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![[SYMPOSIUM]](../../../graphics/sym_logo.gif){kind=logo} Classifying solitary pulmonary nodulesNew imaging methods to distinguish malignant, benign lesions Kathryn Sullivan Hanley, MD; Jeffrey B. Rubins, MD VOL 114 / NO 2 / AUGUST 2003 / POSTGRADUATE MEDICINE
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The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.
This is the second of three articles on lung cancer. This page is best viewed with a browser that supports tables. Preview: Detected in about 1 of 500 chest radiographs, solitary pulmonary nodules are a common problem in primary care. Management of these nodules relies on correct diagnosis of indeterminate lesions, which allows curative resection of early-stage malignant nodules and avoids the morbidity and mortality of surgery for benign ones. In this article, the authors propose an algorithm that incorporates newer imaging and diagnostic methods to facilitate the evaluation and management of solitary pulmonary nodules.
A solitary pulmonary nodule is defined radiographically as an intrapulmonary lung lesion 3 cm (1.18 in) in diameter or less that is not associated with adenopathy or atelectasis (1). A lesion larger than 3 cm is considered a mass and is much more likely to be malignant than a smaller lesion. Because a solitary pulmonary nodule may represent a localized malignant neoplasm that may be amenable to curative resection, the current viewpoint is that it should be considered malignant until proved otherwise (2). Malignant causes of solitary pulmonary nodules include primary bronchogenic carcinoma, bronchoalveolar carcinoma, carcinoid tumors, and metastasis (table 1). However, a series of studies over the past 40 years has shown that 40% to 80% of resected nodules are benign (2-7). Common benign solitary pulmonary nodules include hamartomas and infectious granulomas, but they can be seen in a variety of diseases (2,8).
Management of nodules that are clearly benign or malignant is straightforward. The difficulty is in the evaluation and management of the indeterminate nodule. The goal is to correctly diagnose indeterminate nodules, allowing curative resection of early-stage malignant nodules and avoiding the morbidity and mortality of surgery for benign nodules. Ideally, the decision to resect or observe a nodule should be made within 1 month of presentation (figure 1). Stability and growthThe first step in evaluating solitary pulmonary nodules is to estimate the likelihood of malignancy on the basis of several factors related to the nodules and the patient. Stability of solitary pulmonary nodules on serial imaging studies is the best predictor of a benign cause. Growth of a solitary pulmonary nodule is measured by a change in apparent volume. The time it takes for the apparent volume to double is referred to as the doubling time. Assuming spherical solitary pulmonary nodules with volumes calculated as the product of 4/3 pi X radius (3), one doubling in volume is equivalent to the nodule diameter increasing by only 26% to 28% (2,9). Benign nodules representing acute inflammatory changes have a doubling time of less than 20 days. In contrast, stable granulomas and hamartomas may enlarge slowly and have a doubling time of more than 500 days (2). To evaluate a solitary pulmonary nodule, the physician needs to review a previous imaging study for comparison. If the solitary pulmonary nodule is radiographically stable over 2 years, it can be considered benign (2). Nodules with a doubling time between 25 and 450 days must be assumed to be malignant (2). If no prior imaging study is found, stability can be assessed prospectively if the risk of malignancy is thought to be low on the basis of a clinical risk evaluation. Solitary pulmonary nodules often can be followed radiographically more easily and less expensively by chest radiograph than by chest computed tomography (CT). For nodules that are detected incidentally on chest CT but would be visible on chest radiograph, a baseline chest radiograph should be obtained. Smaller nodules and those in anatomic areas not well visualized by chest radiograph should be observed by chest CT. Density characteristicsSolitary pulmonary nodules that are not clearly benign or malignant by growth characteristics should be evaluated by chest CT for the presence of calcification or fat. Chest CT offers many advantages over chest radiograph for characterizing solitary pulmonary nodules, including better definition of size, shape, calcification, and edge and better sensitivity for detecting small and multiple nodules (2,10). Additionally, chest CT provides better visualization of mediastinal lymphadenopathy and pleural effusions, which may indicate more advanced cancer. Certain defined patterns of calcification in solitary pulmonary nodules are markers of benign disease and have a positive predictive value of 0.93 (11). Symmetrical calcifications, such as those with central, laminar, or diffuse patterns, are associated with benign granulomas (figure 2a). So-called popcorn patterns of calcification (figure 2b) are associated with benign hamartomas. In contrast, asymmetrical calcifications, such as those that are speckled or stippled, and eccentric patterns (figure 2c) can be seen in malignancy and may represent (1) a tumor engulfing a preexisting calcified granuloma, (2) dystrophic calcifications in an area of tumor necrosis, (3) mucinous adenocarcinoma, or (4) carcinoid tumor (9). The presence of fat on chest CT is actually a better indicator of a benign nodule than is calcium. Central fat in a nodule is virtually diagnostic of hamartoma. Patient risk factorsFurther evaluation of solitary pulmonary nodules that are classified as indeterminate after assessing growth and density characteristics depends on the likelihood of malignancy. The three main patient risk factors that contribute to this probability of malignancy are advanced age, a history of cigarette smoking, and a history of extrathoracic cancer diagnosed at most 5 years before detection of a solitary pulmonary nodule (5). Lillington (2) suggested that age greater than 48 years increases the risk of a malignant solitary pulmonary nodule, and Swensen and colleagues (5) confirmed that the probability of malignancy increases as age advances from 35 to 55 to 75 years. Cigarette smoking increases the risk of malignancy by 2% per pack-year (5). In patients with a history of head and neck cancer, up to 75% of solitary pulmonary nodules are metachronous primary lung carcinomas, and 58% in patients with a history of carcinoma of the bladder, breast, cervix, bile duct, esophagus, ovary, prostate, or stomach are malignant (12). In addition, patients with a history of melanoma, sarcoma, or testicular carcinoma are more likely to have a metastasis presenting as a solitary pulmonary nodule (12). The risk of a second primary cancer is 1% to 2% per patient per year for patients who have survived non-small cell lung cancer and 6% per patient per year for those who have survived small cell lung cancer (13). Another patient factor that increases the likelihood of cancer, especially when combined with cigarette smoking, is a history of exposure to asbestos, radiation, or radon. On the other hand, a history of exposure to tuberculosis, travel to an area endemic for fungal infection, or a history of inflammatory connective tissue disease such as rheumatoid arthritis suggests a benign origin for the solitary pulmonary nodule. Radiographic risk factorsThe appearance of the edge of a solitary pulmonary nodule on a radiograph correlates strongly with the probability of cancer. Smooth-edged nodules are more likely benign; ragged-edged ones are more often malignant. Only 20% of nodules with smooth, sharp, and circular margins are malignant (2). About 33% of solitary pulmonary nodules with smooth but lobulated margins are malignant, as are 83% of those with edges having one or more spiculations. Finally, up to 93% of nodules that have edges with multiple spiculations or corona radiata are malignant (2). However, spiculated edges are not diagnostic of malignancy and can be seen in benign inflammatory nodules, especially if found in the location of a previous pneumonia on imaging studies. Nodule size also correlates with the likelihood of malignancy in solitary pulmonary nodules. The probability of malignancy for a nodule increases by about 13% per centimeter in diameter (2,5). For example, a smooth nodule in a 55-year-old nonsmoker has a probability of malignancy of 3% at a diameter of 1 cm (0.39 in), 11% at 2 cm (0.79 in), and 30% at 3 cm (1.18 in) (5). Clinical risk classificationThe likelihood of cancer in solitary pulmonary nodules that are not clearly benign or malignant after assessing growth and density characteristics can be further classified after evaluating the patient and radiographic risk factors. Nodules in patients younger than 35 years who do not have other risk factors for cancer and with smooth, defined edges on imaging studies are low-risk (10). Such nodules can be observed radiographically, if necessary, to assure stability. Nodules with spiculated edges in an older smoker are high-risk and should be promptly evaluated for surgical stage and curative resection if possible. Indeterminate-risk nodules should be evaluated by additional imaging techniques or biopsy, because up to 75% may be malignant (10). New imaging techniquesContrast-enhanced CT and two nuclear imaging studies, positron emission tomography (PET) and technetium Tc 99m depreotide single-photon emission computed tomography (SPECT), are newer techniques that are available to evaluate an indeterminate nodule.
Contrast-enhanced CT Using an enhancement threshold of 15 Hounsfield units, a multicenter study (14) showed that contrast-enhanced CT had a sensitivity of 98%, a specificity of 58%, and an accuracy of 77% for diagnosing malignancy in solitary pulmonary nodules. False-positive results are caused by inflammatory benign lesions, particularly when they have lower precontrast density and appear to have increased uptake on the postenhancement scan. The advantage of this technique is the additional information obtained without using additional imaging methods. Because of the good negative predictive value of contrast-enhanced CT, negative test results can help define benign nodules in centers experienced with this protocol, but enhancing nodules still require further evaluation.
PET and SPECT The radiolabeled glucose analogue 18F-fluoro-2-deoxy-D-glucose is the tracer used to detect the increased anaerobic glucose metabolism characteristic of malignant tumors. Because of increased expression of certain proteins and enzymes in malignant tissue, the tracer enters the cell and is trapped after phosphorylation. It then accumulates over the next 60 minutes. As 18F decays by positron emission, it yields a signal detected during tomography. The sensitivity of PET for malignancy in solitary pulmonary nodules ranges from 80% to 100%. The lower sensitivity is seen with nodules smaller than 1.5 cm (0.59 in). The specificity of PET ranges from 60% to 92% (15). False-negative results occur with smaller lesions (detection limit, 8 mm), elevated serum glucose levels (due to increased dilution of the radiolabeled tracer in nonlabeled serum glucose), and hypometabolic tumors, such as carcinoid tumors and bronchoalveolar carcinoma (16). False-positive results occur with necrotizing granulomas, active infections, and sarcoidosis (16). In addition to detecting malignant solitary pulmonary nodules, fluorodeoxyglucose PET complements CT in detecting malignancy in mediastinal lymph nodes for staging of non-small cell lung cancer. When the two tests are combined, the sensitivity is 93%, the specificity is 97%, and the accuracy is 96% (17). The major limitations of PET are the expense and general lack of access to the specialized equipment. In contrast, technetium Tc 99m depreotide SPECT uses more commonly available nuclear imaging equipment. The sensitivity of this imaging technique for detecting malignancy in solitary pulmonary nodules is 96.6%, the specificity is 73.1%, and the overall accuracy is 91% (18). Thus, although it is less well studied to date, technetium Tc 99m depreotide SPECT has specificity and sensitivity comparable to PET and uses equipment more widely available, making it a promising option. Using these newer imaging techniques, nodules with enhancement on CT or uptake on PET or technetium Tc 99m depreotide SPECT should be managed as malignant nodules. Nodules without uptake on these scans can be followed radiographically to assess stability over 2 years. The role of biopsyAlthough most patients with solitary pulmonary nodules can be evaluated using the noninvasive imaging techniques discussed, a tissue diagnosis of malignancy may be required in some instances. Biopsy is not recommended for patients with a high likelihood of malignancy who are candidates for surgical resection, because confirming malignancy on biopsy would not change management and a biopsy with negative findings would be dismissed as a false-negative result. Biopsies of solitary pulmonary nodules are appropriate for patients who are not candidates for surgical resection because of underlying disease, poor performance status, or evidence of advanced-stage or metastatic cancer. When necessary, biopsy of solitary pulmonary nodules can be obtained with transthoracic needle aspiration biopsy, bronchoscopy, or ultrathin bronchoscopy. In addition, excisional biopsy can be performed by video-assisted thorascopic surgery.
Transthoracic needle aspiration biopsy The most common complication of needle biopsy is pneumothorax, which occurs in 17% to 44% of cases (20). This risk decreases with use of a smaller (21-gauge or 22-gauge) needle; it increases when the solitary pulmonary nodule is small or deep in the lung, if the needle path crosses a fissure, or if the nodule is surrounded by bullae (8). Hemoptysis from focal pulmonary hemorrhage occurs in about 10% of needle biopsies and is the most common cause of the rare death following needle biopsy (20). The rare false-positive result occurs with hyperplasia or atypia. False-negative results are much more common and usually are due to inadequate tissue sampling. The overall accuracy of needle biopsy improves if a cytopathologist is present at the time of biopsy (21).
Bronchoscopic biopsy Traditional fiberoptic bronchoscopy is generally limited to fourth-generation or fifth-generation airways, but ultrathin bronchoscopy uses quartz fibers to make a very small scope that allows visualization of ninth-generation airways. Ultrathin bronchoscopy is still largely experimental, but it may be useful for examination and biopsy of more peripheral solitary pulmonary nodules.
Excisional biopsy SummaryPhysicians often are faced with determining benignity or malignancy in solitary pulmonary nodules in order to refer patients appropriately for curative resection of early-stage malignant nodules and to avoid the morbidity and mortality of a surgical procedure for benign nodules. Nodules are easily deemed benign when they are unchanged on chest radiographs over 2 years or have symmetrical patterns of calcification or central fat on chest CT. Similarly, growing, spiculated lesions in older patients with an extensive smoking history or other risk factors for cancer are easily recognized as likely to be malignant. However, solitary pulmonary nodules classified as indeterminate after consideration of radiologic characteristics and patient risk factors have traditionally posed a diagnostic dilemma. The use of newer imaging modalities, including contrast-enhanced chest CT, fluorodeoxyglucose PET, and technetium Tc 99m SPECT, can help distinguish benign nodules from those that are malignant. References
Dr Hanley is a clinical instructor, Yale Primary Care Residency Program, St Mary's Hospital, Waterbury, Connecticut. Dr Rubins is a staff physician, pulmonary division, Veterans Affairs Medical Center, and associate professor of medicine, University of Minnesota Medical School--Twin Cities, Minneapolis. Correspondence: Jeffrey B. Rubins, MD, Veterans Affairs Medical Center, One Veterans Dr, Mail Code 111N, Minneapolis, MN 55417. E-mail: rubin004@umn.edu.
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