Chest
Volume 132, Issue 3, Supplement, September 2007, Pages 108S-130S
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DIAGNOSIS AND MANAGEMENT OF LUNG CANCER: ACCP GUIDELINES (2ND EDITION)
Evaluation of Patients With Pulmonary Nodules: When Is It Lung Cancer?: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

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Background

Pulmonary nodules are spherical radiographic opacities that measure up to 30 mm in diameter. Nodules are extremely common in clinical practice and challenging to manage, especially small, “subcentimeter” nodules. Identification of malignant nodules is important because they represent a potentially curable form of lung cancer.

Methods

We developed evidence-based clinical practice guidelines based on a systematic literature review and discussion with a large, multidisciplinary group of clinical experts and other stakeholders.

Results

We generated a list of 29 recommendations for managing the solitary pulmonary nodule (SPN) that measures at least 8 to 10 mm in diameter; small, subcentimeter nodules that measure < 8 mm to 10 mm in diameter; and multiple nodules when they are detected incidentally during evaluation of the SPN. Recommendations stress the value of risk factor assessment, the utility of imaging tests (especially old films), the need to weigh the risks and benefits of various management strategies (biopsy, surgery, and observation with serial imaging tests), and the importance of eliciting patient preferences.

Conclusion

Patients with pulmonary nodules should be evaluated by estimation of the probability of malignancy, performance of imaging tests to characterize the lesion(s) better, evaluation of the risks associated with various management alternatives, and elicitation of patient preferences for treatment.

Section snippets

Materials and Methods

To update previous recommendations on the evaluation of patients with pulmonary nodules,3 guidelines on lung cancer diagnosis and management that were published between 2002 and May 2005 were identified by a systematic review of the literature (see “Methodology for Lung Cancer Evidence Review and Guideline Development” chapter). Those guidelines, which include recommendations that are specific to the treatment of patients with pulmonary nodules, were identified for inclusion in this chapter.

SPNs

The SPN is commonly encountered in both primary care and specialty settings. Most lung nodules are detected incidentally on CXRs or CT scans that are obtained for some other purpose. In one study5 from the 1950s, an SPN was found in 1 of 500 CXRs (0.2%) that were obtained in community settings. More recently, almost 7% of 1,000 healthy volunteers in New York who participated in the Early Lung Cancer Action Project6 were found to have between one and three nodules on baseline screening CXR. In

Recommendation

  • 1

    In every patient with an SPN, we recommend that clinicians estimate the pretest probability of malignancy either qualitatively by using clinical judgment or quantitatively by using a validated model. Grade of recommendation, 1C

Imaging Tests

Pulmonary nodule diagnosis begins with imaging studies. CXR and CT are useful and widely available. Recent attention has focused on contrast-enhanced CT and FDG-PET. MRI plays a limited role, if any, in most patients.

CXR

SPN diagnosis should begin with a careful review of the CXR. Nodules located within the chest should be seen in more than one radiographic view, although it is sometimes difficult to visualize nodules in the lateral projection. Occasionally, nipple shadows or articular surfaces of ribs can masquerade as pulmonary nodules. In these cases, the use of nipple markers or apical lordotic projections may help to distinguish normal anatomic structures from abnormal nodular parenchymal lesions.

Depending

Recommendations

  • 2

    In every patient with an SPN that is visible on CXR, we recommend that previous CXRs and other relevant imaging test be reviewed. Grade of recommendation, 1C

  • 3

    In patients who have an SPN that shows clear evidence of growth on imaging tests, we recommend that tissue diagnosis be obtained unless specifically contraindicated. Grade of recommendation, 1C

  • 4

    In a patient with an SPN that is stable on imaging tests for at least 2 years, we suggest that no additional diagnostic evaluation be performed,

Chest CT

Because of lack of superimposition of normal structures, CT is both more sensitive and more specific than CXR for detecting nodules. The likelihood of nodule detection increases with use of thinner slice thickness. Single-arm prospective studies6, 47 of CT screening in high-risk participants found one or more nodules in approximately 25% of participants when 10-mm collimation was used. In contrast, approximately 50% of participants were found to have one or more nodules when 1.25- to 5-mm

Recommendations

  • 6

    In every patient with an indeterminate SPN that is visible on CXR, we recommend that CT of the chest be performed, preferably with thin sections through the nodule. Grade of recommendation, 1C

  • 7

    In every patient with an indeterminate SPN that is visible on chest CT, we recommend that previous imaging tests be reviewed. Grade of recommendation, 1C

  • 8

    In a patient with normal renal function and an indeterminate SPN on CXR or chest CT, we recommend that CT with dynamic contrast enhancement be considered

MRI

MRI has a very limited role in the evaluation of the SPN. Dynamic gadolinium-enhanced MRI of lung nodules has been shown to be nearly comparable to contrast-enhanced CT for differentiating benign from malignant nodules: however, this technique remains experimental because of a lack of consensus regarding standardization.71, 72 Consequently, MRI is not indicated in the workup of the SPN outside investigational settings.

FDG-PET

In this chapter, recommendations address the use of FDG-PET for characterizing SPNs. Recommendations regarding the related issue of when to use FDG-PET for lung cancer staging are presented in these guidelines in the “Noninvasive Staging of Non-small Cell Lung Cancer” chapter.

FDG-PET is a noninvasive functional imaging test that is widely used in clinical oncology for tumor diagnosis, disease staging, and evaluation of treatment response.73, 74 FDG is taken up selectively by malignant tumor

Recommendations

  • 9

    In patients with low-to-moderate pretest probability of malignancy (5 to 60%) and an indeterminate SPN that measures at least 8 to 10 mm in diameter, we recommend that FDG-PET imaging be performed to characterize the nodule. Grade of recommendation, 1B

  • 10

    In patients with an SPN that has a high pretest probability of malignancy (> 60%) or patients with a subcentimeter nodule that measures < 8 to 10 mm in diameter, we suggest that FDG-PET not be performed to characterize the nodule. Grade of

Management Strategies

Once imaging tests have been performed, management alternatives include surgery, transthoracic needle or bronchoscopic biopsy, and observation with serial radiographs, or “watchful waiting.” Each of these approaches has advantages and disadvantages. Surgery is the diagnostic “gold standard” and the definitive treatment for malignant nodules, but surgery should be avoided in patients with benign nodules. Biopsy often establishes a specific benign or malignant diagnosis, but biopsy is invasive,

Shared Decision Making and Patient Preferences

Because different management strategies are associated with similar expected outcomes in many patients with lung nodules, patient preferences should be elicited and used to guide decisions. Some patients may be uncomfortable with adopting a strategy of observation when told that a potentially cancerous lung nodule is present. Others are similarly risk averse about undergoing surgery unless they are certain that cancer is present. All patients should be provided with an estimate of the

Recommendation

  • 11

    In every patient with an SPN, we recommend that clinicians discuss the risks and benefits of alternative management strategies and elicit patient preferences. Grade of recommendation, 1C

Observation or Watchful Waiting

In some patients with lung nodules, observation with serial imaging tests may be used as a diagnostic tool. When this strategy is used, detection of growth at any time is presumptive evidence of malignancy, and surgical resection should be performed in patients who are operative candidates. Two-year radiographic stability is strong presumptive evidence of a benign cause. Because it may be difficult to detect growth in nodules on plain CXRs, CT is usually preferred. Although it may be possible

Recommendations

  • 12

    In patients who have an indeterminate SPN that measures at least 8 to 10 mm in diameter and are candidates for curative treatment, observation with serial CT scans is an acceptable management strategy in the following circumstances: (1) when the clinical probability of malignancy is very low (< 5%); (2) when clinical probability is low (< 30 to 40%) and the lesion is not hypermetabolic by FDG-PET or does not enhance > 15 HU on dynamic contrast CT; (3) when needle biopsy is nondiagnostic and the

Transthoracic Needle Aspiration Biopsy

Needle biopsy of the SPN is usually performed under the guidance of fluoroscopy or, more common, CT. Few studies of needle biopsy have been performed under fluoroscopic guidance and limited enrollment to participants with pulmonary nodules. In one study94 with a very high prevalence of malignancy, a diagnosis was made by fluoroscope-guided needle biopsy in 84% of patients with nodules that measured 2 to 4 cm in diameter. However, in two other studies95, 96 with a lower prevalence of malignancy,

Bronchoscopy

Bronchoscopy is an excellent tool for sampling central airway lesions, mediastinal nodes, and parenchymal masses. Traditionally, bronchoscopy has played a limited role in SPN management outside investigational settings. Diagnostic yields with fluoroscope-guided bronchoscopy for malignant, peripheral pulmonary nodules that measure < 2 cm in diameter have consistently been in the range of 10 to 50%.100, 101, 102, 103 The likelihood of obtaining a specific benign diagnosis is even lower. The

Recommendation

  • 14

    In patients who have an indeterminate SPN that measures at least 8 to 10 mm in diameter and are candidates for curative treatment, it is appropriate to perform a transthoracic needle biopsy or bronchoscopy in the following circumstances: (1) when clinical pretest probability and findings on imaging tests are discordant; for example, when the pretest probability of malignancy is high and the lesion is not hypermetabolic by FDG-PET; (2) when a benign diagnosis that requires specific medical

Surgery

Surgical resection is the “gold standard” diagnostic test and can often be therapeutic. However, only one flawed and inconclusive randomized, controlled trial117, 118, 119 has compared surgery alone with an alternative treatment in patients with resectable lung cancer. The decision to include surgery as part of the diagnostic strategy for the SPN must take into account the benefits of definitive diagnosis and treatment when compared with the surgical risk. Video-assisted thorascopic surgery,

Recommendations

  • 15

    In surgical candidates with an indeterminate SPN that measures at least 8 to 10 mm in diameter, surgical diagnosis is preferred in most circumstances, including the following: (1) when the clinical probability of malignancy is moderate to high (> 60%); (2) when the nodule is hypermetabolic by FDG-PET imaging; (3) when a fully informed patient prefers undergoing a definitive diagnostic procedure. Grade of recommendation, 1C

  • 16

    In patients who have an indeterminate SPN in the peripheral third of the

Patients Who Are Not Surgical Candidates

Management is uncertain in patients who have an SPN and refuse surgery or are judged to be at unacceptably high risk for complications from even a limited pulmonary resection. No randomized trials have compared early treatment before the development of symptoms vs later treatment when symptoms develop. Discussion of potential risks and benefits with patients is limited by the paucity of data. For patients who prefer treatment, the diagnosis of lung cancer should first be confirmed by biopsy

Recommendations

  • 20

    For the patient who has an SPN and is not a surgical candidate and prefers treatment, we recommend that the diagnosis of lung cancer be confirmed by biopsy, unless contraindicated. Grade of recommendation, 1C

  • 21

    For the patient who has a malignant SPN and is not a surgical candidate and prefers treatment, we recommend referral for external-beam radiation or to a clinical trial of an experimental treatment such as stereotactic radiosurgery or radiofrequency ablation. Grade of recommendation, 2C

Small Subcentimeter Pulmonary Nodules

Subcentimeter nodules measure < 8 to 10 mm in diameter, can be solitary or multiple, and are usually detected incidentally on a CT scan that has been ordered for some other reason. As is true for larger nodules, the likelihood of malignancy depends on patient risk factors, nodule size, and certain morphologic characteristics.

Predictors of Malignancy

Patient characteristics have been incompletely studied as predictors of malignancy in individuals with subcentimeter nodules. In the Lung Screening Study,151 abnormal findings on a single low-dose CT screening examination were more common in current smokers and individuals who were at least 65 years of age. The likelihood of malignancy is probably highest in current smokers and lowest in nonsmokers who have nodules that are comparable in size. Extrapolation from studies in patients with larger

Size

Studies of CT screening in volunteers at risk for lung cancer confirm a strong association between nodule diameter and the likelihood of malignancy.4 Data from baseline screening in three US trials49, 151, 152 of low-dose CT show that the probability of malignancy is extremely low (< 1%) in prevalent nodules that measure < 5 mm in diameter. For nodules that measure 5 to 9 mm in diameter, the prevalence of malignancy varies from 2.3 to 6%.151, 152 In one Japanese study,130 the prevalence of

Morphology

In the past decade, we have witnessed a remarkable change in CT terminology to describe the morphology of lung nodules. Morphologic characteristics of small nodules can be visualized by high-resolution CT with thin (approximately 1 mm) slices through the target nodule. On the basis of observations from recent lung cancer screening trials,4 it is now appreciated that nodules may be characterized as solid, partly solid, or pure ground-glass opacities (defined as focal densities in which

Management Strategies

The optimal approach to the management of subcentimeter nodules remains problematic. Expert consensus-based guidelines for radiographic follow-up in patients with small pulmonary nodules were published by members of the Fleischner Society,165 who concluded that the follow- up should be less frequent and often shorter in duration than in patients with larger nodules.

Decisions about the frequency and duration of follow-up for patients with subcentimeter nodules need to weigh multiple

Recommendations

  • 22

    For surgical candidates who have subcentimeter nodules and no risk factors for lung cancer, the frequency and duration of follow-up (preferably with low-dose CT) should depend on the size of the nodule. We suggest the following: (1) that nodules that measure up to 4 mm in diameter not be followed up, but the patient must be fully informed of the risks and benefits of this approach; (2) that nodules that measure > 4 to 6 mm be reevaluated at 12 months without additional follow-up if unchanged;

Recommendations

  • 23

    For surgical candidates who have subcentimeter nodules and one or more risk factors for lung cancer, the frequency and duration of follow-up (preferably with low-dose CT) should depend on the size of the nodule. We suggest the following: (1) that nodules that measure up to 4 mm in diameter be reevaluated at 12 months without additional follow-up if unchanged; (2) that nodules that measure > 4 to 6 mm be followed up sometime between 6 and 12 months and then again between 18 and 24 months if

Multiple Nodules

Multiple nodules and the solitary nodule have similar causes, although for multiple nodules, metastatic disease is the most likely malignant diagnosis and active infectious or inflammatory granulomatous disease is the most likely benign cause. A detailed discussion of diagnosis and treatment in these patients is beyond the scope of this chapter; however, the diagnosis can usually be established by a combination of serologic testing, sputum analysis, bronchoscopy with biopsy or bronchoalveolar

Patients With One or More Additional Nodules Detected During SPN Evaluation

In patients with a known or suspected lung cancer on CXR, CT will frequently identify one or more additional nodules. Studies indicate that most of these additional nodules are benign. A study171 from Japan showed that 10% of patients with suspected lung cancer had a second nodule detected during subsequent evaluation, and 60% of these were benign at surgery. Similarly, Keogan et al172 reported that CT detected a second, indeterminate nodule in 16% of patients with clinically operable stage I

Recommendation

  • 26

    In patients who are candidates for curative treatment for a dominant SPN and one or more additional small nodules, we recommend that each nodule be evaluated individually, as necessary, and curative treatment not be denied unless there is histopathologic confirmation of metastasis. Grade of recommendation, 1C

Solitary Metastasis

In patients with an active or previous extrapulmonary cancer, the SPN can represent a metastasis, a primary lung cancer, or benign disease. Determining the cause of the nodule is important so that appropriate therapy can be offered.

Pulmonary metastasectomy has been offered to selected patients who have an SPN in the setting of an extrapulmonary malignancy because of the potential for cure.175, 176, 177, 178, 179, 180, 181, 182, 183, 184 In this group, 60 to 80% of nodules will be malignant, and

Recommendation

  • 27

    In surgical candidates with a solitary pulmonary metastasis, we recommend that pulmonary metastasectomy be performed when there is no evidence of extrapulmonary malignancy and there is no better available treatment. Grade of recommendation, 1C

Solitary Nodule Caused by Small Cell Carcinoma

SCLCs represent approximately 15 to 20% of all primary lung cancers,203 and 90% of these patients have regional lymph node involvement or metastatic disease at initial presentation.204 Infrequently, surgical resection of an undiagnosed lung nodule reveals the presence of SCLC. Surgery should also be considered in patients who have known SCLC and present with an SPN and no evidence of regional or distant metastasis. In one older study,205 multimodality treatment with surgery and adjuvant

Recommendations

  • 28

    In surgical candidates with an SPN that has been diagnosed as SCLC, we recommend surgical resection with adjuvant chemotherapy, provided that noninvasive and invasive staging exclude the presence of regional or distant metastasis. Grade of recommendation, 1C

  • 29

    In patients who have an SPN and in whom SCLC is diagnosed intraoperatively, we recommend anatomic resection (with systematic mediastinal lymph node sampling or dissection) under the same anesthesia when there is no evidence of nodal

Conclusions

The classical SPN is a common and vexing problem. Patients with an SPN should be evaluated by review of old films, estimation of the probability of malignancy, performance of imaging tests to characterize the nodule better, evaluation of the risks associated with various treatment alternatives, and elicitation of patient preferences for treatment. Subcentimeter nodules are becoming increasingly prevalent, and we still have much to learn about their biology and behavior, although it is already

Acknowledgment

We are indebted to the authors of the First Edition of the ACCP Lung Cancer Guidelines for their contributions to this article. We thank Ellen Schultz for assistance with manuscript preparation.

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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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