Solitary Pulmonary Nodule Imaging

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Solitary Pulmonary Nodule Imaging

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A solitary pulmonary nodule (SPN) is defined as a single, discrete pulmonary opacity that is surrounded by normal lung tissue and is not associated with adenopathy or atelectasis. Radiographically, a nodule is defined as a lesion smaller than 3 cm. Anything larger than 3 cm is termed a mass.^{[1, 2, 3, 4]}

The finding of an SPN on a chest radiograph is a diagnostic dilemma faced by many clinicians. The differential diagnosis may be broad, but implications rest on whether the lesion is benign or malignant. The only findings sufficient to preclude further evaluation are a benign pattern of calcification or stability of nodule size for over 2 years for solid pulmonary nodules. The likelihood of malignancy increases with nodule size, which may influence management strategy. Other nodule features such as shape, edge characteristics, cavitation, and location have not yet been found to be accurate clues for distinguishing benign from malignant nodules. As a result, the majority of nodules are indeterminate.^[1]

The probability of malignancy can be assessed clinically or by quantitative predictive models as falling into one of three risk categories: very low probability (< 5%), low/moderate probability (5-65%), or high probability (>65%). Quantitative predictive models combine clinical and radiologic features to estimate malignancy potential. The most commonly used model from the Mayo Clinic estimates the probability of malignancy using 6 independent predictors: smoking history, older age, history of extrathoracic cancer more than 5 years before nodule detection, nodule diameter, spiculation presence, and upper lobe location.

Most solitary pulmonary nodules are incidental findings on imaging studies of the chest, abdomen, and upper extremities. Occasionally, nodules as small as 5 to 6 mm can be visualized on chest radiography. The imaging tools used to evaluate solitary pulmonary nodules include chest CT and functional imaging (usually FDG-PET). Chest CT, preferably with thin sections, should be obtained in all patients with unclearly characterized solitary pulmonary nodules visible on chest radiography.

The advantages of CT scanning over radiography include better resolution of nodules and detection of nodules as small as 3-4 mm. CT scan images also help to better characterize the morphologic features of various lesions. Multiple nodules and regions that are difficult to assess on chest radiographs are better visualized on CT scan images.^[5] Contrast enhancement is not typically required when imaging a solitary nodule.^[1]

CT is the imaging modality of choice for reevaluation of pulmonary nodules visible on chest radiography and for continued surveillance of nodules for change in size. Radiologic features such as size, border, density, calcification, and growth rate are used to predict malignancy.

Chest radiographs demonstrate poorer resolution than chest computed tomography (CT) scans in determining degree of calcification or size. Visualization of some nodules may be difficult because of superimposed structures.

FDG-PET scans have several limitations because false-positive findings can occur in other infectious or inflammatory conditions that yield metabolically active pulmonary nodules. Moreover, tumors that have lower metabolic rates, such as carcinoid, lepidic-predominant adenocarcinomas and mucinous adenocarcinomas, may be difficult to distinguish from background activity and hence yield false-negative results. FDG-PET scans have lower sensitivity for nodules smaller than 20 mm in diameter and may miss lesions smaller than 10 mm.

When staging lung cancer, MRI provides better imaging for pleural, diaphragm, and chest wall disease than does CT scanning. MRI is comparable to CT in assessing mediastinal involvement and is less useful in assessing the lung parenchyma (especially in assessing pulmonary nodules) because of poorer spatial resolution. Since MRI costs more and is less available, MRI use is reserved for tumors that are difficult to assess on CT (eg, Pancoast tumors).

(The radiologic features of SPNs are demonstrated in the images below.)

Annual low-dose computed tomography (LDCT) screening for lung cancer in high-risk current and former smokers has become a standard of care in the United States, in large part due to the results of the National Lung Screening Trial (NLST). The NLST included 53,452 current or former smokers aged 55 to 74 years with at least a 30 pack-year history of cigarette use. Former smokers had to have quit within the past 15 years. The results showed a 16% reduction in lung cancer-specific mortality (per 100,000 person years).^[6] LDCT screening for lung cancer has led to the detection of more small nodules requiring evaluation.

Concerns associated with LDCT screening include false-negative and false-positive results, incidental findings, overdiagnosis, and cumulative radiation exposure. False-positive LDCT results occur in a substantial proportion of screened persons. While further imaging does resolve most false-positive results, some patients may require invasive procedures. Kinsinger and colleagues reported that of 2106 individuals who were screened according to US Preventive Services Task Force (USPSTF) guidelines, 1257 (59.7%) had a positive test result, including 1184 (56.2%) with one or more nodules that needed to be tracked.^{[7, 8]}

The American College of Chest Physicians (ACCP) released revised guidelines for lung cancer screening that include the following recommendations^{[9, 10]}:

In the revised Fleischner Society guidelines, the minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences.^[11]

The British Thoracic Society (BTS) guidelines include 4 management algorithms and 2 malignancy prediction calculators to help measure the risk of malignancy. To help reduce the number of follow-up CT scans performed, the BTS recommendations include a higher nodule size threshold for follow-up and a reduction of the follow-up period to 1 year for solid pulmonary nodules. Volumetry is recommended as the preferred measurement method.^[12]

Often, solitary pulmonary nodules (SPNs) are discovered first as incidental findings on chest radiographs. The first step is to determine whether the nodule is pulmonary or extrapulmonary. A lateral radiograph, fluoroscopy, or CT scanning of the chest often helps determine the location of the nodule.^{[5, 13]}

Usually, nodules are identifiable by the time they are 8-10 mm on chest radiographs. Occasionally, SPNs can be visualized at 5 mm in diameter. Chest radiographs can provide information regarding nodule size, growth rate, margin characteristics, and calcification pattern, which can aid in the assessment of benign versus malignant lesions.

Some SPN mimics include nipple shadows, soft tissue tumors, bone shadows, pleural plaques, pseudotumors, and round atelectases.

(The different types of solitary pulmonary nodules are seen in the radiographs below.)

Nodules greater than 3 cm in diameter are more likely to be malignant, while those less than 2 cm are more likely to be benign. Note that size alone is of limited value. In individual patients, small nodules can be malignant and larger nodules can be benign.

Comparison of previous chest radiographs of the patient allows assessment of the growth rate. The growth rate refers to the doubling time of a nodule (ie, the time necessary for the nodule’s volume to double). On chest radiographs, a nodule appears as a 2-dimensional representation of a 3-dimensional structure. The volume of a sphere equals 4/3 pr³; therefore, a 26% increase in diameter on a chest radiograph represents one doubling in volume. For example, an increase from 1.0 cm to 1.3 cm equals one doubling, and a 1 cm to 2 cm increase relates to an 8-fold increase in volume.

Bronchogenic carcinomas usually have a doubling time of 20-400 days. Doubling times shorter than 20-30 days are seen in infections, infarction, lymphoma, or fast-growing metastases.

Doubling times greater than 400 days are typically indicative of benign nodules, although on occasion, a low-grade carcinoid tumor may have a doubling time greater than 400 days.

Absence of a change in size of a nodule over 2 years is highly suggestive of a benign lesion.

Determination of the size of small nodules is not without error. On chest radiographs, a 3-mm enlargement may be difficult to appreciate. The use of digitally enhanced films may allow for more accurate measurements of size.

Benign lesions tend to have well-circumscribed, smooth borders. Malignant nodules typically have irregular, lobulated, or spiculated (corona radiata) borders. Of the margin descriptions, the spiculated border is the most sensitive in predicting malignancy; however, it is not unusual for a malignant lesion to have a smooth contour.

Calcification within a nodule is more likely to be seen in a benign nodule; however, approximately 10% of malignant nodules demonstrate calcification. In benign lesions, 5 patterns of calcification are commonly seen: diffuse, central, laminar, concentric, and popcorn (chondroid). The popcorn pattern typically is described in hamartomas (an example of which appears below). A stippled or eccentric pattern is most commonly seen in malignant lesions. CT scanning allows a more accurate detection and assessment of the calcification pattern than plain films do.

CT scanning of the chest allows better assessment of nodules than does plain radiography.^{[14, 15]}Nodules as small as 3-4 mm are detectable on CT scans, and morphologic features of specific diagnosis are better visualized (eg, rounded atelectasis, arteriovenous malformations).

Areas that are difficult to assess on plain radiographs are also better visualized on CT scans, including the lung apices, perihilar regions, and costophrenic angles.

In addition, multiple nodules can be detected on CT scans, malignancy can be staged using the modality, and CT scanning can help guide needle biopsy.

(The characteristics and types of solitary pulmonary nodules, as seen on CT scans, are demonstrated in the images below.)

CT densitometry measures the attenuation coefficients of a particular lesion to determine its density. The results are expressed in Hounsfield units (HU). Some examples of attenuation coefficients are as follows:

Air: -1000 HU

Fat: -50 to -100 HU

Water: 0 HU

Blood: 40-60 HU

Noncalcified nodule: 60-160 HU

Calcified nodule: Greater than 200 HU

Bone: 1000 HU

CT densitometry allows for the detection of occult calcification that may not be appreciated visually, even on high-resolution thin-section CT of the chest. The difficulties with this technique have been in determining the appropriate level of the attenuation coefficients used to classify a lesion with a high probability of being benign.

One study looking at 91 nodules known to be malignant or benign proposed a cutoff of greater than 164 HU for benign lesions. In another study, of 85 nodules classified as benign (using 185 HU as a cutoff), 9% were found to be malignant at biopsy. Densitometry in this setting may provide useful information if used in context with other clinical and radiologic features, but overall, its use has fallen out of favor.

Densitometry also allows detection of fat within a nodule, which is a common feature of benign nodules, especially in hamartomas.

Malignant nodules tend to have greater vascularity than do benign nodules. Assessment of enhancement involves repeated measurement of attenuation of a nodule over a 5-minute period. Nodular enhancement of less than 15 HU suggests that a lesion is benign, and enhancement of greater than 20 HU is more likely associated with malignancy (sensitivity 98%, specificity 73%).

This sign may be seen in hematogenous or vascular causes of pulmonary nodules, such as metastatic deposits or septic emboli.

Cavitation can be seen in malignant and benign nodules. While a thin-walled cavity is highly suggestive of a benign lesion (1 mm or less), a thick-walled cavity is usually indeterminate and is present in benign and malignant lesions.

PET and SPECT scanning

Malignant cells have a higher metabolic rate than do normal cells; therefore, glucose uptake is higher. Thoracic PET imaging uses the isotope fluorine-18 bound to a glucose analog to make fluorine-18-fluorodeoxyglucose (FDG). Increased FDG uptake is seen in most malignant tumors and is the basis of the PET study used to differentiate malignant from benign nodules.^{[16, 17]} FDG uptake can be quantified using the standardized uptake ratio (SUR) to normalize measurements for a patient’s weight and injected dose of radioisotope. This allows comparison of uptake between different lesions and patients. According to the guidelines of the American College of Chest Physicians (ACCP), a standardized uptake value greater than 2.5 is used to identify nodules that have a high probability of malignancy.^[10]

FDG-PET is most cost-effective when the clinical pretest probability of malignancy and the results of the CT are discordant (eg, low pretest probability with chest CT characteristics that are clearly not benign). The ACCP guidelines recommend FDG-PET in persons with solid indeterminate nodules 8 mm or greater in diameter, along with a low to intermediate pretest probability of malignancy.^[10] An additional advantage of FDG-PET imaging is better detection of mediastinal metastases, improving the staging of lung cancers.

High serum glucose concentrations compete in cells with FDG; therefore, uptake of the radioisotope is reduced. In a meta-analysis, the mean sensitivity and specificity for detecting malignancy in focal pulmonary lesions of any size were 96% and 73.5%, respectively. In SPNs, the mean sensitivity and specificity were 93.9% and 85.8%, respectively.^[16]

In FDG-PET scanning, false-positive findings can occur in other metabolically active conditions that produce pulmonary nodules, such as infectious granulomas and inflammatory lesions.

The resolution of PET scanners is 7-8 mm; therefore, they may miss tumors smaller than 10 mm.

In FDG-PET scanning, tumors with low metabolic rates, such as carcinoid tumors and bronchioalveolar cell carcinomas, may not be distinguishable from background uptake.

SPECT scanners have the advantage of being more readily available than PET scanners. Depreotide is a somatostatin analog labeled with technetium-99m (^99mTc), which has been shown to bind to somatostatin receptors expressed on non-small-cell carcinomas. In a study of a small series of patients, depreotide uptake demonstrated a sensitivity and specificity of 93% and 88%, respectively, for malignancy.

[Guideline] Expert Panel on Thoracic Imaging: Kanne JP, Jensen LE, Mohammed TH, et al. ACR Appropriateness Criteria® Radiographically Detected Solitary Pulmonary Nodule. American College of Radiology. Available at https://acsearch.acr.org/docs/69455/Narrative/. 2012; Accessed: September 3, 2018.

Heuvelmans MA, Oudkerk M. Management of subsolid pulmonary nodules in CT lung cancer screening. J Thorac Dis. 2015 Jul. 7 (7):1103-6. [Medline].

Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015 Aug. 70 Suppl 2:ii1-ii54. [Medline].

Alpert JB, Lowry CM, Ko JP. Imaging the solitary pulmonary nodule. Clin Chest Med. 2015 Jun. 36 (2):161-78, vii. [Medline].

Yano Y, Yabuuchi H, Tanaka N, Morishita J, Akasaka T, Matsuo Y, et al. Detectability of simulated pulmonary nodules on chest radiographs: Comparison between irradiation side sampling indirect flat-panel detector and computed radiography. Eur J Radiol. 2013 Jul 1. [Medline].

Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer. 2013 Nov 15. 119 (22):3976-83. [Medline]. [Full Text].

Kinsinger LS, Anderson C, Kim J, Larson M, Chan SH, King HA, et al. Implementation of Lung Cancer Screening in the Veterans Health Administration. JAMA Intern Med. 2017 Mar 1. 177 (3):399-406. [Medline]. [Full Text].

[Guideline] Moyer VA, U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Mar 4. 160 (5):330-8. [Medline]. [Full Text].

[Guideline] Mazzone PJ, Silvestri GA, Patel S, Kanne JP, Kinsinger LS, Wiener RS, et al. Screening for Lung Cancer: CHEST Guideline and Expert Panel Report. Chest. 2018 Apr. 153 (4):954-985. [Medline]. [Full Text].

[Guideline] Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May. 143 (5 Suppl):e93S-e120S. [Medline]. [Full Text].

[Guideline] MacMahon H, Naidich DP, Goo JM, Lee KS, Leung ANC, Mayo JR, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology. 2017 Jul. 284 (1):228-243. [Medline]. [Full Text].

[Guideline] Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015 Aug. 70 Suppl 2:ii1-ii54. [Medline]. [Full Text].

Patel VK, Naik SK, Naidich DP, Travis WD, Weingarten JA, Lazzaro R, et al. A practical algorithmic approach to the diagnosis and management of solitary pulmonary nodules: part 1: radiologic characteristics and imaging modalities. Chest. 2013 Mar. 143(3):825-39. [Medline].

Lee HY, Goo JM, Lee HJ, Lee CH, Park CM, Park EA, et al. Usefulness of concurrent reading using thin-section and thick-section CT images in subcentimetre solitary pulmonary nodules. Clin Radiol. 2009 Feb. 64(2):127-32. [Medline].

Awai K, Murao K, Ozawa A, et al. Pulmonary nodules at chest CT: effect of computer-aided diagnosis on radiologists’ detection performance. Radiology. 2004 Feb. 230(2):347-52. [Medline].

Gould MK, Maclean CC, Kuschner WG, et al. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA. 2001 Feb 21. 285(7):914-24. [Medline].

Ohno Y, Nishio M, Koyama H, Fujisawa Y, Yoshikawa T, Matsumoto S, et al. Comparison of quantitatively analyzed dynamic area-detector CT using various mathematic methods with FDG PET/CT in management of solitary pulmonary nodules. AJR Am J Roentgenol. 2013 Jun. 200 (6):W593-602. [Medline]. [Full Text].

Sanjay Manocha, MD Consulting Staff, Respirology and Critical Care Medicine, Department of Medicine, Humber River Regional Hospital

Sanjay Manocha, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Royal College of Physicians and Surgeons of Canada