An Update on the Evaluation and Management of ...

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Jul 31, 2013 - Ground-glass Opacity. Ground-glass opacification may on occasion present as lung nodules. Such presentation may be suggestive of a.
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An Update on the Evaluation and Management of Small Pulmonary Nodules Alexandre M Furman, Jihane Zaza Dit Yafawi, Ayman O Soubani Future Oncol. 2013;9(6):855-865.

Abstract and Introduction Abstract

The widespread utilization of chest CT scans has increased the importance of the proper evaluation of incidentally found lung nodules. The primary goal in the evaluation of these nodules is to determine whether they are malignant or benign. Clinical factors such as older age, tobacco smoking, and current or remote history of malignancy increase the pretest likelihood of malignancy. Radiological features of these nodules are important in differentiating benign from malignant lesions. However, the etiology of the lung nodules frequently remains indeterminate and requires further evaluation. The approach to the management of indeterminate lung nodules ranges between observation with repeat chest CT scan, further diagnostic studies such as PET scan or invasive procedures to obtain tissue diagnosis. This article reviews the importance of the different radiological features of lung nodules. This is followed by an update on the approach to the management of the different types of small lung nodules. Introduction

With the widespread use of radiographic modalities, such as chest radiographs and computer tomography (CT) of the chest, in the evaluation of a wide variety of patient complaints an ever-increasing number of lung parenchymal abnormalities are being detected. This article will focus on the specific finding of small pulmonary nodules. A pulmonary nodule is a lung parenchymal abnormality measuring 1–30 mm in size, surrounded by normal lung parenchyma and not associated with adenopathy or atelectasis. Any density measuring more than 30 mm is considered a mass and must be presumed malignant until proven otherwise.[1] Pulmonary nodules are detected in 0.2% of chest radiographs and 8–51% of CT scans in screening trials.[2–4] The reported incidence of solitary pulmonary nodules appears to be 150,000 nodules annually in the USA with over 90% of these being incidental. Chest CT is the best imaging technique to identify the origin and location of the nodule as 20% of 'nodules' found on chest x-ray turn out to be nonpulmonary when imaged with another technique. [5–7] These entities include nipple shadows, skin lesion, rib fractures, blood vessel end, confluence of shadows or ECG lead. This article discusses the diagnostic approach to pulmonary nodules, and the clinical and radiological characteristics of benign versus malignant nodules. Lung cancer is the primary etiology of malignant nodules and is the most common cause of cancer-related death in both sexes. There has not been much progress in the overall 5year survival rates in patients with lung cancer and survival remains rather low at 15%. However, an early-detected lung cancer, namely stage IA (T1, N0, M0) that is treated with resection may portend a long-term survival of 80% or better.[8–10] Therefore, it is of utmost importance to identify and treat pulmonary nodules that are strongly suspicious for malignancy. The majority of studies indicate the range of malignancy to be 1.1–12% with a wide range between studies.[2,6,11] Adenocarcinoma is the most likely type of lung cancer identified in lung nodules, whereas small-cell carcinoma is rarely an etiology of malignant lung nodules.[12–13] Carcinoid tumors account for approximately 1–5% of malignant nodules. The etiology of benign lung nodules varies, with infectious granulomas, round pneumonias and abscesses accounting for approximately 70–80% of the cases.[5,12–13] Benign tumors are rare with a reported incidence of 10%, with hamartoma accounting for the majority of these.[13–14] The different causes of pulmonary nodules are outlined in . Table 1. Causes of solitary pulmonary nodules.


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Primary lung cancer Solitary metastasis Neoplastic: malignant Carcinoid Primary lung lymphoma Hamartoma Neoplastic: benign Chondroma Rheumatoid Wagner's granulomatosis Inflammatory Inflammatory bowel syndrome Sarcoidosis (nodular) Tuberculosis Infectious

Fungal infection Round pneumonia Abscess

Vascular Arteriovenous malformation Pulmonary infarction Lung contusion Congenital Pulmonary sequestration Pulmonary atresia

Clinical Factors in the Evaluation of Lung Nodules Age is one of the most important, as well as independent, risk factors for malignancy.[15] Malignancy is an exceedingly rare cause of lung nodules in patients younger than 30 years with a probability for malignancy of 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 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


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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 xray. 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]


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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 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 (15 mm is likely to represent malignancy, whereas a thickness of