Pulmonary nodule: a comprehensive review and update.

C L I N I C A L F E AT U R E S

Pulmonary Nodule: A Comprehensive Review and Update

Hospital Practice 2014.42:7-16. Downloaded from informahealthcare.com by Nyu Medical Center on 04/17/15. For personal use only.

DOI: 10.3810/hp.2014.08.1125

Amit Asija, MD 1 Rajapriya Manickam, MD 1 Wilbert S. Aronow, MD, FCCP, FACC, FAHA 1,2 Dipak Chandy, MD 1 Division of Pulmonary, Critical Care, and Sleep Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY; 2Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, NY 1

Abstract: The incidental detection of solitary pulmonary nodules and ground-glass nodules has increased substantially with the use of computed tomography as a diagnostic modality and is expected to rise exponentially as lung cancer screening guidelines are more widely implemented by primary care physicians. The lesions should then be classified as low, indeterminate, or high risk for malignancy, depending on the clinical and radiological characteristics. Once classified, these lesions should be evaluated and managed as per expert consensus-based recommendations for performing follow-up computed tomography scans and tissue sampling depending on the pretest probability. When weighing the risks and benefits of further investigations, patient preference and suitability for surgery should be taken into consideration as well. Keywords: pulmonary nodule; ground-glass opacity; clinical and radiological risk factors; computed tomography

Introduction

Correspondence: Wilbert S. Aronow, MD, FCCP, FACC, FAHA, Cardiology Division/Westchester Medical Center, New York Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595. Tel: 914-493-5311 Fax: 914-235-6274 E-mail: [email protected]

Chest imaging is extensively done in medicine for various reasons. In recent years, with advancement in computed tomography (CT) technology and its widespread use, lung nodules are common incidental findings. In older studies, in which chest radiography was the diagnostic modality, the number of lung nodules detected were low (0.2%).1 However, with the more widespread usage of CT scans, we are able to pick up smaller nodules that were undetectable before. Hence, the detection of lung nodules has increased dramatically to 8% to 51% as documented by various large lung cancer screening trials.1,2 Lung cancer is the leading cause of death in both men and women in the United States, and the overall 5-year survival rate is only 16%.1 In contrast, patients with an early–stage lung cancer and with tumor size , 3 cm who are undergoing surgical resection3 have a 5-year survival of 70% to 80%. Recent evidence from the National Lung Cancer Screening Trial4 demonstrates a 20% reduction in mortality with screening of lung cancer with low-dose CT scans. Nevertheless, the majority of benign nodules do not warrant any further investigation, and unnecessary surgery should be avoided. This article reviews the definition of lung nodule, ground-glass opacity, clinical and radiological risk factors suggestive of malignancy, and available modalities for risk stratification, and discusses the approach to pulmonary nodules based on current evidence. The term solitary pulmonary nodule (SPN), or coin lesion, is ideally used to describe a single, rounded, well-circumscribed radiographic opacity that is # 3 cm in maximum diameter, completely surrounded by lung parenchyma, and not associated

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with atelectasis, consolidation, hilar adenopathy, or pleural effusion.5 The nomenclature committee of the Fleischner Society for Thoracic Imaging and Diagnosis6,7 described a lung nodule as a “small, approximately spherical, circumscribed focus of abnormal tissue” that appears on the CT scan as a rounded or irregular opacity, well or poorly defined, measuring # 3 cm. A purely linear or sheet-like lesion without a spherical quality is not considered a nodule and is unlikely to be malignant. But even with these definitions, there is lot of discrepancy among radiologist in what would count as a pulmonary nodule as well as in measuring the size or growth of the nodule. Many studies have demonstrated substantial reader variability in identifying pulmonary nodules on imaging.8,9 It is not uncommon to find multiple nodules on a thinsection CT scan. Multiple nodules (. 10) are more likely to be inflammatory or metastatic and less likely to be primary bronchogenic carcinoma and are treated differently. However, when there are $ 1 nodules with a single dominant nodule, it is treated like an SPN. A nodule that does not have specific benign characteristics is called an indeterminate nodule. Nodules , 8 mm in size are categorized as subcentimeter nodules, and those , 4 mm are called micronodules. The prevalence of malignancy in subcentimeter nodules is very low, and hence the follow-up and management are different. Lesions . 3 cm in diameter are termed lung masses and should be considered malignant unless proven otherwise.10 The widespread use of high-resolution CT scans and several large screening trials with low-dose CT (LDCT) scans has led us to discover a new category of faint pulmonary nodules termed ground-glass nodules (GGNs) or subsolid nodules. A GGN is defined as focal nodular area of increased hazy lung attenuation through which normal parenchymal structures like airways, interlobar septa, and vessels are visible, in contrast to the typical solid nodules that obscure lung parenchyma.7 These nodules may have a solid component and are classified as partly solid GGNs or pure GGNs. The GGNs are usually multiple, and their characteristics are distinct from solid nodules. They often tend to be malignant, typically representing the histological spectrum of adenocarcinoma with a very slow growth rate, often demonstrating a doubling time of . 2 years. Hence, the approach for GGNs is different from that for the solid nodule and will be discussed separately.

Risk Stratification

There are multiple causes of lung nodules as listed in Table 1. Most nodules are benign (eg, hamartomas, infections),11 8

but some may also represent bronchogenic carcinoma or metastatic lesions. The prevalence of malignancy in detected nodules in large screening trials varies between 0.2% and 18% across studies depending on the study population and the size of nodules included in the study.12 Once a pulmonary nodule is detected, the next step is to estimate the pretest probability of cancer, using clinical risk factors and CT characteristics. A perfect diagnostic approach should lead to definitive resection for malignant lesions and avoid resection in patients with benign disease. But we do not yet have such an ideal diagnostic study that is cost-effective and noninvasive. Hence, it is crucial to determine the pretest probability of cancer so that appropriate diagnostic studies can be selected. Clinical and radiographic features cannot reliably distinguish malignant from benign lesions but can enable us to risk stratify for malignancy.

Clinical Risk Factors for Malignancy

The major clinical risk factors for an SPN being malignant as follows: Age: Lung cancer is rare in patients aged , 35 years and uncommon in patients aged 35 to , 40 years, but with increasing age, the probability of cancer increases.13 Smoking history: Cigarette smoking is the single most common risk factor for lung cancer, and it increases the relative risk by about 10 times as compared with nonsmokers. The risk increases in direct proportion to the intensity and duration of exposure. Various lung cancer screening studies have reported that almost 50% of all smokers aged . 50 years have . 1 nodule detected during the screening for lung cancer, and 10% tend to develop a new nodule in the next year.14 Some studies have reported that the growth rates of malignant nodules are faster in smokers than in nonsmokers.15 Prior history of cancer: Nodules detected in patients with a prior history of cancer are more likely to be malignant. Studies have shown that these nodules are equally or more likely to be primary lung cancer rather than metastases, and the likelihood seems to depend on the patient’s smoking history and on the histological characteristics of the extrapulmonary neoplasm.16 Lung nodules found in patients with a history of sarcoma, melanoma, or testicular cancer are more likely to be metastases than primary lung cancer. On the other hand, lung nodules in patients with history of breast, prostrate, bladder, or head and neck carcinomas are more likely to be primary lung cancer than metastases. Interstitial lung disease, especially scleroderma and sarcoidosis, are associated with increased incidence of lung

© Hospital Practice, Volume 42, Issue 3, August 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Pulmonary Nodule


Table 1. Causes of Solitary Pulmonary Nodule Infectious • Tuberculosis • Fungal infections (aspergillosis, blastomycosis, cryptococcosis, histoplasmosis, coccidiomycosis) • Atypical mycobacteria • Nocardia • Round pneumonia • Septic emboli • Lung abscess Inflammatory • Sarcoidosis • Wegener’s granulomatosis • Microscopic polyangiitis • Rheumatoid nodule • Pulmonary amyloidosis Neoplastic • Lung cancer • Solitary pulmonary metastasis • Lymphoma • Carcinoid tumors • Teratoma • Leiomyoma • Benign • Hamartoma • Lipoma • Fibroma • Chondroma • Clear cell tumor • Sclerosing hemangioma • Neural tumor • Plasma cell granuloma • Endometriosis Congenital • Lung cyst • Bronchial atresia with mucoid impaction • Lung sequestration Vascular • Arteriovenous malformation • Pulmonary hematoma • Pulmonary infarct • Normal confluence of pulmonary veins • Intrapulmonary lymph node • Pulmonary scar • Rounded atelectasis • Infected bulla Miscellaneous/mimics • Nipple shadow • Cutaneous lesion (eg, wart, mole) • Rib fracture or other bone lesion • Vanishing pseudotumor (loculated pleural fluid)

cancer.17 The prevalence of lung cancer is high in idiopathic pulmonary fibrosis patients (31%) and likely to be in the periphery and lower lobe, and likely to be squamous cell carcinomas, with most of them detected as incidental nodules.18 Chronic obstructive pulmonary disease (COPD), another important smoking-related lung disease, has been considered

a risk factor for lung cancer. However, it is not clear whether the increased risk for lung cancer is attributable to the associated smoking history or the COPD itself. Brenner et al19 did a complicated meta-analysis of 39 studies on the risk of lung cancer in previous lung disease patients after adjusting for smoking status. Though there were wide statistical variations among the studies, combined relative risk (RR) for COPD patients for lung cancer was estimated to be 1.83 (95% CI, 1.60–2.11). However, subgroup analysis among nonsmokers did not show significant association (RR, 1.22; 95% CI, 0.97–1.53) for COPD and lung cancer, whereas adjusting for second-hand smoke showed an RR of 1.49 (95% CI, 1.20–1.85). A more recent study from the United Kingdom analyzed 49 493 patients and found that there is strong correlation between COPD and lung cancer; however, the effect is much less when adjusted for smoking, with an odds ratio of 1 in nonsmokers.20 A family history of a first-degree relative with lung cancer increases the risk of lung cancer.21 Some genetic variants22 and lung cancer susceptibility genes23 have been described. On the other hand, a history of travel to fungal endemic areas may suggest a benign, infectious etiology.24

Radiographic Characteristics

The following characteristics of pulmonary nodules can differentiate benign from malignant lesions: Nodule size: It is well documented that the likelihood of cancer increases with an increase in nodule size. A Mayo Clinic CT screening trial reported that the likelihood of malignancy is 0.2% for nodules # 3 mm, 0.9% for nodules of 4 to 7 mm, 18% for nodules of 8 to 20 mm, and 50% for nodules . 20 mm.2 Nodule location: The SPNs in upper lobes are more likely to be malignant, and the most likely explanation is a higher concentration of inhaled carcinogens in the upper lobes.25 Nodules in upper lobes and peripheral lung zones are easily missed on chest radiographs, as they may be obscured by bony structures. Some studies also suggest that malignancy is 1.5 times more common in the right lung. Nodule margin: Furuya et al26 describe 6 different margin characteristics of pulmonary nodules: round or smooth, lobulated, densely spiculated, ragged, tentacle or polygonal, and with surrounding halo. Nodules with smooth margins usually are benign but can be malignant. Tentacle or polygonal margins are usually seen with inflammatory lesions. On the other hand, nodules with lobulated or spiculated margins are highly likely to be malignant (58% or 88%–94%, respectively).27



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Nodular calcification: No pattern of calcification is specific for malignancy. However, specific patterns like central dense nidus (bull’s eye), diffuse, laminated, or popcorn pattern strongly suggest that the nodule is benign.28 Malignant nodules are usually associated with punctate or eccentric lesions. Chest radiographs are not sensitive enough to detect calcification, and CT imaging with thin cuts is recommended. Nodular attenuation: An attenuation value of –120 to –40 Hounsfield units in a nodule represents fat and is a fairly reliable sign for benign lesions, most likely hamartomas29,30 and rarely lipoid pneumonia, liposarcoma, or renal cell carcinoma. Absence of significant lung nodule enhancement (# 15 Hounsfield units) on CT is strongly predictive of a benign etiology.31 As discussed above, a GGN described as a faint nodular area of increased hazy lung attenuation is more likely to be malignant than are solid nodules, typically representing the histological spectrum of adenocarcinoma with a very slow growth rate, often demonstrating a doubling time of . 2 years. Nodular cavitation: Cavities can be seen both in benign (abscess, infectious granulomas, vasculitides, early Langerhans’ cell histiocytosis, and pulmonary infarction) and malignant (squamous cell carcinoma) lesions. An important factor is the wall thickness. Smooth walls with , 5 mm thickness suggest a benign etiology, whereas irregular, thick (. 15 mm) walls are usually malignant.32 Growth rate (doubling times): The growth rate of a nodule gives an important clue to the character of the nodule. It is typically expressed in terms of the doubling time—the time it takes for the nodule to double in volume. The volume of a sphere equals to 4Πr3/3 (where r is the radius), and hence one doubling in tumor volume corresponds approximately to an increase in nodule diameter by 26%. The doubling time for malignant nodules is variable but is generally between 20 and 400 days,19,20 and hence no change in size of a nodule (radiographic stability) during 2 years of follow-up strongly suggests a benign etiology. However, this is not true with the

slow-growing adenocarcinomas, which are usually detected as small GGNs that have a doubling time of . 700 days. Hasegawa et al15 reported median volume doubling times of pure GGN, partial GGN, and pure solid nodules as 813 days, 457 days, and 149 days, respectively. Hence, a longer follow-up is needed in patients with GGNs. Which method to use to follow the growth rate is controversial, because in 2-dimensional studies the doubling time of smaller nodules causes only a minimal (26%) increase in diameter, which can be easily missed. Revel et al33 found that 2-dimensional measurements obtained with electronic calipers are unreliable for distinguishing benign from malignant lesions based on a growth rate in the 5- to 15-mm range. Hence, volumetric 3-dimensional CT scans34 are advocated, but the data are less clear in subcentimeter nodules.

Pretest Probability

The physician should estimate pretest probability of cancer by using the clinical risk factors and CT characteristics described above and as shown in Table 2. Alternatively, various models using logistic regression have been suggested to assess clinical pretest probability. In the past decade, numerous quantitative models have been developed and validated to assist clinicians in categorizing patients in low-, intermediate-, and high-risk groups. Swensen and coworkers35 have developed a logistic model at the Mayo Clinic for patients with newly discovered SPNs (4–30 mm) and radiologically described as having “indeterminate” probability for malignancy. They identified 6 independent predictors of malignancy: older age, current or past smoking, history of extrathoracic cancer . 5 years before nodule detection, nodule diameter, spiculation, and upper lobe location. This model uses a complicated mathematical model to predict the probability. A similar model was also developed by Gould et al36 and subsequently validated in a population with a higher prevalence of malignancy.37 However, these prediction models are complicated, and they are not superior to qualitative intuitive assessment by expert

Table 2. Estimation of Pretest Probability by Using Clinical Risk Factors and Computer Tomography Characteristics Risk Factors

Low Risk of Cancer

Moderate Risk of Cancer

High Risk of Cancer

Age Smoking Quit smoking Diameter of nodule Nodule margins Prior history of cancer Exposure to asbestos62

, 45 years Never smoked

45–60 years

. 60 years Current smoker ($ 1 pack per day) Current smoker

$ 7 years ago or never smoked , 8 mm Smooth No No

Current smoker (, 1 pack per day) , 7 years ago 8–20 mm Scalloped NA NA

. 20 mm Spiculated, corona radiata Yes Yes

Abbreviation: NA, not applicable.

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clinician.38 The American College of Chest Physicians suggests estimating the pretest probability of malignancy either qualitatively by using clinical judgment or quantitatively by using a validated model.39


Assessing Suitability for Surgery

Along with the pretest probability based on clinical and radiological risk factors, we should also consider patient suitability and the patient’s wishes for curative therapy before starting on an inconvenient, expensive, risky evaluation. The patient may prefer not to be treated at all, especially older patients who have higher risk of malignancy and life-limiting comorbid conditions. In such patients aggressive CT surveillance or any other diagnostic procedure is meaningless. However, patients who would like to be treated but are not suitable for surgery can undergo biopsy and be treated with radiotherapy (external beam, stereotactic) or radiofrequency ablation.

Management Strategies Anatomic Imaging

Chest radiograph: If a nodule is detected incidentally on chest radiograph and has diffuse central, laminated, or popcornpattern calcification or fat density, it can be considered benign and no further testing is required. Likewise, if prior imaging is available and the lesion has been stable for $ 2 years, no further testing is required. However, if none of the signs are present and no prior imaging is available, further evaluation with a CT scan of chest is mandatory.39 Computed tomographic technology: Thin-section (1-mm contiguous images) is recommended for evaluation of nodules. The characteristics of nodules including size, margins, calcification, cavitation, attenuation, lymph nodes, and vascularity are analyzed. As with chest radiographs, prior imaging should be reviewed to establish 2-year stability. If no prior images are available, then based on the size of the nodule, the malignancy risk is computed from the clinical and radiological risk factors as detailed above. Volumetric CT scan analysis: An advanced helical CT scanner with a high axial resolution of , 1.0 mm can scan large anatomic volumes in a single breath and enable 3-dimensional volumetric assessments of lung lesions. The volumetric assessment is primarily applied to detect growth rate or volume doubling time. Studies have shown that volumetric measurement gives accurate volume doubling time and thus helps in distinguishing benign from malignant nodules with sensitivity and specificity of 91% and 90%, respectively.33,34 Growth can be detected as early as 4 to 6 weeks, which enables us to identify malignant lesions

much earlier. However, CT reconstruction of smaller nodules (, 8 mm) tends to cause errors, and the volume doubling time may not be accurate. The other application for volumetric assessment is to evaluate treatment response. More research is required to validate this novel technique and its clinical application. Low-dose CT (LDCT) scan: Radiation exposure and accompanying increased risk for cancer is a major limitation of the routine use of highly efficient multislice detector CT. An LDCT of , 80 mAs/s has an optimal setting that is a trade-off between minimizing radiation and maintaining acceptable image quality. The radiation exposure with LDCT is about 1 to 4 millisieverts, whereas with conventional CT scan the radiation dose is much higher, between 7 and 14 millisieverts depending on the size of the patient.40,41 Recently, various organizations, including the National Comprehensive Cancer Network,40 the American College of Chest Physicians,42 the American Society of Clinical Oncology,43 and the US Preventive Services Task Force (USPSTF)44 have issued guidelines for lung cancer screening in high-risk patients. These guidelines recommend annual low-dose CT scan screening for those at high risk: age 55 to 74 years (except USPSTF, which specifies age group 55 to 80 years) with a 30-pack-year history of smoking, or, if no longer smoking, smoking cessation within the last 15 years. Although the guidelines note that the duration of screening is uncertain, they advise a minimum of 3 scans. The guidelines do not support screening low- and intermediate-risk population.

Functional Imaging

With a fluorodeoxyglucose–positron emission tomography (PET) scan, the metabolic activity of a nodule can be assessed. Malignant nodules show enhanced uptake when compared with benign lesions, which reliably differentiates them from benign nodules with a sensitivity of 87% and specificity of 83%, yielding an accuracy of 91%.12,36 The specificity is superior to that of a CT scan and has less interand intraobserver variation. The metabolic activity can be assessed by 2 methods. The first is quantitative assessment using standardized uptake value (SUV) measurement. A mean SUV . 2.5 is the widely accepted cutoff with optimal sensitivity and specificity to differentiate malignant from benign lesions. The second method is qualitative assessment by visual analysis, where the fluorodeoxyglucose uptake of nodules is compared with the uptake of normal structures within the thorax. Neither method has been found to be superior to the other, and hence



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the American College of Chest Physicians suggests using either method for assessment.39 In addition to the nodules, a PET scan helps in assessing mediastinal lymph nodes for possible metastasis. However, a PET scan has important limitations. It is less sensitive for nodules , 8 to 10 mm and not recommended to evaluate SPN , 1 cm.5,10,45 False-negative scans are seen with a slow-growing, less metabolically active malignancy such as carcinoid tumor and GGNs that represent adenocarcinoma in situ and mucinous adenocarcinomas. Moreover, in subsolid nodules, a PET scan paradoxically shows higher SUV in inflammatory nodules when compared with malignant nodules. Therefore, a PET scan is not reliable in the evaluation of a GGN. False-positive scans occur with infections (fungal infection, tuberculosis) and inflammatory conditions (rheumatoid nodules, sarcoidosis). A PET scan has a high negative predictive value and is reliable in patients with low pretest probability, enabling these patients to be followed without invasive diagnostic studies. 46,47 Intermediate-risk patients with indeterminate lesions on CT scan and negative PET scans should be monitored for $ 2 years to confirm stability or undergo needle biopsy to rule out malignancy.42 On the other hand, in patients with high probability, a negative PET scan is not reliable and not routinely recommended, as it would not significantly change management. It is interesting to note that false-negative PET scans have a favorable prognosis even when treatment is delayed by 238 days.48 Dual time point PET scan, in which the metabolic activity is observed for prolonged periods (. 2 hours), improves sensitivity and possibly specificity. However, the data are insufficient, and this modality is not currently recommended. Another modality is dynamic imaging (CT and magnetic resonance imaging), which enhances nodules after administration of contrast and is a highly sensitive but nonspecific method to identify malignant nodules that are highly vascular. Absence of contrast enhancement strongly suggests a benign lesion.

Diagnostic Testing

When the pretest probability for malignancy is intermediate (∼10%–60%), it almost always warrants tissue diagnosis either by nonsurgical or surgical biopsy.

Nonsurgical Biopsy The options available are CT-guided transthoracic needle biopsy, bronchoscopy-guided needle biopsy using fluoroscopy, endobronchial ultrasound (EBUS), electromagnetic navigation (EMN), or virtual bronchoscopy navigation (VBN). 12

Computer tomography–guided transthoracic needle biopsy has a sensitivity that depends on the size of the nodule, the size of the needle, the number of passes made, and the presence of an on-site pathologist. A review of 11studies found that the median sensitivity for identifying malignancy is $ 90%, with the exception of 3 studies that analyzed nodules # 15 mm, which showed a sensitivity of 70% to 82%.12 Major complications are hemorrhage (1%), pneumothorax (15%), and pneumothorax requiring chest tubes (6%).12 Risk factors for pneumothorax are smoking, smaller lesion, deeper location, emphysema, proximity to fissures, low entry angle to pleura, lateral puncture site, and greater number of needle passes.49,50 Historically, bronchoscopy-guided transbronchial lung biopsy played a limited role in tissue diagnosis of pulmonary nodules, especially for peripheral lesions. The sensitivity for traditional fluoroscopy-guided transbronchial biopsy is 5% to 76% (median 31%).51 The presence of an air bronchogram within the nodule or a bronchus leading to the lesion improves the diagnostic yield (70%).10,51,52 Radial EBUS/transbronchial needle aspiration facilitates localization of peripheral nodules. Meta-analysis shows an improved sensitivity (73%) and specificity (100%) with radial EBUS for peripheral lesions, but the sensitivity for lesions , 25 mm drops to 71%.53 Electromagnetic navigation combines CT imaging with bronchoscopy and uses a positional sensor that determines the direction based on an electromagnetic field generated around the patient’s chest to navigate through the endobronchial tree to the target areas. A small study with 60 patients found that EMN has a diagnostic yield of 74% for peripheral lung lesions.54 The overall yield is 80% irrespective of the size and location of the lesion. Similar results are found in 2 other studies.55,56 A randomized controlled trial found that combined EBUS/EMN has a higher diagnostic yield of 88% than that of EBUS (69%) or EMN (59%) alone.57 A recent meta-analysis on these bronchoscopy-guided techniques found a pooled risk of 1.6% for pneumothorax, and only about 0.7% required chest tube placement.58 Virtual bronchoscopic navigation is another method in which virtual bronchoscopic images of the bronchial path to a peripheral lesion are generated and used as a guide to navigate the bronchoscope. A recent Japanese randomized controlled trial found a higher yield (80%) with VBNassisted EBUS than with nonassisted procedures, 59 but another similar study by the same group did not confirm these results. However, the subgroup analysis showed a higher yield for right upper lobe lesions, lesions invisible



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on posteroanterior radiographs, and lesions in the peripheral third of the lung field.60 Overall, CT–transthoracic needle aspiration (TTNA) has higher risk of pneumothorax, but the sensitivity to detect malignancy especially of peripheral lesions is greater than that of bronchoscopy-guided procedures, even with the newer advanced techniques (radial EBUS, EMN). Even the combined sensitivity is slightly lower than that of TTNA. The choice of test should depend on the nodule location, its relation to the airway, the risk of pneumothorax, and the expertise available. Bronchoscopy-guided procedures are preferred over transthoracic needle biopsy in patients with an air bronchogram in the nodule or a clear pathway leading to the lesion, and in those who are at high risk of pneumothorax. In other patients, CT-TTNA should be considered first.

Surgical Biopsy Surgical resection is the gold standard for diagnosis as well as the definitive therapy for malignant lung nodules. The available modalities are video-assisted thoracoscopy (VATS), thoracotomy, and mediastinoscopy. Video-assisted thoracoscopy is less invasive than traditional thoracotomy, with reported nonfatal complication rates of 5%,61 and it is the strongly preferred diagnostic modality. Smaller size, deeper location, and subsolid nodules may pose technical challenges. Recently, the use of localizing techniques such as ultrasound, fluoroscopy, and hook and wire were found

to increase the diagnostic yield. The diagnosis is usually established by on-site frozen section analysis. If the nodule is found to be malignant, then lobectomy with mediastinal lymph node sampling is recommended. Video-assisted thoracoscopy lobectomy is increasingly being done, although conversion to traditional thoracotomy is warranted in many cases. In patients with low cardiopulmonary reserve, sublobar resection is acceptable for medically unfit patients.

Clinical Algorithm

Overall review of the management of pure solitary and ground-glass nodules is depicted in a clinical algorithm (Figure 1).

Nodule , 8 mm

The optimal approach for the subcentimeter nodule is still evolving. Although the probability of malignancy in this subgroup is low, these nodules are not easily amenable to biopsy or adequate characterization by PET scans. Also, there are concerns about radiation exposure and cost-effectiveness. After considering all these factors, the Fleischner Society made recommendations depending on patients with low or high risk for lung cancer (Table 3).

Nodules 8 to 30 mm

For solid nodules . 8 mm (solitary or dominant), the first step again is evaluation of the probability of cancer, followed by

Figure 1. The Fleischner Society’s clinical algorithm for the management of pure solitary and ground-glass nodule.

Abbreviations: CT, computed tomography; GGN, ground-glass nodule; PET, positron emission tomography. © Hospital Practice, Volume 42, Issue 3, August 2014, ISSN – 2154-8331 13 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

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Table 3. Fleischner Society Recommendations for Management and Follow up of Incidental Pulmonary Nodulea Smaller Than 8 mm Nodule Sizeb

Low Riskc

High Riskd

# 4 mm . 4 to 6 mm

No follow up needed Follow-up LDCT in 12 months; if unchanged, no further follow-up Follow-up LDCT in 6–12 months, and if unchanged, again in 18–24 months Follow-up LDCT in 3, 9, 24 months if remains unchanged; consider dynamic contrast- enhanced CT, PET scan, and/or biopsy

Follow-up LDCTe in 12 months; if unchanged, no further follow-up Follow-up LDCT in 6–12 months, and if unchanged, again in 18–24 months Follow-up LDCT in 3–6 months, 9–12 months, then again in 24 months if remains unchanged. Same as low risk

. 6 to 8 mm . 8 mm

Newly detected indeterminate nodule in persons aged $ 35 years. Average of length and width. c Minimal or absent history of smoking and of other known risk factors. d History of smoking or of other known risk factors e Low dose, thin section, unenhanced CT scan should be used if lung nodule follow up is the only indication for the CT scan. Reprinted from MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary nodules detected on CT scans: A statement from the Fleischner Society. Radiology. 2005;237(2):395–400. With permission from Radiological Society of North America.63 Abbreviations: CT, computed tomography; LDCT, low-dose computed tomography; PET, positron emission tomography. a


b

an assessment of the patient’s surgical risk. Then the patient’s management preference is taken into account. Further management options include careful CT surveillance, diagnostic testing, and surgical resection. If the patient’s surgical risk is high, a nonsurgical biopsy can be considered. If the lesion is benign, it is treated appropriately. Inconclusive results can be followed with CT surveillance, and, if malignant, minimal surgical resection or palliative therapy should be considered. At any point during CT surveillance, if there is evidence of growth, surgical resection or biopsy is advised unless specifically contraindicated.

Ground Glass (Subsolid) Nodule

This group of subsolid nodules, both nonsolid (pure GGN) and partly solid (GGN with solid component , 50%), has a high probability of premalignant and malignant lesions

that are slow growing. Positron emission tomography scans and volumetric assessment can give false-negative results, whereas surgical biopsies are difficult. The Fleischner Society recently recommended guidelines for the management of GGNs (Table 4). For patients with multiple nodules, the follow-up should be based on the largest nodule, and LDCT surveillance should be done as suggested in Table 4.

Conclusion

The incidental detection of SPNs and GGNs has increased substantially with the use of the CT scan as a diagnostic modality and is expected to rise exponentially as lung cancer screening guidelines are more widely implemented. Management and follow-up of pulmonary nodules is routinely done in outpatient settings, but hospital clinicians should also be aware of these recommendations to ensure proper

Table 4. Fleischner Society Recommendations for GGN (Subsolid) Follow-Upa Solitary Pure GGN

Recommendations

# 5 mm . 5 mm Solitary part-solid nodule , 5 mm (solid component) $ 5 mm (solid component) Multiple subsolid/ground-glass nodules Multiple pure GGNs # 5 mm Multiple pure GGNs . 5 mm Multiple GGNs with solid components

No follow-up needed Initial follow-up in 3 months; if persists, then annual surveillance LDCT for minimum of 3 years Initial follow-up in 3 months; if persists, then annual surveillance LDCT for minimum of 3 years Initial follow-up in 3 months; if persists, then CT-guided biopsy or surgical resection Follow-up LDCT at 2 and 4 years; consider alternate causes Initial follow-up in 3 months; if persists, then annual surveillance LDCT for a minimum of 3 years Initial follow-up in 3 months; if persists, consider biopsy or surgical resection for lesion . 5 mm solid component

Note: FDG-PET scan is of limited value and misleading and so is not recommended. Obtain 1-mm-thin CT sections to confirm that the nodule is purely ground glass. Reprinted from Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology. 2013;266(1):304–317. With permission from Radiological Society of North America.64 Abbreviations: LDCT, low-dose computer tomography; FDG-PET, fluorodeoxyglucose–positron emission tomography; GGN, ground glass nodule. a

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follow-up of incidental lung nodules found during a patient’s hospital stay. The USPSTF recommends annual screening for lung cancer with LDCT in patients aged 55 to 80 years who have a 30-pack-year smoking history and currently smoke or have quit within the last 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. The task force does not support screening low- and intermediate-risk populations. All persons enrolled in a screening program should receive smoking cessation interventions. The decision to begin screening should be the result of a thorough discussion of the possible benefits, limitations, and known and uncertain harms. Once a pulmonary nodule is detected, any available prior films should be reviewed to determine if the nodule is new or old, or if there is any change since the prior film. Nodules should then be classified as low, indeterminate, or high risk for malignancy, depending on clinical and radiological characteristics. Once classified, the nodules should be evaluated and managed as per expert consensus-based recommendations for performing follow-up CT scans and tissue sampling depending on the pretest probability. When weighing the risks and benefits of further investigations, patient preference and suitability for surgery should be taken into consideration as well.

Conflict of Interest Statement

Amit Asija, MD, Rajapriya Manickam, MD, Wilbert S. Aronow, MD, FCCP, FACC, FAHA, and Dipak Chandy, MD, have no conflicts of interest to declare.

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