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Advances in imaging of pulmonary nodules

The number of incidentally detected pulmonary nodules has increased with new-generation computed tomography scanners and the introduction of computer-aided detection systems
Joanne Sharkey FRCR
Consultant Radiologist
Gillian Ritchie FRCR
Consultant Radiologist
Kristopher Skwarski FRCP
Consultant Respiratory Physician
Edinburgh Royal Infirmary, Edinburgh, UK
Edwin JR van Beek MD FRCP
SINAPSE Chair of Clinical Radiology, Edinburgh University Medical School
John T Murchison FRCR FRCP
Consultant Radiologist
Edinburgh Royal Infirmary, Edinburgh UK
The management and follow-up of the pulmonary nodule detected on computed tomography (CT) scanning continues to be a subject of topical radiological debate. Given the exponential increase in CT use, and the ability of newer generation CT scanners with thinner collimation to detect more and smaller nodules, the traditional approach of regarding all non-calcified nodules as potentially malignant lesions until proven stable over two years puts major strain on the use of radiology and may no longer be a feasible blanket management strategy.(1) The finding that the majority of smokers who undergo CT have small lung nodules, and that the vast majority of sub-centimetre pulmonary nodules are benign, further highlight the need for a more tailored approach to incidentally CT detected nodule management and follow up.(1–3)
Almost all guidance published for the management of CT detected incidental pulmonary nodules has been developed using data from lung cancer screening programs, and is therefore based largely on middle-aged patients with a smoking history and absence of comorbidity. Guidance to date generally involves multiple CT follow up examinations over at least a two- year period, which when used indiscriminately is a poor utilisation of resource and a substantial source of patient anxiety and radiation exposure. Adding to this, the projection that approximately 20% of patients develop a new pulmonary nodule during their two-year CT follow up, committing them to further CT follow-up, makes defining a patient-tailored nodule management strategy all the more important.(1) 
In order to define an appropriate and individual management strategy for imaging pulmonary nodules, patient preferences and the realistic potential of malignancy of each nodule must be considered. This is based on patient relative risk of malignancy, which considers patient age, smoking pack years, and history of cancer, along with the nodules radiological characteristics, which include size, morphology and doubling time (DT).(1) 
What is a pulmonary nodule?
A pulmonary nodule is defined as ‘a rounded or irregular opacity, well or poorly defined, measuring up to 3cm in diameter’ and the differential diagnosis for this is wide.(4) The primary concern with any nodule is malignancy, particularly bronchogenic carcinoma, but also metastases, carcinoid, or lymphoma. Pulmonary nodules >1cm diameter have a significant risk of malignancy and should be managed as such. However, the vast majority of pulmonary nodules less than 1cm are benign, with the differential including benign tumours and infective, inflammatory, vascular and congenital entities.(5) 
Frequently more than one pulmonary nodule is identified, and it is suggested that up to six nodules can be evaluated as independent ‘solitary’ pulmonary nodules for individual assessment in one examination.(5) In these situations, the patient should be managed according to the protocol for the most concerning of these nodules.
When more than six pulmonary nodules are present, metastatic disease, granulomatous infection, inflammatory or vascular aetiologies should be considered and the patient should be managed as such. Equally, if there is a history of malignancy or infection, the differential diagnosis will move towards that of metastatic or inflammatory disease, requiring a more patient-specific management and follow-up strategy.
Assessment of patient relative risk 
The increased relative risk of lung cancer in smokers compared with non-smokers has long been established.(1,6) Other established risk factors include age over 40 years and occupational exposure to asbestos, uranium and radon.(1,6) While evidence for a lung cancer susceptibility gene has been discovered in the last decade, the apparent increased risk of lung cancer in women compared with men with the same smoking history has become less certain.(1)
Assessment of radiological characteristics
Nodule size is a primary factor in determining the likelihood of a nodule being malignant. In patients without a history of malignancy, the likelihood of malignancy is documented as <1% if the diameter of the nodule is <5mm, 6–28% if between 5 and 10mm, 33–64% if between 10 and 20mm and 64-82% if >20mm.3  Henschke et al also demonstrated no case of delayed diagnosis when a 12-month interval scan was performed to follow up a nodule <5mm, and therefore recommended no earlier interval scanning in these cases.(7) 
The frequency and overall duration of follow up CT imaging of the incidentally detected nodule is also dependent on nodule morphology. Shape can be helpful; however, irregular and spiculated margins more typically seen in malignancy can be benign, particularly in patients with emphysema, and 21% of malignant nodules demonstrate smooth, well-defined margins.(5,6) Lobular outlines imply rapid growth and a round, ground glass nodule is highly suspicious for malignancy.(3,5,6) Oval or polygonal shapes suggest benignity as do flat-shaped nodules in the craniocaudal direction; neoplastic lesions tend to grow in a three-dimensional ratio and are therefore generally spherical.(2,5) 
Densely diffuse, central, concentric and laminated calcification implies benignity but eccentric or stippled calcification can occur with malignancy. Intranodular fat also suggests a benign nodule such as a hamartoma, granuloma or lipoma. Air bronchograms and cavitation within a nodule are more likely to be malignant.(5) Whereas cavitation can be seen in both benign and malignant nodules, malignancy tends to have thicker, more irregular walls compared with benign cavitation.(6) Location can also be helpful in characterising nodules, with primary cancers having a tendency to develop in the upper lobes.(1,5,6)
Nodule density, described as solid, ground glass, or mixed solid and ground glass, influences the likelihood of malignancy.(3,8) Ground glass nodules may represent foci of inflammation, oedema, haemorrhage or fibrosis. However, persistent ground glass nodules typically represent adenocarcinoma in situ, previously referred to as bronchioloalveolar cell carcinoma or atypical adenomatous hyperplasia.(5,9) Similarly, mixed ground glass and solid nodules may be inflammatory or reflect foci of organising pneumonia; however, persistent mixed density nodules have a high probability of malignancy. One author reported up to 90% of mixed ground glass nodules <10mm represented malignancy following surgical sampling and a strong case could be made to manage these nodules differently.(5,9) 
Growth rate
The rate of growth of a tumour is measured as the time taken for the tumour to double in volume and the doubling time (DT) formula is based on an exponential model of nodule growth. The DT of malignant nodules is generally considered between 20 and 400 days.(6,10) Benign nodules have slower or faster DTs, which is why stability over two years, that is, a DT of at least 730 days can be considered benign. Studies have estimated the median DT of malignant tumours to be between 160 and 180 days, although wide variation is reported with up to 22% of stage I carcinomas demonstrating a DT of 465 days or more.(11) 
Sub-solid nodules have been found to have longer DTs, with one report describing mean volume DTs of 149, 457 and 813 for solid, ground glass with a solid component and ground glass nodules, respectively.(8) Longer malignant nodule DTs were also noted in non-smokers relative to those found in smokers. As such, sub-solid nodules, which may represent slow-growing adenocarcinoma, require longer follow up strategies in order to ensure benignity. Of note, the finding of a new solid component in a subsolid pulmonary nodule is concerning for transformation into invasive adenocarcinoma, even if the overall size has decreased.(10) 
Every effort should be made to obtain previous imaging to reduce the need for further surveillance and reduce cumulative dose of follow up CT imaging by performing non-contrast, low dose, thin collimation scans, limited to the area of interest.(6)
Despite neoplastic nodules tending to be spherical in nature, the majority of radiologists measure the maximum diameter of a nodule rather than the volume, which has been shown to underestimate growth. A DT in volume of a sphere corresponds to a 26% increase in its diameter. Therefore a 4mm nodule only has to have increased by 1mm for it to double in size when measured in two-dimensional (2D) format only. Measurement variability is an important factor to be considered in follow-up of lung nodules. Significant inter-observer and intra-observer variation in 2D measurements has been demonstrated such that follow up measurements of pulmonary nodules between 5mm and 15mm were unreliable when attempting to distinguish malignancy from benignity, whereas 2D measurements appear worse when low-dose CT is used.(12) Volumetric analysis to assess growth rate of small lesions is therefore recommended.(6,12)  
Computer-assisted image analysis performed by specific image analysis software also aids pulmonary nodule detection but has drawbacks, including segmentation error and relative increased false positive detection rate.(6) Whatever technique is employed, measurement accuracy is an important consideration and longer CT scan intervals when following up small pulmonary nodules may be required to ensure neither unwarranted invasive investigation nor undetected malignant growth occurs.
Follow up guidelines 
Early guidance of pulmonary nodule management by the American College of Chest Physicians recommended 3-, 6-, 12- and 24- month CT follow up for indeterminate nodules irrespective of size.(1) The Fleischner Society published better defined guidance in 2005 providing more tailored management based on size criteria.1 However, the intervals between follow up scans still seem short when considering the limitations of accurately interpreting sub-centimetre nodule DTs due to inter-scan and inter-observer variation. 
The UK lung cancer (UKLC) trial has published nodule follow up guidelines for a prospective lung nodule study that are largely based on data from the Nelson study.(13,14) The authors state their study may be applicable in everyday clinical practice and their protocol is less intensive than the Fleischner protocol. However, the DT used to model the study is relatively short, at 200 days, particularly when considering ground-glass nodules, and it depends on automated nodule volume measurement that might not be universally available along with a maximum follow up period of 12 months. 
We have developed a local protocol, which makes use of this protocol but extends the follow up to two years for some higher-risk patients to make allowance for longer DTs and the greater inaccuracy of manual diameter measurements that are widely employed in clinical practice. There is little new evidence on how to manage nodules in low risk cases. The UKLC protocol has been developed for high-risk patients but is not that different from the Fleisher low-risk protocol. Accordingly, to simplify matters, we suggest a single follow up protocol for all patients (Figure 1). As a reassurance, we have included a six-month chest X-ray to catch any fast-growing nodules. This may be removed if shown to be ineffective after future audit. 
Clearly, the management of the nodules is not based on size criteria alone. As discussed, patient factors and nodule morphology all require consideration. Patients with known or previous malignancy, infection, and those with multiple nodules require management strategies specific to their scenario, likely involving earlier follow up. Patients under 35 years are unlikely to have lung cancer and the risks of unnecessary radiation exposure are great, requiring case specific management. Similarly, the management of a sub-centimetre nodule in elderly patients or those with co-morbidity should reflect the likelihood of a symptomatic lung cancer developing within their lifetime and a conservative approach may be warranted.
Patients deemed at intermediate-to-high risk of lung cancer following assessment of clinical and radiological nodule factors require further investigation, usually with CT-positron emission tomography (CT-PET) and CT-guided percutaneous biopsy. Most nodules 1cm or more would be considered high-risk and proceed directly to staging and surgical intervention.(9) This strategy is also appropriate for sub-centimetre nodules that demonstrate malignant features or growth. The indications and limitations for each of these strategies are beyond the scope of this paper but are concisely summarised in recent reviews.(6,10) Of note, CT-PET is limited in accurately characterising sub-centimetre nodules and CT biopsy should be avoided as a first-line approach in small, low-risk nodules given the associated complications, even if infrequent.(10,12)
In summary, the number of incidentally detected pulmonary nodules has increased with the introduction of new generation CT scanners and the introduction of computer aided detection systems. It is therefore crucial that appropriate management strategies be employed to identify and manage only those patients with, or at relative increased risk of lung cancer while minimising the burden of over-radiation in the affected population. A strategy for managing such nodules that can be employed in routine practice is suggested.
  1. MacMahon H et al. Guidelines for management of small pulmonary nodules detected on CT scans: A statement from the Fleischner society. Radiology 2005;237:395–400.
  2. Takashima S et al. Small solitary pulmonary nodules (≤1mm) detected at population based CT screening for lung cancer: reliable high resolution CT features of benign lesions. Am J Radiol 2003;180:955–64.
  3. Wahidi MM et al. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer? ACCP evidence based clinical practice guidelines (2nd edition). Chest 2007;132:94s–107s.
  4. Hansell DM et al. Fleischner Society: Glossary of Terms for Thoracic Imaging. Radiology 2008;246:697–722.
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  12. Revel MP et al. Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable? Radiology. 2004;231:453–8.
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