1. Eur Radiol (2007) 17: 449–466
DOI 10.1007/s00330-006-0399-7 CHEST
Catherine Beigelman-Aubry
Catherine Hill
Management of an incidentally discovered
Philippe A. Grenier pulmonary nodule
Received: 28 February 2006
Abstract The incidental finding of a and limitations of complementary
Revised: 30 June 2006 pulmonary nodule on computed investigations requested to character-
Accepted: 14 July 2006 tomography (CT) is becoming an ize indeterminate lung nodules, (3) to
Published online: 5 October 2006 increasingly frequent event. The dis- review the criteria permitting to assess
# Springer-Verlag 2006 covery of such a nodule should evoke the probability of malignancy of
the possibility of a small bronchogenic indeterminate nodules and (4) to
carcinoma, for which excision is report on the new guidelines provided
C. Beigelman-Aubry . C. Hill . indicated without delay. However, by the Fleischner Society for the
P. A. Grenier (*) invasive diagnostic procedures should management of small indeterminate
Service de Radiologie Polyvalente,
Diagnostique et Interventionnelle, be avoided in the case of a benign pulmonary nodules, according to their
Hôpital Pitié-Salpêtrière-Assistance lesion. The objectives of this review prior probability of malignancy.
Publique-Hôpitaux de Paris, article are: (1) to analyze the CT
47-83 boulevard de l’Hôpital, criteria defining benign nodules, nod- Keywords Pulmonary nodule .
75651 Paris cedex 13, France
e-mail: philippe.grenier@psl.aphp.fr ules of high suspicion of malignancy Nodule characterization . Pulmonary
Tel.: +33-1-42178225 and indeterminate nodules, (2) to adenocarcinoma . Bronchioloalveolar
Fax: +33-1-42178224 analyze the diagnostic performances cell carcinoma . Non-solid nodule
Introduction and/or surgical resection associated with potential morbid-
ity, in those with a benign lesion.
The incidental finding of a pulmonary nodule on chest x- Since introduction of helical CT in the early 1990s and
rays or, more recently, on computed tomography (CT) is multidetector row CT in the late 1990s, the detection of
becoming an increasingly frequent event. When discovered nodules as small as 1–2 mm in diameter has become
on a chest x-ray, CT is then performed urgently in order to routine. In fact, the majority of smokers who undergo thin-
confirm the presence of this pulmonary nodule and to section CT have been found to have small lung nodules,
attempt further characterisation of the lesion [1, 2]. The most of which are smaller than 7 mm in diameter [3].
discovery of such a nodule should evoke the possibility of a Although, observer’s nodule detection remains imperfect,
small bronchogenic carcinoma, for which excision is maximum-intensity-projection processing technique re-
indicated without delay. However, invasive diagnostic duces the number of overlooked small nodules, particularly
procedures should be avoided in the case of a benign in the central lung [4]. Computed-aided detection systems
lesion. Similarly, it is necessary to avoid excessive patient have shown to improve the performances of radiologists in
irradiation through an infinite number of follow-up CT detecting small nodules on CT scans with higher sensitivity
examinations. The management of a nodule must therefore than with conventional double reading [5].
be adapted to allow rapid identification of subjects with a The clinical importance of these extremely small
malignant tumour who would benefit from potentially nodules differs substantially from that of larger nodules
curative surgical treatment, whilst avoiding needle biopsy detected on chest radiographs, in that the vast majority are

2. 450
benign. In recent publications on CT screening for lung Table 1 Causes of incidentally discovered solid pulmonary nodules
cancer, the positive relationship of lesion size to likelihood Aetiological classification
of malignancy has been clearly demonstrated [6, 7]. During
the past 5-years, new information regarding prevalence, Neoplastic Primary pulmonary carcinoma (adenocarcino-
biologic characteristics, and growth rate of small lung ma, bronchioloalveolar carcinoma, squamous
cancers has become available, and new guidelines for cell carcinoma, small cell carcinoma)
follow-up and management of small pulmonary nodules Malignant Primary pulmonary lymphoma
detected on CT scans has become highly expected. Primary pulmonary carcinoid
Lung metastasis
Benign Hamartoma, fibroma, chondroma, leiomyoma,
Definition and aetiology of pulmonary nodules lipoma
Infectious or in- Granulomas
A pulmonary nodule is defined as a focal pulmonary lesion flammatory Opportunistic infection
or opacity, round or oval in shape, which measures less Round pneumonia
than 3 cm in diameter. A pulmonary nodule is considered Abscess
small if its largest diameter is 10 mm or less. Above 3 cm in Focal organising pneumonia
size, the lesion is classified as a mass, and the high Cicatrizing fibrosis
probability of malignancy in this case warrants further Necrobiotic nodule in rheumatoid arthritis
investigation by biopsy or surgical resection. Wegener’s granulomatosis
Today, the classification of a pulmonary nodule has been Vascular Pulmonary artery aneurysm
extended to include focal areas of ground glass attenuation
Pulmonary varices
[8], and all small opacities only a few millimetres in size
Pulmonary arteriovenous malformation
discovered incidentally on CT [9]. In general, linear and
Pulmonary infarct
band-like opacities are excluded from this definition, where
Haematoma
the likelihood of malignancy is virtually non-existent.
Miscellaneous Intrapulmonary lymph node
The classic description of a solitary pulmonary nodule is
too restrictive these days, as patients undergoing CT exam- Rounded atelectasis
ination often have more than one nodule present. For a given Bronchogenic cyst
patient, each pulmonary nodule detected must be investigated Mucoid impaction
and managed independently. When greater than six pulmo-
nary nodules are present on chest CT for an individual patient,
the probability of granulomatous lesions or metastases greatly
increases [10]; in this case, the investigation differs totally and along with its relationship to bronchovascular structures
is beyond the scope of this article. and the pleura. A high density reconstruction filter is
The aetiology of pulmonary nodules is diverse, recommended for mediastinal windowing in order to study
comprising of tumours, infection and inflammatory the content and density of the nodule. The evaluation is of
disorders, but also vascular and congenital causes. The course completed by an exhaustive helical study of the
most common malignant lesions are pulmonary metastases entire thorax to confirm if the nodule is solitary, or
and primary bronchopulmonary carcinoma. All histologi- associated with other nodular lesions. This also allows
cal types of cancer may give rise to pulmonary nodules, but assessment of extension in the case of a malignant lesion.
adenocarcinoma is the most frequent. The majority of small Using multislice CT, following a single acquisition of the
nodules are benign, of which 80% are granulomas or entire thorax with thin collimation, it is possible today to
intrapulmonary lymph nodes [11], 10% are hamartomas reconstruct 3 or 5 mm contiguous images for lesion
and 10% are other rarer benign lesions (Table 1). detection, and then 1 mm images of the nodules detected to
ensure accurate characterisation [13]. Another simplified
approach consists of the specific analysis of the pulmonary
Nodule characterisation by CT nodule with 1 mm slice thickness reconstruction, and then
perform a maximum intensity projection with slabs of
Characterisation is based on analysis of the density and around 3 to 5 mm for an easy and confident detection of
morphology of the nodule. Spiral CT acquisition must be multiple lung nodules.
performed over the whole nodule volume using thin
collimation (0.6–1.25 mm) and at least contiguous, but
ideally overlapping, slices [12]. The use of a high spatial Nodule characterisation according to density
resolution reconstruction filter is recommended for pul-
monary windows, enabling precise evaluation of the Nodules are classified into three main categories based on
interface between the nodule and the lung parenchyma, their density, solid, non-solid, and part-solid (mixed)

3. 451
nodules. “Solid nodules” are seen most frequently and are raises several possibilities. This could represent a
the subject of traditional descriptions [14, 15]. They are of multicentric bronchioloalveolar cell carcinoma or adeno-
soft tissue density and obscure the contour of vessels with carcinoma. It could also signify a primary pulmonary
which they are in contact (Fig. 1). adenocarcinoma associated with foci of atypical adeno-
“Non-solid nodules” have a density inferior to vessels, matous hyperplasia or foci of desquamative interstitial
appearing as areas of focal ground glass. The outline of pneumonia in a smoker [22]. Finally, although less
vessels in contact with or traversing such lesions is not commonly, it could correspond to pulmonary metastases
effaced (Fig. 2). Specific management of these nodules is exhibiting a lepidic growth pattern, as described in
required. Firstly, inflammatory or infectious lesions must malignant melanoma [23].
be excluded, which rapidly resolve with anti-inflammatory “Mixed nodules”, or part-solid nodules, have a non-solid
and/or anti-infectious treatment [16]. If a lesion persists ground glass component within which there exists a solid
after 1 month of treatment, it becomes a persistent or component of soft tissue density [24–26] (Fig. 4). These
chronic non-solid nodule, which could be neoplastic or mixed, or part-solid, nodules may be due to infectious or
non-neoplastic in nature [17] (Fig. 2). Non-neoplastic inflammatory lesions which resolve with specific treat-
causes comprise foci of desquamative interstitial pneumo- ment, in particular organising pneumonia (Fig. 5). If such a
nia in a smoker or pulmonary fibrosis [18] (Fig. 3). lesion persists after 1-month of treatment, it becomes a
Neoplastic causes may be benign, specifically atypical persistent or chronic mixed nodule, which is highly
adenomatous hyperplasia, or malignant, consisting of suspicious of malignancy [16, 17, 24]. This usually
adenocarcinoma or bronchioloalveolar cell carcinoma. corresponds to a primary adenocarcinoma. The solid tissue
Malignant nodules generally correspond to non-invasive areas may reflect either alveolar collapse, foci of fibrosis,
or minimally invasive cancers [19, 20]. Atypical adeno- intra-alveolar mucus, or foci of invasive carcinoma [25].
matous hyperplasia is considered a pre-cancerous dysplasia According to a study of 94 patients who underwent video-
with the potential to evolve into adenocarcinoma or assisted thorascopic surgery for an indeterminate pulmo-
bronchioloalveolar cell carcinoma [21]. In the majority of nary nodule, Yoon et al. demonstrated that 90% of nodules
cases, these lesions are small in size, measuring less than measuring less than or equal to 10 mm diameter with a
5 mm in diameter. Above this size, the lesion becomes ground glass component were malignant, whereas only
highly suspicious for adenocarcinoma. The presence of 30% of nodules of the same size with no ground glass
multiple ground glass nodules in other pulmonary regions component fulfilled the histological criteria for malignancy
(p< 0.01) [27].
Morphological analysis
The “shape” of a nodule rarely contributes to the
aetiological diagnosis. However, the characteristic mor-
phology of a pulmonary nodular lesion may, exceptionally,
be sufficiently typical to allow specific diagnosis of a
benign lesion. Pulmonary arteriovenous malformations
(Fig. 6), aspergilloma within pre-existing cavities, rounded
atelectasis, bronchoceles and mucoid impaction are perfect
examples of this. For other lesions, nodule shape is not very
helpful in differentiating between a benign and malignant
origin. For example, a lobulated outline implies an area of
more rapid growth within a lesion. This sign is often
associated with malignancy, but may be seen in up to 25%
of benign nodules [14] (Fig. 7).
However, it must be emphasized that a ground glass
nodule round in shape suggests malignancy (Fig. 2),
whereas a polygonal shape with or without concave
margins of a solid as well as a non-solid nodule suggests
benignancy [17, 28, 29] (Fig. 8).
Fig. 1 18-mm solid nodule with well-defined margins surrounded “Size” is never a definitive criterion, but remains an
by some linear opacities located in the superior segment of the right excellent indicator of the probability of nodule malignancy.
lower lobe. This nodule appears linked to an obstructed bronchus
(bronchus positive sign). The bronchial wall appears slightly The standard size value used is an average of the largest
thickened in its segment close to the nodule. At surgery, the nodule and smallest cross-sectional diameters of the most
was due to an invasive adenocarcinoma representative area of the nodule. In ongoing low-dose

4. 452
Fig. 2 Round shaped non-
solid nodules with regular
margins in two different
patients. Primary adenocarcino-
mas. a 46-year-old women
presenting with a 8-mm nodule
in the right lower lobe. At
surgery the nodule was due to
bronchioloalveolar cell carci-
noma. b 32-year-old male smo-
ker presenting with a 9-mm
non-solid nodule in the lingula.
At surgery, the diagnosis was
non-invasive adenocarcinoma
CT-lung-cancer-screening studies of at risk populations, ing less than 5 mm varies between 0.1–1%. The prevalence
the prevalence of cancer among nodules detected measur- varies between 1–30% for nodules measuring 5–10 mm,
and 30–80% for nodules over 10 mm [30].
Assessment of margin characteristics is never a defin-
itive discriminant criterion between benign and malignant
Fig. 3 Focal area of ground glass (arrow) taking the appearance of
a non-solid nodule in the right upper lobe of a 53-year-old female
smoker. The nodule has a polygonal shape and is seen abutting the Fig. 4 Part-solid (mixed) nodule in the right upper lobe of a 54-
fissure. It was unchanged on a 3-month follow-up CT scan. After year-old female smoker. The ground glass component of the lesion
surgery the nodule was due to a focal area of desquamative contains bubble like lucencies. The pathological diagnosis was
interstitial pneumonia primary adenocarcinoma

5. 453
Fig. 5 Mixed nodule containing bubble like lucencies in the left examination 2 months later (right). The presumed diagnosis was
upper lobe (left). The lesion decreased in size after 1 month of focal organizing pneumonia
antibiotics (middle) and disappeared entirely on the follow-up CT
nodules, but may contribute in the probability of malig- appearance of benign and malignant nodules is directly
nancy. Well-defined, smooth and regular margins suggest proportional to the quantity of emphysema around the
nodule benignancy [31]. However, 21% of malignant nodule [33]. For Nambu et al., well-defined margins,
nodules have well-defined and regular margins, in spiculations and pleural indentations of non-solid nodules
particular pulmonary metastases [14]. Ill-defined, irregular are highly suggestive of neoplastic lesions. In their series,
or spiculated margins strongly suggest malignancy (Fig. 9), 34/38 (89%) of neoplastic lesions were well defined in
even though they may be observed in cases of focal more than 50% of the circumference [29].
organising pneumonia or lymphomatoid granulomatosis The “location of a nodule” within an upper lobe
[15, 32]. It is important to highlight that in patients with increases the probability of cancer, as primary broncho-
emphysema, this aspect loses its value for differentiating pulmonary carcinomas occur more frequently in the upper
between benignity and malignancy, and the overlap in the lobes. Nodules 3–9 mm in size, triangular or ovoid in
Fig. 6 Small (7-mm) pulmo-
nary nodule discovered in the
right lower lobe of a 20-year-old
woman corresponding to a pul-
monary arteriovenous malfor-
mation. Coronal oblique
reformation after MDCT acqui-
sition (left). 10-mm thick slab in
the same orientation with max-
imum intensity projection
(right). The nodule presents with
a double vascular connexion
reflecting the afferent pulmona-
ry artery and efferent pulmonary
vein

6. 454
Fig. 7 58-year-old man pre-
senting a spherical (10-mm)
nodule with regular and well-
defined contours in the upper
part of the left upper lobe. The
nodule contains a small calcifi-
cation (arrow head) and small
areas of fat (−50 HU; arrow).
These characteristics allow for
the diagnosis of pulmonary
hamartoma in spite of the pre-
sence of a small lobulation
shape, and attached to a fissure are often intrapulmonary strongly suggestive of adenocarcinoma, bronchioloalveolar
lymph nodes [28, 34]. “Clustering” of several nodules in a cell carcinoma or lymphoma [35–37] (Fig. 10).
particular location suggests an infectious or granulomatous Pseudocavities visible within a nodule on CT appear as
cause, although a nodule accompanied by small satellite small round lucencies with well-defined margins, resem-
nodules may also be seen in bronchopulmonary carcinoma. bling small air bubbles. These lucencies are in fact
equivalent to an air bronchogram, where the small bronchi
or bronchioles are orientated perpendicular to the plane of
Analysis of nodule content imaging. In the case of adenocarcinoma or bronchioloal-
veolar cell carcinoma, this sign represents lepidic tumoral
An “air bronchogram and/or pseudocavitation” are more growth which respects the pulmonary architecture and
frequently observed in malignant (30%) than benign (5%) bronchi. An air bronchogram may appear to be slightly
lesions. Concerning a malignant nodule, this sign is distorted or dilated. This is seen in particular when
Fig. 8 Small (6-mm) pulmo-
nary nodule with a polygonal
shape, and regular and well-
defined contours, located in the
peripheral part of the lung,
corresponding to an intrapul-
monary lymph node. Sagittal
reformatted image (left). Volu-
metric rendering view after seg-
mentation of the nodule (right)

7. 455
Fig. 10 25-mm solid nodule containing in the periphery pseudo-
cavitations and bubble like lucencies. At surgery, the nodule was a
primary adenocarcinoma
Fig. 9 17-mm nodule having spiculated margins and located within
the left lower lobe. The lumen of a subsegmental bronchus is
occluded by the nodular lesion (CT bronchus sign; arrow). At chondrosarcoma or synovial sarcoma, as pulmonary me-
surgery, the lesion was a primary adenocarcinoma
tastases in these circumstances may be entirely calcified.
Round, central, target or concentric laminated calcification
retractile fibrodesmoplastic reaction is present within the suggests the diagnosis of tuberculoma. “Popcorn” calcifi-
tumour. A nodule with a similar appearance of an air cation indicates calcification of cartilaginous origin, and
bronchogram or pseudocavitation, with or without dilata- therefore the diagnosis of hamartoma. However, the
tion, may also be encountered in focal organising pneu- radiological diagnosis of hamartoma requires further
monia [32, 35] (Fig. 5). Air bronchogram and air criteria to be fulfilled [39]. Conversely, eccentric or
containing space within a non-solid nodule have also dispersed calcification is highly suggestive of a malignant
proven to be more frequent in neoplastic than non- lesion and may be seen in 6% of pulmonary cancers [14,
neoplastic lesions [29] (Fig. 4). 40].
“Cavitation” is more frequent in malignant lesions, but The presence of “fat” within a pulmonary nodule is
may be seen in lung abscesses. Benign cavitating lesions always a formal criterion for benignancy. A density
more often have distinct, regular internal contours and thin between −40 and −120 HU is strongly suggestive of the
walls, whereas malignant nodules typically have thick and diagnosis of hamartoma (Fig. 7). The CT criteria for
irregular walls. The majority of cavitating nodules with a radiological diagnosis of hamartoma include round shape,
wall thickness above 16 mm are malignant, whilst those smooth and regular margins, diameter less than 25 mm, and
with a wall thickness less than 4 mm are usually benign presence of intralesional fat, with or without popcorn
[38]. calcification [39]. More rarely, fat may be due to a fat-
The search for calcification remains an important stage containing granulomas or lipoma.
[14]. The presence of calcification is always a contributory
factor in suggesting malignancy or benignancy. Diffuse
nodule “calcification” is highly characteristic of an old Complementary investigations
granulomatous lesion and is sufficient evident alone to
definitively confirm benignancy (Fig. 11). The only Subsequent to the CT study, the nodule may be classified
exception is a known previous history of osteosarcoma, into one of the following three categories: benign, highly

8. 456
Fig. 11 Entirely calcified nod-
ule of the upper part of the left
upper lobe. Diffuse and intense
calcification of the nodule
leads to the diagnosis of post-
tuberculosis granuloma in spite
of the spiculated contours of
the nodule
suspicious for malignancy or indeterminate. Nodules quantitatively from benign nodules [41–43]. The degree of
considered as benign are those showing diffuse calcifica- uptake of iodinated contrast material is directly linked to
tion, or a specific criterion for benignity outlined in Table 2. the probability of malignancy and nodule vascularisation
No further investigation of these lesions is necessary when [44]. This technique was the subject of a multi-centre study
the nodule is entirely calcified. A simple radiographic which demonstrated that an increased enhancement of 15
surveillance until two years of stability is only requested in HU was the most effective threshold [44]. This threshold
other situations. allows an excellent sensitivity and moderate specificity for
Nodules possessing a single criterion defined as highly the diagnosis of a malignant nodule. The weak specificity
suspicious of malignancy, outlined in Table 3, must be is related to the fact that numerous benign lesions may
subject to histological confirmation by biopsy or surgical show increased enhancement due to rich vascularisation, in
resection. Indeterminate nodules, representing around 70% particular hamartomas and certain infectious lesions. On
of cases, include all other nodules of which criteria are the other hand, the excellent sensitivity leads to a very high
summarised in Table 4. The management of indeterminate negative predictive value. So, a nodule with either no or
nodule is variable and is based on complementary very little enhancement following contrast injection can be
investigations, including the study of contrast uptake by considered as a benign lesion, for which simple radiolog-
the nodule on CT, Positron Emission Tomography (PET), ical surveillance is sufficient. However, the technique of
evaluation of nodule growth, and nodule biopsy. measuring contrast enhancement must be precise. This
consists of a volumetric helical acquisition with thin
collimation on the entire nodule before, and then at 1, 2,
Nodule contrast uptake on CT 3 and 4 min after contrast injection. An injection rate of
2 ml/s is recommended of a total of 420 mg of iodine/kg.
The principle is based on the fact that blood flow in The density measurement must be made at the centre of the
malignant pulmonary nodules differs qualitatively and
Table 3 Criteria defining a nodule as highly suspicious of
Table 2 Criteria defining a benign nodule malignancy (a single criterion is sufficient)
Benign nodule criteria Criteria defining a nodule as highly suspicious of malignancy
Diffuse, dense calcification Persistent non-solid (focal) ground glass nodule measuring 10 mm
Vessels converging towards either side of the nodule (pulmonary or more in diameter
arteriovenous malformation) or vessels converging towards the Persistent mixed (or part solid) nodules
pleural side of the nodule/comet-tail sign (rounded atelectasis) Solid nodule measuring 20 mm or more in diameter
Diagnostic criteria of hamartoma (round shape, smooth, regular Solid nodule with spiculated contours
contours, containing fat density, +/– popcorn calcification) Solid nodule containing air bronchogram or pseudocavitation
Benign-type calcification (central, target, laminated, concentric) Solid nodule containing eccentric or dispersed calcifications

9. 457
Table 4 Criteria defining an indeterminate nodule investigation of thoracic and extra-thoracic extension with
Indeterminate nodule criteria tumour characterisation. When the nodule is less than 1 cm
in diameter or of ground glass attenuation on CT, PET is
Persistent ground glass nodule measuring less than 10 mm in not indicated as it contributes little to nodule characterisa-
diameter tion and overall evaluation in these situations [54]. With
Solid nodule of less than 20 mm in diameter with integrated PET/CT, additional certainty to the presence or
Non-spiculated contours absence of FDG uptake in the pulmonary nodule can be
No air bronchogram or pseudocavitation achieved because morphologic criteria and functional CT
No malignant-type calcification criteria are available simultaneously [55].
No intralesional fat or benign-type calification
Evaluation of nodule growth
nodule, over a region representing at least 60% of the
nodule’s surface area. Given that measurement of the In the course of surveillance, this entails repeated CT
density is difficult for heterogeneous lesions and those less examinations in order to screen for growth, reduction in
than 1 cm in diameter, in practice this technique only yields size or resolution of the nodule [56, 57]. In order to limit
reliable information for homogenous nodules equal to or the number of surveillance CT examinations required, a
above 8 mm in diameter. search for previous imaging is always recommended for
In another study of solitary pulmonary nodules present comparison. This is often sufficient to demonstrate the
in 131 patients, after injection of 120 ml of contrast with stability or significant growth of a nodule. In all cases,
repeated acquisitions every 20 s over a period of 3 min, surveillance examinations should be performed at low dose
enhancement of 30 HU or more was the retained criterion using thin collimation, without contrast injection, and if
for malignancy [45]. The sensitivity and negative pre- possible limited to the volume of interest.
dictive value for the diagnosis of malignancy were 99 and The “doubling time” (DT) of a nodule can be calculated
97% respectively. The specificity and positive predictive using the following formula:
value for malignancy were 54 and 71% respectively, the
overall diagnostic accuracy being 78%. As part of the same DT ¼ ðt: ln 2Þ lnðV f=ViÞ
study, the peak enhancement value within the nodule
positively correlated with both the concentration of
microvessels present within the lesion on histological where Vi is the initial volume of the nodule, Vf the final
examination and the scoring of immunological markers for volume, t the time interval between observations and ln the
vascular endothelial growth factor. logarithmic value. This formula is based on an exponential
model of nodule growth.
The doubling time of most malignant solid nodules is
Positron emission tomography (PET) between 30 and 400 days. Nodules displaying more rapid
or slower doubling times are typically benign in origin [58,
PET provides in vivo functional mapping of 2-F18-fluoro- 59]. Radiological stability, either on chest radiography or
2-deoxy-D-Glucose (FDG) fixation, which is elevated in CT, over a period greater than 2 years implies a doubling
neoplastic lesions [46–49]. Today, the value of this time of at least 730 days, which is generally considered to
technique in the diagnosis of malignant pulmonary nodules be a reliable indicator of a benign lesion [56, 60].
is well documented. A recent meta-analysis reported a Several studies have estimated that the average doubling
sensitivity of 90% and a specificity of 83% for diagnosing time of tumours lies between 160 and 180 days, assuming a
malignancy [50]. Yet, certain histological types with low constant growth rate. However, all of these studies
metabolism such as low-grade adenocarcinoma, bronchio- recognise a large variation in the volume doubling time
loalveolar cell carcinoma and carcinoid tumours, may give of nodules detected, and in one study 22% of tumours had a
rise to false negative results for this technique [51–54]. volume doubling time of 465 days or more.
False positives may also be seen with infectious or Non-solid nodules, both ground glass and mixed, may
inflammatory processes, and granulomatous disorders have a much longer doubling time [61]. Hasegawa and coll.
such as Wegener’s disease or sarcoidosis, which trap have reported an analysis of the growth rates of small
FDG. In addition, the diagnostic performance of PET cancers detected during a 3-year screening program [62].
decreases considerably for lesions less than 6 mm in size. The average volume doubling time was 189 days for solid
Taking into account its high negative predictive value, if nodules, 457 days for mixed nodules and 813 days for
a pulmonary lesion of 10 mm or more does not fix with ground glass nodules. These results therefore suggest the
FDG, clinical and radiological surveillance may be need for more prolonged surveillance of ground glass
proposed, thereby avoiding surgery. Another interest of nodules than for solid nodules. It is important to remember
the technique lies also in the possibility of combining that, according to the high probability of malignancy,

10. 458
mixed nodules persistent after 1 month of antibiotic operators. This variation in measurement is above the
therapy should be resected without delay. During increase in diameter expected for a nodule of 5 mm which
surveillance of ground glass nodules, the appearance of doubles in volume (Fig. 12). In order to avoid this
a soft-tissue component is a highly suspicious sign of limitation, it was proposed that the growth rate of all small
malignancy, even if the overall size of the nodule nodules could be evaluated by repeated volume measure-
remains stable or diminishes [63]. ments, rather than measurements of diameter. Volume
Once it has decided to follow a nodule with serial CT, measurement requires specific image analysis software,
most radiologists measure the maximum diameter of the which allows segmentation and three-dimensional recon-
nodule at each examination. Authors have compared struction of the nodule in order to appreciate the variations
diameter and cross-sectional area measurement with vol- in morphology, and to automatically calculate the volume.
ume measurement in the assessment of lung tumour growth Several types of software are available from the con-
with serial CT [64]. They demonstrated that growth structors. The three-dimensional measurements are clearly
assessment of lung tumours measuring less than 3 cm on more reliable than a surface measurement, and moreover
CT serial CT scans with non-volumetric measurements the measurement of diameter [66, 67]. The very good
frequently disagrees with growth assessment with volu- reproducibility of volume measurements by the same and
metric measurements. different observers has been demonstrated [68, 69].
A pulmonary nodule may be considered as a sphere; and Furthermore, simple visual analysis of the three-dimen-
a doubling in volume of a sphere corresponds to an increase sional reconstructed nodule image allows detection of all
of only 26% of its diameter according to the formula
modifications of shape, as well as asymmetric growth of
V ¼4 3πr3, where r is the radius. Therefore, it may be the nodule, not visible on CT [67, 68] (Fig. 13). The
difficult to evaluate an increase or decrease in the axial majority of nodules are correctly segmented by the
diameter of a nodule between two successive CT software, even those in contact with the thoracic wall,
examinations, or even of no value for small nodules less mediastinum, and vessels. Segmentation errors remain few;
than or equal to 5 mm in size. In fact, a nodule of 5 mm however, one must be aware that contact between a
which doubles in volume will only increase in diameter by pulmonary vessel and a nodule may lead to a variable
1.25 mm. Revel et al. manually measured the diameter of integration of the vessel within the segmented volume,
nodules less than 20 mm in size in the course of evaluating depending on their orientation and regularity of calibre.
the reproducibility of iterative measurements [65]. They These contacts may vary according to the degree of
demonstrated that this type of measurement varied by inspiration between two CT examinations and this may
1.3 mm for the most reproducible operator, with a variation interfere with the temporal growing calculation and
of between −1.73 and +1.73 for three independent doubling time. For this reason, it is always necessary to
Fig. 12 Small (6-mm) indeter-
minate nodule (arrow) inciden-
tally depicted in a 58-year-old
smoker in the right upper lobe
(left). Air collection in the centre
of the nodule was due to an air
bronchogram. After 3-month
follow-up, the lesion was per-
sistent and there was no change
measurable on 2D dimensions
(right)

11. 459
Fig. 13 The same patient as in
Fig. 12. The three-dimensional
reconstructions of the nodule on
the initial CT scan (left) and on
the 3-month follow-up CT scan
(right). There was an increase of
26% in volume of the nodule
after 3 months, leading to a
surgical resection of the nodule
by videothoracoscopy. The
pathological diagnosis was
adenocarcinoma
control the quality of full inspiration breath hold during approach to biopsy [71, 72], and guide direct transbron-
acquisition and the quality of segmentation in a multi- chial biopsy [73]. If the bronchus positive sign is absent
angular fashion. or the nodule is situated peripherally, then “percutaneous
Volumetric nodule comparison between two CT exam- needle” biopsy is most appropriate. CT may be useful in
inations requires software allowing rapid selection of the biopsy planning by specifying lesion depth and the point
pertinent images, with the best possible correlation to aid of the needle in order to aid the approach, and to avoid
comparison. The reproducibility of volumetric measure- the needle path traversing a bulla or fissure. Even
ments for the same nodule between different CT examina- lesions less than 10 mm in diameter may be biopsied in
tions remains dependent on the acquisition and image this way. Although the minimum size varies according
reconstruction parameters used (slice thickness, kV, mAs, to the expertise of the radiologist, a diameter of at least
reconstruction filter, and pulmonary volume). It is therefore 7 mm is usually required. The main complications of
recommended to use the same acquisition and image pneumothorax and haemorrhage are seen in 5–30% of
reconstruction parameters on forced suspended inspiration, cases [74–78]. Fine-needle aspiration biopsy yields
when repeat CT is carried out for nodule surveillance. malignant cells in more than 90% of malignant nodules.
Beyond these parameters, there exists an inherent variabil- This percentage may be optimised by the presence of an
ity of this method of measurement. Goodman et al. have onsite cytopathologist at the time of biopsy, allowing
raised caution requirements in applying semi-automated repeated sampling if insufficient cells are obtained [79].
volumetric measurements, because the overall variability But for those teams not lucky enough to have an onsite
between scans in vivo is still substantial with wide cytopathologist, the use of coaxial cutting needles is
confidence limits of 13.1% (±26.6%) [70]. For this reason, recommended which yield more voluminous biopsy
it is recommended to act on variations in nodule volume of samples and allow histological examination in all
≥20%. A variation of 20% should not be considered as cases. This technique improves the accuracy of specific
significant as it could be due to the method of measurement. diagnosis of benign lesions, without significant increase
in the complication rate [80]. However, this technique
may only be used for nodules measuring greater than
Nodule biopsy 7 mm in diameter. Whatever the technique performed, a
non-specific negative result cannot be taken as con-
Several options are possible, including bronchoscopi- firmation of the absence of cancer.
cally-guided biopsy, percutaneous transthoracic biopsy, “Thoracotomy” is the most invasive, but most effective,
video-assisted thoracoscopy and thoracotomy. Imaging method to obtain a histological diagnosis, as it is based on
techniques can be useful in directing the choice. If the the whole lesion. The operative mortality of thoracotomy is
nodule is linked to a narrowed or obstructed bronchus 3–7% for malignant nodules and less than 1% for benign
(Fig. 1), a bronchus is visible within the nodule nodules [81].
(bronchus positive sign) or an endobronchial lesion is The development of the technique of “video-assisted
detected on CT, then “bronchoscopy targeting” to the thoroscopy” has allowed a decrease in peri-operative
appropriate level is recommended and often diagnostic. morbidity and hospitalisation time [82]. Even very small
In such a case, the CT examination can optimize the nodules may be sampled using this technique. However,

12. 460
these nodules must remain within 20 mm of the visceral Probability of malignancy
peripheral or fissural pleura in order to be visualised or
palpated during the procedure. CT may be used to guide The “probability of malignancy” of an indeterminate
and help the surgeon during video-assisted thoroscopy. nodule is dependent on several factors: previous history
Advanced localisation of lesions to be resected is possible of cancer, patient age, smoking history, nodule size, and
using different methods [83–85], which are of greatest density.
interest for the smallest lesions. Pre-operative localisation
– A previous history of malignancy significantly in-
of a nodule may be carried out by injection of Methylene
creases the probability of malignancy of a nodule,
Blue along the needle track [86, 87], or by percutaneous
depending on the nature and stage of the primary
placement of a hook wire in proximity to the nodule, under
cancer [95].
CT guidance [88].
In the study by Ginsberg et al. based on nodules
resected by video-assisted thoroscopy in 426 patients,
250 patients had a malignant nodule resected.
Management strategies for an indeterminate nodule
Amongst these, 108 were found in patients with a
known cancer and 32 in patients with no previous
Management of the indeterminate nodule depends on the
cancer history (P0.3) [96].
clinical probability of malignancy and the size of the
In a retrospective study of 3,446 thoracic CT
nodule [3, 60, 89]. Clinical information such as patient age,
examinations reported by Benjamin et al., 334 patients
previous history of primary carcinoma, presence of
had a pulmonary nodule less than 10 mm detected.
previous smoking history or symptoms may be useful in
Among the 87 nodules characterised by biopsy or
suggesting a diagnosis, and guiding the type of manage-
surveyed for over 2 years, 77 were benign and 10
ment of the nodule. For example, a newly discovered
malignant. Nine of the 10 malignant nodules were
pulmonary nodule in a young adult presenting with a
discovered in patients with a previous history of
peripheral soft-tissue sarcoma is highly suggestive of a
cancer [97].
solitary pulmonary metastasis, rather than a primary lung
Of 74 children with known extra-thoracic malignancy
tumour.
at least one pulmonary nodule was found in 49 (66%)
Certain authors have proposed a more rational approach,
patients. Of these, 70% of the nodules 5 mm were
named Bayesian, based on the principles of decisional
regarded as benign [98].
analysis [90, 91]. Bayesian analysis may be useful to obtain
In patients with a known lung cancer, the discovery
the best evaluation of malignant probability. It uses the
of a small pulmonary nodule measuring less than
likelihood ratios using clinical and radiological signs in
10 mm, situated in the same lobe as the primary cancer
order to estimate the probability of malignancy.
or another lobe, is associated with a probability of
Malignant probability for all nodules can be calculated
nodule malignancy of around 5–25% [99]. Of 141
using the software available on the website of Dr Gurney
patients with resectable bronchogenic carcinoma, 62
(http://www.chestx-ray.com). Artificial intelligence has
patients (44%) had a total of 138 additional small
also been used [92, 93] and artificial neural networks
(10 mm) pulmonary nodules. One hundred and
appear to be of significant help in differentiating between
thirty-two of these nodules (95.7%) were proven to be
benign and malignant nodules.
benign [100]. In another study, 88 (16%) of 551
Decision analysis models have suggested that the
patients with bronchogenic carcinoma had small non-
majority of effective and relatively inexpensive manage-
calcified nodules. Seventy percent of these nodules
ment strategies for solitary pulmonary nodules depend on
turned out to be benign, 11% were malignant, and
the probability of the nodule being cancerous. Several
19% were indeterminate [101]. A similar result was
studies, published in the middle of the 1980s, enabled the
found in a retrospective analysis of 223 patients with
suggestion that the most pertinent strategy in terms of cost-
resectable lung cancer: 75% of all 71 nodules 10 mm
effectiveness was simple surveillance for nodules with a
coexisting with lung cancer were benign [99].
low probability of malignancy (less than 5%), immediate
– The older the subject, the more the probability of
surgical resection for those with a high probability of
malignancy increases. Conversely, lung cancer is very
malignancy (≥60%) and biopsy for those with a probability
unusual in subjects less than 40 years old, and even
of malignancy between 5 and 60% [94]. Unfortunately,
rarer in the under 35 s. In elderly subjects, the presence
these studies did not take into account newer imaging
of co-morbidity must also be taken into consideration,
techniques, specifically nodule contrast uptake on CT and
as the risks of surgical intervention may outweigh
PET, in order to produce a better pre-operative stratification
those of progression of a small lung cancer [102]. In
of indeterminate nodules.
effect, the probability that a small nodule could evolve
into a cancer causing the death of the patient becomes
less likely. With advancing age, co-morbidity increases

13. 461
and life expectancy diminishes. So an indeterminate pulmonary fibrosis, or immunodeficiency were fol-
nodule of 5 mm, discovered incidentally in a patient lowed by successive CT examinations [115]. In the
aged 85 years with associated co-morbidity, has little follow-up, eight nodules cleared. None of the small
chance of transforming into a symptomatic lung cancer nodules grew on follow up images within 12 months.
during the patient’s lifetime and does not warrant Three patients developed lung cancer in other nodules
surveillance [103]. On the other hand, non-calcified measuring 5 mm or more. These nodules grew on
nodules over 8 mm in size may represent a substantial follow up interval of 3–13 months. On the basis of
malignant risk and this must be taken into account. these data, the calculated chance that a non-calcified
– Malignant nodules grow more rapidly in smokers than small nodule (4 mm) will grow with 3, 6 and 12
in non-smokers. The risk of cancer in smokers months (95% confident interval) was 0.89, 1.01 and
increases proportionally with the degree and duration 1.28% respectively. Therefore, the authors concluded
of cigarette smoking. This increased risk is less that a short-term follow-up imaging 12 months for
apparent in females [104–107]. The relative risk of nodules measuring 4 mm or less is not necessary
developing lung cancer for male smokers is 10 times [115].
greater than for non-smokers, the risk being 15 to 35%
higher for very heavy smokers. Factors other than
smoking must also be taken into account such as
exposure to asbestos, uranium or radon [108–110], and Recommendations for the management
finally links to genetic factors [111, 112]. of an indeterminate pulmonary nodule
– The probability of malignancy increases with increas-
ing nodule size. In smokers, the percentage of all Indeterminate nodules are the object of recommendations
nodules less than 4 mm which develop into pulmonary for management recently drawn up by the Fleischner
cancer is very low (less than 1%). Although for Society [103] (Table 5).
nodules measuring between 8 and 10 mm, this As 99% of all nodules measuring 4 mm or less are
probability is 10 to 20% [7, 57, 113]. Swensen et al. benign, and because these small opacities are seen very
have reported the results of a non-controlled, non- frequently on thin-slice CT examinations, systematic
randomised, open trial carried out at the Mayo Clinic, surveillance of them is no longer recommended. A single
where an annual low-dose thoracic CT was offered to control CT examination is recommended at 12 months, but
927 smokers and 593 previous smokers, aged 50 years only when the morphology of the nodule is suspicious (ill-
or over with more than a 20 pack/year history [114]. defined or irregular contours), or in subjects with a high
Following 4 years of surveillance, 3356 non-calcified risk of malignancy.
nodules were identified in 74% of subjects. Sixty-one For nodules measuring between 4 and 8 mm, the best
percent of nodules measured less than 4 mm, 31% strategy is surveillance. The timing of these control
between 4 and 7 mm, 8% between 8 and 20 mm, and examinations is given in Table 4. This varies according
less than 1% above 20 mm. The false positive rate for to the nodule size (4–6, or 6–8 mm) and type of patients,
malignancy was 96% for all nodules, and 92.9% for specifically at low or high risk of malignancy concerned.
nodules measuring over 4 mm. Sixty primary pulmo- For those nodules measuring over 8 mm, there are
nary cancers were detected in 66 (4%) of the patients. different management options available, including dynam-
The cancers represented 2% of the 3,356 nodules de- ic CT study of enhancement following bolus contrast
tected, comprising 31 prevalence cancers, 34 incidence injection, PET, percutaneous needle biopsy or video-
cancers detected on the surveillance examinations, and assisted thoracoscopic resection. The use of these different
3 interval cancers revealed between screening exam- approaches depends on the expertise and equipment
inations. These bronchopulmonary cancers measured available on different sites. In high-risk patients, the
between 5 and 50 mm in size, with an average of optimal strategy probably remains that of biopsy or nodule
14.4 mm and median of 10 mm. resection; in low risk patients, the alternatives offered by an
In patients with a previous history of cancer, nodules iodinated contrast uptake study or a PET scan are of
less than 5 mm had a high probability of being benign, interest. Only nodules showing contrast enhancement
whilst those between 5 and 10 mm had a higher greater than 15 HU or significant FDG uptake are biopsied
probability of being malignant (P0.001) [96]. or surgically resected. The others are subject to CT
The chance of growth in non-calcified nodules surveillance at 3, 9 and 24 months in the absence of change.
measuring 4 mm, or less, in diameter in a 3–6- It is important to highlight that these recommendations
month period of patients with non-previous history of are only applicable to incidentally discovered nodules in
malignancy or immune disorder is small. In a series, adults, in other words, those not linked to a known
414 patients of 65.6-year-old average having a single underlying illness. These recommendations are excluded in
or multiple small (4 mm) non-calcified nodules on the following clinical situations.
CT scans and no history of neoplasm, infection,

14. 462
Table 5 Fleischner Society recommendations for the surveillance years or more (modified from McMahon et al. Radiology 2005
and management pulmonary nodules discovered incidentally on CT [103], with permission)
of an indeterminate nodule discovered recently in a patient aged 35
Nodule sizea Patient with low cancer riskb Patient at high riskc
≤4 mm No surveillanced Surveillance CT at 12 months
If no change, surveillance discontinued
4–6 mm Surveillance CT at 12 months Surveillance CT at 6–12 months, then at 18–24
months if no changee
If no significant change, surveillance discontinued
6–8 mm Surveillance CT at 6–12 months, then at Surveillance CT at 3–6 months, then at 9–12
18–24 months if no change months and 24 months if no change
8 mm Study of nodule enhancement on contrast CT or PET scan Nodule biopsy or resection
If contrast CT or PET scan positive, nodule Alternatively, study of nodule enhancement on
biopsy or resection contrast CT or PET scan
If negative, surveillance CT at 3, 9 and 24
months if no change
a
Average of largest and smallest axial diameters of the nodule
b
No smoking history and absence of other risk factors
c
Previous or current smoking history, or other risk factors
d
Risk of malignancy (0.01%) is substantially lower than for an asymptomatic smoker
e
Non-solid nodule: prolonged surveillance necessary to exclude an indolent adenocarcinoma
In patients with a suspected or known cancer, the nodule CT are more important in the younger population. In
could be secondary to a pulmonary metastasis and must consequence, unless there is a known history of primary
therefore be managed according to a protocol adapted to cancer, multiple control CT scans should be avoided for
the clinical situation. Pertinent factors include the site, cell incidentally discovered small nodules. In such a case, a
type and stage of the primary tumour, and the impact of single low-dose CT may be recommended at between 6 and
detection of a pulmonary metastasis on the clinical 12 months. In patients with unexplained fever, certain
management of the illness. In such a situation, repeated clinical situations such as a neutropenic patient with a
surveillance CT examinations may be indicated to study the fever, the presence of a nodule may indicate active
growth of the nodule. infection and short-term surveillance or biopsy may be
In subjects aged less than 35 years, pulmonary cancer is appropriate.
rare (1%), and the risks induced by repeated exposure to
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