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British Journal of Radiology (2007) 80, 708-712
© 2007 British Institute of Radiology
doi: 10.1259/bjr/46019726
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Full paper

Evolution of lung nodules ≤5 mm detected with low-dose CT in asymptomatic smokers

M Bellomi, MD 1,2 G Veronesi, MD 3 C Rampinelli, MD 1 S Ferretti, MD 1 E De Fiori, MD 2 and P Maisonneuve, MD 4

1 School of Medicine, University of Milano, 7 Via Festa del Perdono, 20122 Milan, Italy, Departments of 2 Radiology, 3 Thoracic Surgery and 4 Epidemiology and Biostatistics, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy

Correspondence: Prof. Massimo Bellomi, MD, Professor of Radiology, School of Medicine University of Milan, Dept. of Radiology European Institute of Oncology, 435 Via Ripamonti, Milan 20141, Italy. E-mail: massimo.bellomi{at}ieo.it


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 References
 
Low-dose CT is widely employed for the early diagnosis of lung cancer in high-risk populations even if screening programmes have not been clinically validated yet; however, the optimum follow-up schedule for small lung nodules of uncertain status has not been defined. The aim of this study was to assess outcomes for small pulmonary nodules (diameter ≤5 mm) detected by CT in asymptomatic smokers

In 2000–2001, 1035 high-risk people were enrolled in an observational study for the early detection of lung cancer by yearly CT. The prevalence, incidence and evolution of small lung solid nodules are described

238 solid lung nodules ≤ 5 mm were identified at initial low-dose CT in 165 people (prevalence 15.9%). 26% of them were not detected in the following 4 years, 43.3% did not change and 10.1% grew to >5 mm; three were removed and found to be malignant (all T1N0); the remaining 21 were followed yearly

In the following year, 79 new small nodules were detected (incidence 7.9%). 11.4% were not detected in the subsequent 3 years, 79.7% did not change, 2.5% grew to > 5 mm and were followed yearly

In conclusion, prevalent and incident nodules ≤5 mm detected by low-dose CT screening for lung cancer can be safely checked at 1 year intervals.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 References
 
CT is the most accurate technique for detecting lung nodules [1]. Spiral CT protocols that reduce radiation exposure (low-dose CT) have been shown to detect early lung cancer in a high-risk population [2–4]; however, few data regarding the impact of this modality on lung cancer mortality are available [3, 5]. A problem with lung cancer screening using low-dose spiral CT is the frequent finding of undetermined non-calcified lung nodules for which the best clinical management is uncertain [5]. Technological improvements, most recently the introduction of multidetectors with their ability to reconstruct thinner sections, have led to an increase in the number of small nodules detected [6, 7], which require the development of diagnostic algorithms for their management. Various protocols [8–10] have been proposed for the diagnostic work-up of small nodules (mainly <1 cm) involving follow-up, contrast enhancement, biopsy and positron emission tomography (PET). The diagnostic approach to nodules ≤5 mm (here defined as "small nodules") remains more problematic: surgical biopsy is not justified in view of the high probability of benign disease, and the nodules are also too small to warrant PET or fine-needle aspiration biopsy.

Continued observation, with a view to detecting nodule growth, appears as the only feasible method for indicating the benign or malignant nature of such small nodules. Nevertheless, deciding the frequency of follow-up examination is not trivial, as one must consider the risk of progression, exposure to X-rays, costs and patient anxiety.

In this study, we report the results obtained with our follow-up schedules for lung solid nodules ≤5 mm in smokers enrolled in a programme for early detection of lung cancer. We assess the prevalence and incidence of these nodules and their evolution over 4 years of follow-up.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 References
 
From June 2000 to June 2001, 1035 volunteers were enrolled in a single-institution observational study to assess the efficacy of low-dose spiral chest CT, repeated yearly, in the early detection of lung cancer. Follow-up continues; we report results of 5-yearly CTs. Inclusion criteria were age 50 years or above, smoker or former smoker (minimum 20 pack-years) and no history of malignant disease. Volunteers were recruited with the aid of a press campaign. Eligible participants had to sign a written informed consent document approved by the Ethics Committee of our Institute each year for the 5 study years.

CT scans were obtained from June 2000 to June 2003 with a Highspeed Advantage CT scanner (GE Medical Systems, Milwaukee, WI) using the following settings: 1 s tube rotation, 140 kVp, 40 mA, 2:1 pitch, 10 mm section thickness and 5 mm reconstruction interval. From June 2003 the low-dose CT was performed with a Light Speed CT16 (GE Medical Systems) with the following parameters: 0.8 s tube rotation, 140 kVp, 40 mA, 35 mm/rot, 2.5 mm slice thickness. The CT examination was performed as the person held his/her breath. The effective dose equivalent per person was estimated at 0.81 mSv for the single slice and 0.90 mSv for the 16-slice CT. Scans were examined on a workstation monitor (Advantage Windows 3.1; General Electric Corporation, Milwaukee, WI) by two independent radiologists using lung (WW 1260, WL –480) and mediastinum (WW 400, WL 40) windows. The presence of nodules was defined as a focal non-linear density. Lesion diameter was determined, using electronic calipers, as the longest axis of the nodule in the axial plane in the lung window. Disagreements were resolved by a collective discussion involving a senior radiologist. If the maximum diameter was ≤5 mm, only solid or part-solid nodules [11] were considered as nodules.

Volunteers with no pulmonary nodules or calcified nodules at baseline proceeded to four successive annual examinations. Management of volunteers with one or more nodules depended on nodule size. Those with non-calcified lung nodules 5–7 mm in size were recalled 3 months later to repeat low-dose CT to check for growth; if no growth was detected, they were put back to yearly low-dose CT (1 year after first low-dose CT scan). Nodule enhancement [12] was obtained for solid nodules with positive CT density as part of the diagnostic work-up. The enhancement <10 Hounsfield units (HU) was considered suggestive of benign lesions if >30 HU was suggestive of malignant lesions, while enhancement between 10 and 30 was considered dubious and non-conclusive for a diagnosis.

If the nodule was ≥8 mm, 18FDG PET was performed. Lesions larger than 20 mm, or considered suspicious on PET or CT contrast enhancement (i.e. >30 HU) were biopsied. Volunteers with one or more nodules of maximum diameter ≤5 mm proceeded to four successive annual routine examinations. Volunteers were informed prior to study entry that they would not be informed of the presence of nodules ≤5 mm, but that the information would be recorded on the clinical record forms (CFRs). At successive low-dose CTs, previously identified nodules were re-examined to determine whether they had disappeared (no longer detected), had grown in size (>5 mm) or remained unchanged (≤5 mm).

All the anagraphic and clinical data of volunteers were recorded in a specially designed database (Access 2000©; Microsoft Corporation, Redmond, WA) where each nodule was assigned an identification number and its maximum axial diameter measured each year was reported.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 References
 
From June 2000 to June 2001, the 1035 volunteers (739 men, 296 women, mean age 58 years, range 50–84) received their first low-dose CT. They had smoked an average of 26 cigarettes a day for a mean of 37 years. At recruitment, 145 (14%) had been ex-smokers for a mean of 9 years.

A total of 996 (96%) volunteers returned for low-dose CT in the second year, 972 (94%) returned in the third year, 958 (93%) returned in the fourth year and 889 (86%) presented for the fifth examination. A total of 146 (14%) failed to attend for CT over the 5 years of the study, 27 of these died and 21 had medical conditions unrelated to lung cancer; thus, overall compliance was 937 (90.5%).

Prevalent small nodules
A total of 238 non-calcified solid nodules of diameter ≤5 mm (mean 3.55 mm, range 2–5 mm) were detected in 165 of the 1035 volunteers, giving a person prevalence in this population of 15.9 % (Table 1Go). In the same cohort of 1035 subjects, as previously described [13], 61 nodules >5 mm were detected in 42 volunteers (person prevalence 4.1%), 11 of which were cancers.


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  		Table 1. Size changes in 238 solid nodules≤5 mm found at baseline low-dose CT in 165 volunteers

 
At the second scan (year 2), five volunteers and their eight small nodules were lost to follow-up. Among those who re-presented, 190 (82.6%) of the 230 small nodules remained unchanged, 33 (14.3%) had disappeared and 7 (3.0%) had grown to >5 mm.

Of the seven grown nodules, three had grown to >7 mm (4.7 to 10.2 mm, 4.8 to 7.2 mm, 5 to 10 mm). The three patients with >7 mm nodules underwent PET (suspicious for cancer) and surgical biopsy (positive frozen section). Lobectomy with radical lymph node dissection followed. Pathological examination demonstrated two adenocarcinomas (Figure 1Go) and one large-cell neuroendocrine tumour, all stage T1N0. Two patients are alive and disease free 3 years after surgery. The third patient was diagnosed with a second primary lung adenocarcinoma the next year (2002) and died of distant metastases in 2003.


Figure 1
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  		Figure 1. (a) Small solid lung nodule (maximum axial diameter 4.9 mm) detected during first low-dose CT on 24 June 2000. (b) At the second year scan (23 June 2001), the nodule had grown to 8.3 mm, and after positive PET was removed surgically (pT1N0 adenocarcinoma).

 
The diameter of one of the other four nodules increased from 4.5 to 6.8 mm. The patient refused further examinations and treatments but agreed to continue yearly low-dose CT. The diameter of the nodule increased: 7.3 mm, 7.5 mm and 8.4 mm in the third, fourth and fifth years, respectively. The patient continues yearly follow up.

The remaining three nodules (in three patients) grew slightly: 4.8 to 5.4 mm, 4.9 to 5.2 mm, 4.6 to 5.1 mm. The patients continued with yearly low-dose CT. The mean nodule diameter increased from 4.8 mm at baseline to 5.6 in year 5 (Figure 2Go).


Figure 2
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  		Figure 2. Size changes in the 24(out of 238) small nodules detected at first CT that had grown during the subsequent 4 years. +Nodules removed surgically and diagnosed as carcinoma.

 
In the second year, nine other lung cancers unrelated to previously identified nodules were diagnosed and treated.

At the third scan (year 3), five volunteers, each with single small nodule, were lost to follow-up, 167 (90%) of the 185 remaining prevalent small nodules had not changed, 11 (5.9%) had disappeared and 7 (3.8%) had increased in size to between 5.1 and 6.3 mm. The volunteers continued with yearly follow-up (Table 1Go). Also in the third year, seven other lung cancers unrelated to previously identified nodules were diagnosed and treated.

At the fourth scan (performed with 16-slice CT), eight additional volunteers with 25 small nodules were lost to follow-up, 121 (85.2%) of the 142 remaining prevalent small nodules had not changed, 15 (10.5%) had disappeared and 6 (4.2%) had grown to a mean of 5.3 mm (range 5.1–6.2 mm) (Table 1Go). Also in the fourth year, an additional six lung cancers were diagnosed and treated in the cohort.

At the fifth year, 10 volunteers (11 small nodules) were lost to follow-up, 103 (93.6%) of the 121 small nodules had not changed, 3 (2.7%) had disappeared and 4 (3.6%) had grown to a mean of 5.2 mm (maximum diameter 5.6 mm). In the same year five additional lung cancers were diagnosed and treated.

11 small nodules (mean diameter 3.2 mm, range 2–4.9 mm) detected at first scan, but not evident at the second or third scan, were detected again at a subsequent scan. These nodules were considered unchanged.

A total of 28 out of 165 volunteers of the present series were lost at follow-up CT exams: 7 of them were unreachable; 11 spontaneously withdrew from the study and were healthy in December 2005; 5 died (4 from non-neoplastic disease and 1 from prostate cancer) and 5 withdrew because of other intercurrent disease (4 cardiovascular disease and 1 breast cancer).

Incident small nodules
Of the 828 volunteers negative at first scan, 34 were lost to follow-up at the second scan, and 63 had 79 new small nodules (51 single and 12 multiple) that had not been present initially, nor when the first CT was retrospectively evaluated. The person incidence was 8.2% (nodule incidence 9.5%) (Table 2Go).


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  		Table 2. Size changes in 79 solid nodules≤5 mm detected in second year low dose CT in 63 volunteers

 
At the third year, 74 (93.7%) of the 79 previously incident small nodules remained unchanged (in 61 volunteers), 5 (6.3%) in 2 volunteers had disappeared and none had grown. At the fourth year, 1 of the 74 incident small nodules had disappeared and 1 had grown to 5.6 mm: the patient continued on yearly follow-up and the nodule was 5.7 mm by the fifth year. At the fifth year, three volunteers (three nodules) were lost to follow-up, three had disappeared and one had grown to 5.6 mm (this nodule was kept on yearly follow-up).


   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
References
 
Screening programmes are aimed at healthy individuals, and the detection of an abnormality provokes concern in both the screened person and the physician. Small pulmonary nodules are often detected in volunteers undergoing low-dose CT for early lung cancer [13, 14] and the detection rate is expected to increase following the introduction of multislice CT [7].

In our study, single-slice CT identified small nodules in 15% of a high-risk population of volunteers in the first year (prevalence) and 8% of volunteers in the second year (incidence).

The hypothesis of our study was that follow-up for lung nodules smaller than 5 mm in diameter (small nodules) identified by yearly low-dose CT in a high-risk population could be safely performed at 1 year intervals. The corollary was that the small proportion of small nodules that were malignant would be identified at successive yearly scans using the criteria of growth rate and size increase above 5 mm. Such nodules would prompt additional investigations to secure a diagnosis. Any malignancy would thus be detected when still at an early stage and when surgery would most likely be curative.

We found that about 90% of the small nodules detected at first CT scan disappeared or remained unchanged over the successive 4 years. Conversely, 24 of the 238 (10%) small nodules, identified in 24 of 165 volunteers (14.5%), grew to >5 mm. Only three of these enlarging nodules were surgically biopsied, because of fast growth rate. All three were found to be malignant and were resected; importantly, they were all pT1N0. The malignancy rate was thus 1.2% over 4 years. We considered that 20 of the remaining 21 growing nodules were too small (5–7 mm) and too slow growing to justify invasive diagnostic procedures or surgical resection; nevertheless, yearly low-dose CT continues. The long doubling time observed for some of the nodules is unusual for a solid lesion [15], but the constant increase in diameter over the years makes a measurement mistake unlikely; on the other hand, hamartomas, benign tumours or other benign lesions are able to grow [16]. The patient with the remaining growing nodule refused treatment but continued follow-up: the nodule had increased to 8.4 mm by the fifth year of the study and the patient is continuing with yearly scans but refusing further diagnostic procedures.

These findings provide corroboration of our hypotheses, and support the idea that a prevalent pulmonary small nodule can be safely monitored at 1 year intervals.

Small nodules incident at the second year scan generally alarm physicians more than prevalent ones [2]. We detected 79 such nodules; however, none aroused sufficient suspicion over the next 3 years to justify PET or invasive diagnostic procedures. Based on this finding, we suggest that the appearance of a new small nodule on follow-up (with low-dose CT) should not generate alarm, much less prompt repetition of CT scans at shorter intervals.

Our findings are in line with those of other recent studies. In the screening series of Swensen et al [17] none of the tumours diagnosed had a diameter <5 mm; Henschke et al [18] reported no malignancies among 378 nodules <5 mm detected in 2000 subjects and recommended annual repeated CT screening to define interim growth in this population.

The strengths of our study are the high compliance rate of the screened population, uniformity of nodule management and long (4 years) follow-up.

A limit of the study is the use of a single-slice CT scanner with poorer resolution than a multidetector CT, rendering measurements of nodule diameter less accurate [19]. However when the study began (2000) only single-slice spiral CT was available. These instrument characteristics may explain why 11 prevalent nodules were not identified at the second or third year CT, but were detected again in subsequent years. On the other hand, when 16-slice CT was used, the rate of new incident solid nodules did not change compared with previous years and no significant changes in nodule diameter was found.

Another limit of the present study is the lack of pathological diagnosis of the slowly growing nodules, because those volunteers were not operated but kept on yearly follow-up. Finally, 28 out of 165 subjects with prevalent small nodules were lost at follow-up CTs, even though the clinical information is missing in just seven cases.

We conclude that prevalent and incident nodules less than 5 mm in diameter, identified by low-dose CT screening, can be safely checked at 1 year intervals. This follow-up schedule allowed identification of early-stage malignancies in all cases, while avoiding unnecessary anxiety and useless radiation in the majority of those being screened. Malignancies were identified in 1.2% of prevalent small nodules in 4 years of follow up. We are continuing once yearly observations in this cohort.


   Acknowledgments
 
The authors wish to thank the following foundations for their financial support to the study: The Italian Association for Cancer Research (AIRC), The Foundation of the European Institute of Oncology

Received for publication August 31, 2006. Revision received November 23, 2006. Accepted for publication December 4, 2006.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 References
 

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