Review
Diagnosis and management of pulmonary nodules Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Expert Rev. Respir. Med. 8(6), 677–691 (2014)
Rebecca Krochmal1, Sixto Arias2, Lonny Yarmus2, David Feller-Kopman2 and Hans Lee*2 1 Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, 110 South Paca Street, Second Floor, Baltimore, MD 21201, USA 2 Section of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Zayed Building 7125L, Baltimore, MD 21287, USA *Author for correspondence: [email protected]
informahealthcare.com
There are an increased number of pulmonary nodules discovered on CT scan images in part due to those performed for lung cancer screening. Risk stratification and patient involvement is critical in determining management ranging from interval imaging to invasive biopsy or surgery. A definitive diagnosis requires tissue biopsy. The choice of a particular biopsy technique depends on the risks/benefits of the procedure, the diagnostic yield and local expertise. This review will focus on the evaluation and management of pulmonary nodules based on the Fleischner Society and American College of Chest Physician guidelines. There have been recent changes to both societies’ recommendations for incidental detection of solid and subsolid nodules, risk stratification, imaging, minimally invasive diagnostic techniques and definitive surgical options. KEYWORDS: bronchoscopy • CT screening • lung cancer • solitary pulmonary nodule • transthoracic needle biopsy • VATS
Approximately 67 million computed tomographies (CT) are currently performed annually in the USA [1]. With the results of the National Lung Screening Trial (NLST) showing a significant improvement in mortality in selected patients at high risk for lung cancer, and CT screening being suggested by many cancer societies and the US Preventive Services Task Force (USPSTF), the number of chest CTs, and incidentally found pulmonary nodules are likely to increase significantly in the coming years [2,3]. Pulmonary nodules are defined as an individual, well-circumscribed radiographic opacity up to 3 cm in diameter completely surrounded by aerated lung [4]. The incidental finding of pulmonary nodules on CT scans represents a challenge to clinicians as the large majority (even in highrisk populations) will be benign; however, the opportunity to diagnose an early/curable stage of lung cancer would not want to be missed. This needs to be weighed against the risk of complications from an unnecessary invasive biopsy or surgery for non-cancerous pulmonary nodules as well as the anxiety produced by both the finding of the nodule and its evaluation. The decision-making for any patient with a pulmonary nodule starts with risk stratification and patient counseling on the risks and benefits of different management strategies. Recently, two major societies have revised their guideline recommendations: American College of Chest 10.1586/17476348.2014.948855
Physicians (ACCP) (2013) and Fleischner Society (2005) [5–7]. We will review the latest management strategies based on these guidelines, as well as their subtle differences, and detail options for further diagnostic management. Risk stratification
The management of patients with pulmonary nodules starts with risk stratification through patient history and review of current/prior imaging. Given the fact that lung cancer remains the second most commonly diagnosed malignancy among men and women and the leading cause of cancer deaths among both sexes, there is a continued need to risk-stratify pulmonary nodules to guide diagnosis and future management [8]. This is especially true since when diagnosed at an early stage, lung cancer is potentially a curable disease [9]. However, patient preference must be an integral component of decision-making. Those with limited life expectancy and significant comorbidities may choose to forgo further evaluation. In others, the anxiety of just a mere potential of cancer can be an emotional burden and these patients may benefit from a more direct diagnostic strategy. Whether it is detected incidentally or on lung cancer screening, the abnormality may lead to a significant level of stress and a reduction in health-related quality of life [10]. Wiener et al. noted a variety
2014 Informa UK Ltd
ISSN 1747-6348
677
Review
Krochmal, Arias, Yarmus, Feller-Kopman & Lee
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Table 1. Models to estimate clinical probability of malignancy of incidentally detected pulmonary nodules. Model
Study sample
Nodule size and imaging
Independent predictors of malignancy
OR (95% CI)
Comments
Mayo Clinic
Retrospective review of 419 patients at single center without previous history of lung cancer Mean age 65 years in those with malignant nodules
4–30 mm 23% prevalence of malignancy Chest radiography
Age (per year) Prior or current smoking history Remote history (>5 years) of extrathoracic malignancy Diameter (mm) Upper lobe location Spiculation
1.0 (1.0–1.1) 2.2 (1.2–4.2) 3.8 (1.4–10.5) 1.13 (1.1–1.2) 2.2 (1.3–3.8) 2.8 (1.5–5.5)
No mention of nodule attenuation Model accuracy good (AUC of ROC 0.83 ± 0.02)
[12]
Veterans Affairs
Prospective analysis of 375 patients (98% men) at 10 VA medical centers Mean age 65.9 ± 10.7 years
7–30 mm 54% prevalence of malignancy Chest radiography and PET scan
Age (per 10 years) Prior or current smoking history Diameter (mm) Time since smoking cessation (per 10 years)
2.2 7.9 1.1 0.6
No mention of nodule attenuation Model accuracy good (AUC of ROC 0.79; 95% CI: 0.74–0.84)
[13]
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Analysis of 12,314 patients of 77,465 patients enrolled in intervention arm of PLCO screening trial at 10 sites
1–30 mm, lung mass >30 mm, pleural mass, hilar or mediastinal lymphadenopathy excluding calcified lymph nodes, major atelectasis or infiltrate defined as consolidation or alveolar opacity 1.9% prevalence of malignancy Chest radiography
Education (none vs some or higher) Duration of smoking (per 20 years) Pack-years (per 20 pack-years) BMI (‡30 vs 8
3, 9 and 24 months if low or high risk
Contrast-enhanced CT, PET CT and/or biopsy may be considered
American College of Chest Physician Solid
£4
None
With or without risk factors for lung cancer§
Solid
>4–6
12 months
If no risk factors for cancer
Solid
>4–6
Between 6 and 12 months then 18 and 24 months
If risk factors for cancer
Solid
>6–8
Between 6 and 12 months then at 18–24 months
If no risk factors for cancer
Solid
>6–8
Between 3 and 6 months then 9–12 months and finally at 24 months if unchanged
If risk factors for cancer
†
Low risk includes a minimal or absent smoking history or other risk factors. High risk includes a history of smoking or other risk factors. Lung cancer risk factors include a smoking history and previous history of lung cancer. CT: Computed tomography. Adapted from [5,7]. ‡ §
follow-up imaging should be performed without need for additional screening if stable. Twelve-month follow-up for 4–6 mm solid pulmonary nodules should be performed, again in patients without risk factors. If risk factors for lung cancer are present, 4–6 mm solid pulmonary nodules should be followed at 6–12 months and again at 18–24 months if stable. Finally, solid pulmonary nodules measuring 6–8 mm necessitate repeat imaging at 6–12 months then again at 18–24 months, if stable in those without lung cancer risk factors. In those with one or more risk factors, repeat imaging should occur at 3–6 months, 9–12 months and finally at 24 months, if stable as per the ACCP guidelines (TABLE 3). Such recommendations are based partly on studies of lowdose CT screening showing a less than 1% probability of malignancy in pulmonary nodules 5
3 months then annually for 3–5 years
Part-solid
£5 (solid component)
Not specifically mentioned
If neoplastic, considered minimally invasive adenocarcinoma with near 100% disease-free survival if surgically resected
Part-solid
>5 (solid component)
3 months to confirm persistence
Malignant until proven otherwise Measure solid component PET/CT for nodules >10 mm Biopsy or surgical resection if part-solid component persistent and ‡5 mm
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Fleischner Society
American College of Chest Physician Pure ground glass
£5
None
3 month follow-up if >10 mm; biopsy and/or surgery is persists
Pure ground glass
>5
Annual follow-up for at least 3 years
If interval growth or development of solid component, proceed with non-surgical biopsy or surgical resection
Part-solid
£8 (entire nodule)
3, 12 and 24 months then annually for 1–3 years
If interval increase, likely malignant and necessitates consideration for surgical resection versus non-surgical biopsy
Part-solid
>8 (entire nodule)
3 months to confirm persistence
If persistent, PET, non-surgical biopsy and/or surgical resection If initially >15 mm, proceed directly to PET, non-surgical biopsy and/or surgical resection
CT: Computed tomography.
low- and high-risk patients with consideration for contrastenhanced CT, PET and/or biopsy if interval growth is noted. Neither the ACCP nor the Fleischner Society recommendations advocate for use of low-dose CT for follow-up imaging of the nodule in question, however, this could be considered to minimize radiation exposure. TABLE 3 notes the differences between the current ACCP and the Fleischner Society guidelines for solid pulmonary nodules. Subsolid pulmonary nodules
The new Fleischner Society guidelines for subsolid pulmonary nodules differentiate ground glass opacities through which parenchymal structures may be visualized from those with a concomitant solid component. As such, typical ground glass opacities are referred to as pure ground glass nodules (GGN) and those with obscuring of underlying parenchymal architecture as well as a solid component as part-solid GGNs. Pure and part-solid GGNs together comprise subsolid pulmonary nodules. Solitary pulmonary nodules, whether pure or partsolid, must be distinguished from multiple nodules. In comparison, the ACCP guidelines note part-solid pulmonary nodules to be those with a solid component and more than 50% ground glass opacity. 682
The removal of previous smoking history as a risk factor in the new Fleischner Society guidelines for subsolid pulmonary nodules should be noted. This is due to previous data demonstrating a lack of necessity for different management guidelines in patients with and without risk factors [47]. However, risk stratification based on a history of tobacco dependence remains an integral component of both the Fleischner Society and the ACCP guidelines for solid pulmonary nodules (TABLE 4). Subsolid pulmonary nodule size is a distinguishing characteristic of the new Fleischner Society guidelines. Solitary pure GGNs £5 mm in size do not necessitate follow-up CT surveillance (grade IC recommendation), based on data demonstrating stable or indolent progression of atypical adenomatous hyperplasia (AAH) to carcinoma [48]. The ACCP guidelines are the same. However, solitary pure GGNs >5 mm should have followup imaging in 3 months to confirm persistence then annual follow-up imaging thereafter for a minimum of 3 years (grade IB recommendation per the Fleischner Society guidelines). Somewhat similarly, there is a grade 2C recommendation from the ACCP for yearly CT surveillance for at least 3 years with the caveat that those >10 mm may necessitate early follow-up at 3 months. It has been suggested that overdiagnosis of benign Expert Rev. Respir. Med. 8(6), (2014)
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Diagnosis & management of pulmonary nodules
or unchanged pulmonary nodules that may be isolated foci of AAH, adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma may be avoided with sequential imaging [49]. Such recommendations are rooted in evidence that suggests that persistent pure GGNs may be benign in up to 20% of cases, but may also be manifestations of preinvasive AAH or AIS [50,51]. Invasive adenocarcinoma is greater in pure GGNs >10 mm, with reports varying from 10 to 50% [51–54]. Additionally, pulmonary nodule size >10 mm and a history of lung cancer have been shown to predispose to interval growth [55]. Similar to solid pulmonary nodules, large pure GGNs have also been found to be more likely to be invasive [50,52]. A 3-month follow-up CT scan should be performed to confirm persistence, given the fact that both pure and part-solid GGNs may resolve in the interim [56]. The need for follow-up of solitary part-solid nodules is also differentiated by size. The recommendation by the Fleischner Society is a CT in 3 months, again to confirm persistence. If again present, with a solid component 5 mm. Both organizations suggest the use of PET CT for additional characterization should the pulmonary nodules persist at follow-up. Proceeding directly to additional diagnostic modalities in part-solid pulmonary nodules >15 mm is preferred by the ACCP. The Fleischner Society recommendations also suggest initial use of PET CT for part-solid pulmonary nodules 8–10 mm in size prior to diagnostic interventions for both prognostication and preoperative staging based on available data [63–65]. While the management of incidentally detected solid and subsolid pulmonary nodules is summarized above, those detected on screening CT remain poorly understood. Special consideration should be placed on pulmonary nodules detected on screening CT given the intrinsic high risk of the patient population. The recently released USPSTF guidelines advocate for annual low-dose screening CT in current or former smokers who quit less than 15 years ago with a 30 pack-year smoking history [66]. However, unlike incidentally detected nodules, no suggested intervals for radiographic follow-up currently exist for pulmonary nodules detected on low-dose screening CT. Bach et al. demonstrated a wide range in prevalence of pulmonary nodules detected on screening CT in a systematic review of CT screening studies. Baseline prevalence of non-calcified pulmonary nodules necessitating additional work-up ranged from 11 to 51%, while prevalence at baseline and 1-year followup of definitive lung cancer nodules was 0.2–3.7%, with the vast majority of detected nodules being non-cancerous in origin. Necessity for further CT imaging ranged from 1 to 44%, but follow-up imaging intervals were unfortunately poorly reported in the studies [67]. Standardization of guidelines for the management of pulmonary nodules detected in screening CT is needed as it varied throughout all studies and is likely to become more of an issue as more screening CTs are completed. Both the Fleischner Society and the ACCP guidelines utilize pulmonary nodule diameter as measured on CT. However, volumetric analysis may supplant this in the future once larger prospective studies are performed. de Hoop et al. noted a 202% increase in volume and 254% increase in mass when 13 GGNs detected on screening were followed over a mean of 33 months. Diameter increased by 53% in the same study [68]. Volumetric measurement of growth was used to follow 69 patients with 87 nodules in another study, which ultimately affected management. Observation was changed to biopsy in seven patients, though only three patients were found to have a malignant pulmonary nodule [69]. Multiple nodules
Multiple pure GGNs, all of which are 5 mm without a concomitant dominant lesion, then initial follow-up CT should be performed at 3 months followed by yearly for at least 3 years. This grade 1B recommendation is based on the same evidence that supports the necessity of repeat imaging in solitary pure GGNs. Admittedly, there is conflicting evidence regarding malignancy potential of solitary versus multiple pure GGNs. This is due to a study suggesting that invasive carcinoma was more likely to manifest from larger pulmonary nodules when multiple nodules were evaluated [71]. There are no definitive ACCP guidelines for management of multiple pulmonary nodules. However, since ACCP lung cancer staging guidelines necessitate pathologic diagnosis, the largest pulmonary nodule and/or the highest stage of nodule could guide clinical decision-making. The Fleischner Society manages multiple subsolid pulmonary nodules with an identifiable dominant lesion somewhat differently when compared with the ACCP. If the nodules persist on repeat 3-month CT imaging, a diagnostic approach should be pursued. This is especially true for part-solid pulmonary nodules >5 mm because of a higher risk of malignancy due to the part-solid component. This grade 1C recommendation is supported by evidence indicating that multiple subsolid pulmonary nodules will usually be simultaneous primary lung malignancies necessitating surgical resection [71]. Multiple primary lung cancers have previously been found in 8% of surgically resected lung removed via wedge resection, segmentectomy, lobectomy or a combination [72]. Transthoracic needle biopsy
Current ACCP recommendations advocate for proceeding with non-surgical biopsy of solid pulmonary nodules when the estimated probability of malignancy is low to moderate (5–65%). This is due to a decision analysis, which indicated biopsy to be the preferred option when malignancy risk was between 3 and 68% due to diagnostic yield and rate of complications. Based on a prior study by the same authors, patient’s age, nodule diameter and smoking history were found to increase likelihood of malignancy in solid nodules as calculated from Bayes’ theorem. Using the newly created likelihood ratios, a decision analysis for the appropriate management strategy was then created. The authors noted a probability of 5-year survival of 0–12% when an observation strategy allowing for doubling time was employed. Utilizing a biopsy/observation strategy produced the longest life expectancy when the probability of cancer was between 3 and 48%, while probabilities between 49 and 68% led to slightly longer life expectancies when biopsy/surgery was utilized [73]. Percutaneous transthoracic needle biopsy (TTNB), usually performed with CT scan guidance, has demonstrated high diagnostic yield [74]. Factors such as nodule size, proximity to 684
the pleura, needle size, number of needle passes and presence of an onsite cytopathologist have shown to increase sensitivity. Gould et al. reviewed 11 new TTNB studies during development and identified a median malignancy rate of 68% (range 46–83%) [7]. Admittedly, non-diagnostic results were present anywhere from less than 1 to 55% of the time, with a median non-diagnostic result of less than 6%. Sensitivity was noted to be greater than or equal to 90% in most of these studies aside from three where nodules £15 mm in diameter were included, where sensitivity decreased to 70–82% [7]. One such study of pulmonary nodules 90%) nodules [77]. Shimizu et al. noted similar results with CT-guided TTNB of subsolid pulmonary nodules. Forty-three ground glass predominant nodules had a sensitivity of 51%, while 53 solid predominant nodules yielded a sensitivity of 76% [78]. In comparison, CT-guided 18- or 20-gauge core needle biopsies had a sensitivity of greater than 90% by Kim et al. despite size or amount of ground glass [74]. One additional study by Infante et al. found similar results with use of CT-guided core needle biopsies of subsolid pulmonary nodules. They noted a diagnostic yield of 84% among 16 of 19 participants; however, those with non-diagnostic results (two-thirds of subjects) were later discovered to have malignancy [79]. Based in part from these studies, the Fleischner Society guidelines do not recommend TTNB for pure GGNs if nonsurgical management is preferred. This again is due to a lower diagnostic yield as well as the potential for misleading results. As per the findings of Shimizu et al., the diagnostic yield was only 35% for predominantly GGN
Diagnosis and management of pulmonary nodules Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Expert Rev. Respir. Med. 8(6), 677–691 (2014)
Rebecca Krochmal1, Sixto Arias2, Lonny Yarmus2, David Feller-Kopman2 and Hans Lee*2 1 Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, 110 South Paca Street, Second Floor, Baltimore, MD 21201, USA 2 Section of Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 1800 Orleans Street, Zayed Building 7125L, Baltimore, MD 21287, USA *Author for correspondence: [email protected]
informahealthcare.com
There are an increased number of pulmonary nodules discovered on CT scan images in part due to those performed for lung cancer screening. Risk stratification and patient involvement is critical in determining management ranging from interval imaging to invasive biopsy or surgery. A definitive diagnosis requires tissue biopsy. The choice of a particular biopsy technique depends on the risks/benefits of the procedure, the diagnostic yield and local expertise. This review will focus on the evaluation and management of pulmonary nodules based on the Fleischner Society and American College of Chest Physician guidelines. There have been recent changes to both societies’ recommendations for incidental detection of solid and subsolid nodules, risk stratification, imaging, minimally invasive diagnostic techniques and definitive surgical options. KEYWORDS: bronchoscopy • CT screening • lung cancer • solitary pulmonary nodule • transthoracic needle biopsy • VATS
Approximately 67 million computed tomographies (CT) are currently performed annually in the USA [1]. With the results of the National Lung Screening Trial (NLST) showing a significant improvement in mortality in selected patients at high risk for lung cancer, and CT screening being suggested by many cancer societies and the US Preventive Services Task Force (USPSTF), the number of chest CTs, and incidentally found pulmonary nodules are likely to increase significantly in the coming years [2,3]. Pulmonary nodules are defined as an individual, well-circumscribed radiographic opacity up to 3 cm in diameter completely surrounded by aerated lung [4]. The incidental finding of pulmonary nodules on CT scans represents a challenge to clinicians as the large majority (even in highrisk populations) will be benign; however, the opportunity to diagnose an early/curable stage of lung cancer would not want to be missed. This needs to be weighed against the risk of complications from an unnecessary invasive biopsy or surgery for non-cancerous pulmonary nodules as well as the anxiety produced by both the finding of the nodule and its evaluation. The decision-making for any patient with a pulmonary nodule starts with risk stratification and patient counseling on the risks and benefits of different management strategies. Recently, two major societies have revised their guideline recommendations: American College of Chest 10.1586/17476348.2014.948855
Physicians (ACCP) (2013) and Fleischner Society (2005) [5–7]. We will review the latest management strategies based on these guidelines, as well as their subtle differences, and detail options for further diagnostic management. Risk stratification
The management of patients with pulmonary nodules starts with risk stratification through patient history and review of current/prior imaging. Given the fact that lung cancer remains the second most commonly diagnosed malignancy among men and women and the leading cause of cancer deaths among both sexes, there is a continued need to risk-stratify pulmonary nodules to guide diagnosis and future management [8]. This is especially true since when diagnosed at an early stage, lung cancer is potentially a curable disease [9]. However, patient preference must be an integral component of decision-making. Those with limited life expectancy and significant comorbidities may choose to forgo further evaluation. In others, the anxiety of just a mere potential of cancer can be an emotional burden and these patients may benefit from a more direct diagnostic strategy. Whether it is detected incidentally or on lung cancer screening, the abnormality may lead to a significant level of stress and a reduction in health-related quality of life [10]. Wiener et al. noted a variety
2014 Informa UK Ltd
ISSN 1747-6348
677
Review
Krochmal, Arias, Yarmus, Feller-Kopman & Lee
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Table 1. Models to estimate clinical probability of malignancy of incidentally detected pulmonary nodules. Model
Study sample
Nodule size and imaging
Independent predictors of malignancy
OR (95% CI)
Comments
Mayo Clinic
Retrospective review of 419 patients at single center without previous history of lung cancer Mean age 65 years in those with malignant nodules
4–30 mm 23% prevalence of malignancy Chest radiography
Age (per year) Prior or current smoking history Remote history (>5 years) of extrathoracic malignancy Diameter (mm) Upper lobe location Spiculation
1.0 (1.0–1.1) 2.2 (1.2–4.2) 3.8 (1.4–10.5) 1.13 (1.1–1.2) 2.2 (1.3–3.8) 2.8 (1.5–5.5)
No mention of nodule attenuation Model accuracy good (AUC of ROC 0.83 ± 0.02)
[12]
Veterans Affairs
Prospective analysis of 375 patients (98% men) at 10 VA medical centers Mean age 65.9 ± 10.7 years
7–30 mm 54% prevalence of malignancy Chest radiography and PET scan
Age (per 10 years) Prior or current smoking history Diameter (mm) Time since smoking cessation (per 10 years)
2.2 7.9 1.1 0.6
No mention of nodule attenuation Model accuracy good (AUC of ROC 0.79; 95% CI: 0.74–0.84)
[13]
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Analysis of 12,314 patients of 77,465 patients enrolled in intervention arm of PLCO screening trial at 10 sites
1–30 mm, lung mass >30 mm, pleural mass, hilar or mediastinal lymphadenopathy excluding calcified lymph nodes, major atelectasis or infiltrate defined as consolidation or alveolar opacity 1.9% prevalence of malignancy Chest radiography
Education (none vs some or higher) Duration of smoking (per 20 years) Pack-years (per 20 pack-years) BMI (‡30 vs 8
3, 9 and 24 months if low or high risk
Contrast-enhanced CT, PET CT and/or biopsy may be considered
American College of Chest Physician Solid
£4
None
With or without risk factors for lung cancer§
Solid
>4–6
12 months
If no risk factors for cancer
Solid
>4–6
Between 6 and 12 months then 18 and 24 months
If risk factors for cancer
Solid
>6–8
Between 6 and 12 months then at 18–24 months
If no risk factors for cancer
Solid
>6–8
Between 3 and 6 months then 9–12 months and finally at 24 months if unchanged
If risk factors for cancer
†
Low risk includes a minimal or absent smoking history or other risk factors. High risk includes a history of smoking or other risk factors. Lung cancer risk factors include a smoking history and previous history of lung cancer. CT: Computed tomography. Adapted from [5,7]. ‡ §
follow-up imaging should be performed without need for additional screening if stable. Twelve-month follow-up for 4–6 mm solid pulmonary nodules should be performed, again in patients without risk factors. If risk factors for lung cancer are present, 4–6 mm solid pulmonary nodules should be followed at 6–12 months and again at 18–24 months if stable. Finally, solid pulmonary nodules measuring 6–8 mm necessitate repeat imaging at 6–12 months then again at 18–24 months, if stable in those without lung cancer risk factors. In those with one or more risk factors, repeat imaging should occur at 3–6 months, 9–12 months and finally at 24 months, if stable as per the ACCP guidelines (TABLE 3). Such recommendations are based partly on studies of lowdose CT screening showing a less than 1% probability of malignancy in pulmonary nodules 5
3 months then annually for 3–5 years
Part-solid
£5 (solid component)
Not specifically mentioned
If neoplastic, considered minimally invasive adenocarcinoma with near 100% disease-free survival if surgically resected
Part-solid
>5 (solid component)
3 months to confirm persistence
Malignant until proven otherwise Measure solid component PET/CT for nodules >10 mm Biopsy or surgical resection if part-solid component persistent and ‡5 mm
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Fleischner Society
American College of Chest Physician Pure ground glass
£5
None
3 month follow-up if >10 mm; biopsy and/or surgery is persists
Pure ground glass
>5
Annual follow-up for at least 3 years
If interval growth or development of solid component, proceed with non-surgical biopsy or surgical resection
Part-solid
£8 (entire nodule)
3, 12 and 24 months then annually for 1–3 years
If interval increase, likely malignant and necessitates consideration for surgical resection versus non-surgical biopsy
Part-solid
>8 (entire nodule)
3 months to confirm persistence
If persistent, PET, non-surgical biopsy and/or surgical resection If initially >15 mm, proceed directly to PET, non-surgical biopsy and/or surgical resection
CT: Computed tomography.
low- and high-risk patients with consideration for contrastenhanced CT, PET and/or biopsy if interval growth is noted. Neither the ACCP nor the Fleischner Society recommendations advocate for use of low-dose CT for follow-up imaging of the nodule in question, however, this could be considered to minimize radiation exposure. TABLE 3 notes the differences between the current ACCP and the Fleischner Society guidelines for solid pulmonary nodules. Subsolid pulmonary nodules
The new Fleischner Society guidelines for subsolid pulmonary nodules differentiate ground glass opacities through which parenchymal structures may be visualized from those with a concomitant solid component. As such, typical ground glass opacities are referred to as pure ground glass nodules (GGN) and those with obscuring of underlying parenchymal architecture as well as a solid component as part-solid GGNs. Pure and part-solid GGNs together comprise subsolid pulmonary nodules. Solitary pulmonary nodules, whether pure or partsolid, must be distinguished from multiple nodules. In comparison, the ACCP guidelines note part-solid pulmonary nodules to be those with a solid component and more than 50% ground glass opacity. 682
The removal of previous smoking history as a risk factor in the new Fleischner Society guidelines for subsolid pulmonary nodules should be noted. This is due to previous data demonstrating a lack of necessity for different management guidelines in patients with and without risk factors [47]. However, risk stratification based on a history of tobacco dependence remains an integral component of both the Fleischner Society and the ACCP guidelines for solid pulmonary nodules (TABLE 4). Subsolid pulmonary nodule size is a distinguishing characteristic of the new Fleischner Society guidelines. Solitary pure GGNs £5 mm in size do not necessitate follow-up CT surveillance (grade IC recommendation), based on data demonstrating stable or indolent progression of atypical adenomatous hyperplasia (AAH) to carcinoma [48]. The ACCP guidelines are the same. However, solitary pure GGNs >5 mm should have followup imaging in 3 months to confirm persistence then annual follow-up imaging thereafter for a minimum of 3 years (grade IB recommendation per the Fleischner Society guidelines). Somewhat similarly, there is a grade 2C recommendation from the ACCP for yearly CT surveillance for at least 3 years with the caveat that those >10 mm may necessitate early follow-up at 3 months. It has been suggested that overdiagnosis of benign Expert Rev. Respir. Med. 8(6), (2014)
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Chinese University of Hong Kong on 02/04/15 For personal use only.
Diagnosis & management of pulmonary nodules
or unchanged pulmonary nodules that may be isolated foci of AAH, adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma may be avoided with sequential imaging [49]. Such recommendations are rooted in evidence that suggests that persistent pure GGNs may be benign in up to 20% of cases, but may also be manifestations of preinvasive AAH or AIS [50,51]. Invasive adenocarcinoma is greater in pure GGNs >10 mm, with reports varying from 10 to 50% [51–54]. Additionally, pulmonary nodule size >10 mm and a history of lung cancer have been shown to predispose to interval growth [55]. Similar to solid pulmonary nodules, large pure GGNs have also been found to be more likely to be invasive [50,52]. A 3-month follow-up CT scan should be performed to confirm persistence, given the fact that both pure and part-solid GGNs may resolve in the interim [56]. The need for follow-up of solitary part-solid nodules is also differentiated by size. The recommendation by the Fleischner Society is a CT in 3 months, again to confirm persistence. If again present, with a solid component 5 mm. Both organizations suggest the use of PET CT for additional characterization should the pulmonary nodules persist at follow-up. Proceeding directly to additional diagnostic modalities in part-solid pulmonary nodules >15 mm is preferred by the ACCP. The Fleischner Society recommendations also suggest initial use of PET CT for part-solid pulmonary nodules 8–10 mm in size prior to diagnostic interventions for both prognostication and preoperative staging based on available data [63–65]. While the management of incidentally detected solid and subsolid pulmonary nodules is summarized above, those detected on screening CT remain poorly understood. Special consideration should be placed on pulmonary nodules detected on screening CT given the intrinsic high risk of the patient population. The recently released USPSTF guidelines advocate for annual low-dose screening CT in current or former smokers who quit less than 15 years ago with a 30 pack-year smoking history [66]. However, unlike incidentally detected nodules, no suggested intervals for radiographic follow-up currently exist for pulmonary nodules detected on low-dose screening CT. Bach et al. demonstrated a wide range in prevalence of pulmonary nodules detected on screening CT in a systematic review of CT screening studies. Baseline prevalence of non-calcified pulmonary nodules necessitating additional work-up ranged from 11 to 51%, while prevalence at baseline and 1-year followup of definitive lung cancer nodules was 0.2–3.7%, with the vast majority of detected nodules being non-cancerous in origin. Necessity for further CT imaging ranged from 1 to 44%, but follow-up imaging intervals were unfortunately poorly reported in the studies [67]. Standardization of guidelines for the management of pulmonary nodules detected in screening CT is needed as it varied throughout all studies and is likely to become more of an issue as more screening CTs are completed. Both the Fleischner Society and the ACCP guidelines utilize pulmonary nodule diameter as measured on CT. However, volumetric analysis may supplant this in the future once larger prospective studies are performed. de Hoop et al. noted a 202% increase in volume and 254% increase in mass when 13 GGNs detected on screening were followed over a mean of 33 months. Diameter increased by 53% in the same study [68]. Volumetric measurement of growth was used to follow 69 patients with 87 nodules in another study, which ultimately affected management. Observation was changed to biopsy in seven patients, though only three patients were found to have a malignant pulmonary nodule [69]. Multiple nodules
Multiple pure GGNs, all of which are 5 mm without a concomitant dominant lesion, then initial follow-up CT should be performed at 3 months followed by yearly for at least 3 years. This grade 1B recommendation is based on the same evidence that supports the necessity of repeat imaging in solitary pure GGNs. Admittedly, there is conflicting evidence regarding malignancy potential of solitary versus multiple pure GGNs. This is due to a study suggesting that invasive carcinoma was more likely to manifest from larger pulmonary nodules when multiple nodules were evaluated [71]. There are no definitive ACCP guidelines for management of multiple pulmonary nodules. However, since ACCP lung cancer staging guidelines necessitate pathologic diagnosis, the largest pulmonary nodule and/or the highest stage of nodule could guide clinical decision-making. The Fleischner Society manages multiple subsolid pulmonary nodules with an identifiable dominant lesion somewhat differently when compared with the ACCP. If the nodules persist on repeat 3-month CT imaging, a diagnostic approach should be pursued. This is especially true for part-solid pulmonary nodules >5 mm because of a higher risk of malignancy due to the part-solid component. This grade 1C recommendation is supported by evidence indicating that multiple subsolid pulmonary nodules will usually be simultaneous primary lung malignancies necessitating surgical resection [71]. Multiple primary lung cancers have previously been found in 8% of surgically resected lung removed via wedge resection, segmentectomy, lobectomy or a combination [72]. Transthoracic needle biopsy
Current ACCP recommendations advocate for proceeding with non-surgical biopsy of solid pulmonary nodules when the estimated probability of malignancy is low to moderate (5–65%). This is due to a decision analysis, which indicated biopsy to be the preferred option when malignancy risk was between 3 and 68% due to diagnostic yield and rate of complications. Based on a prior study by the same authors, patient’s age, nodule diameter and smoking history were found to increase likelihood of malignancy in solid nodules as calculated from Bayes’ theorem. Using the newly created likelihood ratios, a decision analysis for the appropriate management strategy was then created. The authors noted a probability of 5-year survival of 0–12% when an observation strategy allowing for doubling time was employed. Utilizing a biopsy/observation strategy produced the longest life expectancy when the probability of cancer was between 3 and 48%, while probabilities between 49 and 68% led to slightly longer life expectancies when biopsy/surgery was utilized [73]. Percutaneous transthoracic needle biopsy (TTNB), usually performed with CT scan guidance, has demonstrated high diagnostic yield [74]. Factors such as nodule size, proximity to 684
the pleura, needle size, number of needle passes and presence of an onsite cytopathologist have shown to increase sensitivity. Gould et al. reviewed 11 new TTNB studies during development and identified a median malignancy rate of 68% (range 46–83%) [7]. Admittedly, non-diagnostic results were present anywhere from less than 1 to 55% of the time, with a median non-diagnostic result of less than 6%. Sensitivity was noted to be greater than or equal to 90% in most of these studies aside from three where nodules £15 mm in diameter were included, where sensitivity decreased to 70–82% [7]. One such study of pulmonary nodules 90%) nodules [77]. Shimizu et al. noted similar results with CT-guided TTNB of subsolid pulmonary nodules. Forty-three ground glass predominant nodules had a sensitivity of 51%, while 53 solid predominant nodules yielded a sensitivity of 76% [78]. In comparison, CT-guided 18- or 20-gauge core needle biopsies had a sensitivity of greater than 90% by Kim et al. despite size or amount of ground glass [74]. One additional study by Infante et al. found similar results with use of CT-guided core needle biopsies of subsolid pulmonary nodules. They noted a diagnostic yield of 84% among 16 of 19 participants; however, those with non-diagnostic results (two-thirds of subjects) were later discovered to have malignancy [79]. Based in part from these studies, the Fleischner Society guidelines do not recommend TTNB for pure GGNs if nonsurgical management is preferred. This again is due to a lower diagnostic yield as well as the potential for misleading results. As per the findings of Shimizu et al., the diagnostic yield was only 35% for predominantly GGN
