An Update on the Evaluation and Management of Small Pulmonary Nodules

Alexandre M Furman; Jihane Zaza Dit Yafawi; Ayman O Soubani

Disclosures

Future Oncol. 2013;9(6):855-865. 

In This Article

Radiological Evaluation of Pulmonary Nodules

Noncontrast chest CT with 1–3 mm collimations through the nodule is necessary in the evaluation of the majority of lung nodules. Three to five slices should be obtained through the nodule to determine its internal and edge characteristics.[5] Administration of intravenous contrast may be necessary in certain situations to determine the enhancement of the nodule and/or to evaluate the mediastinum for the presence of lymphadenopathy. Other benefits of chest CT include confirmation of the pulmonary origin of the nodule, number of nodules, location, size and coexisting abnormalities, as well as evaluation of the best approach to biopsy. The following radiological features are important in the evaluation of lung nodules.

Size

The size of the pulmonary nodule is very important. As previously noted, lesions >30 mm in size should be considered malignant until proven otherwise, as the literature shows the probability of these nodules being malignant is approaching 93–97%.[22,26] In general, the possibility of malignancy increases with size. In a large review, lesions <10 mm, 11–20 mm, 21–30 mm and >30 mm had likelihood ratios for malignancy of 0.52, 0.74, 3.7 and 5.2, respectively.[20]

Growth Rate

Tumor growth rate is one of the most important radiological signs that determine an underlying etiology. Therefore, at the start of the evaluation of any lung nodule an attempt must be made at obtaining older images for comparison (Figure 1). The importance of the growth rate is based on an observation that the majority of malignant lesions have a doubling time of 20–400 days.[27–29] Shorter doubling times are associated with infectious processes, while longer doubling times are characteristic of benign tumors. An exception to this rule includes slow-growing tumors, such as bronchioloalveolar carcinoma (recently renamed as adenocarcinoma in situ), which may take more than 2 years to show a change in size. Another exception is a rapidly growing metastasis from tumors such as osteosarcoma and choriosarcoma. However, in these cases there are usually other manifestations of the disease making the diagnosis more obvious.[30] Accurate estimation of the tumor size is best made with thin section cuts. One must be attuned to the fact that a nodule is in fact a 3D structure and that its volume doubles long before doubling in diameter occurs. As an example, a spherical nodule with a diameter of 2 cm and a volume of 33 cm3 would have only increased to 2.5 cm, while doubling its volume to 66 cm3:

Where V is the volume of the sphere. This makes the estimation of volume using 2D measurements somewhat challenging and imprecise. Software for 3D reconstruction and precise volumetric analysis of the nodule is available, however, this algorithm is not widely available and its validity has not yet been established, thus its application in clinical practice is unknown.[31] In general, lung nodules that appear stable in size in similar projections within the same diagnostic modality are considered to be more likely to be benign. Such stability equates to a doubling time of over 730 days and is beyond the growth rate of nearly all malignant tumors. Although the 2-year size stability rule remains a solid indicator of the probable benign nature of the nodule, there have been some recent challenges due to difficulties in identifying changes in diameter of 1–2 mm (representing doubling of the volume in nodules 5–8 mm), as well as the fact that the lesion may display growth in an asymmetric fashion.[32,33] A primary exception to the 2-year rule is the presence of ground-glass opacification, which may represent a slowly growing tumor and, therefore, should be followed for a longer period of time. One must also realize that in determination of the size of the abnormality some adjacent inflammatory changes, atelectasis or scarring may be included in the measurement, making the nodule appear larger. However, a tumor may undergo necrosis, cavitation or hemorrhage, which may also alter its size.

Figure 1.

Chest computed tomography images 14 months apart that show an increase in the size of a left upper lobe nodule.
Biopsy revealed non-small-cell carcinoma.

Edge Characteristics

Different edge characteristics of the lung nodule may predict a malignancy potential of the lung nodule; however, none of these characteristics are diagnostic. Some of these edge characteristics are apparent on a plain chest x-ray. However, these are best described with thin-slice chest-CT. The presence of a spiculated edge, also called a corona radiata, has a positive predictive value (PPV) range of 88–94% for malignancy, however, it may be seen in some benign lesions such as resolving and/or organizing pneumonia, tuberculoma, lipoid pneumonia and massive progressive fibrosis.[20,34–37] Review of the literature reveals the apparent likelihood ratio for malignancy of a lung nodule with spiculated margins of 5.54 as compared with 0.3 for a smoothly marginated nodule. Lobulation of the nodule contour also portends a risk of malignancy with a PPV of 80%. Such contours indicate an uneven growth of the tumor, which is typical of the malignancy. However, up to 25% of benign nodules may display such lobulation.[20] A smooth contour, on the other hand, is suggestive of a benign nature of the lesion (Figure 2). However, up to a third of malignant nodules, especially metastatic lesions, may have smooth margins, therefore, the presence of a smooth contour is not a reliable sign.[36,38] The presence of satellite lesions, tiny densities surrounding the primary nodule, is a characteristic feature of granulomatous disease and has a PPV of 90% for benign etiology.[20,27,39]

Figure 2.

Chest computed tomography images showing a left upper noncalcified nodule with a smooth surface.
Excision revealed a hamartoma.

Calcification

The presence and pattern of calcification of the nodule is one of the most important radiological signs in evaluating lung nodules, which is best seen on a noncontrast, thin-slice chest-CT. Organized calcification patterns, such as popcorn, laminar, central and diffuse, are suggestive of benign etiology, with popcorn calcification being characteristic for hamartomas (33% of all cases) and diffuse, laminar or central calcification suggesting granulomatous disease as the underlying etiology.[40] Calcification can be present in up to 13% of malignant lesions as a result of dystrophic calcification of the necrosing tumor, engulfment of an adjacent granuloma and/or metastasis from certain malignancies, such as osteosarcoma, chondrosarcoma or mucinous-secreting carcinomas. In these cases the calcification takes an eccentric or punctuate pattern.[26,35,41,42]

Contrast Enhancement

Use of intravenous contrast to detect and quantify enhancement is another useful method of differentiation between malignant and benign lung nodules. Given the biology of any malignant neoplasm one would expect increased vascularity within such tumors and, therefore, an increased uptake of intravenous contrast compared with the surrounding normal tissue.[21,43,44] A useful indicator of poor enhancement is the attainment of <15 Hounsfield units (HU) of attenuation after intravenous contrast administration and this is correlated with benign etiology in 98% of cases, with a specificity of 58% and a PPV of 68%.[45] In one study a more elegant approach is described with the use of single acquisition using a dual-energy scanner. With this technique a peak enhancement >25 HU, as well as 15-min 'wash-out' acquisition of 5–31 HU of attenuation showed sensitivity and specificity for malignancy of 94 and 90%, respectively.[46] A note must be made with regards to some exceptions that may display similarly avid uptake of contrast, such as active granuloma, hamartoma, arteriovenous malformation and organizing pneumonia.[45,47] Moreover, some malignant lesions of smaller size (<8 mm), lesions with central necrosis and mucin-producing adenocarcinoma in situ may display lower uptake of contrast and, therefore, lower attenuation.[43–45,48]

Ground-glass Opacity

Ground-glass opacification may on occasion present as lung nodules. Such presentation may be suggestive of a premalignant condition such as adenomatous hyperplasia and frank malignancy in 34–43% of cases, especially adenocarcinoma in situ, and mixed subtype adenocarcinoma.[49–53] An appearance of the solid nodule with ground-glass opacification surrounding it is also suggestive of malignancy and the solid component usually represents invasive adenocarcinoma.[52]

Shape & Internal Characteristics

A polygonal shape of the nodule is highly characteristic of a benign etiology. This finding is rather infrequent thus portending a sensitivity of 20–28%.[54] The internal appearance of the nodule can also be helpful in the determination of the etiology. Presence of the air bronchogram within the nodule is suggestive of malignancy, especially adenocarcinoma in situ. In one study an air bronchogram sign was present in 30% of malignant lesions and in only 6% of benign lesions.[55] Common benign etiologies of lung nodules with an air bronchogram include pulmonary lymphoma, sarcoidosis and round pneumonia.[35,55,56] Cavitation can be present in both benign and malignant lesions. As such, an important characteristic to note is the thickness of the cavity wall. A thickness of >15 mm is likely to represent malignancy, whereas a thickness of <4 mm is likely to be present in benign lesions.[23,57,58] However, given such a large overlap this remains an unreliable feature. The presence of fat density within a nodule is highly suggestive of a benign etiology such as hamartomas (50% of hamartomas may have fat density within the nodule). However, on occasion such densities may be noted in metastatic lesions of tumors, such as liposarcoma or renal cell carcinoma.[59]

Location

Lung nodules in the right lung and in the upper lobes have a higher probability for malignancy.[17,45] Some studies indicate that 70% of all lung cancers are located in the upper lobes.[21,28] However, benign lesions have similar probabilities of being located in any of the lung fields.[45] This predilection of malignant lesions is of unclear etiology but may be related to the higher concentration of inhaled carcinogens in the upper lobe from cigarette smoking.

PET-scan Characteristics

This technology uses the glucose analog 18F-fluorodeoxyglucose (FDG), which is, when administered intravenously, taken up by tissue, similar to glucose, but is not metabolized further. Given a general principle of malignant lesions having higher metabolic activity it would be expected that FDG would accumulate with a higher concentration in such lesions. PET scanning, therefore, detects and measures the uptake of FDG by tissues expressed by the standardized uptake value. The probability of malignancy in lesions showing standardized uptake value of ≥2.5 approaches 90%. A negative PET scan portends a <5% chance of a lesion being malignant.[60–62] The degree of uptake by a malignant lesion may also have a prognostic implication.[63] Several important issues with PET sensitivity must be kept in mind. Some lesions with inherently low metabolic activity, such as adenocarcinoma in situ and carcinoid tumors, as well as physiologic state of hyperglycemia, may be associated with false-negative PET results.[62,63] Lesions that are less than 8 mm in size are exceedingly hard for PET to detect. A variety of infectious and inflammatory conditions, such as tuberculosis, fungal infections and sarcoidosis, may be associated with high FDG uptake.[62,64] Therefore, it is essential for a patient with a positive PET scan to be further assessed with tissue biopsy.

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