The patient is a 57-year-old man with a history of smoking and cough.
Figure 1. Chest Radiographic Findings
The frontal chest radiograph shows an ill-defined left upper lobe nodule. The lungs, mediastinum, and pleura are otherwise normal.
Figure 2. CT Findings
Axial CT shows a solitary, spiculated left upper lobe nodule associated with a bronchus.
What is the differential diagnosis?
Figure 3. Overall Cross-section
Cross section of a similar lesion shows an irregular, radiating margin on the right and a more rounded margin on the left.
Figure 4. Histology
Tumor is surrounded by stroma infiltrated by chronic inflammatory cells.
What is the differential diagnosis?
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Solitary Pulmonary Nodule
Discussion: Two recent reviews describe the evaluation and management of solitary pulmonary nodules [1,2]. A brief illustrated description of the evaluation of such nodules follows.
A nodule may be defined as a "round intraparenchymal opacity, at least moderately well-marginated" and 2 to 30 mm in diameter . When determined to be solitary by CT, such a lesion has been referred to as a solitary pulmonary nodule (SPN). When similar opacities exceed 3 cm in size, the term mass is used, and the diagnosis is more likely to be cancer.
Numerous causes of SPNs exist, but the primary significance of an SPN lies in its potential for malignancy, so investigation of patients presenting with SPNs is primarily directed at establishing or excluding this diagnosis. It is, therefore, important to realize what the frequency of malignancy in a given patient's SPN is, and what factors modify this frequency.
Overall, the accepted frequency of malignancy in an SPN in an adult patient is around 40%, but this frequency varies depending on the selection criteria for patients . Important factors that modify this frequency include:
The probability of cancer increases with age, number of cigarettes smoked, and history of previous cancer. The interactions of these factors have been combined with radiographic aspects of the nodule to arrive at the likelihood of cancer . A summary of some of the probabilities has been presented by Swensen, et al . Alternatively, calculations of the probability in a specific patient may be performed on line.
Unfortunately, even small nodules may harbor malignancy. There is no lower size limit that excludes carcinoma. In the era of CT, small nodules have been found to have a higher prevalence of malignancy than was previously thought. One CT study revealed that 51% of 355 malignant nodules measured less than 2 cm, and 9% measured less than 1 cm in diameter .
Another study evaluating nodules (not all solitary) less than 1 cm in size that were resected at video-assisted thoracoscopic surgery found that a surprisingly high frequency (58% (38/65)) of these nodules were malignant . The larger the nodule size, the greater the frequency of malignancy .
In a small number of cases, certain morphologic characteristics may indicate that a given SPN is benign. Such lesions include arteriovenous malformations, rounded atelectasis, mycetomas, pleural plaques, rib fractures, and mucous plugs. Many of the diagnostic features are visible on plain radiography, but all are better appreciated with CT.
If fat is visualized within a nodule, the diagnosis of hamartoma may be made with confidence. Also, if characteristic chondroid ("popcorn") calcification is seen, the diagnosis of hamartoma is assured. In a study of 47 hamartomas, 30 cases were correctly identified by CT: 18 demonstrated fat (38%), 10 had fat and calcium (21%), and 2 (4%) had characteristic calcification patterns . Hamartomas are usually round/oval with well-defined, smooth or lobular contours. They may demonstrate growth. Unfortunately, they are most often encountered in the same age range in which malignancy is typically seen.
Lesions that are well-defined are often, but not always, benign. Bronchogenic carcinomas are frequently ill-defined or even grossly spiculated, but they may be well-defined. Further, solitary metastases are characteristically well-defined. Generally speaking, a well-defined contour favors a benign diagnosis, but lacks specificity. An ill-defined contour suggests malignancy, and a spiculated margin is very suggestive of malignancy . Finally, an air broncho-/bronchiologram in an SPN on CT favors the diagnosis of malignancy 
The presence of certain patterns of calcification within an SPN favors a benign diagnosis, but the mere presence of calcium within a nodule does not ensure that the nodule is benign. CT is more sensitive than radiographs for the demonstration and characterization of calcification within SPNs; it may reveal calcification in about 1/3 of nodules that are not definitely calcified on radiographs .
Benign patterns of calcification include:
Patterns of calcification that are not definitely benign include speckled calcification and eccentric calcification. The latter appearance may occur when a granuloma is engulfed by an adjacent carcinoma.
Bronchogenic carcinomas may calcify in 7% of cases . Usually a substantial, noncalcified, soft tissue mass is present. Calcification in bronchogenic carcinomas is often difficult to detect on chest radiographs, but may easily be seen with CT.
Two circumstances must be remembered:
Nodule Growth Rate
A nodule is generally considered benign if it has shown no growth over a two-year period. Rarely, slowly growing cancers will be encountered (particularly bronchioloalveolar carcinoma). Further, if a nodule has been stable for some time and then begins to grow, it should be regarded with suspicion. Very rarely, a cancer may appear to decrease in size, only to demonstrate growth later. Therefore, if a nodule is seen to decrease in size and is thus considered benign, it should be followed to resolution or, at least, radiographic stability.
Benign nodules (hamartomas, infectious granulomas, sarcoid granulomas, etc) may grow, so growth does not necessarily ensure malignancy.
Doubling time refers to the time required for a nodule to double its volume. Calculations are based on the formula for the volume of a sphere (4/3 pi r3). Thus, a nodule has doubled its volume when it increases its diameter by a factor of 1.26. For example, a 1 cm nodule has doubled in volume when it reaches a diameter of 1.26 cm. For simplicity, a nodule may be said to have doubled in volume when it increases in diameter by 25%.
A pulmonary nodule that doubles its volume in less than 30 days (usually infections) or more than 450 days is usually benign . Nodules doubling at a rate between 30 and 450 days may be malignant.
PET Scanning and CT Nodule Enhancement Protocols
PET scanning uses a radioactive glucose analog, 18-fluorodeoxyglucose (FDG), that emits positrons; this tracer is taken up by cells in proportion to their metabolic activity. Therefore, because malignancies are very metabolically active, they avidly take up FDG more than surrounding normal tissue. In a meta-analysis of 40 studies examining 1474 nodules, PET showed a sensitivity of 96.8% and a specificity of 77.8% for the detection of malignancy within a pulmonary nodule . Sensitivity probably decreases for nodules less than 1 cm, but few data for PET performance in such nodules are available.
While PET is very sensitive for the detection of malignancy within an SPN, false positive results (often infections, such as mycobacterial disease or fungal infections) do occur. Furthermore, malignancies with low metabolic activity, such as bronchioloalveolar carcinoma and carcinoid tumors, may not be easily detected with PET.
Finally, intravenous injection of iodinated contrast material results in enhancement of vascular, neoplastic, or inflammatory lesions . A prospective study showed that if a nodule enhances less than 15 HU (Hounsfield units) at each of 4 time points following injection of contrast, it is likely benign (granuloma or benign neoplasm). However, if a nodule enhances more than 15 HU at any of the 4 time points, 32% of lesions were benign (granulomas or neoplasms) and 68% were malignant; thus, such enhancement is not helpful for discriminating benign from malignant .
Diagnosis: Solitary Pulmonary Nodule: Adenocarcinoma
References: To return to reference section after viewing abstract, click here before clicking on "abstract".
1. Ost D, Fein A, Feinsilver S. The solitary pulmonary nodule. N Engl J Med 2003; 348:2535-2542.
2. Leef III J, Klein J. The solitary pulmonary nodule. Radiol Clin N Am 2002; 40:123-143.
3. Cummings S, Lillington G, Richard R. Estimating the probability of malignancy in solitary pulmonary nodules. A Bayesian approach. Am Rev Respir Dis. 1986; 134:449-52. Abstract
4. Swensen S, Silverstein M, Ilstrup D, Schleck C, Edell E. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997; 157:849-855. Abstract
5. Siegelman S, Khouri N, Leo F, Fishman E, Braverman R, Zerhouni E. Solitary pulmonary nodules: CT assessment. Radiology 1986:160:307-312. Abstract
6. Munden R, Pugatch R, Liptay M, Sugarbaker D, Le L. Small pulmonary lesions detected at CT: clinical importance. Radiology 1997; 202:105-110. Abstract
7. Siegelman S, Khouri N, Scott Jr W, Leo F, Hamper U, Fishman E, Zerhouni E. Pulmonary hamartoma: CT findings. Radiology 1986; 160:313-317. Abstract
8. Kuriyama K, Tateishi R, Doi O, Higashiyama M, Kodama K, Inoue E, Narumi Y, et al. Prevalence of air bronchograms in small peripheral carcinomas of the lung on thin-section CT: comparison with benign tumors. AJR 1991; 156:921-924. Abstract
9. Zerhouni E, Stitik F, Siegelman S, Naidich D, Sagel S, Proto A, et al. CT of the pulmonary nodule: a cooperative study. Radiology 1986; 160:319-327. Abstract
10. Gould M, Maclean C, Kuschner W, Rydzak C, Owens D. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions. A meta-analysis. JAMA 2001; 285:914-924. Abstract
11. Swensen S, Viggiano R, Midthun D, Müller N, Sherrick A, Yamashita K, Naidich D, Patz EF, et al. Lung nodule enhancement at CT: multicenter study. Radiology 2000; 214:73-80. Abstract
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Differential Diagnosis: The differential diagnosis of a solitary pulmonary nodule is extensive. Malignancy, especially bronchogenic carcinoma, is one of the most common etiologies of an SPN. Other pulmonary malignancies, including isolated metastases, lymphoma, and carcinoid tumors, are less common causes. Infections are also a very common cause, particularly granulomatous infections such as tuberculosis. Fungal infections may also cause solitary pulmonary nodules. Other causes of solitary pulmonary nodules include benign lesions, such as hamartomas and sclerosing hemangiomas and vascular lesions such as pulmonary varices and arteriovenous malformations. Non-infectious inflammatory conditions such as amyloidosis, rheumatoid arthritis, and Wegener's granulomatosis, commonly result in multiple nodules but may occasionally cause solitary lesions. Rounded atelectasis may also present as a solitary pulmonary nodule. One must also consider the possibility that the appearance of an SPN on a radiograph is the result of a pleural lesion (calcified pleural plaques often present in this fashion). Finally, lesions of the bony thorax or entirely outside the thorax that project over the lung on a radiograph may present as an SPN. Such lesions include nipples, moles, rib fractures, osteochondromas, and patient jewelry and hair.
Differential diagnosis: The tumor is forming glands. A PAS-D stain also showed mucus production by the tumor. The tumor, an adenocarcinoma, could be a primary lung tumor or a metastasis from another site. History of another tumor and immunohistochemical tests can help to make the correct diagnosis.
Primary tumors that frequently metastasize to the lung as solitary nodules include: malignant melanoma and colon, breast, and renal carcinomas, sarcomas, and nonseminomatous testicular tumors.
Diagnosis: Adenocarcinoma. No other primary site was found.
To see other common primary lung tumors that present as solitary pulmonary nodules, click here.