Evaluation and Management of the Solitary Pulmonary Nodule

DAVID OST and ALAN FEIN

North Shore University Hospital, Manhasset, New York

	INTRODUCTION

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The finding of a solitary pulmonary nodule (SPN) on a chest radiograph is a common problem in pulmonary medicine. SPNs are seen in 0.09 to 0.2% of chest radiographs and are caused by a variety of conditions, ranging from benign granulomas to lung cancer (1). Because solitary nodules are often malignant and because 5-yr survival after resection of a solitary bronchogenic carcinoma is 40 to 80%, it is important to promptly identify malignant nodules to ensure optimal treatment (4, 5). Similarly, it is important to avoid the morbidity and mortality associated with thoracotomy in patients with benign disease. Therefore, the goal of the evaluation and management of solitary pulmonary nodules is to promptly identify and bring to surgery all patients with operable malignant nodules while avoiding thoracotomy in patients with benign nodules. Traditional approaches have emphasized assessment of the probability of malignancy, the so-called Bayesian approach. The Bayesian approach estimates the prevalence of malignancy in the population, assesses risk factors predictive of malignancy as demonstrated by history and chest radiograph, and selects a management strategy based on the adjusted probability of malignancy. The development of new diagnostic tests and surgical techniques requires that this traditional approach be reevaluated. This commentary will focus on the role of newer imaging methods in this process and on strategies for SPNs of indeterminate origin.

	DEFINITION

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A solitary pulmonary nodule or "coin lesion" has been defined as a single spherical lesion completely surrounded by lung without associated atelectasis or adenopathy. In published series, the size of SPNs has varied from 1 to 6 cm. However, it is now recognized that lesions larger than 3 cm are almost always malignant; therefore, the current convention is that SPNs are 3 cm or less in diameter (6). Larger lesions should be referred to as pulmonary masses and should be managed with the understanding that they are most likely malignant; prompt diagnosis and resection are usually advisable.

	ESTIMATING THE PROBABILITY OF MALIGNANCY

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Knowledge of the causes of SPNs, the incidence of malignancy, and risk factors associated with malignancy is critical to estimating the probability of malignancy. Baseline imaging studies, including chest radiography (CXR) and computed tomography (CT), may help the clinician determine whether a lesion is likely to be malignant. Once this information is collected, the clinician can then make a clinical risk classification of the nodule as either likely to be benign, malignant, or indeterminate.

Etiology

SPNs are caused by a variety of benign and malignant processes. Of the benign lesions, 80% are caused by infectious granulomas, 10% are caused by hamartomas, and the remaining 10% are caused by a variety of rarer disorders including noninfectious granulomas and other benign tumors (9, 10).

Incidence

The incidence of malignancy in SPN varies in different series considerably based on the definition of SPN used (e.g., 1 to 6 cm), selection criteria of patients (e.g., all surgical patients), as well as the referral pattern of the study center. The incidence of malignancy therefore ranges from 10 to 68% in the literature (8).

Risk Factors

Although definitive diagnosis requires histologic analysis, a medical history can help the clinician identify those patients who are more likely to have malignant SPNs. Attention should be paid to those risk factors that have the greatest influence on the likelihood of malignancy (14). Among the many risk factors that have been studied, age, smoking history, hemoptysis, nodule size, edge characteristics on CT, and prior history of malignancy have been shown to be among the most useful. History of exposure to carcinogens, travel history to areas endemic for pulmonary mycoses, and prior pulmonary diseases are other important considerations. Sex and presence of symptoms are not associated with a higher incidence of malignancy.

Baseline Imaging

Imaging of the SPN may further help the clinician differentiate benign from malignant lesions. Baseline imaging modalities available include chest X-rays and CT.

Chest radiographs. Chest radiographs (CXR) are the primary initial imaging modality for SPNs. CXRs can provide useful information regarding nodule size, growth rate, margin characteristics, and calcification. Other findings, such as cavitation and satellite lesions are less reliable in distinguishing benign from malignant nodules.

The margin characteristic of a SPN can provide an indication of whether or not a lesion is malignant. The so-called "corona radiata" sign, with fine linear strands extending outward from the nodule, is also associated with a high probability of malignancy. In two series, this pattern accurately predicted malignancy in 88 to 94% of cases (6, 15).

Calcification within a nodule may be an indicator of a benign lesion. A laminated or central pattern is typical of a granuloma, whereas the classic "popcorn" pattern is most often seen in hamartomas. Diffuse calcification patterns are also characteristic of benign lesions. However, not all patterns of calcification are associated with a benign diagnosis. Calcification patterns that are stippled or eccentric have been associated with malignancy, and it is therefore important to differentiate these patterns from those associated with benign lesions. CT is more sensitive than plain films for detecting calcifications.

Computed tomography and high-resolution computed tomography. Chest CT supplements routine CXRs by providing better visualization of the nodule, improved sensitivity for calcification, improved sensitivity for multiple lesions, and guiding transthoracic needle aspiration biopsies (TNAB).

CT densitometry involves the measure of attenuation values, expressed in Hounsfield units (HU), to quantify the density of a nodule. CT phantoms allow identification of 35 to 55% of all subsequently identified benign lesions, and in one large multicenter trial, only one nodule identified as benign by CT phantom was later found to be malignant (6). In this study, a 264-H reference was used, which may have accounted for the low incidence of malignancy among nodules identified as benign by CT. Other investigators have found a higher false negative rate using a more conventional 185-H reference phantom (16). However, only 30% of all nodules identified as indeterminate before use of a CT phantom will be identified as benign after testing with the CT phantom. Because of this, the CT phantom is not widely used in clinical practice.

Clinical Risk Classification

After completing an initial history and physical examination, assessment of risk factors, CXR, and usually a CT scan, the clinician is able to classify the SPN into one of three categories: benign, malignant, or indeterminate.

"Benign" SPNs are those which have been demonstrated to be stable on serial CXR for 2 yr or more, have a characteristic benign calcification pattern, or are present in patients younger than 35 yr of age in the absence of other risk factors. In patients younger than age 35 with a SPN without additional risk factors, we recommend that serial CXR or CT be used to follow the SPN over time. Initially, radiographs should be taken every 3 mo for 1 yr, then every 4 to 6 mo for the second year.

"Malignant" SPNs are those considered to have a high enough probability of malignancy such that thoracotomy without any further diagnostic tests is indicated. One example would be a new nodule of large size in an older patient with a heavy smoking history and a spiculated pattern on CXR. Our approach in these cases is to use a video-assisted thoracoscopic procedure to obtain a frozen section. When a positive frozen section is obtained, the procedure is converted to a formal thoracotomy with lobectomy.

The third category, which many patients fall into, are those nodules considered to be radiologically indeterminate. After a standard evaluation including chest radiographs and CT scanning, 70 to 75% of nodules that remain indeterminate will be malignant. The management of these nodules remains controversial. Options include newer imaging techniques, doing invasive diagnostic procedures such as bronchoscopy or needle biopsy, or proceeding to thoracotomy (see Figure 1).

View larger version (22K): [in this window] [in a new window]   Figure 1.   Approach to solitary pulmonary nodules of indeterminate origin. VATS = video-assisted thoracoscopic surgery. *Lobectomy if nodule is determined to be malignant. VATS recommended if possible; in cases of prior pleural disease, this may not be possible.

Biopsy

Biopsy may help to avoid thoracotomy if a benign diagnosis is obtained; however, there is a significant risk of a false-negative result depending on the technique. The traditional options have been bronchoscopy or TNAB. Ultrathin bronchoscopy is a new technique that may be useful but is still investigational.

Bronchoscopy may be useful if the lesion is 2.0 cm or larger in size. The diagnostic yield of bronchoscopy for a SPN varies widely in the literature from 20 to 80%, depending on the size of the nodule and the incidence of malignancy in the study population (17, 18). The yield in malignant lesions depends on the size of the nodule, as well as its proximity to the bronchial tree. In nodules less than 15 mm in diameter the yield is 10%, for those 2 to 3 cm in diameter the yield is 40 to 60% (12). In lesions in which CT reveals a bronchus leading to the lesion, bronchoscopy has a 70% yield (19). Bronchoscopy is relatively low-risk, with an overall complication rate of 5%, including 3.8% incidence of pneumothorax, 1.2% hemorrhage, and 0.24% death (20). However, in the majority of patients, bronchoscopy will be of limited utility and will have a relatively low yield (12, 21).

Ultrathin bronchoscopy has been used to allow direct visualization of more peripheral lesions in smaller airways. By using quartz fibers, the size of bronchoscopes can be decreased significantly, allowing visualization of the airways to the ninth generation (22). This technique has been used experimentally, but whether this will translate into a clinically significant increase in sensitivity has yet to be determined.

Patients with SPNs less than 2.0 cm are usually not good candidates for bronchoscopy, and in these cases, TNAB should be considered. TNAB has a diagnostic yield of up to 95% in peripheral pulmonary lesions (23); for malignant lesions, sensitivity is 80 to 95% and specificity is 50 to 88% (22) The positive predictive value in one study of 222 patients by Conces and coworkers was 98.6% with a negative predictive value of 96.6% (28). TNAB is also useful in small nodules, with a diagnostic yield of over 60% in malignant nodules less than 2 cm in diameter (29). However, other series have shown a false-negative rate of 3 to 29% (23). Complication rates are higher than those of bronchoscopy, with up to a 30% incidence of pneumothorax, although many of these do not require chest tube placement. Success and complication rates are highly operator-dependent and are affected by the location of the nodule.

Lesions that do not yield a specific benign diagnosis with either bronchoscopy or TNAB require careful radiographic follow-up, additional diagnostic tests, or thoracotomy because of the number of false-negative results. The false-negative rate will be very dependent upon the baseline probability of malignancy. In areas where there is a high prevalence of endemic mycosis or in an otherwise low-risk patient, a negative TNAB may be sufficient to justify a strategy of radiographic follow-up. If the pretest probability of malignancy is high, then the false-negative rate will be too high to exclude malignancy. In this type of population, the utility of TNAB will be much less. TNAB might be useful in this setting for those patients who refuse surgery unless a specific diagnosis of cancer can be established or for those patients with very high surgical risk.

Thoracotomy

This is the most definitive method for determining the diagnosis in patients with SPNs. Thoracotomy in patients with malignant nodules carries an operative mortality of 3 to 7%. Resectability rates for SPN range from 80 to 100%. Resection of benign nodules carries a mortality of less than 1% (7).

Recent advances in endoscopic surgical techniques have made thoracoscopic resection of pulmonary nodules an option in selected patients at some centers. Video-assisted thoracoscopic surgery (VATS) offers the potential benefits of lower perioperative morbidity and decreased length of hospital stay (30). Available data suggest that VATS may be most successful for peripheral lesions and some central lesions in the lower lobe (30). Conversion to open thoracotomy is required in up to 24% of cases (30).

New Imaging Techniques

Contrast-enhanced CT. Newer techniques have utilized the degree of contrast enhancement on spiral CT to differentiate benign from malignant lesions. The blood supply of malignant lesions is both qualitatively and quantitatively different from that of benign lesions. These differences have been documented in terms of vascularity, pharmacodynamics, and metabolism. Littleton and coworkers first reported that conventional tomograms using intravenous contrast enhancement could potentially distinguish benign from malignant lesions (33). Other investigators have subsequently used the degree of contrast enhancement on CT to assess the likelihood of malignancy (34) Using an attenuation of 20 HU as the threshold for a positive test, sensitivity and specificity for malignancy was 95 to 100% and 70 to 93%, respectively (39).

False-negative and false positive results have been reported with this technique. The use of the ratio of SPN-to-aorta enhancement has been proposed as one way to minimize the number of false-negative results. In a study by Zhang and Kono, no malignant nodules had a SPN-to-aorta ratio less than 6% (39). This ratio may be complementary to the 20-HU threshold value for identifying malignant nodules and may minimize the false-negative rate. False-positive results have also been reported, primarily associated with inflammatory nodules (34). Using the SPN-to-aorta ratio or the 20-HU threshold does not always discriminate between inflammatory and malignant lesions, because both are associated with increased contrast uptake. Further differentiation may be possible by assessing the precontrast attenuation, enhancement patterns on dynamic CT scans, and appearance of the time- attenuation curve (39). Inflammatory lesions have decreased precontrast attenuation, more frequent irregular peripheral enhancement, and more rapid time-attenuation curve decline compared with malignant lesions. This technique, although promising, is not yet in widespread use and awaits further validation. Whether or not this technique offers any additional information when compared with positron emission tomography (PET) scanning is not clear. The ability to differentiate benign from malignant lesions during one test as well as the widespread availability of spiral CT makes this an attractive alternative.

Positron emission tomography. PET uses uptake of 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) to measure glucose metabolism in different tissues. Importantly, it has been demonstrated that there is increased uptake of FDG by lung tumors compared with normal tissue. A number of investigators have used this to differentiate benign from malignant SPNs (40). The sensitivity and specificity of PET for malignancy was 89 to 100% and 79 to 100%, respectively. Diagnostic accuracy was excellent, ranging from 89 to 100% (40). False-negatives can occur, most notably in association with bronchioloalveolar carcinoma, carcinoids, and in tumors less than 10 mm in diameter (48, 49). Some gamma cameras can now be converted to add PET capability, but whether or not these modified gamma cameras have equivalent sensitivity, specificity, and spacial resolution requires further study at this time.

As with other diagnostic tests, the negative and positive predictive value of PET will depend upon the prevalence of malignancy in the population being studied. Therefore, the pretest probability of malignancy is important in determining the optimal management strategy and impacts directly on the utility of PET in the diagnosis of SPNs.

The impact of PET on diagnosis of SPN has been studied using decision analysis. In a study by Dewan and coworkers, PET imaging alone was superior to the traditional Bayesian approach or PET combined with the Bayesian approach in correctly classifying lesions as benign or malignant (47). A decision-analysis model to assess cost-effectiveness also found that a CT-plus-PET strategy was often superior to conventional approaches (50). In this analysis, one of the major benefits of PET, offsetting its high cost, was a reduction in the number of patients who went to surgery. Depending upon the pretest probability of malignancy, PET decreased surgical procedures by an estimated 15%. The total estimated cost savings of the CT-plus-PET strategy ranged from $91 to $2,200 per patient in this study (50).

Importantly, the most cost-effective strategy for SPN evaluation was dependent upon the pretest probability of malignancy. The CT-plus-PET strategy had the most favorable incremental cost-effectiveness ratio (ICER) when the pretest probability of having a malignant nodule was 0.12 to 0.69 (50). When the pretest probability was less than 0.12, a wait-and-watch strategy proved to have the best ICER. If the pretest probability of malignancy was between 0.69 and 0.90, a CT strategy followed by either biopsy or surgery was best, and when the pretest probability was greater than 0.90, a surgical strategy was best (50).

Another potential benefit of PET imaging is detection of occult metastases and improved staging. The diagnostic approach to the SPN typically emphasizes distinguishing benign from malignant disease. It is important to realize that concurrent with this process the clinician is staging the disease to determine the appropriate treatment. PET offers the advantage of simultaneous diagnostic and staging information. Although most patients with a SPN do not have evidence of metastatic disease at presentation by CT, up to 14% of patients otherwise eligible for surgery will demonstrate occult extrathoracic disease upon subsequent whole-body PET imaging (51, 52). Similarly, a patient without mediastinal adenopathy by CT scan may have occult nodal involvement. The sensitivity and specificity of CT scans for mediastinal lymph node involvement are 55 to 88% and 76 to 85%, respectively (53). The sensitivity and specificity of PET in the presence of abnormal lymph nodes on CT are 94% and 82%, respectively (64). Importantly, PET sensitivity is not independent of CT. This means that the sensitivity of PET for detecting metastatic disease is different depending upon whether there is mediastinal lymph node enlargement on CT. In the absence of abnormal lymph node enlargement on CT, the sensitivity decreases and the specificity increases. In this setting, the sensitivity and specificity of PET are 64% and 97%, respectively (64). In most studies, PET has been complementary to CT in staging disease and assessing lymph node involvement (65, 66). In one prospective study, CT had a diagnostic accuracy of 64%, PET 88%, and the combination of CT + PET 96% (65). In the setting of a SPN without significant adenopathy on CT, the complementary relationship between CT and PET might be significantly less, because much of the added value for staging of lymph nodes comes from the ability to distinguish hilar from subaortic lymph nodes and paramediastinal tumors from tracheobronchial lymph nodes. In addition, a PET scan that demonstrates increased uptake in mediastinal lymph nodes may also represent a false positive, so any positive result should prompt further invasive staging to prove that the patient is unresectable. However, given these limitations, the ability to detect occult mediastinal lymph node involvement may still be of clinical value.

Choice of Strategy for the Indeterminate Nodule

In this group of patients, management decisions can be clarified by asking two additional questions. First, what is the patient's surgical risk and is this acceptable given the probability of malignancy? For patients with little surgical risk, a lower probability of malignancy may be sufficient to facilitate the decision to proceed to thoracotomy. Conversely, in those with high surgical risk, additional diagnostic testing may be warranted to justify the surgical risk. Thus, the threshold for this decision depends not only on the probability of malignancy, but also on the surgical risk for that patient (see Figure 1).

Second, if a diagnostic technique is ordered, will a negative result alter the treatment plan or will the patient still go to surgery? Additional diagnostic tests are most useful if a negative result would be sufficient for the clinician to elect a strategy of careful observation. If there would be no change in the treatment plan irrespective of the diagnostic result, then proceeding to surgery is an acceptable choice.

Based on the literature and on cost-effectiveness analysis, our preferred approach to patients with indeterminate nodules favors PET scanning. PET scanning allows more precise risk stratification for patients with indeterminate nodules. For older patients with concurrent medical illnesses, where the surgical risk may be significantly increased, avoiding unnecessary surgery is important. If the PET scan is negative, a strategy of serial CT scan follow-up is justified. Similarly, a positive PET scan justifies the risk associated with surgery because malignancy is likely. In other cases, there may be little absolute difference between strategies. For patients without comorbidities but with a relatively high risk of cancer, early thoracotomy is still an option. As Cummings and associates have emphasized, additional factors, such as patient preference, are important in cases when the potential differences between choice of strategies are likely to be small (67).

	SUMMARY

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The approach to the SPN involves a careful evaluation of the patient, beginning with a history and physical examination with particular attention to risk factors for malignancy. Old CXRs should be obtained and a CT scan is usually indicated if the nodule is not demonstrated to be stable for 2 yr or more. Additional imaging with CT with contrast infusion or PET, or both, may help to further define the nodule. An estimate of the probability of malignancy is then made and a strategy of observation, biopsy, or thoracotomy is chosen on the basis of the probability of malignancy, as well as an individual assessment of the patient. Future developments need to improve case finding techniques, to assess the impact of newer technologies on decision analysis, and to integrate this with the effect of new multimodality treatments for lung cancer.

	Footnotes

Correspondence and requests for reprints should be addressed to David Ost, M.D., North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. E-mail: dost{at}nshs.edu

(Received in original form December 28, 1998 and in revised form February 11, 2000).

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