2. tion, with a view to achieving the highest nodule that would qualify for this proto- CT. If the nodule did not exhibit un-
possible cure rate while gaining further col (2). equivocally benign characteristics (be-
insight into the behavior and character- The rationale for recommending serial nign pattern of calcification, smooth
istics of small malignant lesions. There- follow-up studies for all indeterminate margins, and size less than 20 mm), it
fore, patients whose nodules are detected small nodules is that some of them will was followed up with thin-section CT at
Radiology
incidentally during the course of CT per- turn out to be cancers and that early in- 3 months and subsequently at 6, 12, and
formed for other reasons should not nec- tervention will provide an opportunity 24 months in the absence of change.
essarily be treated in the same way as for cure. The “downside” of this policy Only one cancer was less than 5 mm in
subjects in a screening program. Nonethe- includes potential morbidity and mor- diameter at the time of detection in the
less, although CT screening has not as yet tality from surgery for benign nodules baseline (10-mm-collimation) study. The
been proved to help reduce mortality from and other false-positive findings, poor results of the repeat screening were re-
lung cancer, these programs provide an utilization of limited resources, in- ported in 2001. Seven new cancers were
important source of information for deter- creased health care costs, unnecessary detected at the repeat screening; three of
mining the optimal management of “inci- patient anxiety, loss of credibility for these were 5 mm in size (defined as the
dental” nodules detected in other situa- radiologists who may seem to recom- average of the length and width in that
tions. mend excessive numbers of CT scans study); all the other proved cancers were
Our intent in this position statement is with little benefit, and increased radia- larger (8).
to provide practical guidelines for the tion burden for the affected popula- Swensen et al (7) reported the results of
management of small pulmonary nod- tion. The radiation issue is particularly the Mayo Clinic Lung Cancer Screening
ules that are detected during the course important in younger patients and Trial after completion of three annual
of CT examinations performed for pur- must be taken into account in deter- low-dose CT examinations in 1520 smok-
poses other than lung cancer screening. mining appropriate follow-up strategies ers. The subjects were aged 50 years or
We recognize that this issue is complex (10 –13). older and had a smoking history of 20
and difficult to reduce to a simple algo- There remains a growing need to reex- pack-years or more. Two years after base-
rithm. We also realize that the definition amine the radiologic approach to small line screening, 2832 noncalcified pulmo-
of a pulmonary nodule is itself elusive, nodules, particularly when CT is per-
nary nodules had been identified in 1049
and that not all focal opacities qualify as formed for indications other than screen-
(69%) participants. Thirty-six lung can-
nodules. Yet, we believe that there is a ing. Several fundamental issues need to
cers were diagnosed with the aid of CT
practical need in the medical community be considered before an imaging strategy
(2.6% of participants, 1.4% of nodules):
for guidance in this area. is recommended. Since the decision to
26 at baseline (prevalence) and 10 at sub-
perform follow-up studies relies on size,
sequent annual (incidence) CT examina-
lesion characteristics (eg, morphology),
BACKGROUND tions. Thirty-two (80%) of these cancers
and growth rates (typically described as
were larger than 8 mm, and only one was
doubling time), an understanding of
smaller than 5 mm at the time of detec-
Available data indicate that fewer than these features and their relationship to
tion. Two cancers were detected by using
1% of very small ( 5-mm) nodules in malignancy should dictate further evalu-
sputum cytology, and there were two in-
patients without a history of cancer will ation. In addition, the patient’s risk pro-
terval cancers.
demonstrate malignant behavior (ie, de- file, including age and smoking history,
tectable growth or metastases over a pe- needs to be integrated into the diagnostic Benjamin et al (14) reported the results
riod of 2 or more years) (5,7,9). Nonethe- algorithm. of a retrospective review of 334 non-
less, multiple follow-up examinations screening cases in which a lung nodule or
over a 2-year period are commonly per- nodules were detected that were less than
Nodules Detected on CT Scans 10 mm in their long axis and for which
formed when such nodules are detected
incidentally. Guidelines for the manage- During the past 5 years, new informa- follow-up CT was recommended. These
ment of the solitary pulmonary nodule tion regarding the morphology, biologic nodules were identified from 3446 con-
were published in 2003 by the American characteristics, and growth rates of small secutive chest CT studies performed at
College of Chest Physicians (2) and in a lung cancers has become available from their institution. Among patients with a
review in by Ost and colleagues in the CT lung cancer screening programs nodule, 87 patients had “definitive” fol-
New England Journal of Medicine (1). How- throughout the world. Selected studies low-up results (2 years without change or
ever, neither of these articles specifically are summarized below as representative biopsy). Nodules in 10 (11%) of these
addressed the issue of the very small nod- of the present state of knowledge in this patients were malignant. Nine of these
ule that is detected as an incidental find- area. cases were metastases from known pri-
ing on a CT scan. Ost and colleagues con- Henschke et al (9) published the initial mary tumors, and one turned out to be a
cluded by recommending CT follow-up results from the Early Lung Cancer Ac- metastasis from an occult primary tumor.
at 3, 6, 12, 18, and 24 months for all tion Project CT screening project in 1999. This high incidence of metastases is a
“low-probability” indeterminate nodules They enrolled 1000 asymptomatic smok- reflection of the patient population that
(ie, nodules with a low likelihood of be- ers or ex-smokers with at least 10 pack- was used for this study, in that 56% of
ing cancer), regardless of size (1). The years of cigarette smoking who were aged the included patients had a known pri-
American College of Chest Physicians 60 years or older. Screening CT studies mary tumor. The authors of that article
recommendation for management of in- were performed with 10-mm collima- suggested that the malignancy rate in
determinate solitary nodules was similar, tion. The investigators found noncalci- small nodules in patients without a
with the proposal for 3-, 6-, 12-, and 24- fied nodules in 23% of subjects and ma- known neoplasm may be as low as 1%
month CT follow-up intervals, also with- lignant nodules in 2.7%. All detected and that follow-up may not be necessary
out any specified lower size limit for a nodules were subjected to thin-section in such cases.
396 Radiology November 2005 MacMahon et al
3. Nodule Size pers, or software that performs auto- diameter of 20.3 mm in 12 months,
mated volumetric measurement of the whereas a similar nodule with a doubling
On the basis of analysis of information
nodule (15). The minified display used time of 240 days would reach a diameter
from the ongoing Mayo Clinic CT
for hard copy makes accurate measure- of only 7.1 mm in the same period.
Screening Trial, Midthun et al (4) re-
ment of subcentimeter nodules virtually
ported that fewer than 1% of very small
Radiology
impossible. Even with a state-of-the-art
( 5-mm) nodules in patients without a Relative Risk
soft-copy display and electronic calipers,
history of cancer were malignant. They
substantial inter- and intrareader varia- Sone et al (22) reported the results of a
indicated a likelihood of malignancy of
tions in two-dimensional measurements CT screening program carried out in Ja-
0.2% for nodules smaller than 3 mm,
have been documented (16). Revel and pan in 1996 –1998 that enrolled 5483
0.9% for those 4 –7 mm, 18% for those colleagues (16) determined that two-di- subjects. They found an equal prevalence
8 –20 mm, and 50% for those larger than mensional measurements obtained with (0.5%) of lung cancer in smokers and
20 mm. electronic calipers were unreliable as a nonsmokers, although the death rate
Henschke and colleagues (5) recently basis for distinguishing benign from ma- from lung cancer in smokers in Japan is
addressed the issue of optimal follow-up lignant solid nodules in the 5–15-mm approximately four times higher than
intervals for nodules smaller than 5 mm size range. Limited studies (15,17) that that in nonsmokers (23). This discrep-
in diameter. They performed a retrospec- have been performed with automated ancy may be explained by an overdiag-
tive review of a total of 2897 baseline three-dimensional analysis suggest that nosis bias, as many of these slow-growing
screening studies performed between such systems can be considerably more cancers in nonsmokers might never have
1993 and 2002 in order to identify those accurate and consistent than unaided been detected or become symptomatic if
subjects with noncalcified nodules that, radiologists in determining interval the subjects had not been screened. It is
at initial detection, were (a) smaller than changes in small nodules. However, Kos- unclear how many of the nonsmokers in
5 mm in diameter and (b) 5–9 mm in tis and colleagues (18) have shown that this study may have been affected by sec-
diameter. In accordance with the screen- even sophisticated automated volume- ond-hand smoke and whether this phe-
ing program guidelines, indeterminate measurement methods are susceptible to nomenon, or underreporting of smoking
nodules were rescanned at 3-, 6-, and 12- errors due to motion artifacts or segmen- by screening subjects, might account for
month intervals, while some in the tation problems, particularly in the case the relatively high lung cancer mortality
5–9-mm range that had particularly sus- of very small nodules. in nonsmokers in Japan compared with
picious morphology were recommended that in the United States (24).
for biopsy. On the basis of the results of The relative risk for developing lung
these follow-up studies and biopsies, the Growth Rate
carcinoma in male smokers was about 10
authors determined that when the largest Hasegawa et al (19) reported an analy- times that in nonsmokers in the eight
noncalcified nodule was smaller than 5 sis of the growth rates of small lung can- prospective studies reviewed for the 1982
mm in diameter (378 patients), a fol- cers detected during a 3-year mass screen- report of the Surgeon General on “The
low-up study in 12 months would have ing program. They classified nodules as Health Consequences of Smoking” (25).
resulted in no case of delayed diagnosis, ground-glass opacity, as ground-glass For heavy smokers, the risk was 15–35
compared with more aggressive short- opacity with a solid component, or as times greater (25,26). Despite initial evi-
term follow-up. However, when the larg- solid. Mean volume doubling times were dence suggesting an increased risk of
est nodule was 5–9 mm in diameter, ap- 813 days, 457 days, and 149 days, respec- lung cancer in women compared with
proximately 6% of cases (all of which tively, for these three types, all of which that in men with an equal smoking his-
were malignant) showed interval nodule were significantly different. In addition, tory, this has not been confirmed in
growth detectable on 4 – 8-month fol- the mean volume doubling time for can- more recent studies (27–30).
low-up scans. Therefore, they recom- cerous nodules in nonsmokers was signif- A history of lung cancer in first-degree
mended that patients with nodules no icantly longer than that for cancerous relatives is also a notable risk factor, and
larger than 5 mm in diameter on a base- nodules in smokers. The mean volume strong evidence for a specific lung cancer
line screening CT scan should be referred doubling time was also significantly susceptibility gene has been discovered
for repeat annual screening in 12 months longer for nodules not visible on chest recently (31,32). Other established risk
time, with no interval scans. This recom- radiographs (presumably a function of factors include exposure to asbestos, ura-
mendation differs only slightly from the their smaller average size and/or their nium, and radon (33–35). However, cig-
current protocol for the ongoing Na- lesser average opacity). These data further arette smoke remains the overwhelm-
tional Lung Screening Trial, in which pa- support the use of extended follow-up ingly dominant culprit.
tients with nodules smaller than 4 mm in intervals for small nonsolid or partly Several large screening programs are
diameter are recommended to return for solid nodules, even in high-risk patients. continuing, and we will learn more from
screening after 12 months, without inter- Authors of a number of other series these studies in the next several years.
val scans or other work-up. Note that (20,21) have confirmed similar findings Although the available data are still in-
these recommendations refer to high-risk and have estimated the median tumor complete, certain tentative conclusions
subjects who have enrolled in a screening doubling times, assuming a constant can be drawn at the present:
program. growth rate to be in the 160 –180-day 1. Approximately half of all smokers
A further practical issue arises in the range. Authors of all of these reports, over 50 years of age have at least one lung
follow-up to detect interval growth of however, recognize wide variations, and nodule at the time of an initial screening
very small nodules. Comparison of cur- in one study 22% of tumors had a vol- examination. In addition, approximately
rent and previous scans can be performed ume doubling time of 465 days or more 10% of screening subjects develop a new
by using hard copy with manual mea- (21). Note that a 5-mm nodule with a nodule during a 1-year period (36).
surement, soft copy with electronic cali- doubling time of 60 days will reach a 2. The probability that a given nodule
Volume 237 Number 2 Fleischner Society Statement on CT of Small Pulmonary Nodules 397
4. is malignant increases according to its
size (4,5). Even in smokers, the percent- Recommendations for Follow-up and Management of Nodules Smaller than
8 mm Detected Incidentally at Nonscreening CT
age of all nodules smaller than 4 mm that
will eventually turn into lethal cancers is Nodule Size
very low ( 1%), whereas for those in the (mm)* Low-Risk Patient† High-Risk Patient‡
Radiology
8-mm range the percentage is approxi- 4 No follow-up needed §
Follow-up CT at 12 mo; if
mately 10%–20% (4,7,8,37). unchanged, no further follow-up
3. Cigarette smokers are at greater risk 4–6 Follow-up CT at 12 mo; if Initial follow-up CT at 6–12 mo then
for lethal cancers, and malignant nodules unchanged, no further follow-up at 18–24 mo if no change
6–8 Initial follow-up CT at 6–12 mo then Initial follow-up CT at 3–6 mo then
in smokers grow faster, on average, than at 18–24 mo if no change at 9–12 and 24 mo if no change
do those in nonsmokers (19,25,26). Also, 8 Follow-up CT at around 3, 9, and 24 Same as for low-risk patient
the cancer risk for smokers increases in mo, dynamic contrast-enhanced
proportion to the degree and duration of CT, PET, and/or biopsy
exposure to cigarette smoke (38). Note.—Newly detected indeterminate nodule in persons 35 years of age or older.
4. Certain features of nodules correlate * Average of length and width.
† Minimal or absent history of smoking and of other known risk factors.
with likelihood of malignancy, cell type, ‡ History of smoking or of other known risk factors.
and growth rate. For instance, small §
The risk of malignancy in this category ( 1%) is substantially less than that in a baseline CT scan
purely ground-glass opacity (nonsolid) of an asymptomatic smoker.
nodules that have malignant histopatho- Nonsolid (ground-glass) or partly solid nodules may require longer follow-up to exclude
logic features tend to grow very slowly, indolent adenocarcinoma.
with a mean volume doubling time on
the order of 2 years (19). Solid cancers, on
the other hand, tend to grow more rap-
idly, with a mean volume doubling time be subjected to a minimum of four or five this regard. Rather, we have elected to
on the order of 6 months. The growth follow-up CT examinations before being focus on the issue of follow-up imaging
rate of partly solid nodules tends to fall designated benign and the patient being of smaller nodules. Specifically, for what
between these extremes, and this partic- reassured (1,2). As summarized above, kinds of lesions is it appropriate to fol-
ular morphologic pattern is highly pre- data from ongoing CT screening pro- low, and if followed, at what intervals?
dictive of adenocarcinoma (39 – 41). grams with multidetector CT with 5-mm Therefore, we propose a set of guidelines,
5. Increasing patient age generally cor- collimation indicate that approximately summarized in the Table, for the man-
relates with increasing likelihood of ma- half of all smokers over 50 years of age agement of small pulmonary nodules de-
lignancy. Lung cancer is uncommon in have at least one lung nodule on the ini- tected on CT scans.
patients younger than 40 years and is rare tial scan (36). In addition, approximately Note that the recommendations
in those younger than 35 years (42). At 10% of screening subjects develop a new shown in the Table apply only to adult
the other end of the age scale, although nodule over a 1-year period, and about patients with nodules that are “inciden-
the likelihood of cancer increases, surgi- 12% can be expected to have one or more tal” in the sense that they are unrelated
cal intervention carries greater risks. Also, additional nodules that were missed on to known underlying disease. The follow-
the likelihood of a small nodule evolving the original scan (36). Assuming similar ing examples describe patients to whom
into a cancer that will cause premature demographics, approximately 20% of pa- the above guidelines would not apply.
death becomes a lesser concern as comor- tients who have a nodule detected on CT Patients known to have or suspected of
bidity increases in a person and predicted scans can be expected to have at least one having malignant disease.—Patients with a
survival decreases with advancing years. new nodule detected during the cur- cancer that may be a cause of lung me-
rently recommended 2-year minimum tastases should be cared for according to
follow-up period, which will in turn the relevant protocol or specific clinical
Management Approach
mandate another series of follow-up CT situation. Pertinent factors will include
A number of investigators have already studies with similar opportunities for the site, cell type, and stage of the pri-
raised serious concerns about current new nodules to be detected during the mary tumor and whether early detection
management strategies for the indeter- additional follow-up period. Therefore, of lung metastases will affect care. In this
minate small nodule, particularly after strict application of the existing recom- setting, frequent follow-up CT may be
encountering an overwhelming number mendations would result in multiple fol- indicated.
of such abnormalities on CT scans low-up studies over 2 or more years for a Young patients.—Primary lung cancer is
(7,14,36). In the study by Henschke et al large proportion of all patients who un- rare in persons under 35 years of age
(5) described earlier, the authors found dergo thoracic CT. ( 1% of all cases), and the risks from
no cancers in patients in whom the larg- In the case of nodules larger than 8 radiation exposure are greater than in the
est noncalcified nodule was less than 5 mm, additional options such as contrast older population. Therefore, unless there
mm in diameter on the initial scan (zero material– enhanced CT, positron emis- is a known primary cancer, multiple fol-
of 378 patients). Thus there was no ad- sion tomography (PET), percutaneous low-up CT studies for small incidentally
vantage in performing short-interval fol- needle biopsy, and thoracoscopic resec- detected nodules should be avoided in
low-up for nodules smaller than 5 mm in tion can be considered (43– 46). Because young patients. In such cases, a single
their study, even in high-risk patients. these approaches depend greatly on low-dose follow-up CT scan in 6 –12
Therefore, we recommend altering the available expertise and equipment and months should be considered.
existing recommendations, which indi- have limited applicability to nodules in Patients with unexplained fever.—In cer-
cate that every indeterminate nodule, re- the subcentimeter range, we have chosen tain clinical settings, such as a patient
gardless of size and morphology, should not to offer detailed recommendations in presenting with neutropenic fever, the
398 Radiology November 2005 MacMahon et al
5. presence of a nodule may indicate active conclusive evidence, as yet, that serial CT malignancy and should be managed ac-
infection, and short-term imaging fol- studies with early intervention for de- cordingly (39). Depending on the cir-
low-up or intervention may be appropri- tected cancers can reduce disease-specific cumstances, follow-up imaging studies or
ate. mortality, even in high-risk patients (7). intervention may be appropriate. Con-
Previous CT scans, chest radiographs, Therefore, we do not recommend fol- servative management is generally ap-
and other pertinent imaging studies low-up CT for every small indeterminate
Radiology
propriate for nodules in very elderly pa-
should be obtained for comparison nodule. tients or in those with major comorbid
whenever possible, as they may serve to Management decisions should not be disease. Interval growth of any nodule
demonstrate either stability or interval based on nodule size alone. While any suggests an active process, and further
growth of the nodule in question. calcification in a small nodule favors a evaluation or intervention should be
A low-dose, thin-section, unenhanced benign cause, central, laminar, or dense considered in such cases.
technique should be used, with limited diffuse patterns of calcification are reli- It is impossible to ignore medicolegal
longitudinal coverage, when follow-up of able evidence of benignancy (49). Fat considerations when discussing manage-
a lung nodule is the only indication for content suggests a hamartoma or occa- ment of pulmonary nodules. The current
the CT examination. sionally a lipoid granuloma or lipoma practice in the United States of recom-
(50). Solid versus nonsolid appearance, mending follow-up studies for all inde-
spiculation, or other characteristics influ- terminate opacities is partly related to
DISCUSSION ence the likelihood of malignancy and perceived liability if a cancer should de-
probable growth rate in any given case velop (59). When the medical commu-
Not every focal opacity qualifies as a nod- (19,39,49,51,52). Longer follow-up in- nity has preached the importance of
ule. Unfortunately, the familiar lung tervals are appropriate for nonsolid early detection of cancer for so long, it
nodule has eluded all efforts at precise (ground-glass opacity) and very small may prove difficult to convince physi-
definition. A committee of the Fleischner opacities (19,40). For instance, even if cians and the public that follow-up CT of
Society on CT nomenclature described malignant, a nonsolid nodule that is every nodule in every patient is unneces-
the pathologic definition of a nodule as a smaller than 6 mm will probably not sary. Nonetheless, it is our hope that the
“small, approximately spherical, circum- grow perceptibly in much less than 12 guidelines presented here will support a
scribed focus of abnormal tissue” and the months (19,40). Also, as discussed earlier, practical and medically appropriate ap-
radiologic definition as a “round opacity, it has been established that accurate mea- proach to the management of inciden-
at least moderately well marginated and surement of growth in subcentimeter tally detected small pulmonary nodules.
no greater than 3 cm in maximum diam- nodules is problematic (16). The recommendations presented here
eter” (47). Therefore, a linear or essen- Other features such as clustering of are based on our current understanding
tially two-dimensional opacity that does multiple nodules in a single location in of pulmonary nodules, and we expect
not have an approximately spherical the lung tend to favor an infectious pro- that they will continue to evolve as more
component is not a nodule. In general, cess, although a dominant nodule with information becomes available.
purely linear or sheetlike lung opacities adjacent small satellite nodules can be
are unlikely to represent neoplasms and seen in primary lung cancer (53,54). For a
do not require follow-up, even when the single nodule, upper lobe location in- References
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