Solitary pulmonary nodules (SPNs) are very common. A radiologist in an active practice may see one or more per day. Many more are not perceived. At chest radiography, an SPN is seldom evident until it is at least 9 mm in diameter (4), and nearly 90% of newly discovered SPNs on chest radiographs may be visible in retrospect on prior radiographs (5). The importance of an SPN derives from the frequency with which it represents a primary bronchogenic cancer. The causes of an SPN are many (Table 7-1), but more than 95% fall into one of three groups: (i) malignant neoplasms, either primary or metastatic; (ii) infectious granulomas, either tuberculous or fungal (Fig. 7-1); and (iii) benign tumors, notably hamartoma(2). In addition to specific radiologic features, clinical history is important in considering the likely cause of an SPN (Fig. 7-2). Bronchogenic carcinoma is rare in patients under 30 years of age and is more common in cigarette smokers than nonsmokers. History of a
known primary tumor makes a metastasis more likely than a new (or second) primary tumor. Certain regions of the country are endemic for fungal disease and therefore have a higher prevalence of benign nodules than other regions.

Management options with an SPN include further imaging workup, declaration of benign etiology and no further evaluation, follow-up (usually with CT), or tissue diagnosis (either with percutaneous or transbronchial biopsy or via surgical resection). Management algorithms should take into account radiologic and clinical factors. Such additional information may obviate further workup (Fig. 7-3).

Two rules must be remembered when evaluating an SPN: first, a "nodule" is not confirmed to be within the lung unless it is seen in the lung on both posteroanterior (PA) and lateral chest radiographs or it is seen in the lung on a chest CT. Second, the current radiograph or CT scan should be compared with prior radiologic studies, when available, to confirm the chronicity of the nodule. Following these two basic rules will, on occasion, prevent unnecessary further workup and concern.

Four important considerations in the evaluation of an SPN are (i) attenuation characteristics, (ii) rate of growth, (iii) shape, and (iv) size. Each of these will be discussed separately; however, it should be noted that no single radiologic feature or combination of features is entirely specific for lung carcinoma or other primary malignant tumors.

The presence or absence of calcium is the most important feature that distinguishes benign from malignant nodules. Unfortunately, 45% of benign nodules are not calcified (6). Benignity can be confirmed confidently if the lesion is smaller than 3 cm in diameter, is smoothly marginated, and exhibits one
of the following patterns of calcification: large central nidus, laminated, popcorn, or diffuse. All other patterns of calcification are less specific, as further described later. SPNs smaller than 9 mm in diameter are rarely visible on chest radiographs, and a nodule of this size that is clearly seen is likely to be diffusely calcified and benign (Fig. 7-1). Dual-energy subtraction chest radiography can better depict calcification in pulmonary nodules compared with conventional chest radiography (7). So-called popcorn calcifications, which are randomly distributed, often overlapping rings of calcium, are seen when cartilage is present, such as with a hamartoma (Fig. 7-4). Large areas of dystrophic calcium are essentially diagnostic of benign nodules, usually granulomas, and the exceptions are extremely rare. Any calcium in a nodule makes the nodule more likely to be benign. When calcium is detected on thin-section CT (=3-mm sections), even when not diffuse and not obviously benign in nature, the likelihood of benignity is high enough to warrant follow-up imaging. This management is recommended, however, only for nodules that are otherwise smoothly marginated, 3 cm or smaller in diameter, and not increasing in size at a rate compatible with bronchogenic carcinoma (Fig. 7-5) (8). The presence of eccentric calcium in a nodule occasionally represents a sign of "scar carcinoma," where the cancer has arisen from a granuloma or engulfed a fibrotic, calcified granuloma. Central calcification in a spiculated SPN should be viewed with suspicion, because most benign SPNs have smooth or minimally lobulated margins. Calcifications in lung cancers may appear amorphous, stippled, or diffuse, and some can have dense foci of calcification or be entirely calcified, with a pattern resembling that of benign disease. These last two patterns
can be seen in carcinoid tumors, metastatic osteosarcoma, and chondrosarcomas. Stippled calcification can be seen in metastases from mucin-secreting tumors such as colon or ovarian cancers.

If fat is present within a nodule, the most likely diagnosis is hamartoma, and less likely diagnoses are lipoma or myelolipoma. Exceptions include metastatic liposarcoma or renal cell carcinoma, which rarely present as fat-containing nodules on CT. Pulmonary hamartomas are benign lesions consisting of an abnormal mixture of the normal constituents of the lung. Most pulmonary hamartomas contain masses of cartilage and may also contain fat or cystic collections of fluid (Figs. 7-6 and 7-7). They grow slowly and are usually solitary (see Fig. 7-4). More than 90% are peripheral in location
(9). Pulmonary hamartomas can range up to 10 cm in diameter, although most are less than 4 cm, and are usually spherical, lobulated, or notched with a very well-defined edge. In patients without prior malignancy, focal fat attenuation (-40 to -120 Hounsfield units) is a reliable indicator of a hamartoma (10).

On CT, nodules can be described as solid, partly solid, or nonsolid. Aerated lung is visible through a nonsolid (ground-glass) nodule. Whereas most cancerous nodules are solid, partly solid nodules are most likely to be malignant and are often caused by bronchioloalveolar cell carcinoma (Figs. 7-8, 7-9, 7-10). Air bronchograms and bronchiolograms are seen more commonly in pulmonary carcinomas than in benign nodules.

An SPN that exhibits no growth for at least 2 years is generally considered benign (11). However, even benign lesions, such as granulomas, can grow slowly. Therefore, growth alone cannot be used to predict malignancy. Bronchogenic carcinomas usually take between 1 and 18 months to double in volume (12). A volume doubling is a change in diameter of about 1.25 times the previous diameter. Doubling times that are faster than 1 month suggest infection, infarction, histiocytic lymphoma, or a fast-growing metastasis from tumors such as germ cell tumor, lymphoma, melanoma, and soft tissue sarcoma (Table 7-2) (13). Doubling times slower than 18 months suggest granuloma, hamartoma, bronchial carcinoid, salivary gland adenoid cystic carcinoma, thyroid carcinoma metastases, and round atelectasis. However, there are exceptions, and cancerous tumors with doubling times of more than 730 days may appear stable during a 2-year observation period. Growth is more accurately assessed on CT than on chest radiography, and diameters measured with electronic calipers are preferable to diameters measured manually. However, many factors, including size of the nodule and determination of the nodule margin, can limit the accuracy of measurement. It is difficult to reliably show changes in size that are smaller than 2 mm, and even a substantial increase in volume may be missed with small nodules.

Edge characteristics indicative of malignancy include irregularity, spiculation, and lobulation (Fig. 7-11) (14). A corona radiata, described as numerous strands radiating from the nodule into the surrounding lung, is very suggestive of bronchogenic carcinoma, although there are exceptions in which a corona radiata is seen in benign lesions such as infectious granulomas and other chronic inflammatory lesions (15). The "tail sign" consists of a linear opacity that extends from a peripheral nodule to the visceral pleura; for some years this sign was regarded as a reliable sign of malignancy. Studies have shown, however,
that up to half of nodules showing the tail sign represent benign granulomas (16), and therefore the tail sign is a nonspecific feature of peripherally located pulmonary lesions that cannot be used to distinguish a benign from a malignant lesion. Lobulation and notching are seen with both benign and malignant nodules and are not very useful discriminating features (Figs. 7-12 and 7-13). A well-defined, smooth, nonlobulated edge is most compatible with hamartoma, granuloma, or metastasis. However, a smooth margin does not indicate benignity, as up to one third of malignant lesions have smooth margins

(Fig. 7-14) (17). Therefore, the previously mentioned signs are more helpful in their absence. Adjacent tiny nodules, called satellite nodules, are strongly associated with benignity (Fig. 7-12) but do not allow a confident diagnosis of benignity, as 10% of dominant nodules with satellite nodules will be malignant (Fig. 7-15) (6).

SPNs with irregular-walled cavities thicker than 16 mm tend to be malignant, whereas benign cavitated lesions usually have thinner, smoother walls. However, because there is considerable overlap, cavity wall characteristics cannot be used to confidently differentiate benign and malignant SPNs (Figs. 7-16 and 7-17) (18).

Sequential thin-section CT (1- to 3-mm section width) performed through an entire nodule with a single breath hold provides information regarding nodule size, attenuation, edge characteristics, and the presence of calcification, cavitation, or fat. In some cases, the findings will provide evidence that the nodule is benign. However, the cause of many SPNs will remain undetermined. If the nodule is at least 10 mm in diameter, a contrast–enhanced CT may be performed. The nodule is examined with 3-mm collimation before and after administration of intravenous contrast material. Contrast-enhanced images are acquired at 1-minute intervals up to 4 minutes after injection of contrast material. Nodule enhancement of less than 15 Hounsfield units after administration of contrast material is strongly indicative of benignity. Although enhancement
of more than 15 Hounsfield units is more likely to represent malignancy, the false-positive rate is high and is caused by active inflammatory disease such as granulomas or organizing pneumonias. Therefore, nodule enhancement is a sensitive but nonspecific indicator of malignancy (19).

Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose of SPNs larger than 1 cm in diameter is being used with increased frequency to determine whether a lesion is malignant or benign (20). For SPNs 1 to 3 cm in diameter, sensitivity and specificity are approximately 94% and 83%, respectively (21). False-positive PET findings are associated with focal infections, inflammation, and granulomatous diseases such as tuberculosis and sarcoidosis. False-negative PET findings are seen with carcinoid and bronchioloalveolar cell carcinoma, tumors that have a low metabolic rate. Sensitivity and specificity of PET decreases with nodules smaller than 1 cm in diameter.

Radiologists are frequently asked to perform percutaneous fine-needle aspiration biopsy (FNAB) of pulmonary nodules. CT allows for biopsy of many nodules as small as 5 mm in diameter. In patients who are not candidates for surgery, FNAB can be performed to confirm and determine the histologic type of malignancy. In patients who are candidates for surgery, FNAB can confirm benign disease. Contraindications to FNAB include inability of the patient to hold the breath, lie immobile on the CT table for more than 30 minutes, or refrain from coughing. Relative contraindications include bleeding diatheses, previous pneumonectomy, severe emphysema, severe hypoxemia, pulmonary artery hypertension, or nodules in which successful biopsy cannot be performed because of their small size or location. FNAB has a sensitivity of 86% and a specificity of 98.8% in the diagnosis of malignancy (22). Sensitivity decreases for nodules 5 to 7 mm in diameter and in patients with lymphoma. When the FNAB sample is interpreted as malignant or if a specific benign condition is diagnosed (Fig. 7-18), further decisions regarding care are dictated by the
diagnosis. When a nonspecific benign condition is diagnosed, such as atypical bronchioloalveolar hyperplasia or inflammation without organisms on a smear or a culture, further evaluation with core-needle biopsy or clinical and radiologic follow-up is required. The most common complications of FNAB are pneumothorax and hemorrhage, with pneumothorax occurring in 25% of patients.

The ability to detect very small nodules improves with each new generation of CT scanner. The majority of cigarette smokers who undergo thin-section CT have been found to have small lung nodules, most of which are smaller than 7 mm in diameter (23). Guidelines for follow-up and management of noncalcified nodules detected on nonscreening CT scans were developed before widespread use of multidetector row CT and still indicate that every indeterminate nodule should be followed with serial CT for a minimum of 2 years. Recently, the Fleischner Society published guidelines for management of SPNs that are detected incidentally on CT scans (24). The Fleischner Society recommendations apply only to adult patients (35 years of age or older) with nodules that are “incidental in the sense that they are unrelated to known underlying disease.” In patients under age 35, unless they have a known primary cancer, the guidelines suggest that a single low-dose follow-up CT in 6 to 12 months be considered. Patients with a cancer that may be a cause of lung metastases should be cared for according to the relevant protocol or specific clinical situation. Longer follow-up intervals are recommended for nonsolid (ground-glass) and very small opacities. An abbreviated set of recommendations for nodule follow-up, based on the Fleischner guidelines, is shown in Table 7-3.

The differential diagnosis for multiple pulmonary nodules is different from that for SPNs (Table 7-4), although there is some overlap. In more than 95% of patients with multiple pulmonary nodules, the etiology of the nodules is (a) metastases or (b) tuberculous or fungal granulomas (Fig. 7-19) (2). Determining that the nodules are cavitary is useful in narrowing the list of diagnostic possibilities (Figs. 7-20, 7-21, 7-22; Table 7-5) (25). A cavity is defined as a gas-filled space within a zone of pulmonary consolidation or within a mass or nodule that is produced by the expulsion of a necrotic part of the lesion via the bronchial tree; the lucent portion is surrounded by a wall of varied thickness, and there may or may not be an accompanying fluid level (1). Those disorders that can result in cavitary nodules can also result in nodules that are not cavitary or that are not appreciated as cavitary on a chest radiograph; therefore, the mnemonic for cavitary nodules, "CAVITY" (Table 7-5), can be remembered as a guide for all cases of multiple pulmonary nodules.

The great majority of patients who have multiple noncalcified nodules on chest radiographs have metastases. This is even more likely to be the diagnosis when the patient has a known or suspected primary malignancy. The larger and more variable in size that the nodules are, the more likely they are to be neoplastic. Metastases are usually spherical with well-defined margins; as a rule, they vary considerably in size. In autopsy series, the most common sources of metastases from extrathoracic malignancies to the lungs include tumors of the breast, colon (Figs. 7-23 and 7-24), kidney, uterus, prostate, head, and neck (26). Other tumors that have a high incidence of pulmonary metastases, but are not as prevalent in the population and therefore not encountered as frequently, include choriocarcinoma, osteosarcoma, Ewing sarcoma, testicular tumors (Figs. 7-25 and 7-26), melanoma, and thyroid carcinoma. The most common sites of origin of cavitary metastases are the uterine cervix (Fig. 7-27), colon, and head and neck (Fig. 7-28) (27). Squamous cell carcinoma cavitates twice as often as adenocarcinoma (27). Calcification of metastases is seen most commonly with osteosarcoma and chondrosarcoma (Fig. 7-29) or after successful treatment of metastases (28). A miliary nodular pattern of metastases is seen most commonly with thyroid or renal carcinoma, bone sarcoma, trophoblastic disease,
or melanoma. On occasion, an SPN will be seen in a patient with a known primary tumor. In a patient over age 35 with a squamous cell cancer elsewhere in the body, the solitary lung lesion is usually a separate primary tumor. If the patient has adenocarcinoma elsewhere, there is an equal chance that the solitary nodule is a primary lung cancer or a solitary metastasis. Cancer of the colon is the most common source of a solitary pulmonary metastasis. If there is a soft tissue or skeletal sarcoma or a melanoma elsewhere, the solitary lung lesion is most often a metastasis (29).

The most common sources of septic emboli are infected venous catheters (including pacemaker wires) (Fig. 7-30), valvular endocarditis, septic thrombophlebitis, and indwelling prosthetic devices. Septic embolism is a well-known complication of intravenous drug abuse. The diagnosis of septic emboli is usually established by positive blood cultures, although the radiologic findings, especially those on CT of the chest, may be visible before blood cultures become positive (30). The usual radiographic and CT appearance consists of multiple peripheral pulmonary opacities that occur in any portion of the lungs but more prevalent in the lower lungs because of the greater pulmonary blood flow to this region. The lesions are usually either round or wedge shaped, as with a pulmonary infarct. Approximately 50% of the lesions cavitate (30). The presence of a distinct vessel leading to the apex of a peripheral area
of consolidation, seen in bland and infected infarcts, has been termed the feeding vessel sign (31). This sign is not specific for but is more commonly seen with pulmonary emboli than in other conditions. The combination of multiple peripheral nodules or wedge-shaped consolidations, some of which are cavitated, and a distinct feeding vessel in the appropriate clinical setting is highly suggestive of the diagnosis of septic emboli (Fig. 7-31) (30).

Pulmonary arteriovenous malformations (AVMs) are fistulous vascular communications between a pulmonary artery and vein (95%) (Fig. 7-32) or a systemic artery and pulmonary vein (5%) that can be single or multiple. When multiple, nearly 90% of cases are associated with Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasis), a syndrome of epistaxis, telangiectasia of skin and mucous membranes, and gastrointestinal bleeding. AVMs are usually a congenital defect of
capillary structure, but they can be acquired in cirrhosis, cancer, trauma, surgery, or certain infections. The typical radiographic appearance of an AVM is a sharply defined, lobulated oval/round mass, from less than 1 cm to several centimeters in size, associated with an enlarged feeding artery and draining vein. On CT, AVMs will typically demonstrate marked contrast enhancement (Fig. 7-33). Shunting from the fistula can result in hypoxia, systemic abscesses, or infarction, notably of the brain, because the right-to-left shunting of blood bypasses the filtering capacity of the lung (32). Multiple AVMs can be confused with metastases if the enlarged feeding vessels are overlooked.

Pneumatoceles are cystic air collections within the lung that result from infection (most notably Streptococcus pneumoniae, Escherichia coli, Klebsiella, and Staphylococcus); blunt or penetrating trauma to the chest; or hydrocarbon inhalation (as from furniture polish or kerosene). In the case of trauma, the pneumatocele represents a laceration that evolves from a lung opacity to a thin-walled cystic structure to a linear scar. Depending on the stage of evolution, a pneumatocele may resemble a cavitary mass, and when multiple they may resemble and be misdiagnosed as metastases or multifocal lung abscesses if the clinical history is not taken into consideration.

Congenital lesions, including sequestration, diaphragmatic hernia, and bronchogenic cyst, can appear as cavitary nodules or masses on chest radiography and are therefore included in the differential diagnosis of cavitary nodules. These entities are discussed further in Chapters 6 and 16.