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Diagnostic Approach to the Solitary Pulmonary Nodule Vasileios S. Skouras, MD1,2
Nichole T. Tanner, MD, MSCR1
1 Division of Pulmonary and Critical Care Medicine, Medical University
of South Carolina, Charleston, South Carolina 2 Department of Pulmonary Medicine, 401 General Army Hospital, Athens, Greece
Gerard A. Silvestri, MD, MS1
Address for correspondence Gerard A. Silvestri, MD, MS, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, 98 Jonathan Lucas Street, Charleston, SC 29425 (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
nonsurgical surgical guided-bronchoscopy thoracoscopy solitary pulmonary nodule ► transthoracic needle biopsy
The number of solitary pulmonary nodules (SPNs) detected each year is expected to increase dramatically with the implementation of lung cancer screening. Although some will have radiographic features highly specific for benignity, the rest are considered indeterminate and require further investigation. The management options include continued surveillance or immediate diagnostic sampling. The decision to proceed with immediate sampling is determined by nodule characteristics (i.e., density and size), and patient risk factors and preferences. Sampling is achieved either by surgical or by nonsurgical techniques, and the choice between the two is influenced by the probability of malignancy. Surgical methods are preferred in SPNs with high probability of malignancy because they provide both a definitive diagnosis and treatment in a single procedure. In contrast, when the probability of malignancy is low to moderate nonsurgical sampling is preferred. The following is a review of the diagnostic management options available when approaching an SPN.
Solitary Pulmonary Nodule The solitary pulmonary nodule (SPN) is defined as a single radiographic opacity 3 cm in diameter surrounded by lung parenchyma.1–3 SPNs are documented in 8 to 51% of all chest computed tomographic (CT) scans and are considered separately from pulmonary lesions accompanied by additional radiographic abnormalities (e.g., atelectasis, pleural effusion, or enlarged intrathoracic lymph nodes).1–4 In the United States an estimated 4.5 to14 million chest CTs are performed annually.5 This number is expected to increase due to the recent recommendation for lung cancer (LC) screening in high-risk populations with low-dose CT (LDCT).2,5–7 The implementation of LC screening has the potential to increase the number of detected pulmonary nodules by an estimated 875,000 per year.7 In contrast to lung masses, which measure > 3 cm and are often malignant, the differential diagnosis of SPN is extensive (►Table 1). The prevalence of malignancy in SPNs depends on
Issue Theme Lung Cancer; Guest Editor, M. Patricia Rivera, MD
the clinical setting, ranging from 2 to 86% for incidentally discovered nodules and from 1.1 to 12% for those that are screen detected.2,3,5 Whereas the overall 5-year survival from lung cancer is 16% for all comers, the 5-year survival for those with stage I disease is 73%.8 Early detection is therefore ideal because it allows for a better chance of survival. This notion is supported by the results of the National Lung Screening Trial (NLST), which demonstrated a 20% reduction in lung cancer–specific mortality with LDCT screening of high-risk patients.9 In the NLST 25% of those screened had a positive finding that required further evaluation; however, the majority of screen-detected nodules were benign and managed with serial imaging. There are some instances where the detection of an SPN requires no further evaluation. This includes obtaining prior imaging that confirms size stability or decrease during a 2-year period. There are also certain radiographic findings with a high specificity for nonmalignancy (e.g., benign pattern of calcification, intranodular fat, feeding artery and vein).3 In the absence of the foregoing, the SPN is deemed
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1358559. ISSN 1069-3424.
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Semin Respir Crit Care Med 2013;34:762–769.
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• Infectious disease Tuberculosis (tuberculoma) Round pneumonia Lung abscess Fungal disease Parasitic disease Atypical mycobacteria Nocardia Pneumocystis jiroveci Measles Septic embolus
• Benign tumor Hamartoma Chondroma Fibroma Neurofibroma Schwannoma Lipoma Sclerosing hemangioma Plasma cell granuloma Endometriosis
• Malignant tumor Lung cancer Pulmonary carcinoid Solitary metastasis Teratoma Leiomyoma
• Inflammatory disease Organizing pneumonia Rheumatoid arthritis Granulomatosis with polyangiitis Microscopic polyangiitis Sarcoidosis
• Vascular origin Arteriovenous malformation Pulmonary infarct Pulmonary artery aneurysm Pulmonary venous varix Hematoma
• Lymphatic origin Intrapulmonary or subpleural lymph node Lymphoma
• Miscellaneous Rounded atelectasis Lipoid pneumonia Amyloidosis Mucoid impaction Infected bulla Pulmonary scar Pleural thickening, mass or fluid (pseudotumor)
• Congenital malformation Bronchogenic cyst Lung sequestration Bronchial atresia with mucoid impaction
“indeterminate.”2,3 If malignant, an SPN represents earlystage disease and warrants further evaluation.2,3,10 Given the small size of SPNs, evaluation with invasive means can be difficult, and management can pose a diagnostic dilemma. The following is a comprehensive review of the options for the diagnostic approach to an SPN following the decision to forgo watchful waiting with serial imaging. These include both minimally invasive and surgical techniques.
Indications for Sampling Indeterminate SPNs An algorithm of how to determine the probability of malignancy of an SPN and when to intervene is covered in detail earlier in this issue by Ost et al. Briefly, the indications for sampling (►Fig. 1) are based on two principal nodule features: density (solid vs subsolid) and size ( 8 mm vs > 8 mm).3 In the case of solid SPNs, sampling is considered based on the pretest probability of malignancy. Those with a high probability of malignancy generally undergo immediate sampling.3,11–13 In solid SPNs > 8 mm, the probability of malignancy varies significantly but can be estimated with the use of quantitative models that take into account radiographic features (i.e., size, spiculation, location and fluorodeoxyglucose-uptake on positron-emission tomography [PET] or > 15 HU enhancement contrast-enhanced computed tomography [CT]) and patient demographics (i.e., age, smoking status, history of malignancy).2–4 Alternatively, the probability of malignancy in solid SPNs 8 mm is uniformly low (< 1% in SPNs < 4 mm and 2–6% in SPNs 4–8 mm), obviating the need for immediate sampling.3 A different approach is recommended for subsolid nodules, which do not require immediate sampling despite the
high prevalence of malignancy (up to 63%). Their significantly low rates of growth allow subsolid nodules to be characterized safely based on their biological behavior during surveillance.3,14,15 Sampling is then indicated when any SPN (solid or subsolid) demonstrates malignant characteristics (increase in size or density or both) during follow-up.3
Sampling Techniques to Diagnose Indeterminate SPNs Once the decision to proceed to diagnostic sampling of an SPN is made, the most appropriate initial sampling method must be determined. The choice between nonsurgical versus surgical sampling is influenced by the probability of malignancy and the patient’s surgical risk (►Fig. 1).3,12,16 Determining which nonsurgical approach (conventional bronchoscopy, guided-bronchoscopy, transthoracic needle sampling) or surgical technique (video-assisted thoracoscopic surgery [VATS], open thoracotomy) depends on several factors. These include nodule location, risk for complication, and technology and skill availability.3,17
Surgical versus Nonsurgical Sampling Generally, surgical resection is preferred for SPNs with the highest probability for malignancy because it allows for diagnosis and treatment with a single procedure. In these cases, it has been shown that the likelihood of an unnecessary surgery is low.3,12 As the certainty for malignancy lessens (i.e., low to moderate pretest probability), however, the likelihood of performing an unnecessary surgery increases and ranges from 35 to 90%.3,11 The use of minimally invasive procedures in those SPNs with low to moderate pretest probability of LC serves to reduce the number of patients who undergo Seminars in Respiratory and Critical Care Medicine
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Table 1 Differential diagnosis of the solitary pulmonary nodule2
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Fig. 1 Flow diagram to assist the selection of the indeterminate solitary pulmonary nodules requiring sampling and the choice of the appropriate initial method for this purpose (based on ACCP guidelines3). Nodules presenting malignant biological behavior (increase in size and/or density) during radiographic follow-up are considered of high probability for malignancy and should be managed as such. &Patient preferences should be considered concurrently with the estimation of the probability for malignancy because the selection of any diagnostic strategy does not significantly alter life expectancy. ^The same approach is suggested in case of discordance between clinical probability and functional tests (positron-emission tomography or dynamic computed tomography). # In high surgical risk patients with nodules of low–moderate probability for malignancy, immediate nonsurgical sampling should be avoided and substituted by surveillance. PET, positron-emission tomography; TTNA, transthoracic needle aspiration; TTNB, transthoracic needle biopsy; VATS, video-assisted thoracoscopic surgery.
surgery for benign disease.3,11–13 A decision analysis demonstrated a slightly longer life expectancy when surgery was used first in nodules with high probability of malignancy, whereas nonsurgical biopsy had a small advantage in nodules determined to be at a moderate probability of cancer.11 Surgical sampling should be considered as the first diagnostic test in individuals with high malignant probability SPNs at low risk for surgical morbidity and mortality.3 When the patient’s surgical risk is high, nonsurgical sampling of moderate to high probability nodules is recommended to establish a malignant diagnosis and proceed to alternative curative-intent treatment options, such as stereotactic body radiotherapy (SBRT).3 However, in high-surgicalrisk individuals who also present high risk for pneumothorax (e.g., severe emphysema) or nondiagnostic results with nonsurgical techniques, SBRT without a tissue diagnosis is a management option after discussion in a multidisciplinary setting.18 For high-surgical-risk individuals with low to Seminars in Respiratory and Critical Care Medicine
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moderate probability SPNs, initial surveillance with serial CT is suggested followed by noninvasive sampling if malignant characteristics develop.3
Selection of the Most Appropriate Technique Nodule location is the most important factor when choosing between nonsurgical techniques. For centrally located lesions, which represent the minority of SPNs, sampling by bronchoscopy is the preferred initial approach given its high sensitivity for malignancy (88%) and minimal complication rate.17,19 Transthoracic needle sampling has a diagnostic yield of 90% and should be considered for peripherally located SPNs, especially if the risk for pneumothorax is low as in those without emphysema and when only one pleural surface will be traversed by the needle.3 In those patients at high risk for a pneumothorax due to underlying lung disease, it is reasonable to consider guided bronchoscopy when the technology is available. The yield for this technique though diminishes
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Diagnostic Approach to the SPN
The Role of Individual Preferences in the Selection of Sampling Methods A decision analysis conducted by Cummings et al demonstrated that the average life expectancy in patients with SPNs does not significantly change due to the sampling technique chosen.11 It is therefore important that patient preference be considered in the diagnostic approach to pulmonary nodules.3 Some individuals insist upon a single procedure that provides both a definitive diagnosis and treatment despite the risk inherent to surgery, whereas others would rather first attempt a less sensitive but less invasive method.3,12,13 An informed and shared decision-making process should be emphasized in the management and diagnostic approach to SPNs.3
Methods for Sampling Indeterminate SPNs The goal of nodule sampling is to obtain tissue or isolated cells from the SPN for histological and/or cytological evaluation.21 The sensitivity and specificity of each procedure for obtaining a diagnosis is directly related to the ability to provide adequate and representative material.17,21 Sampling methods are classified into surgical and nonsurgical, with the former giving the highest diagnostic yield, whereas the latter are less invasive and associated with acceptable diagnostic performance in certain instances.3,5
Nonsurgical Methods Sputum Cytology This noninvasive method aims to detect atypical cells from expectorated sputum; however, it is highly inaccurate given that representative cells from a focal pulmonary lesion may not communicate with the airways.17 Positive results are most commonly seen in patients with central or large (> 2.4 cm) tumors, hemoptysis, and low forced expiratory volume in 1 second (FEV1) values; at least three samples are required to achieve the peak sensitivity.22,23 The sensitivity and specificity of the method for the diagnosis of malignancy are 66% (71% for central and 49% for peripheral lesions) and 99%, respectively.17 Due to significantly low sensitivity in peripheral lesions, which represent the majority of SPNs, sputum cytology is not a useful diagnostic approach.3,24
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Bronchoscopy Bronchoscopy is the least invasive method available to obtain representative material from an SPN.25 Conventional bronchoscopy, however, is limited in that the diameter of the bronchoscope prevents navigation to the most distal airways and does not allow for direct visualization of lesions that are more peripherally located.7,17 Bronchoscopy has a higher yield in the workup of centrally located (inner one third of the lung) SPNs.17 The prevalence of centrally located SPNs in screening trials is only 12% with a mere 8% associated with an endobronchial abnormality during bronchoscopy.24
Centrally Located Nodules Depending on their pattern of presentation (endobronchial, submucosal, or peribronchial), central lesions can be sampled with the use of various modalities (forceps biopsy, brushing, washing, and needle aspiration).17,25 When the tumor is visible, as with exophytic endobronchial lesions, direct forceps biopsy with a minimum of three specimens has the highest sensitivity (74%) for the detection of malignancy.17 The combined use of sampling modalities increases the sensitivity to 88% (range: 71–97%).17 Sampling of central lesions is generally safe without major complications; minor complications such as transient fever or clinically insignificant bleeding may rarely occur.19 The disadvantage to conventional bronchoscopy in the diagnostic approach to SPNs is that it is of maximum benefit in the minority of cases.10,17,24
Peripherally Located Nodules Sampling of peripheral lesions, which by definition are beyond the visual range of bronchoscopy, can only be blindly performed by obtaining transbronchial biopsies with or without brushing, needle aspiration, or bronchoalveolar lavage (BAL) specimens, from the pulmonary segment identified by chest CT.17,25 As a result, the sensitivity of conventional bronchoscopy for the detection of malignancy in peripheral SPNs is low (49%) and decreases further for establishing a specific benign diagnosis.17,26 Transbronchial biopsy has an estimated complication rate of 1.5% and 0.5% for pneumothorax and bleeding, respectively.27 The addition of imaging modalities such as fluoroscopy and CT scan to guide sampling increases the sensitivity of the bronchoscopy.25 Although CT guidance is superior (overall sensitivity: 62% vs 53%) to traditional fluoroscopy, the higher radiation exposure associated with CT and logistical issues including transport of patients, staff, and equipment to the radiology suite favor the use of fluoroscopy in clinical practice.25 In a systematic review of 34 studies, the addition of fluoroscopy to multimodality conventional bronchoscopy had a pooled sensitivity of 78% (range: 36–88%) for the detection of malignancy in peripheral pulmonary lesions (both nodules and masses).17 The pooled sensitivity of transbronchial biopsy was 57% and was found to depend on the number of received specimens (45% for one to 70% for six specimens) and the presence of a bronchus extending to the peripheral lesion on CT (60% vs 25%).17 Nodule size is the factor that most impacts the yield of bronchoscopy in the diagnostic approach to peripheral SPNs. In lesions > 2 cm Seminars in Respiratory and Critical Care Medicine
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when the nodule is located peripherally (i.e., adjacent to the pleura) or when there is absence of a bronchus leading to the nodule.3 The choice of surgical approach factors in the morbidity and mortality type of procedure and the curative intent for a malignant diagnosis.12 The recommended management of stage I lung cancer patients includes lobectomy with systemic sampling of regional lymph nodes to achieve complete resection of the tumor and accurate staging.3 Although this approach is feasible by both surgical techniques, open thoracotomy presents a higher mortality (1.7–5.3% vs 2%) and complication (35% vs 26%) rate for this purpose compared with VATS.3,12,20 Thus VATS is the preferred surgical approach, followed by open thoracotomy when the SPN cannot be thoracoscopically localized.3
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the sensitivity was nearly twice as high as in nodules < 2 cm (63% vs 34%).17 Ultrathin (external diameter < 3 mm) bronchoscopes that can be advanced beyond the segmental bronchi (up to sixth-generation bronchi), have been found to increase the diagnostic yield (70%, 95% CI, 65–75%) of conventional bronchoscopy in peripheral SPNs regardless of nodule size.5,28
Newer bronchoscopic guidance technology has recently emerged that improves upon conventional bronchoscopy for diagnosing peripheral SPNs and can also facilitate sampling of nonendobronchial (peribronchial or submucosal) central lesions.5
available, namely electromagnetic navigation bronchoscopy (EMNB) and virtual bronchoscopy (VB). By reconstructing chest CT images, both create virtual bronchoscopic images and provide a path to the lesion of interest. In addition, EMNB offers real-time directions during the procedure that are similar to those of a global positioning system guiding a car to a destination.5 In a meta-analysis by Wang Memoli et al, the diagnostic yield of EMNB and VB was 67% and 72%, respectively.5 Similar results (yield of 68% in prospective and 71% in retrospective studies) were reported in a recent systematic review. Several studies have shown that, although the diagnostic yield of EMNB is not affected by nodule size, it does improve (67% vs 79%) with the presence of a bronchus-sign on CT.17,30,31
Radial Endobronchial Ultrasound
Multimodality-Guided Bronchoscopy
Radial endobronchial ultrasound (R-EBUS) is a probe bearing an ultrasound transducer on its tip that provides a 360degree radial image of surrounding structures.17 The exact location of a peripheral SPN can be confirmed by inserting this probe through the working channel of the bronchoscope into the airways and advancing it sequentially into each segment of the lobe containing the nodule until the characteristic image is observed (►Fig. 2).17 Following nodule localization, sampling can be performed by transbronchial biopsy (TBB), brushing, BAL, or needle aspiration.25 The diagnostic yield of R-EBUS in the evaluation of peripheral SPNs is 71% (95% CI, 65–75%) and its sensitivity for the detection of malignancy is 73% (95% CI, 70–76%).5,29 The yield of the technique improves as the prevalence of malignancy and the size of the nodule increase (78% for > 2 cm vs 56% for 2 cm).29 The only major complication is pneumothorax, which is very rare (pooled rate: 1%) with only 0.4% requiring chest tube placement.29
The combined use of navigational bronchoscopy with R-EBUS improves diagnostic yield beyond either technique alone.17 In a randomized controlled trial that included 118 patients with peripheral nodules, R-EBUS and EMNB combined had a diagnostic yield of 88%. This was significantly higher than that of R-EBUS (69%) or EMNB (59%) alone and independent of nodule size and location.32 Another study of 53 nodules demonstrated a diagnostic yield of 93% when R-EBUS was used to confirm the EMNB location much higher than the reported 48% yield without R-EBUS.33 In the same study, sampling by catheter aspiration was superior to forceps biopsy, especially when R-EBUS could not confirm nodule location.33 Similarly, another trial done in 199 individuals with peripheral nodules found that VB with R-EBUS had an 80% diagnostic yield significantly versus a 67% diagnostic yield with R-EBUS alone.34 The addition of ultrathin bronchoscopes to VB significantly increases the diagnostic yield when nodules are located in the peripheral one third of the lung (65 vs 52%) or in the right upper lobe (81% vs 53%).28
Guided Bronchoscopy
Navigational Bronchoscopy Navigational bronchoscopy expands upon conventional bronchoscopy by providing guidance through the tracheobronchial tree, thereby improving the accurate localization and sampling of peripheral nodules.5 There are two technologies
Fig. 2 Characteristic endobronchial ultrasound image (B) of a peripheral pulmonary nodule (A) localized with the use of a radial endobronchial ultrasound (R-EBUS) probe. Seminars in Respiratory and Critical Care Medicine
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Guided Bronchoscopy versus Conventional Bronchoscopy Dolina et al demonstrated that the use of guided bronchoscopy with three-dimensional imaging to map out a pathway to a peripheral nodule is superior to the use of two-dimensional CT images regardless of experience.35 In a metaanalysis assessing the overall performance of guided-bronchoscopy in the evaluation of peripheral nodules, Wang Memoli et al reported a pooled diagnostic yield of 70% (95% CI, 67–73%), which is significantly higher than that of conventional bronchoscopy (49%).5,26 The yields of R-EBUS (71.1%) and VB (72%) were higher than the overall weighted diagnostic yield, whereas the highest yield (73.2%) was seen with the use of a guide sheath to maintain the position for biopsy after the localization of the nodule.5 The most common complication of guided bronchoscopy was pneumothorax, with an overall rate of 1.5% (range: 0–7.5%), only one third (0.6%) of which required chest tube placement. The incidence of respiratory failure requiring intubation was 0.1%, and there were no deaths or significant bleeding reported.5 The falsenegative rate of both conventional and guided bronchoscopy is not known, but it is estimated to be high enough to warrant further investigation in the case of negative or nondiagnostic
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results, especially when the suspicion for malignancy is high.3,17
Transthoracic Needle Sampling Transthoracic needle sampling obtains tissue directly from the SPN by placing a needle through the chest wall.21 The procedure can be performed under fluoroscopic or CT guidance; however, CT has a sensitivity of 92% for lesion localization versus 88% for fluoroscopy.17 Two types of needles are available for use: thin aspiration needles and core biopsy needles. The fine needle aspirates (transthoracic needle aspiration [TTNA]) provide material for cytology, whereas the larger needles, which cut core biopsies (transthoracic needle biopsy [TTNB]), provide specimens for histology.17,36 The performance of this technique is related to the location, the size of the lesion, the guidance modality used to locate the lesion, the size of the needle, the number of passes, and the presence of rapid on-site evaluation of the received samples.3,17 Although TTNA is comparable to TTNB for diagnosing malignant lesions, it is less likely to provide enough material for mutational analysis (44–50% vs 100%) or to establish a specific nonmalignant diagnosis.17,37,38 The overall sensitivity and specificity of transthoracic needle sampling for the diagnosis of malignancy in peripheral nodules is 90% (95% CI, 88–91%) and 97% (95% CI, 96–98%), respectively.17 When nodule size is 15 mm the sensitivity decreases to 70 to 82%.17 Although the false-positive rate is low at 1%, the high false-negative rate (20–30%) requires further investigation and/or observation when the results are negative or nondiagnostic.17 Although a positive result for a specific benign disease is valuable in the right clinical context, it should be remembered that the false-positive rate for nonmalignant diagnoses can be up to 50%.17,39 Pneumothorax and hemorrhage are the two main complications of transthoracic needle sampling.3,17 In a crosssectional analysis of 15,865 adult patients that had undergone TTNB, the incidence of postprocedure hemorrhage was 1% with 18% of patients with hemorrhage requiring blood transfusion.40 In contrast, pneumothorax was observed in 15% of patients, approximately half (6.6%) of whom required chest tube placement.40 The same study identified older age (60–69 years), smoking status, and chronic obstructive pulmonary disease (COPD) as risk factors for pneumothorax.
Surgical Methods Surgery is the gold standard for diagnosing SPNs because complete excision allows for both a definitive diagnosis and curative treatment in a single procedure.3 There are a variety of surgical techniques that are used alone or in combination, including thoracoscopy and open thoracotomy.3,13
Video-Assisted Thoracoscopic Surgery (VATS) VATS is the least invasive surgical technique available for the excisional biopsy of a pulmonary nodule.3 The procedure, which is performed under general anesthesia, induces an iatrogenic pneumothorax in the lung containing the nodule. A
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trocar is inserted through the seventh intercostal space, which allows the thoracoscope to enter the hemithorax.13 Additional trocars are placed to allow the use of other instruments, such as stapling devices, cautery, or laser.13 Following localization of the nodule, wedge resection is suggested with intraoperative examination of frozen sections by pathology to exclude or establish malignancy.3 In the case of malignancy, curative treatment with lobectomy and accurate staging with systematic lymph node sampling should follow in all patients with adequate respiratory reserve.3,16 The main limitation of the VATS is that it does not allow for digital palpation of lung tissue to localize nodules that are not directly visible with the thoracoscope.3,41 Failure to localize the nodule of concern results in conversion to an open thoracotomy in up to 45% of the cases. 42 To improve upon this, a variety of techniques have emerged that allow for better lesion localization. These include the use of hookand-wire, radioguidance, methylene blue, percutaneous microcoils, bronchoscopically placed fiducials, ultrasonography, and fluoroscopy with contrast material.3,43 When the nodule is accurately localized and resected the sensitivity of results from frozen section analysis is dependent upon the size of the nodule (87% for nodules < 1.1cm, 94% for nodules 1.1–1.5 cm).3,44 Moreover, it can be difficult to differentiate between malignant diagnoses on frozen section.3,44 Although there is a paucity of extensive data related to the complications of thoracoscopic nodule resection, because it is less invasive than thoracotomy it likely has a lower morbidity rate and shorter hospital length of stay.13 In two small studies, VATS diagnostic resection of nodules had no associated mortality and a complication rate of 5%.45,46
Open Thoracotomy Open thoracotomy is the most invasive surgical method for diagnosing SPNs and is generally recommended when the surgeon fails to locate the SPN with VATS.47 In patients with malignant nodules, thoracotomy has a mortality rate of 1.7 to 5.3% when diagnostic wedge resection is followed by curative lobectomy.12 The resection of benign nodules alone is associated with a mortality of 0.5%.12 The complication rate in patients undergoing wedge resection has been found to be 15%.48 Although thoracotomy allows for the digital palpation to localize nonvisible nodules, there are certain instances (i.e., nodule < 1 cm in size, deep in location, or subsolid in attenuation) in which alternative localization techniques mentioned previously must be employed.41
Summary The number of solitary pulmonary nodules detected each year in the United States is expected to increase with lung cancer screening. Malignant SPNs represent the earliest stage of lung cancer, and their timely detection allows for a better chance of survival. Malignancy can rarely be excluded by radiographic features; thus the majority of SPNs are indeterminate and require further investigation with either continued surveillance or immediate diagnostic sampling. Seminars in Respiratory and Critical Care Medicine
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The decision to proceed with immediate sampling is determined by nodule characteristics (density and size) and patient risk factors for malignancy. Sampling is achieved by either surgical or nonsurgical techniques, and the choice between the two is influenced by nodule probability of malignancy and patient surgical risk. Surgical methods are preferred in SPNs with high probability of malignancy because they provide both a definitive diagnosis and treatment in a single procedure. When the probability of malignancy is low to moderate or the surgical risk is high, nonsurgical sampling is preferred. Centrally located nodules can be sampled with bronchoscopic techniques. Nonsurgical sampling of peripheral nodules, which represent the majority of SPNs, may be performed either with transthoracic needle techniques or guided bronchoscopy. Life expectancy in individuals with SPNs does not significantly change due to the diagnostic strategy chosen; thus individual preferences should be considered in the diagnostic approach to pulmonary nodules.
14 Henschke CI, Yankelevitz DF, Mirtcheva R, McGuinness G, McCau-
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33 Eberhardt R, Morgan RK, Ernst A, Beyer T, Herth FJ. Comparison of
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suction catheter versus forceps biopsy for sampling of solitary pulmonary nodules guided by electromagnetic navigational bronchoscopy. Respiration 2010;79(1):54–60 Ishida T, Asano F, Yamazaki K, et al; Virtual Navigation in Japan Trial Group. Virtual bronchoscopic navigation combined with endobronchial ultrasound to diagnose small peripheral pulmonary lesions: a randomised trial. Thorax 2011;66(12):1072–1077 Dolina MY, Cornish DC, Merritt SA, et al. Interbronchoscopist variability in endobronchial path selection: a simulation study. Chest 2008;133(4):897–905 Birchard KR. Transthoracic needle biopsy. Semin Intervent Radiol 2011;28(1):87–97 Klein JS, Salomon G, Stewart EA. Transthoracic needle biopsy with a coaxially placed 20-gauge automated cutting needle: results in 122 patients. Radiology 1996;198(3):715–720 Böcking A, Klose KC, Kyll HJ, Hauptmann S. Cytologic versus histologic evaluation of needle biopsy of the lung, hilum and mediastinum. Sensitivity, specificity and typing accuracy. Acta Cytol 1995;39(3):463–471 Priola AM, Priola SM, Cataldi A, et al. Accuracy of CT-guided transthoracic needle biopsy of lung lesions: factors affecting diagnostic yield. Radiol Med (Torino) 2007;112(8):1142–1159 Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med 2011;155(3):137–144 Pittet O, Christodoulou M, Pezzetta E, Schmidt S, Schnyder P, Ris HB. Video-assisted thoracoscopic resection of a small pulmonary
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nodule after computed tomography-guided localization with a hook-wire system. Experience in 45 consecutive patients. World J Surg 2007;31(3):575–578 Suzuki K, Nagai K, Yoshida J, et al. Video-assisted thoracoscopic surgery for small indeterminate pulmonary nodules: indications for preoperative marking. Chest 1999;115(2):563–568 Miyoshi T, Kondo K, Takizawa H, et al. Fluoroscopy-assisted thoracoscopic resection of pulmonary nodules after computed tomography—guided bronchoscopic metallic coil marking. J Thorac Cardiovasc Surg 2006;131(3):704–710 Marchevsky AM, Changsri C, Gupta I, Fuller C, Houck W, McKenna RJ Jr. Frozen section diagnoses of small pulmonary nodules: accuracy and clinical implications. Ann Thorac Surg 2004;78(5):1755–1759 Allen MS, Deschamps C, Lee RE, Trastek VF, Daly RC, Pairolero PC. Video-assisted thoracoscopic stapled wedge excision for indeterminate pulmonary nodules. J Thorac Cardiovasc Surg 1993;106(6): 1048–1052 Mack MJ, Hazelrigg SR, Landreneau RJ, Acuff TE. Thoracoscopy for the diagnosis of the indeterminate solitary pulmonary nodule. Ann Thorac Surg 1993;56(4):825–830, discussion 830–832 Chen S, Zhou J, Zhang J, et al. Video-assisted thoracoscopic solitary pulmonary nodule resection after CT-guided hookwire localization: 43 cases report and literature review. Surg Endosc 2011; 25(6):1723–1729 Salati M, Refai M, Pompili C, Xiumè F, Sabbatini A, Brunelli A. Major morbidity after lung resection: a comparison between the European Society of Thoracic Surgeons Database system and the Thoracic Morbidity and Mortality system. J Thorac Dis 2013; 5(3):217–222
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Diagnostic Approach to the SPN
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Diagnostic Approach to the Solitary Pulmonary Nodule Vasileios S. Skouras, MD1,2
Nichole T. Tanner, MD, MSCR1
1 Division of Pulmonary and Critical Care Medicine, Medical University
of South Carolina, Charleston, South Carolina 2 Department of Pulmonary Medicine, 401 General Army Hospital, Athens, Greece
Gerard A. Silvestri, MD, MS1
Address for correspondence Gerard A. Silvestri, MD, MS, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, 98 Jonathan Lucas Street, Charleston, SC 29425 (e-mail: [email protected]).
Abstract
Keywords
► ► ► ► ►
nonsurgical surgical guided-bronchoscopy thoracoscopy solitary pulmonary nodule ► transthoracic needle biopsy
The number of solitary pulmonary nodules (SPNs) detected each year is expected to increase dramatically with the implementation of lung cancer screening. Although some will have radiographic features highly specific for benignity, the rest are considered indeterminate and require further investigation. The management options include continued surveillance or immediate diagnostic sampling. The decision to proceed with immediate sampling is determined by nodule characteristics (i.e., density and size), and patient risk factors and preferences. Sampling is achieved either by surgical or by nonsurgical techniques, and the choice between the two is influenced by the probability of malignancy. Surgical methods are preferred in SPNs with high probability of malignancy because they provide both a definitive diagnosis and treatment in a single procedure. In contrast, when the probability of malignancy is low to moderate nonsurgical sampling is preferred. The following is a review of the diagnostic management options available when approaching an SPN.
Solitary Pulmonary Nodule The solitary pulmonary nodule (SPN) is defined as a single radiographic opacity 3 cm in diameter surrounded by lung parenchyma.1–3 SPNs are documented in 8 to 51% of all chest computed tomographic (CT) scans and are considered separately from pulmonary lesions accompanied by additional radiographic abnormalities (e.g., atelectasis, pleural effusion, or enlarged intrathoracic lymph nodes).1–4 In the United States an estimated 4.5 to14 million chest CTs are performed annually.5 This number is expected to increase due to the recent recommendation for lung cancer (LC) screening in high-risk populations with low-dose CT (LDCT).2,5–7 The implementation of LC screening has the potential to increase the number of detected pulmonary nodules by an estimated 875,000 per year.7 In contrast to lung masses, which measure > 3 cm and are often malignant, the differential diagnosis of SPN is extensive (►Table 1). The prevalence of malignancy in SPNs depends on
Issue Theme Lung Cancer; Guest Editor, M. Patricia Rivera, MD
the clinical setting, ranging from 2 to 86% for incidentally discovered nodules and from 1.1 to 12% for those that are screen detected.2,3,5 Whereas the overall 5-year survival from lung cancer is 16% for all comers, the 5-year survival for those with stage I disease is 73%.8 Early detection is therefore ideal because it allows for a better chance of survival. This notion is supported by the results of the National Lung Screening Trial (NLST), which demonstrated a 20% reduction in lung cancer–specific mortality with LDCT screening of high-risk patients.9 In the NLST 25% of those screened had a positive finding that required further evaluation; however, the majority of screen-detected nodules were benign and managed with serial imaging. There are some instances where the detection of an SPN requires no further evaluation. This includes obtaining prior imaging that confirms size stability or decrease during a 2-year period. There are also certain radiographic findings with a high specificity for nonmalignancy (e.g., benign pattern of calcification, intranodular fat, feeding artery and vein).3 In the absence of the foregoing, the SPN is deemed
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1358559. ISSN 1069-3424.
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Semin Respir Crit Care Med 2013;34:762–769.
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• Infectious disease Tuberculosis (tuberculoma) Round pneumonia Lung abscess Fungal disease Parasitic disease Atypical mycobacteria Nocardia Pneumocystis jiroveci Measles Septic embolus
• Benign tumor Hamartoma Chondroma Fibroma Neurofibroma Schwannoma Lipoma Sclerosing hemangioma Plasma cell granuloma Endometriosis
• Malignant tumor Lung cancer Pulmonary carcinoid Solitary metastasis Teratoma Leiomyoma
• Inflammatory disease Organizing pneumonia Rheumatoid arthritis Granulomatosis with polyangiitis Microscopic polyangiitis Sarcoidosis
• Vascular origin Arteriovenous malformation Pulmonary infarct Pulmonary artery aneurysm Pulmonary venous varix Hematoma
• Lymphatic origin Intrapulmonary or subpleural lymph node Lymphoma
• Miscellaneous Rounded atelectasis Lipoid pneumonia Amyloidosis Mucoid impaction Infected bulla Pulmonary scar Pleural thickening, mass or fluid (pseudotumor)
• Congenital malformation Bronchogenic cyst Lung sequestration Bronchial atresia with mucoid impaction
“indeterminate.”2,3 If malignant, an SPN represents earlystage disease and warrants further evaluation.2,3,10 Given the small size of SPNs, evaluation with invasive means can be difficult, and management can pose a diagnostic dilemma. The following is a comprehensive review of the options for the diagnostic approach to an SPN following the decision to forgo watchful waiting with serial imaging. These include both minimally invasive and surgical techniques.
Indications for Sampling Indeterminate SPNs An algorithm of how to determine the probability of malignancy of an SPN and when to intervene is covered in detail earlier in this issue by Ost et al. Briefly, the indications for sampling (►Fig. 1) are based on two principal nodule features: density (solid vs subsolid) and size ( 8 mm vs > 8 mm).3 In the case of solid SPNs, sampling is considered based on the pretest probability of malignancy. Those with a high probability of malignancy generally undergo immediate sampling.3,11–13 In solid SPNs > 8 mm, the probability of malignancy varies significantly but can be estimated with the use of quantitative models that take into account radiographic features (i.e., size, spiculation, location and fluorodeoxyglucose-uptake on positron-emission tomography [PET] or > 15 HU enhancement contrast-enhanced computed tomography [CT]) and patient demographics (i.e., age, smoking status, history of malignancy).2–4 Alternatively, the probability of malignancy in solid SPNs 8 mm is uniformly low (< 1% in SPNs < 4 mm and 2–6% in SPNs 4–8 mm), obviating the need for immediate sampling.3 A different approach is recommended for subsolid nodules, which do not require immediate sampling despite the
high prevalence of malignancy (up to 63%). Their significantly low rates of growth allow subsolid nodules to be characterized safely based on their biological behavior during surveillance.3,14,15 Sampling is then indicated when any SPN (solid or subsolid) demonstrates malignant characteristics (increase in size or density or both) during follow-up.3
Sampling Techniques to Diagnose Indeterminate SPNs Once the decision to proceed to diagnostic sampling of an SPN is made, the most appropriate initial sampling method must be determined. The choice between nonsurgical versus surgical sampling is influenced by the probability of malignancy and the patient’s surgical risk (►Fig. 1).3,12,16 Determining which nonsurgical approach (conventional bronchoscopy, guided-bronchoscopy, transthoracic needle sampling) or surgical technique (video-assisted thoracoscopic surgery [VATS], open thoracotomy) depends on several factors. These include nodule location, risk for complication, and technology and skill availability.3,17
Surgical versus Nonsurgical Sampling Generally, surgical resection is preferred for SPNs with the highest probability for malignancy because it allows for diagnosis and treatment with a single procedure. In these cases, it has been shown that the likelihood of an unnecessary surgery is low.3,12 As the certainty for malignancy lessens (i.e., low to moderate pretest probability), however, the likelihood of performing an unnecessary surgery increases and ranges from 35 to 90%.3,11 The use of minimally invasive procedures in those SPNs with low to moderate pretest probability of LC serves to reduce the number of patients who undergo Seminars in Respiratory and Critical Care Medicine
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Table 1 Differential diagnosis of the solitary pulmonary nodule2
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Fig. 1 Flow diagram to assist the selection of the indeterminate solitary pulmonary nodules requiring sampling and the choice of the appropriate initial method for this purpose (based on ACCP guidelines3). Nodules presenting malignant biological behavior (increase in size and/or density) during radiographic follow-up are considered of high probability for malignancy and should be managed as such. &Patient preferences should be considered concurrently with the estimation of the probability for malignancy because the selection of any diagnostic strategy does not significantly alter life expectancy. ^The same approach is suggested in case of discordance between clinical probability and functional tests (positron-emission tomography or dynamic computed tomography). # In high surgical risk patients with nodules of low–moderate probability for malignancy, immediate nonsurgical sampling should be avoided and substituted by surveillance. PET, positron-emission tomography; TTNA, transthoracic needle aspiration; TTNB, transthoracic needle biopsy; VATS, video-assisted thoracoscopic surgery.
surgery for benign disease.3,11–13 A decision analysis demonstrated a slightly longer life expectancy when surgery was used first in nodules with high probability of malignancy, whereas nonsurgical biopsy had a small advantage in nodules determined to be at a moderate probability of cancer.11 Surgical sampling should be considered as the first diagnostic test in individuals with high malignant probability SPNs at low risk for surgical morbidity and mortality.3 When the patient’s surgical risk is high, nonsurgical sampling of moderate to high probability nodules is recommended to establish a malignant diagnosis and proceed to alternative curative-intent treatment options, such as stereotactic body radiotherapy (SBRT).3 However, in high-surgicalrisk individuals who also present high risk for pneumothorax (e.g., severe emphysema) or nondiagnostic results with nonsurgical techniques, SBRT without a tissue diagnosis is a management option after discussion in a multidisciplinary setting.18 For high-surgical-risk individuals with low to Seminars in Respiratory and Critical Care Medicine
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moderate probability SPNs, initial surveillance with serial CT is suggested followed by noninvasive sampling if malignant characteristics develop.3
Selection of the Most Appropriate Technique Nodule location is the most important factor when choosing between nonsurgical techniques. For centrally located lesions, which represent the minority of SPNs, sampling by bronchoscopy is the preferred initial approach given its high sensitivity for malignancy (88%) and minimal complication rate.17,19 Transthoracic needle sampling has a diagnostic yield of 90% and should be considered for peripherally located SPNs, especially if the risk for pneumothorax is low as in those without emphysema and when only one pleural surface will be traversed by the needle.3 In those patients at high risk for a pneumothorax due to underlying lung disease, it is reasonable to consider guided bronchoscopy when the technology is available. The yield for this technique though diminishes
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Diagnostic Approach to the SPN
The Role of Individual Preferences in the Selection of Sampling Methods A decision analysis conducted by Cummings et al demonstrated that the average life expectancy in patients with SPNs does not significantly change due to the sampling technique chosen.11 It is therefore important that patient preference be considered in the diagnostic approach to pulmonary nodules.3 Some individuals insist upon a single procedure that provides both a definitive diagnosis and treatment despite the risk inherent to surgery, whereas others would rather first attempt a less sensitive but less invasive method.3,12,13 An informed and shared decision-making process should be emphasized in the management and diagnostic approach to SPNs.3
Methods for Sampling Indeterminate SPNs The goal of nodule sampling is to obtain tissue or isolated cells from the SPN for histological and/or cytological evaluation.21 The sensitivity and specificity of each procedure for obtaining a diagnosis is directly related to the ability to provide adequate and representative material.17,21 Sampling methods are classified into surgical and nonsurgical, with the former giving the highest diagnostic yield, whereas the latter are less invasive and associated with acceptable diagnostic performance in certain instances.3,5
Nonsurgical Methods Sputum Cytology This noninvasive method aims to detect atypical cells from expectorated sputum; however, it is highly inaccurate given that representative cells from a focal pulmonary lesion may not communicate with the airways.17 Positive results are most commonly seen in patients with central or large (> 2.4 cm) tumors, hemoptysis, and low forced expiratory volume in 1 second (FEV1) values; at least three samples are required to achieve the peak sensitivity.22,23 The sensitivity and specificity of the method for the diagnosis of malignancy are 66% (71% for central and 49% for peripheral lesions) and 99%, respectively.17 Due to significantly low sensitivity in peripheral lesions, which represent the majority of SPNs, sputum cytology is not a useful diagnostic approach.3,24
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Bronchoscopy Bronchoscopy is the least invasive method available to obtain representative material from an SPN.25 Conventional bronchoscopy, however, is limited in that the diameter of the bronchoscope prevents navigation to the most distal airways and does not allow for direct visualization of lesions that are more peripherally located.7,17 Bronchoscopy has a higher yield in the workup of centrally located (inner one third of the lung) SPNs.17 The prevalence of centrally located SPNs in screening trials is only 12% with a mere 8% associated with an endobronchial abnormality during bronchoscopy.24
Centrally Located Nodules Depending on their pattern of presentation (endobronchial, submucosal, or peribronchial), central lesions can be sampled with the use of various modalities (forceps biopsy, brushing, washing, and needle aspiration).17,25 When the tumor is visible, as with exophytic endobronchial lesions, direct forceps biopsy with a minimum of three specimens has the highest sensitivity (74%) for the detection of malignancy.17 The combined use of sampling modalities increases the sensitivity to 88% (range: 71–97%).17 Sampling of central lesions is generally safe without major complications; minor complications such as transient fever or clinically insignificant bleeding may rarely occur.19 The disadvantage to conventional bronchoscopy in the diagnostic approach to SPNs is that it is of maximum benefit in the minority of cases.10,17,24
Peripherally Located Nodules Sampling of peripheral lesions, which by definition are beyond the visual range of bronchoscopy, can only be blindly performed by obtaining transbronchial biopsies with or without brushing, needle aspiration, or bronchoalveolar lavage (BAL) specimens, from the pulmonary segment identified by chest CT.17,25 As a result, the sensitivity of conventional bronchoscopy for the detection of malignancy in peripheral SPNs is low (49%) and decreases further for establishing a specific benign diagnosis.17,26 Transbronchial biopsy has an estimated complication rate of 1.5% and 0.5% for pneumothorax and bleeding, respectively.27 The addition of imaging modalities such as fluoroscopy and CT scan to guide sampling increases the sensitivity of the bronchoscopy.25 Although CT guidance is superior (overall sensitivity: 62% vs 53%) to traditional fluoroscopy, the higher radiation exposure associated with CT and logistical issues including transport of patients, staff, and equipment to the radiology suite favor the use of fluoroscopy in clinical practice.25 In a systematic review of 34 studies, the addition of fluoroscopy to multimodality conventional bronchoscopy had a pooled sensitivity of 78% (range: 36–88%) for the detection of malignancy in peripheral pulmonary lesions (both nodules and masses).17 The pooled sensitivity of transbronchial biopsy was 57% and was found to depend on the number of received specimens (45% for one to 70% for six specimens) and the presence of a bronchus extending to the peripheral lesion on CT (60% vs 25%).17 Nodule size is the factor that most impacts the yield of bronchoscopy in the diagnostic approach to peripheral SPNs. In lesions > 2 cm Seminars in Respiratory and Critical Care Medicine
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when the nodule is located peripherally (i.e., adjacent to the pleura) or when there is absence of a bronchus leading to the nodule.3 The choice of surgical approach factors in the morbidity and mortality type of procedure and the curative intent for a malignant diagnosis.12 The recommended management of stage I lung cancer patients includes lobectomy with systemic sampling of regional lymph nodes to achieve complete resection of the tumor and accurate staging.3 Although this approach is feasible by both surgical techniques, open thoracotomy presents a higher mortality (1.7–5.3% vs 2%) and complication (35% vs 26%) rate for this purpose compared with VATS.3,12,20 Thus VATS is the preferred surgical approach, followed by open thoracotomy when the SPN cannot be thoracoscopically localized.3
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the sensitivity was nearly twice as high as in nodules < 2 cm (63% vs 34%).17 Ultrathin (external diameter < 3 mm) bronchoscopes that can be advanced beyond the segmental bronchi (up to sixth-generation bronchi), have been found to increase the diagnostic yield (70%, 95% CI, 65–75%) of conventional bronchoscopy in peripheral SPNs regardless of nodule size.5,28
Newer bronchoscopic guidance technology has recently emerged that improves upon conventional bronchoscopy for diagnosing peripheral SPNs and can also facilitate sampling of nonendobronchial (peribronchial or submucosal) central lesions.5
available, namely electromagnetic navigation bronchoscopy (EMNB) and virtual bronchoscopy (VB). By reconstructing chest CT images, both create virtual bronchoscopic images and provide a path to the lesion of interest. In addition, EMNB offers real-time directions during the procedure that are similar to those of a global positioning system guiding a car to a destination.5 In a meta-analysis by Wang Memoli et al, the diagnostic yield of EMNB and VB was 67% and 72%, respectively.5 Similar results (yield of 68% in prospective and 71% in retrospective studies) were reported in a recent systematic review. Several studies have shown that, although the diagnostic yield of EMNB is not affected by nodule size, it does improve (67% vs 79%) with the presence of a bronchus-sign on CT.17,30,31
Radial Endobronchial Ultrasound
Multimodality-Guided Bronchoscopy
Radial endobronchial ultrasound (R-EBUS) is a probe bearing an ultrasound transducer on its tip that provides a 360degree radial image of surrounding structures.17 The exact location of a peripheral SPN can be confirmed by inserting this probe through the working channel of the bronchoscope into the airways and advancing it sequentially into each segment of the lobe containing the nodule until the characteristic image is observed (►Fig. 2).17 Following nodule localization, sampling can be performed by transbronchial biopsy (TBB), brushing, BAL, or needle aspiration.25 The diagnostic yield of R-EBUS in the evaluation of peripheral SPNs is 71% (95% CI, 65–75%) and its sensitivity for the detection of malignancy is 73% (95% CI, 70–76%).5,29 The yield of the technique improves as the prevalence of malignancy and the size of the nodule increase (78% for > 2 cm vs 56% for 2 cm).29 The only major complication is pneumothorax, which is very rare (pooled rate: 1%) with only 0.4% requiring chest tube placement.29
The combined use of navigational bronchoscopy with R-EBUS improves diagnostic yield beyond either technique alone.17 In a randomized controlled trial that included 118 patients with peripheral nodules, R-EBUS and EMNB combined had a diagnostic yield of 88%. This was significantly higher than that of R-EBUS (69%) or EMNB (59%) alone and independent of nodule size and location.32 Another study of 53 nodules demonstrated a diagnostic yield of 93% when R-EBUS was used to confirm the EMNB location much higher than the reported 48% yield without R-EBUS.33 In the same study, sampling by catheter aspiration was superior to forceps biopsy, especially when R-EBUS could not confirm nodule location.33 Similarly, another trial done in 199 individuals with peripheral nodules found that VB with R-EBUS had an 80% diagnostic yield significantly versus a 67% diagnostic yield with R-EBUS alone.34 The addition of ultrathin bronchoscopes to VB significantly increases the diagnostic yield when nodules are located in the peripheral one third of the lung (65 vs 52%) or in the right upper lobe (81% vs 53%).28
Guided Bronchoscopy
Navigational Bronchoscopy Navigational bronchoscopy expands upon conventional bronchoscopy by providing guidance through the tracheobronchial tree, thereby improving the accurate localization and sampling of peripheral nodules.5 There are two technologies
Fig. 2 Characteristic endobronchial ultrasound image (B) of a peripheral pulmonary nodule (A) localized with the use of a radial endobronchial ultrasound (R-EBUS) probe. Seminars in Respiratory and Critical Care Medicine
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Guided Bronchoscopy versus Conventional Bronchoscopy Dolina et al demonstrated that the use of guided bronchoscopy with three-dimensional imaging to map out a pathway to a peripheral nodule is superior to the use of two-dimensional CT images regardless of experience.35 In a metaanalysis assessing the overall performance of guided-bronchoscopy in the evaluation of peripheral nodules, Wang Memoli et al reported a pooled diagnostic yield of 70% (95% CI, 67–73%), which is significantly higher than that of conventional bronchoscopy (49%).5,26 The yields of R-EBUS (71.1%) and VB (72%) were higher than the overall weighted diagnostic yield, whereas the highest yield (73.2%) was seen with the use of a guide sheath to maintain the position for biopsy after the localization of the nodule.5 The most common complication of guided bronchoscopy was pneumothorax, with an overall rate of 1.5% (range: 0–7.5%), only one third (0.6%) of which required chest tube placement. The incidence of respiratory failure requiring intubation was 0.1%, and there were no deaths or significant bleeding reported.5 The falsenegative rate of both conventional and guided bronchoscopy is not known, but it is estimated to be high enough to warrant further investigation in the case of negative or nondiagnostic
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results, especially when the suspicion for malignancy is high.3,17
Transthoracic Needle Sampling Transthoracic needle sampling obtains tissue directly from the SPN by placing a needle through the chest wall.21 The procedure can be performed under fluoroscopic or CT guidance; however, CT has a sensitivity of 92% for lesion localization versus 88% for fluoroscopy.17 Two types of needles are available for use: thin aspiration needles and core biopsy needles. The fine needle aspirates (transthoracic needle aspiration [TTNA]) provide material for cytology, whereas the larger needles, which cut core biopsies (transthoracic needle biopsy [TTNB]), provide specimens for histology.17,36 The performance of this technique is related to the location, the size of the lesion, the guidance modality used to locate the lesion, the size of the needle, the number of passes, and the presence of rapid on-site evaluation of the received samples.3,17 Although TTNA is comparable to TTNB for diagnosing malignant lesions, it is less likely to provide enough material for mutational analysis (44–50% vs 100%) or to establish a specific nonmalignant diagnosis.17,37,38 The overall sensitivity and specificity of transthoracic needle sampling for the diagnosis of malignancy in peripheral nodules is 90% (95% CI, 88–91%) and 97% (95% CI, 96–98%), respectively.17 When nodule size is 15 mm the sensitivity decreases to 70 to 82%.17 Although the false-positive rate is low at 1%, the high false-negative rate (20–30%) requires further investigation and/or observation when the results are negative or nondiagnostic.17 Although a positive result for a specific benign disease is valuable in the right clinical context, it should be remembered that the false-positive rate for nonmalignant diagnoses can be up to 50%.17,39 Pneumothorax and hemorrhage are the two main complications of transthoracic needle sampling.3,17 In a crosssectional analysis of 15,865 adult patients that had undergone TTNB, the incidence of postprocedure hemorrhage was 1% with 18% of patients with hemorrhage requiring blood transfusion.40 In contrast, pneumothorax was observed in 15% of patients, approximately half (6.6%) of whom required chest tube placement.40 The same study identified older age (60–69 years), smoking status, and chronic obstructive pulmonary disease (COPD) as risk factors for pneumothorax.
Surgical Methods Surgery is the gold standard for diagnosing SPNs because complete excision allows for both a definitive diagnosis and curative treatment in a single procedure.3 There are a variety of surgical techniques that are used alone or in combination, including thoracoscopy and open thoracotomy.3,13
Video-Assisted Thoracoscopic Surgery (VATS) VATS is the least invasive surgical technique available for the excisional biopsy of a pulmonary nodule.3 The procedure, which is performed under general anesthesia, induces an iatrogenic pneumothorax in the lung containing the nodule. A
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trocar is inserted through the seventh intercostal space, which allows the thoracoscope to enter the hemithorax.13 Additional trocars are placed to allow the use of other instruments, such as stapling devices, cautery, or laser.13 Following localization of the nodule, wedge resection is suggested with intraoperative examination of frozen sections by pathology to exclude or establish malignancy.3 In the case of malignancy, curative treatment with lobectomy and accurate staging with systematic lymph node sampling should follow in all patients with adequate respiratory reserve.3,16 The main limitation of the VATS is that it does not allow for digital palpation of lung tissue to localize nodules that are not directly visible with the thoracoscope.3,41 Failure to localize the nodule of concern results in conversion to an open thoracotomy in up to 45% of the cases. 42 To improve upon this, a variety of techniques have emerged that allow for better lesion localization. These include the use of hookand-wire, radioguidance, methylene blue, percutaneous microcoils, bronchoscopically placed fiducials, ultrasonography, and fluoroscopy with contrast material.3,43 When the nodule is accurately localized and resected the sensitivity of results from frozen section analysis is dependent upon the size of the nodule (87% for nodules < 1.1cm, 94% for nodules 1.1–1.5 cm).3,44 Moreover, it can be difficult to differentiate between malignant diagnoses on frozen section.3,44 Although there is a paucity of extensive data related to the complications of thoracoscopic nodule resection, because it is less invasive than thoracotomy it likely has a lower morbidity rate and shorter hospital length of stay.13 In two small studies, VATS diagnostic resection of nodules had no associated mortality and a complication rate of 5%.45,46
Open Thoracotomy Open thoracotomy is the most invasive surgical method for diagnosing SPNs and is generally recommended when the surgeon fails to locate the SPN with VATS.47 In patients with malignant nodules, thoracotomy has a mortality rate of 1.7 to 5.3% when diagnostic wedge resection is followed by curative lobectomy.12 The resection of benign nodules alone is associated with a mortality of 0.5%.12 The complication rate in patients undergoing wedge resection has been found to be 15%.48 Although thoracotomy allows for the digital palpation to localize nonvisible nodules, there are certain instances (i.e., nodule < 1 cm in size, deep in location, or subsolid in attenuation) in which alternative localization techniques mentioned previously must be employed.41
Summary The number of solitary pulmonary nodules detected each year in the United States is expected to increase with lung cancer screening. Malignant SPNs represent the earliest stage of lung cancer, and their timely detection allows for a better chance of survival. Malignancy can rarely be excluded by radiographic features; thus the majority of SPNs are indeterminate and require further investigation with either continued surveillance or immediate diagnostic sampling. Seminars in Respiratory and Critical Care Medicine
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Diagnostic Approach to the SPN
Diagnostic Approach to the SPN
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The decision to proceed with immediate sampling is determined by nodule characteristics (density and size) and patient risk factors for malignancy. Sampling is achieved by either surgical or nonsurgical techniques, and the choice between the two is influenced by nodule probability of malignancy and patient surgical risk. Surgical methods are preferred in SPNs with high probability of malignancy because they provide both a definitive diagnosis and treatment in a single procedure. When the probability of malignancy is low to moderate or the surgical risk is high, nonsurgical sampling is preferred. Centrally located nodules can be sampled with bronchoscopic techniques. Nonsurgical sampling of peripheral nodules, which represent the majority of SPNs, may be performed either with transthoracic needle techniques or guided bronchoscopy. Life expectancy in individuals with SPNs does not significantly change due to the diagnostic strategy chosen; thus individual preferences should be considered in the diagnostic approach to pulmonary nodules.
14 Henschke CI, Yankelevitz DF, Mirtcheva R, McGuinness G, McCau-
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Diagnostic Approach to the SPN
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