the accurate determination of SPN prevalence.

Another important consideration is that these studies screened populations at higher risk for malignancy and therefore did not address the prevalence of SPN in the population at large. It remains unclear whether or how the prevalence of SPN is affected by age and smoking.

For obtaining reproducible information, it is important that future studies of SPN prevalence exclude patients with multiple nodules, as well as patients with masses that measure > 3 cm in diameter. For accurate calculation of SPN prevalence, the number of patients with at least one SPN must be reported, instead of the number of total nodules or the number of abnormal CT scans. An ideal study design would enroll a large cross-section of the population and analyze SPN rates in the overall population as well as subgroup of subjects with risk factors for lung cancer, such as smoking status, age, and sex. A study restricted to a specific geographic location would be of greatest interest to physicians in that area. Alternatively, a multicenter study could be stratified by location.

The prevalence of malignancy in detected nodules also varied across studies. A key factor that may account for these differences is the dissimilarity in the sizes of the pulmonary opacities included in each study, with larger nodules having a higher probability of malignancy.

Our second question dealt with the prevalence of malignancy in nodules with varying characteristics. A consistent finding among studies was the association between increasing nodule size and the likelihood of malignancy, as well as the exceedingly low incidence of malignancy in nodules < 5 mm in size. On the basis of this observation, the Fleischner Society3 recommends that no follow-up is necessary in patients with nodules that measure up to 4 mm in size, provided that they have no risk factors for lung cancer.

On the basis of current data, the edge and morphology characteristics of a nodule are less instructive in determining the probability of malignancy. Although there is a trend toward a lower incidence of malignancy in smooth and solid nodules, no firm conclusions can be drawn, primarily because of the lack of a standardized terminology to describe SPN morphology and the resulting inconsistency between studies.

Our third question addressed the histologic type and growth rate of small pulmonary nodules with varying characteristics. Once again, definitions, classification systems, and results differed across studies. The pure ground-glass malignant pulmonary nodule stood out as an entity that has a long VDT and is predominantly caused by BAC.

The study by Hasegawa et al10 showed that a lesion that has ground-glass attenuation and seems to be stable over a 2-year period could still be malignant, challenging the time-honored rule of 2-year radiographic stability as a sign of a benign process. Whether such lesions represent clinically important cases of lung cancer or "overdiagnosed" cases of indolent lung cancer is a question that has not been resolved.

Our last question addressed the performance characteristics and complication rates of tests for SPN diagnosis. The accurate measurement of the sensitivity and specificity of a diagnostic test requires the use of an appropriate reference standard and depends on disease prevalence. Surgical excision of a suspected malignant nodule remains the "gold standard," but the associated risk and expense demand a search for an alternative diagnostic test that is minimally invasive and accurate. At present, the most extensively studied diagnostic test is the PET scan. Data convincingly showed that PET imaging was relatively sensitive for identifying malignancy, but specificity was more variable and often poor to fair. CT-guided tissue sampling yields specific malignant diagnoses but suffers from sampling bias, which dictates additional workup if biopsy results are nondiagnostic in patients with a high pretest probability of malignancy. The associated pneumothorax rate, albeit high, infrequently leads to significant morbidity.


   Conclusions
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
Our report sought evidence related to the prevalence of SPNs, the prevalence of malignancy in patients with SPNs, characteristics of SPNs associated with malignancy, and accuracy of tests that are used for SPN diagnosis. It is clear that further research is needed to address vital questions such as the prevalence of SPNs in the population at large, the characteristics that indicate malignancy, and the best management strategy. Essential steps toward more rigorous research must include the establishment of consensus on classification schema for radiographic opacities, especially with regard to size and morphology, and collaboration among researchers to conduct large-scale clinical trials.


   Footnotes
 
Abbreviations: BAC = bronchioloalveolar carcinoma; HRCT = high-resolution CT; PET = positron-emission tomography; PLCO = Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; SPN = solitary pulmonary nodule; VDT = volume doubling time

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 30, 2007. Accepted for publication June 5, 2007.


   References
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 Materials and Methods
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 References
 

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