Andrew D. Lerner and Samir S. Makani
A solitary pulmonary nodule (SPN) is a well-circumscribed spherical lesion completely surrounded by pulmonary parenchyma. SPNs may be distinguished from other focal lung opacities because (1) they are not associated with atelectasis, lymphadenopathy, or pneumonia; (2) they are not pleural or mediastinal based; and (3) they are less than 3 cm in diameter. Nodules larger than 3 cm are typically considered to be “masses,” which are more likely than SPNs to be malignant.
Lung nodules commonly are diagnosed on chest radiographs and computed tomography (CT) scans. For example, up to half of smokers aged 50 or older may have pulmonary nodules on CT scan. More than 150,000 patients per year in the United States seek medical attention because of an incidental finding of a lung nodule on an imaging study. While many SPNs are benign, some may represent early stage (T1N0M0), bronchogenic carcinoma for which treatment has an excellent prognosis. Thus, it is important to determine which SPNs can be safely observed and which ones require diagnostic interventions or thoracotomy with resection. A comprehensive diagnostic approach is especially advantageous for patients at high risk for malignancy.
ETIOLOGIES OF SOLITARY PULMONARY NODULES
The two most common etiologies of SPNs are malignancy and granulomatous disease (e.g., tuberculosis, coccidioidomycosis, and histoplasmosis). SPN-associated malignancies are either primary lung cancer or metastatic disease. Bronchogenic carcinoma presents as an SPN in 10% to 20% of cases. Most malignant SPNs are adenocarcinomas, although squamous cell carcinoma, adenocarcinoma in situ, carcinoid tumors, and even small-cell carcinomas can present as SPNs. Approximately 5% of SPNs are metastastic lesions from other cancers such as colon, breast, kidney, testicular, sarcoma, or malignant melanoma. The possibility of discovering treatable cancer underlies the importance of prompt SPN evaluation and management, especially in patients with significant risk factors (e.g., smoking) or a previous history of cancer.
According to the large National Lung Cancer Screening Trial in 2011, 96.4% of SPNs identified in over 26,000 patients were false positive or benign. However, there is great variability in the rates of malignancy in patients with SPN, which depend on many clinical and radiologic factors. Benign nodules are typically infection-related granulomas, from tuberculous or fungal infections, or hamartomas. Less common causes include Pneumocystis jirovecii infection and viral infections (e.g., cytomegalovirus); both causes can appear nodular. Other less common causes include resolving pneumonia, lung abscess, pulmonary infarction, Kaposi sarcoma, pulmonary arteriovenous malformation, pulmonary contusion, pulmonary sequestration, Wegener granulomatosis, rheumatoid arthritis, mucoid impaction, dirofilariasis, and bronchogenic cysts.
CLINICAL AND RADIOGRAPHIC EVALUATION
Typically, an SPN is first detected as an incidental finding on chest imaging that was done for other reasons. The initial clinical approach is to identify risk factors that may help differentiate the presence of benign from a malignant nodule. A detailed history is an essential first step. It should include a smoking and occupational history, inquiry about previous cancer, and a detailed evaluation of the patient’s home and travel environments (especially areas endemic for histoplasmosis or coccidioidomycosis). For example, nonsmoking, younger patients living in areas endemic for fungal disease are likely to have benign nodules associated with granulomatous disease.
A careful physical examination should focus on signs of other malignancies, such as melanoma, breast cancer, and testicular carcinoma. Unexplained hypoxemia may suggest arteriovenous malformation. Skin tests, interferon-gamma release assays, and serological tests for fungal infections can be helpful if tuberculosis or fungal diseases are suspected, especially in endemic areas.
Multiple imaging modalities may be used to evaluate SPNs, including posteroanterior (PA) and lateral chest radiographs, thoracic CT scans, and dynamic positron emission tomography (PET) scans. CT scans, especially thin-section studies, are cost effective and have become commonplace in the routine evaluation of SPNs. In fact, many SPNs are first detected and radiographically evaluated when patients undergo chest CT scanning for other purposes. Thoracic CT scans allow assessment of the nodule itself and of the mediastinum for potential lymphadenopathy. Inclusion of the upper abdomen allows the adrenals to be evaluated for metastases. Recent data also suggest the potential for use of serial CT imaging in high-risk patient populations for lung cancer screening (see Chapter 101).
Two radiographic features can be used with some degree of confidence to predict that a lesion will be benign: calcification and the absence of growth over time. An SPN is more likely benign if calcifications follow one of four distinct patterns: (1) central calcification; (2) ring or halo pattern; (3) diffusely speckled calcification; or (4) dense, irregular pattern termed popcorn calcification. It is noteworthy, however, that small, eccentric calcifications within an SPN can be due to malignancy that is embedded within scar tissue. Comparison of the SPN’s size to the findings from prior images (if they are available) is an excellent way to estimate its growth characteristics.
Other radiographic features may be helpful as well. For example, clustering of multiple nodules in a single location tends to favor infection rather than malignancy. However, radiographic characteristics such as the shape, location, margins of the lesion, or presence of cavitation are unreliable for differentiating malignant from benign SPNs. Lobulation and larger size tend to be associated with malignancy, although these characteristics are not definitive.
PET imaging is a useful and noninvasive diagnostic modality for SPN evaluation. A pooled meta-analysis disclosed that the sensitivity and specificity of PET scanning for SPN-related malignancy are approximately 87% and 83%, respectively. Combination PET-CT is more sensitive for malignant nodules than CT or PET imaging alone. However, the sensitivity of PET scanning is low for nodules below 7 mm in diameter. In addition, false negatives may occur with tumors that have low metabolic activity, such as carcinoid tumors and adenocarcinomas in situ (historically called bronchioloalveolar carcinomas). This is due to the lack of a glucose-1 transporter, which leads to low fluorodeoxyglucose (FDG) uptake. On the other hand, false positives may occur with several nonmalignant etiologies such as active infections (e.g., tuberculosis and fungal etiologies) and inflammatory conditions (e.g., sarcoidosis and rheumatoid nodules). PET-CT findings cannot definitively confirm or rule out malignancy and should not be considered to be identical to a tissue diagnosis. Nevertheless, for low-risk patients with an SPN over 7 mm, a normal (no uptake) PET-CT has a high negative predictive value.
A special consideration is necessary when an SPN occurs in a patient with a history of malignancy. Tissue diagnosis may be a critical diagnostic step in those circumstances because conclusive evidence of metastatic disease may dictate further therapy. Pulmonary “metastatectomy” of the SPN may favorably influence survival, especially in patients with soft tissue sarcoma, melanoma, and colon cancer. On the other hand, an SPN can’t be presumed to be metastatic in patients with a history of cancer, since there is a 50% likelihood that it will be either benign or a different, treatable primary malignancy. Metastatic disease is more likely if (1) the known primary tumor is an adenocarcinoma; (2) the lung lesion appears within 12 months after treatment of the primary tumor; (3) the patient is young and a nonsmoker; (4) the primary tumor was associated with metastatic lymphadenopathy; or (5) the location of the nodule is in the periphery or in the lower lobe. In the absence of known extrapulmonary malignancy, the SPN proves to be a metastasis in fewer than 5% of cases.
In summary, four clinical features are generally cited that suggest a benign etiology: (1) absence of growth of the nodule over a 2-year period; (2) absence of risk factors for cancer; (3) presence of calcium in characteristic patterns on imaging studies; and (4) age less than 35 years. Risks for malignancy increase with age, smoking history, and nodule size, although the probability for malignancy cannot be accurately based on any single characteristic.
MANAGEMENT
Surveillance Imaging
Management of patients with SPN includes balancing the goals of limiting the number of unnecessary lung resections for benign disease and expediting potential curative resections in patients with malignancy. This is especially important because of the relatively high survival rate of stage 1A non-small cell lung cancer compared with the high mortality of unresected cancer.
The clinical and radiologic factors described in the previous section help define the probability of cancer. The initial diagnostic and management decisions should be individualized based on the probability of cancer, as well as the patient’s preferences, the patient’s age, and other comorbid conditions. However, the 2005 Fleischner Society guidelines describe a useful standard management approach to SPNs in patients over 35 years of age. The guidelines recommend specific schedules for follow-up high-resolution CT scanning, and have helped decrease unnecessary imaging and radiation exposure. They were developed for SPNs that were discovered incidentally—not those that are associated with underlying disease or known malignancy. In those cases, follow-up is determined by two main factors: the nodule’s size and the patient’s risk for lung cancer. Risk for lung cancer is defined as low risk (minimal or absent history of smoking and of other known risk factors) or high risk (history of smoking or of other known risk factors). Size is determined by the widest diameter of the nodule. The recommendations are described in the Table 38-1.
Ground glass opacities (GGOs), although not technically classified as SPNs, warrant specific consideration. GGOs are CT findings of focal, noncalcified, veil-like opacifications of the lung, which do not obscure the vascular structures and do not yield air bronchograms. They are common nonspecific findings on CT scans, and represent a broad differential including pulmonary fibrotic disease, pulmonary edema, acute respiratory distress syndrome, and other pulmonary infections (i.e., Pneumocystis jirovecii and fungal pneumonias). Persistent GGO nodules, however, may represent malignancy, especially adenocarcinoma in situ. A recent retrospective study evaluated the management of GGO nodules with serial imaging and, in some cases, biopsy and resection. While approximately 90% of them resolved or do not grow during follow-up, those GGOs that grew in size or developed a solid component over time were highly associated with malignancy, specifically adenocarcinoma. Thus, surveillance imaging of persistent GGO nodules for up to 5 years may be necessary to evaluate them for the presence of slow-growing adenocarcinomas.
