Eur Radiol (2007) 17: 449–466DOI 10.1007/s00330-006-0399-7 CHEST

Catherine Beigelman-AubryCatherine HillPhilippe A. Grenier

Received: 28 February 2006Revised: 30 June 2006Accepted: 14 July 2006Published online: 5 October 2006# Springer-Verlag 2006

Management of an incidentally discovered

pulmonary nodule

Abstract The incidental finding of apulmonary nodule on computedtomography (CT) is becoming anincreasingly frequent event. The dis-covery of such a nodule should evokethe possibility of a small bronchogeniccarcinoma, for which excision isindicated without delay. However,invasive diagnostic procedures shouldbe avoided in the case of a benignlesion. The objectives of this reviewarticle are: (1) to analyze the CTcriteria defining benign nodules, nod-ules of high suspicion of malignancyand indeterminate nodules, (2) toanalyze the diagnostic performances

and limitations of complementaryinvestigations requested to character-ize indeterminate lung nodules, (3) toreview the criteria permitting to assessthe probability of malignancy ofindeterminate nodules and (4) toreport on the new guidelines providedby the Fleischner Society for themanagement of small indeterminatepulmonary nodules, according to theirprior probability of malignancy.

Keywords Pulmonary nodule .Nodule characterization . Pulmonaryadenocarcinoma . Bronchioloalveolarcell carcinoma . Non-solid nodule

Introduction

The incidental finding of a pulmonary nodule on chest x-rays or, more recently, on computed tomography (CT) isbecoming an increasingly frequent event. When discoveredon a chest x-ray, CT is then performed urgently in order toconfirm the presence of this pulmonary nodule and toattempt further characterisation of the lesion [1, 2]. Thediscovery of such a nodule should evoke the possibility of asmall bronchogenic carcinoma, for which excision isindicated without delay. However, invasive diagnosticprocedures should be avoided in the case of a benignlesion. Similarly, it is necessary to avoid excessive patientirradiation through an infinite number of follow-up CTexaminations. The management of a nodule must thereforebe adapted to allow rapid identification of subjects with amalignant tumour who would benefit from potentiallycurative surgical treatment, whilst avoiding needle biopsy

and/or surgical resection associated with potential morbid-ity, in those with a benign lesion.

Since introduction of helical CT in the early 1990s andmultidetector row CT in the late 1990s, the detection ofnodules as small as 1–2 mm in diameter has becomeroutine. In fact, the majority of smokers who undergo thin-section CT have been found to have small lung nodules,most of which are smaller than 7 mm in diameter [3].Although, observer’s nodule detection remains imperfect,maximum-intensity-projection processing technique re-duces the number of overlooked small nodules, particularlyin the central lung [4]. Computed-aided detection systemshave shown to improve the performances of radiologists indetecting small nodules on CT scans with higher sensitivitythan with conventional double reading [5].

The clinical importance of these extremely smallnodules differs substantially from that of larger nodulesdetected on chest radiographs, in that the vast majority are

C. Beigelman-Aubry . C. Hill .P. A. Grenier (*)Service de Radiologie Polyvalente,Diagnostique et Interventionnelle,Hôpital Pitié-Salpêtrière-AssistancePublique-Hôpitaux de Paris,47-83 boulevard de l’Hôpital,75651 Paris cedex 13, Francee-mail: philippe.grenier@psl.aphp.frTel.: +33-1-42178225Fax: +33-1-42178224

benign. In recent publications on CT screening for lungcancer, the positive relationship of lesion size to likelihoodof malignancy has been clearly demonstrated [6, 7]. Duringthe past 5-years, new information regarding prevalence,biologic characteristics, and growth rate of small lungcancers has become available, and new guidelines forfollow-up and management of small pulmonary nodulesdetected on CT scans has become highly expected.

Definition and aetiology of pulmonary nodules

A pulmonary nodule is defined as a focal pulmonary lesionor opacity, round or oval in shape, which measures lessthan 3 cm in diameter. A pulmonary nodule is consideredsmall if its largest diameter is 10 mm or less. Above 3 cm insize, the lesion is classified as a mass, and the highprobability of malignancy in this case warrants furtherinvestigation by biopsy or surgical resection.

Today, the classification of a pulmonary nodule has beenextended to include focal areas of ground glass attenuation[8], and all small opacities only a few millimetres in sizediscovered incidentally on CT [9]. In general, linear andband-like opacities are excluded from this definition, wherethe likelihood of malignancy is virtually non-existent.

The classic description of a solitary pulmonary nodule istoo restrictive these days, as patients undergoing CT exam-ination often have more than one nodule present. For a givenpatient, each pulmonary nodule detectedmust be investigatedand managed independently. When greater than six pulmo-nary nodules are present on chest CT for an individual patient,the probability of granulomatous lesions ormetastases greatlyincreases [10]; in this case, the investigation differs totally andis beyond the scope of this article.

The aetiology of pulmonary nodules is diverse,comprising of tumours, infection and inflammatorydisorders, but also vascular and congenital causes. Themost common malignant lesions are pulmonary metastasesand primary bronchopulmonary carcinoma. All histologi-cal types of cancer may give rise to pulmonary nodules, butadenocarcinoma is the most frequent. The majority of smallnodules are benign, of which 80% are granulomas orintrapulmonary lymph nodes [11], 10% are hamartomasand 10% are other rarer benign lesions (Table 1).

Nodule characterisation by CT

Characterisation is based on analysis of the density andmorphology of the nodule. Spiral CT acquisition must beperformed over the whole nodule volume using thincollimation (0.6–1.25 mm) and at least contiguous, butideally overlapping, slices [12]. The use of a high spatialresolution reconstruction filter is recommended for pul-monary windows, enabling precise evaluation of theinterface between the nodule and the lung parenchyma,

along with its relationship to bronchovascular structuresand the pleura. A high density reconstruction filter isrecommended for mediastinal windowing in order to studythe content and density of the nodule. The evaluation is ofcourse completed by an exhaustive helical study of theentire thorax to confirm if the nodule is solitary, orassociated with other nodular lesions. This also allowsassessment of extension in the case of a malignant lesion.Using multislice CT, following a single acquisition of theentire thorax with thin collimation, it is possible today toreconstruct 3 or 5 mm contiguous images for lesiondetection, and then 1 mm images of the nodules detected toensure accurate characterisation [13]. Another simplifiedapproach consists of the specific analysis of the pulmonarynodule with 1 mm slice thickness reconstruction, and thenperform a maximum intensity projection with slabs ofaround 3 to 5 mm for an easy and confident detection ofmultiple lung nodules.

Nodule characterisation according to density

Nodules are classified into three main categories based ontheir density, solid, non-solid, and part-solid (mixed)

Table 1 Causes of incidentally discovered solid pulmonary nodules

Aetiological classification

Neoplastic Primary pulmonary carcinoma (adenocarcino-ma, bronchioloalveolar carcinoma, squamouscell carcinoma, small cell carcinoma)

Malignant Primary pulmonary lymphomaPrimary pulmonary carcinoidLung metastasis

Benign Hamartoma, fibroma, chondroma, leiomyoma,lipoma

Infectious or in-flammatory

GranulomasOpportunistic infectionRound pneumoniaAbscessFocal organising pneumoniaCicatrizing fibrosisNecrobiotic nodule in rheumatoid arthritisWegener’s granulomatosis

Vascular Pulmonary artery aneurysmPulmonary varicesPulmonary arteriovenous malformationPulmonary infarctHaematoma

Miscellaneous Intrapulmonary lymph nodeRounded atelectasisBronchogenic cystMucoid impaction

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nodules. “Solid nodules” are seen most frequently and arethe subject of traditional descriptions [14, 15]. They are ofsoft tissue density and obscure the contour of vessels withwhich they are in contact (Fig. 1).

“Non-solid nodules” have a density inferior to vessels,appearing as areas of focal ground glass. The outline ofvessels in contact with or traversing such lesions is noteffaced (Fig. 2). Specific management of these nodules isrequired. Firstly, inflammatory or infectious lesions mustbe excluded, which rapidly resolve with anti-inflammatoryand/or anti-infectious treatment [16]. If a lesion persistsafter 1 month of treatment, it becomes a persistent orchronic non-solid nodule, which could be neoplastic ornon-neoplastic in nature [17] (Fig. 2). Non-neoplasticcauses comprise foci of desquamative interstitial pneumo-nia in a smoker or pulmonary fibrosis [18] (Fig. 3).Neoplastic causes may be benign, specifically atypicaladenomatous hyperplasia, or malignant, consisting ofadenocarcinoma or bronchioloalveolar cell carcinoma.Malignant nodules generally correspond to non-invasiveor minimally invasive cancers [19, 20]. Atypical adeno-matous hyperplasia is considered a pre-cancerous dysplasiawith the potential to evolve into adenocarcinoma orbronchioloalveolar cell carcinoma [21]. In the majority ofcases, these lesions are small in size, measuring less than5 mm in diameter. Above this size, the lesion becomeshighly suspicious for adenocarcinoma. The presence ofmultiple ground glass nodules in other pulmonary regions

raises several possibilities. This could represent amulticentric bronchioloalveolar cell carcinoma or adeno-carcinoma. It could also signify a primary pulmonaryadenocarcinoma associated with foci of atypical adeno-matous hyperplasia or foci of desquamative interstitialpneumonia in a smoker [22]. Finally, although lesscommonly, it could correspond to pulmonary metastasesexhibiting a lepidic growth pattern, as described inmalignant melanoma [23].

“Mixed nodules”, or part-solid nodules, have a non-solidground glass component within which there exists a solidcomponent of soft tissue density [24–26] (Fig. 4). Thesemixed, or part-solid, nodules may be due to infectious orinflammatory lesions which resolve with specific treat-ment, in particular organising pneumonia (Fig. 5). If such alesion persists after 1-month of treatment, it becomes apersistent or chronic mixed nodule, which is highlysuspicious of malignancy [16, 17, 24]. This usuallycorresponds to a primary adenocarcinoma. The solid tissueareas may reflect either alveolar collapse, foci of fibrosis,intra-alveolar mucus, or foci of invasive carcinoma [25].According to a study of 94 patients who underwent video-assisted thorascopic surgery for an indeterminate pulmo-nary nodule, Yoon et al. demonstrated that 90% of nodulesmeasuring less than or equal to 10 mm diameter with aground glass component were malignant, whereas only30% of nodules of the same size with no ground glasscomponent fulfilled the histological criteria for malignancy(p< 0.01) [27].

Morphological analysis

The “shape” of a nodule rarely contributes to theaetiological diagnosis. However, the characteristic mor-phology of a pulmonary nodular lesion may, exceptionally,be sufficiently typical to allow specific diagnosis of abenign lesion. Pulmonary arteriovenous malformations(Fig. 6), aspergilloma within pre-existing cavities, roundedatelectasis, bronchoceles and mucoid impaction are perfectexamples of this. For other lesions, nodule shape is not veryhelpful in differentiating between a benign and malignantorigin. For example, a lobulated outline implies an area ofmore rapid growth within a lesion. This sign is oftenassociated with malignancy, but may be seen in up to 25%of benign nodules [14] (Fig. 7).

However, it must be emphasized that a ground glassnodule round in shape suggests malignancy (Fig. 2),whereas a polygonal shape with or without concavemargins of a solid as well as a non-solid nodule suggestsbenignancy [17, 28, 29] (Fig. 8).

“Size” is never a definitive criterion, but remains anexcellent indicator of the probability of nodule malignancy.The standard size value used is an average of the largestand smallest cross-sectional diameters of the mostrepresentative area of the nodule. In ongoing low-dose

Fig. 1 18-mm solid nodule with well-defined margins surroundedby some linear opacities located in the superior segment of the rightlower lobe. This nodule appears linked to an obstructed bronchus(bronchus positive sign). The bronchial wall appears slightlythickened in its segment close to the nodule. At surgery, the nodulewas due to an invasive adenocarcinoma

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CT-lung-cancer-screening studies of at risk populations,the prevalence of cancer among nodules detected measur-

ing less than 5 mm varies between 0.1–1%. The prevalencevaries 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. 2 Round shaped non-solid nodules with regularmargins in two differentpatients. Primary adenocarcino-mas. a 46-year-old womenpresenting with a 8-mm nodulein the right lower lobe. Atsurgery the nodule was due tobronchioloalveolar cell carci-noma. b 32-year-old male smo-ker presenting with a 9-mmnon-solid nodule in the lingula.At surgery, the diagnosis wasnon-invasive adenocarcinoma

Fig. 3 Focal area of ground glass (arrow) taking the appearance ofa non-solid nodule in the right upper lobe of a 53-year-old femalesmoker. The nodule has a polygonal shape and is seen abutting thefissure. It was unchanged on a 3-month follow-up CT scan. Aftersurgery the nodule was due to a focal area of desquamativeinterstitial pneumonia

Fig. 4 Part-solid (mixed) nodule in the right upper lobe of a 54-year-old female smoker. The ground glass component of the lesioncontains bubble like lucencies. The pathological diagnosis wasprimary adenocarcinoma

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nodules, but may contribute in the probability of malig-nancy. Well-defined, smooth and regular margins suggestnodule benignancy [31]. However, 21% of malignantnodules have well-defined and regular margins, inparticular pulmonary metastases [14]. Ill-defined, irregularor spiculated margins strongly suggest malignancy (Fig. 9),even though they may be observed in cases of focalorganising pneumonia or lymphomatoid granulomatosis[15, 32]. It is important to highlight that in patients withemphysema, this aspect loses its value for differentiatingbetween benignity and malignancy, and the overlap in the

appearance of benign and malignant nodules is directlyproportional to the quantity of emphysema around thenodule [33]. For Nambu et al., well-defined margins,spiculations and pleural indentations of non-solid nodulesare highly suggestive of neoplastic lesions. In their series,34/38 (89%) of neoplastic lesions were well defined inmore than 50% of the circumference [29].

The “location of a nodule” within an upper lobeincreases the probability of cancer, as primary broncho-pulmonary carcinomas occur more frequently in the upperlobes. Nodules 3–9 mm in size, triangular or ovoid in

Fig. 5 Mixed nodule containing bubble like lucencies in the leftupper lobe (left). The lesion decreased in size after 1 month ofantibiotics (middle) and disappeared entirely on the follow-up CT

examination 2 months later (right). The presumed diagnosis wasfocal organizing pneumonia

Fig. 6 Small (7-mm) pulmo-nary nodule discovered in theright lower lobe of a 20-year-oldwoman corresponding to a pul-monary arteriovenous malfor-mation. Coronal obliquereformation after MDCT acqui-sition (left). 10-mm thick slab inthe same orientation with max-imum intensity projection(right). The nodule presents witha double vascular connexionreflecting the afferent pulmona-ry artery and efferent pulmonaryvein

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shape, and attached to a fissure are often intrapulmonarylymph nodes [28, 34]. “Clustering” of several nodules in aparticular location suggests an infectious or granulomatouscause, although a nodule accompanied by small satellitenodules may also be seen in bronchopulmonary carcinoma.

Analysis of nodule content

An “air bronchogram and/or pseudocavitation” are morefrequently observed in malignant (30%) than benign (5%)lesions. Concerning a malignant nodule, this sign is

strongly suggestive of adenocarcinoma, bronchioloalveolarcell carcinoma or lymphoma [35–37] (Fig. 10).

Pseudocavities visible within a nodule on CT appear assmall round lucencies with well-defined margins, resem-bling small air bubbles. These lucencies are in factequivalent to an air bronchogram, where the small bronchior bronchioles are orientated perpendicular to the plane ofimaging. In the case of adenocarcinoma or bronchioloal-veolar cell carcinoma, this sign represents lepidic tumoralgrowth which respects the pulmonary architecture andbronchi. An air bronchogram may appear to be slightlydistorted or dilated. This is seen in particular when

Fig. 7 58-year-old man pre-senting a spherical (10-mm)nodule with regular and well-defined contours in the upperpart of the left upper lobe. Thenodule contains a small calcifi-cation (arrow head) and smallareas of fat (−50 HU; arrow).These characteristics allow forthe diagnosis of pulmonaryhamartoma in spite of the pre-sence of a small lobulation

Fig. 8 Small (6-mm) pulmo-nary nodule with a polygonalshape, and regular and well-defined contours, located in theperipheral part of the lung,corresponding to an intrapul-monary lymph node. Sagittalreformatted image (left). Volu-metric rendering view after seg-mentation of the nodule (right)

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retractile fibrodesmoplastic reaction is present within thetumour. A nodule with a similar appearance of an airbronchogram or pseudocavitation, with or without dilata-tion, may also be encountered in focal organising pneu-monia [32, 35] (Fig. 5). Air bronchogram and aircontaining space within a non-solid nodule have alsoproven to be more frequent in neoplastic than non-neoplastic lesions [29] (Fig. 4).

“Cavitation” is more frequent in malignant lesions, butmay be seen in lung abscesses. Benign cavitating lesionsmore often have distinct, regular internal contours and thinwalls, whereas malignant nodules typically have thick andirregular walls. The majority of cavitating nodules with awall thickness above 16 mm are malignant, whilst thosewith a wall thickness less than 4 mm are usually benign[38].

The search for calcification remains an important stage[14]. The presence of calcification is always a contributoryfactor in suggesting malignancy or benignancy. Diffusenodule “calcification” is highly characteristic of an oldgranulomatous lesion and is sufficient evident alone todefinitively confirm benignancy (Fig. 11). The onlyexception is a known previous history of osteosarcoma,

chondrosarcoma or synovial sarcoma, as pulmonary me-tastases in these circumstances may be entirely calcified.Round, central, target or concentric laminated calcificationsuggests the diagnosis of tuberculoma. “Popcorn” calcifi-cation indicates calcification of cartilaginous origin, andtherefore the diagnosis of hamartoma. However, theradiological diagnosis of hamartoma requires furthercriteria to be fulfilled [39]. Conversely, eccentric ordispersed calcification is highly suggestive of a malignantlesion and may be seen in 6% of pulmonary cancers [14,40].

The presence of “fat” within a pulmonary nodule isalways a formal criterion for benignancy. A densitybetween −40 and −120 HU is strongly suggestive of thediagnosis of hamartoma (Fig. 7). The CT criteria forradiological diagnosis of hamartoma include round shape,smooth and regular margins, diameter less than 25 mm, andpresence of intralesional fat, with or without popcorncalcification [39]. More rarely, fat may be due to a fat-containing granulomas or lipoma.

Complementary investigations

Subsequent to the CT study, the nodule may be classifiedinto one of the following three categories: benign, highly

Fig. 9 17-mm nodule having spiculated margins and located withinthe left lower lobe. The lumen of a subsegmental bronchus isoccluded by the nodular lesion (CT bronchus sign; arrow). Atsurgery, the lesion was a primary adenocarcinoma

Fig. 10 25-mm solid nodule containing in the periphery pseudo-cavitations and bubble like lucencies. At surgery, the nodule was aprimary adenocarcinoma

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suspicious for malignancy or indeterminate. Nodulesconsidered as benign are those showing diffuse calcifica-tion, or a specific criterion for benignity outlined in Table 2.No further investigation of these lesions is necessary whenthe nodule is entirely calcified. A simple radiographicsurveillance until two years of stability is only requested inother situations.

Nodules possessing a single criterion defined as highlysuspicious of malignancy, outlined in Table 3, must besubject to histological confirmation by biopsy or surgicalresection. Indeterminate nodules, representing around 70%of cases, include all other nodules of which criteria aresummarised in Table 4. The management of indeterminatenodule is variable and is based on complementaryinvestigations, including the study of contrast uptake bythe nodule on CT, Positron Emission Tomography (PET),evaluation of nodule growth, and nodule biopsy.

Nodule contrast uptake on CT

The principle is based on the fact that blood flow inmalignant pulmonary nodules differs qualitatively and

quantitatively from benign nodules [41–43]. The degree ofuptake of iodinated contrast material is directly linked tothe probability of malignancy and nodule vascularisation[44]. This technique was the subject of a multi-centre studywhich demonstrated that an increased enhancement of 15HU was the most effective threshold [44]. This thresholdallows an excellent sensitivity and moderate specificity forthe diagnosis of a malignant nodule. The weak specificityis related to the fact that numerous benign lesions mayshow increased enhancement due to rich vascularisation, inparticular hamartomas and certain infectious lesions. Onthe other hand, the excellent sensitivity leads to a very highnegative predictive value. So, a nodule with either no orvery little enhancement following contrast injection can beconsidered as a benign lesion, for which simple radiolog-ical surveillance is sufficient. However, the technique ofmeasuring contrast enhancement must be precise. Thisconsists of a volumetric helical acquisition with thincollimation on the entire nodule before, and then at 1, 2,3 and 4 min after contrast injection. An injection rate of2 ml/s is recommended of a total of 420 mg of iodine/kg.The density measurement must be made at the centre of the

Table 2 Criteria defining a benign nodule

Benign nodule criteria

Diffuse, dense calcificationVessels converging towards either side of the nodule (pulmonaryarteriovenous malformation) or vessels converging towards thepleural side of the nodule/comet-tail sign (rounded atelectasis)Diagnostic criteria of hamartoma (round shape, smooth, regularcontours, containing fat density, +/– popcorn calcification)Benign-type calcification (central, target, laminated, concentric)

Table 3 Criteria defining a nodule as highly suspicious ofmalignancy (a single criterion is sufficient)

Criteria defining a nodule as highly suspicious of malignancy

Persistent non-solid (focal) ground glass nodule measuring 10 mmor more in diameterPersistent mixed (or part solid) nodulesSolid nodule measuring 20 mm or more in diameterSolid nodule with spiculated contoursSolid nodule containing air bronchogram or pseudocavitationSolid nodule containing eccentric or dispersed calcifications

Fig. 11 Entirely calcified nod-ule of the upper part of the leftupper lobe. Diffuse and intensecalcification of the noduleleads to the diagnosis of post-tuberculosis granuloma in spiteof the spiculated contours ofthe nodule

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nodule, over a region representing at least 60% of thenodule’s surface area. Given that measurement of thedensity is difficult for heterogeneous lesions and those lessthan 1 cm in diameter, in practice this technique only yieldsreliable information for homogenous nodules equal to orabove 8 mm in diameter.

In another study of solitary pulmonary nodules presentin 131 patients, after injection of 120 ml of contrast withrepeated acquisitions every 20 s over a period of 3 min,enhancement of 30 HU or more was the retained criterionfor malignancy [45]. The sensitivity and negative pre-dictive value for the diagnosis of malignancy were 99 and97% respectively. The specificity and positive predictivevalue for malignancy were 54 and 71% respectively, theoverall diagnostic accuracy being 78%. As part of the samestudy, the peak enhancement value within the nodulepositively correlated with both the concentration ofmicrovessels present within the lesion on histologicalexamination and the scoring of immunological markers forvascular endothelial growth factor.

Positron emission tomography (PET)

PET provides in vivo functional mapping of 2-F18-fluoro-2-deoxy-D-Glucose (FDG) fixation, which is elevated inneoplastic lesions [46–49]. Today, the value of thistechnique in the diagnosis of malignant pulmonary nodulesis well documented. A recent meta-analysis reported asensitivity of 90% and a specificity of 83% for diagnosingmalignancy [50]. Yet, certain histological types with lowmetabolism such as low-grade adenocarcinoma, bronchio-loalveolar cell carcinoma and carcinoid tumours, may giverise to false negative results for this technique [51–54].False positives may also be seen with infectious orinflammatory processes, and granulomatous disorderssuch as Wegener’s disease or sarcoidosis, which trapFDG. In addition, the diagnostic performance of PETdecreases considerably for lesions less than 6 mm in size.

Taking into account its high negative predictive value, ifa pulmonary lesion of 10 mm or more does not fix withFDG, clinical and radiological surveillance may beproposed, thereby avoiding surgery. Another interest ofthe technique lies also in the possibility of combining

investigation of thoracic and extra-thoracic extension withtumour characterisation. When the nodule is less than 1 cmin diameter or of ground glass attenuation on CT, PET isnot indicated as it contributes little to nodule characterisa-tion and overall evaluation in these situations [54]. Withintegrated PET/CT, additional certainty to the presence orabsence of FDG uptake in the pulmonary nodule can beachieved because morphologic criteria and functional CTcriteria are available simultaneously [55].

Evaluation of nodule growth

In the course of surveillance, this entails repeated CTexaminations in order to screen for growth, reduction insize or resolution of the nodule [56, 57]. In order to limitthe number of surveillance CT examinations required, asearch for previous imaging is always recommended forcomparison. This is often sufficient to demonstrate thestability or significant growth of a nodule. In all cases,surveillance examinations should be performed at low doseusing thin collimation, without contrast injection, and ifpossible limited to the volume of interest.

The “doubling time” (DT) of a nodule can be calculatedusing the following formula:

DT ¼ t: ln 2ð Þ�ln V f=Við Þ

where V i is the initial volume of the nodule, Vf the finalvolume, t the time interval between observations and ln thelogarithmic value. This formula is based on an exponentialmodel of nodule growth.

The doubling time of most malignant solid nodules isbetween 30 and 400 days. Nodules displaying more rapidor slower doubling times are typically benign in origin [58,59]. Radiological stability, either on chest radiography orCT, over a period greater than 2 years implies a doublingtime of at least 730 days, which is generally considered tobe a reliable indicator of a benign lesion [56, 60].

Several studies have estimated that the average doublingtime of tumours lies between 160 and 180 days, assuming aconstant growth rate. However, all of these studiesrecognise a large variation in the volume doubling timeof nodules detected, and in one study 22% of tumours had avolume doubling time of 465 days or more.

Non-solid nodules, both ground glass and mixed, mayhave a much longer doubling time [61]. Hasegawa and coll.have reported an analysis of the growth rates of smallcancers detected during a 3-year screening program [62].The average volume doubling time was 189 days for solidnodules, 457 days for mixed nodules and 813 days forground glass nodules. These results therefore suggest theneed for more prolonged surveillance of ground glassnodules than for solid nodules. It is important to rememberthat, according to the high probability of malignancy,

Table 4 Criteria defining an indeterminate nodule

Indeterminate nodule criteria

Persistent ground glass nodule measuring less than 10 mm indiameterSolid nodule of less than 20 mm in diameter withNon-spiculated contoursNo air bronchogram or pseudocavitationNo malignant-type calcificationNo intralesional fat or benign-type calification

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mixed nodules persistent after 1 month of antibiotictherapy should be resected without delay. Duringsurveillance of ground glass nodules, the appearance ofa soft-tissue component is a highly suspicious sign ofmalignancy, even if the overall size of the noduleremains stable or diminishes [63].

Once it has decided to follow a nodule with serial CT,most radiologists measure the maximum diameter of thenodule at each examination. Authors have compareddiameter and cross-sectional area measurement with vol-ume measurement in the assessment of lung tumour growthwith serial CT [64]. They demonstrated that growthassessment of lung tumours measuring less than 3 cm onCT serial CT scans with non-volumetric measurementsfrequently disagrees with growth assessment with volu-metric measurements.

A pulmonary nodule may be considered as a sphere; anda doubling in volume of a sphere corresponds to an increaseof only 26% of its diameter according to the formulaV ¼4

�3πr3, where r is the radius. Therefore, it may be

difficult to evaluate an increase or decrease in the axialdiameter of a nodule between two successive CTexaminations, or even of no value for small nodules lessthan or equal to 5 mm in size. In fact, a nodule of 5 mmwhich doubles in volume will only increase in diameter by1.25 mm. Revel et al. manually measured the diameter ofnodules less than 20 mm in size in the course of evaluatingthe reproducibility of iterative measurements [65]. Theydemonstrated that this type of measurement varied by1.3 mm for the most reproducible operator, with a variationof between −1.73 and +1.73 for three independent

operators. This variation in measurement is above theincrease in diameter expected for a nodule of 5 mm whichdoubles in volume (Fig. 12). In order to avoid thislimitation, it was proposed that the growth rate of all smallnodules could be evaluated by repeated volume measure-ments, rather than measurements of diameter. Volumemeasurement requires specific image analysis software,which allows segmentation and three-dimensional recon-struction of the nodule in order to appreciate the variationsin morphology, and to automatically calculate the volume.Several types of software are available from the con-structors. The three-dimensional measurements are clearlymore reliable than a surface measurement, and moreoverthe measurement of diameter [66, 67]. The very goodreproducibility of volume measurements by the same anddifferent observers has been demonstrated [68, 69].

Furthermore, simple visual analysis of the three-dimen-sional reconstructed nodule image allows detection of allmodifications of shape, as well as asymmetric growth ofthe nodule, not visible on CT [67, 68] (Fig. 13). Themajority of nodules are correctly segmented by thesoftware, even those in contact with the thoracic wall,mediastinum, and vessels. Segmentation errors remain few;however, one must be aware that contact between apulmonary vessel and a nodule may lead to a variableintegration of the vessel within the segmented volume,depending on their orientation and regularity of calibre.These contacts may vary according to the degree ofinspiration between two CT examinations and this mayinterfere with the temporal growing calculation anddoubling 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-oldsmoker in the right upper lobe(left). Air collection in the centreof the nodule was due to an airbronchogram. After 3-monthfollow-up, the lesion was per-sistent and there was no changemeasurable on 2D dimensions(right)

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control the quality of full inspiration breath hold duringacquisition and the quality of segmentation in a multi-angular fashion.

Volumetric nodule comparison between two CT exam-inations requires software allowing rapid selection of thepertinent images, with the best possible correlation to aidcomparison. The reproducibility of volumetric measure-ments for the same nodule between different CT examina-tions remains dependent on the acquisition and imagereconstruction parameters used (slice thickness, kV, mAs,reconstruction filter, and pulmonary volume). It is thereforerecommended to use the same acquisition and imagereconstruction parameters on forced suspended inspiration,when repeat CT is carried out for nodule surveillance.Beyond these parameters, there exists an inherent variabil-ity of this method of measurement. Goodman et al. haveraised caution requirements in applying semi-automatedvolumetric measurements, because the overall variabilitybetween scans in vivo is still substantial with wideconfidence limits of 13.1% (±26.6%) [70]. For this reason,it is recommended to act on variations in nodule volume of≥20%. A variation of <20% should not be considered assignificant as it could be due to the method of measurement.

Nodule biopsy

Several options are possible, including bronchoscopi-cally-guided biopsy, percutaneous transthoracic biopsy,video-assisted thoracoscopy and thoracotomy. Imagingtechniques can be useful in directing the choice. If thenodule is linked to a narrowed or obstructed bronchus(Fig. 1), a bronchus is visible within the nodule(bronchus positive sign) or an endobronchial lesion isdetected on CT, then “bronchoscopy targeting” to theappropriate level is recommended and often diagnostic.In such a case, the CT examination can optimize the

approach to biopsy [71, 72], and guide direct transbron-chial biopsy [73]. If the bronchus positive sign is absentor the nodule is situated peripherally, then “percutaneousneedle” biopsy is most appropriate. CT may be useful inbiopsy planning by specifying lesion depth and the pointof the needle in order to aid the approach, and to avoidthe needle path traversing a bulla or fissure. Evenlesions less than 10 mm in diameter may be biopsied inthis way. Although the minimum size varies accordingto the expertise of the radiologist, a diameter of at least7 mm is usually required. The main complications ofpneumothorax and haemorrhage are seen in 5–30% ofcases [74–78]. Fine-needle aspiration biopsy yieldsmalignant cells in more than 90% of malignant nodules.This percentage may be optimised by the presence of anonsite cytopathologist at the time of biopsy, allowingrepeated sampling if insufficient cells are obtained [79].But for those teams not lucky enough to have an onsitecytopathologist, the use of coaxial cutting needles isrecommended which yield more voluminous biopsysamples and allow histological examination in allcases. This technique improves the accuracy of specificdiagnosis of benign lesions, without significant increasein the complication rate [80]. However, this techniquemay only be used for nodules measuring greater than7 mm in diameter. Whatever the technique performed, anon-specific negative result cannot be taken as con-firmation of the absence of cancer.

“Thoracotomy” is the most invasive, but most effective,method to obtain a histological diagnosis, as it is based onthe whole lesion. The operative mortality of thoracotomy is3–7% for malignant nodules and less than 1% for benignnodules [81].

The development of the technique of “video-assistedthoroscopy” has allowed a decrease in peri-operativemorbidity and hospitalisation time [82]. Even very smallnodules may be sampled using this technique. However,

Fig. 13 The same patient as inFig. 12. The three-dimensionalreconstructions of the nodule onthe initial CT scan (left) and onthe 3-month follow-up CT scan(right). There was an increase of26% in volume of the noduleafter 3 months, leading to asurgical resection of the noduleby videothoracoscopy. Thepathological diagnosis wasadenocarcinoma

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these nodules must remain within 20 mm of the visceralperipheral or fissural pleura in order to be visualised orpalpated during the procedure. CT may be used to guideand help the surgeon during video-assisted thoroscopy.Advanced localisation of lesions to be resected is possibleusing different methods [83–85], which are of greatestinterest for the smallest lesions. Pre-operative localisationof a nodule may be carried out by injection of MethyleneBlue along the needle track [86, 87], or by percutaneousplacement of a hook wire in proximity to the nodule, underCT guidance [88].

Management strategies for an indeterminate nodule

Management of the indeterminate nodule depends on theclinical probability of malignancy and the size of thenodule [3, 60, 89]. Clinical information such as patient age,previous history of primary carcinoma, presence ofprevious smoking history or symptoms may be useful insuggesting a diagnosis, and guiding the type of manage-ment of the nodule. For example, a newly discoveredpulmonary nodule in a young adult presenting with aperipheral soft-tissue sarcoma is highly suggestive of asolitary pulmonary metastasis, rather than a primary lungtumour.

Certain authors have proposed a more rational approach,named Bayesian, based on the principles of decisionalanalysis [90, 91]. Bayesian analysis may be useful to obtainthe best evaluation of malignant probability. It uses thelikelihood ratios using clinical and radiological signs inorder to estimate the probability of malignancy.

Malignant probability for all nodules can be calculatedusing the software available on the website of Dr Gurney(http://www.chestx-ray.com). Artificial intelligence hasalso been used [92, 93] and artificial neural networksappear to be of significant help in differentiating betweenbenign and malignant nodules.

Decision analysis models have suggested that themajority of effective and relatively inexpensive manage-ment strategies for solitary pulmonary nodules depend onthe probability of the nodule being cancerous. Severalstudies, published in the middle of the 1980s, enabled thesuggestion that the most pertinent strategy in terms of cost-effectiveness was simple surveillance for nodules with alow probability of malignancy (less than 5%), immediatesurgical resection for those with a high probability ofmalignancy (≥60%) and biopsy for those with a probabilityof malignancy between 5 and 60% [94]. Unfortunately,these studies did not take into account newer imagingtechniques, specifically nodule contrast uptake on CT andPET, in order to produce a better pre-operative stratificationof indeterminate nodules.

Probability of malignancy

The “probability of malignancy” of an indeterminatenodule is dependent on several factors: previous historyof cancer, patient age, smoking history, nodule size, anddensity.

– A previous history of malignancy significantly in-creases the probability of malignancy of a nodule,depending on the nature and stage of the primarycancer [95].In the study by Ginsberg et al. based on nodulesresected by video-assisted thoroscopy in 426 patients,250 patients had a malignant nodule resected.Amongst these, 108 were found in patients with aknown cancer and 32 in patients with no previouscancer history (P<0.3) [96].In a retrospective study of 3,446 thoracic CTexaminations reported by Benjamin et al., 334 patientshad a pulmonary nodule less than 10 mm detected.Among the 87 nodules characterised by biopsy orsurveyed for over 2 years, 77 were benign and 10malignant. Nine of the 10 malignant nodules werediscovered in patients with a previous history ofcancer [97].Of 74 children with known extra-thoracic malignancyat least one pulmonary nodule was found in 49 (66%)patients. Of these, 70% of the nodules <5 mm wereregarded as benign [98].In patients with a known lung cancer, the discoveryof a small pulmonary nodule measuring less than10 mm, situated in the same lobe as the primary canceror another lobe, is associated with a probability ofnodule malignancy of around 5–25% [99]. Of 141patients with resectable bronchogenic carcinoma, 62patients (44%) had a total of 138 additional small(<10 mm) pulmonary nodules. One hundred andthirty-two of these nodules (95.7%) were proven to bebenign [100]. In another study, 88 (16%) of 551patients with bronchogenic carcinoma had small non-calcified nodules. Seventy percent of these nodulesturned out to be benign, 11% were malignant, and19% were indeterminate [101]. A similar result wasfound in a retrospective analysis of 223 patients withresectable lung cancer: 75% of all 71 nodules <10 mmcoexisting with lung cancer were benign [99].

– The older the subject, the more the probability ofmalignancy increases. Conversely, lung cancer is veryunusual in subjects less than 40 years old, and evenrarer in the under 35 s. In elderly subjects, the presenceof co-morbidity must also be taken into consideration,as the risks of surgical intervention may outweighthose of progression of a small lung cancer [102]. Ineffect, the probability that a small nodule could evolveinto a cancer causing the death of the patient becomesless likely. With advancing age, co-morbidity increases

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and life expectancy diminishes. So an indeterminatenodule of 5 mm, discovered incidentally in a patientaged 85 years with associated co-morbidity, has littlechance of transforming into a symptomatic lung cancerduring the patient’s lifetime and does not warrantsurveillance [103]. On the other hand, non-calcifiednodules over 8 mm in size may represent a substantialmalignant risk and this must be taken into account.

– Malignant nodules grow more rapidly in smokers thanin non-smokers. The risk of cancer in smokersincreases proportionally with the degree and durationof cigarette smoking. This increased risk is lessapparent in females [104–107]. The relative risk ofdeveloping lung cancer for male smokers is 10 timesgreater than for non-smokers, the risk being 15 to 35%higher for very heavy smokers. Factors other thansmoking must also be taken into account such asexposure to asbestos, uranium or radon [108–110], andfinally links to genetic factors [111, 112].

– The probability of malignancy increases with increas-ing nodule size. In smokers, the percentage of allnodules less than 4 mm which develop into pulmonarycancer is very low (less than 1%). Although fornodules measuring between 8 and 10 mm, thisprobability is 10 to 20% [7, 57, 113]. Swensen et al.have reported the results of a non-controlled, non-randomised, open trial carried out at the Mayo Clinic,where an annual low-dose thoracic CT was offered to927 smokers and 593 previous smokers, aged 50 yearsor over with more than a 20 pack/year history [114].Following 4 years of surveillance, 3356 non-calcifiednodules were identified in 74% of subjects. Sixty-onepercent of nodules measured less than 4 mm, 31%between 4 and 7 mm, 8% between 8 and 20 mm, andless than 1% above 20 mm. The false positive rate formalignancy was 96% for all nodules, and 92.9% fornodules measuring over 4 mm. Sixty primary pulmo-nary cancers were detected in 66 (4%) of the patients.The cancers represented 2% of the 3,356 nodules de-tected, comprising 31 prevalence cancers, 34 incidencecancers detected on the surveillance examinations, and3 interval cancers revealed between screening exam-inations. These bronchopulmonary cancers measuredbetween 5 and 50 mm in size, with an average of14.4 mm and median of 10 mm.In patients with a previous history of cancer, nodulesless than 5 mm had a high probability of being benign,whilst those between 5 and 10 mm had a higherprobability of being malignant (P<0.001) [96].The chance of growth in non-calcified nodules

measuring 4 mm, or less, in diameter in a 3–6-month period of patients with non-previous history ofmalignancy or immune disorder is small. In a series,414 patients of 65.6-year-old average having a singleor multiple small (<4 mm) non-calcified nodules onCT scans and no history of neoplasm, infection,

pulmonary fibrosis, or immunodeficiency were fol-lowed by successive CT examinations [115]. In thefollow-up, eight nodules cleared. None of the smallnodules grew on follow up images within 12 months.Three patients developed lung cancer in other nodulesmeasuring 5 mm or more. These nodules grew onfollow up interval of 3–13 months. On the basis ofthese data, the calculated chance that a non-calcifiedsmall nodule (<4 mm) will grow with 3, 6 and 12months (95% confident interval) was <0.89, 1.01 and1.28% respectively. Therefore, the authors concludedthat a short-term follow-up imaging <12 months fornodules measuring 4 mm or less is not necessary[115].

Recommendations for the managementof an indeterminate pulmonary nodule

Indeterminate nodules are the object of recommendationsfor management recently drawn up by the FleischnerSociety [103] (Table 5).

As 99% of all nodules measuring 4 mm or less arebenign, and because these small opacities are seen veryfrequently on thin-slice CT examinations, systematicsurveillance of them is no longer recommended. A singlecontrol CT examination is recommended at 12 months, butonly when the morphology of the nodule is suspicious (ill-defined or irregular contours), or in subjects with a highrisk of malignancy.

For nodules measuring between 4 and 8 mm, the beststrategy is surveillance. The timing of these controlexaminations is given in Table 4. This varies accordingto the nodule size (4–6, or 6–8 mm) and type of patients,specifically at low or high risk of malignancy concerned.

For those nodules measuring over 8 mm, there aredifferent management options available, including dynam-ic CT study of enhancement following bolus contrastinjection, PET, percutaneous needle biopsy or video-assisted thoracoscopic resection. The use of these differentapproaches depends on the expertise and equipmentavailable on different sites. In high-risk patients, theoptimal strategy probably remains that of biopsy or noduleresection; in low risk patients, the alternatives offered by aniodinated contrast uptake study or a PET scan are ofinterest. Only nodules showing contrast enhancementgreater than 15 HU or significant FDG uptake are biopsiedor surgically resected. The others are subject to CTsurveillance at 3, 9 and 24 months in the absence of change.

It is important to highlight that these recommendationsare only applicable to incidentally discovered nodules inadults, in other words, those not linked to a knownunderlying illness. These recommendations are excluded inthe following clinical situations.

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In patients with a suspected or known cancer, the nodulecould be secondary to a pulmonary metastasis and musttherefore be managed according to a protocol adapted tothe clinical situation. Pertinent factors include the site, celltype and stage of the primary tumour, and the impact ofdetection of a pulmonary metastasis on the clinicalmanagement of the illness. In such a situation, repeatedsurveillance CTexaminations may be indicated to study thegrowth of the nodule.

In subjects aged less than 35 years, pulmonary cancer israre (<1%), and the risks induced by repeated exposure to

CT are more important in the younger population. Inconsequence, unless there is a known history of primarycancer, multiple control CT scans should be avoided forincidentally discovered small nodules. In such a case, asingle low-dose CT may be recommended at between 6 and12 months. In patients with unexplained fever, certainclinical situations such as a neutropenic patient with afever, the presence of a nodule may indicate activeinfection and short-term surveillance or biopsy may beappropriate.

Table 5 Fleischner Society recommendations for the surveillanceand management pulmonary nodules discovered incidentally on CTof an indeterminate nodule discovered recently in a patient aged 35

years or more (modified from McMahon et al. Radiology 2005[103], with permission)

Nodule sizea Patient with low cancer riskb Patient at high riskc

≤4 mm No surveillanced Surveillance CT at 12 monthsIf no change, surveillance discontinued

4–6 mm Surveillance CT at 12 months Surveillance CT at 6–12 months, then at 18–24months if no changee

If no significant change, surveillance discontinued6–8 mm Surveillance CT at 6–12 months, then at

18–24 months if no changeSurveillance CT at 3–6 months, then at 9–12months and 24 months if no change

>8 mm Study of nodule enhancement on contrast CT or PET scan Nodule biopsy or resectionIf contrast CT or PET scan positive, nodulebiopsy or resection

Alternatively, study of nodule enhancement oncontrast CT or PET scan

If negative, surveillance CT at 3, 9 and 24months if no change

aAverage of largest and smallest axial diameters of the nodulebNo smoking history and absence of other risk factorscPrevious or current smoking history, or other risk factorsdRisk of malignancy (<0.01%) is substantially lower than for an asymptomatic smokereNon-solid nodule: prolonged surveillance necessary to exclude an indolent adenocarcinoma

References

1. Berger WG, Erly WK, Krupinski EA,Standen JR, Stern RG (2001) Thesolitary pulmonary nodule on chestradiography: can we really tell if thenodule is calcified? AJR Am JRoentgenol 176:201–204

2. Wormanns D, Diederich S (2004) Char-acterization of small pulmonary nodulesby CT. Eur Radiol 14:1380–1391

3. Swensen SJ, Silverstein MD, IlstrupDM, Schleck CD, Edell ES (1997) Theprobability of malignancy in solitarypulmonary nodules: application tosmall radiologically indeterminatenodules. Arch Intern Med 157:849–855

4. Gruden JF, Ouanounou S, Tigges S,Norris SD, Klausner TS (2002) Incre-mental benefit of maximum-intensity-projection images on observer detectionof small pulmonary nodules revealedby multidetector CT. AJR Am JRoentgenol 179:149–157

5. Rubin GD, Lyo JK, Paik DS,Sherbondy AJ, Chow LC, Leung AN,Mindelzun R, Schraedley-DesmondPK, Zinck SE, Naidich DP, Napel S(2005) Pulmonary nodules onmulti-detector row CT scans:performance comparison of radiologistsand computer-aided detection.Radiology 234:274–283

6. Midthun DE, Swensen SJ, Jett JR,Hartman TE (2003) Evaluation of nod-ules detected by screening for lung cancerwith low dose spiral computed tomogra-phy. Lung Cancer 41(suppl 2):S40

7. Henschke CI, Yankelevitz DF, NaidichDP, McCauley DI, McGuinness G,Libby DM, Smith JP, Pasmantier MW,Miettinen OS (2004) CT screening forlung cancer: suspiciousness of nodulesaccording to size on baseline scans.Radiology 231:164–168

462

8. Yang ZG, Sone S, Takashima S, Li F,Honda T, Maruyama Y, Hasegawa M,Kawakami S (2001) High-resolutionCT analysis of small peripheral lungadenocarcinomas revealed on screeninghelical CT. AJR Am J Roentgenol176:1399–1407

9. Munden RF, Hess KR (2001) “Ditzels”on chest CT: survey of members of theSociety of Thoracic Radiology. AJRAm J Roentgenol 176:1363–1369

10. Laurent F, Remy J (2002) Managementstrategy of pulmonary nodules. J Radiol83:1815–1821

11. Kradin RL, Spirn PW, Mark EJ (1985)Intrapulmonary lymph nodes: clinical,radiologic, and pathologic features.Chest 87:662–667

12. Diederich S, Lenzen H, Windmann R,Puskas Z, Yelbuz TM, Henneken S,Klaiber T, Eameri M, Roos N, PetersPE (1999) Pulmonary nodules: experi-mental and clinical studies at low-doseCT. Radiology 213:289–298

13. Schoepf UJ, Becker CR, ObuchowskiNA, Rust GF, Ohnesorge BM, Kohl G,Schaller S, Modic MT, Reiser MF(2001) Multi-slice computed tomogra-phy as a screening tool for coloncancer, lung cancer and coronary arterydisease. Eur Radiol 11:1975–1985

14. Erasmus JJ, Connolly JE, McAdamsHP, Roggli VL (2000) Solitary pulmo-nary nodules. Part I. Morphologicevaluation for differentiation of benignand malignant lesions. Radiographics20:43–58

15. Zwirewich CV, Vedal S, Miller RR,Muller NL (1991) Solitary pulmonarynodule: high-resolution CT and radio-logic-pathologic correlation. Radiology179:469–476

16. Henschke CI, Yankelevitz DF,Mirtcheva R, McGuinness G,McCauley D, Miettinen OS (2002) CTscreening for lung cancer: frequencyand significance of part-solid and non-solid nodules. AJR Am J Roentgenol178:1053–1057

17. Li F, Sone S, Abe H, Macmahon H,Doi K (2004) Malignant versus benignnodules at CT screening for lung can-cer: comparison of thin-section CTfindings. Radiology 233:793–798

18. Nakajima R, Yokose T, Kakinuma R,Nagai K, Nishiwaki Y, Ochiai A (2002)Localized pure ground-glass opacity onhigh-resolution CT: histologic charac-teristics. J Comput Assist Tomogr26:323–329

19. Asamura H, Suzuki K, Watanabe S,Matsuno Y, Maeshima A, Tsuchiya R(2003) A clinicopathological study ofresected subcentimeter lung cancers: afavorable prognosis for ground glassopacity lesions. Ann Thorac Surg76:1016–1022

20. Nakata M, Sawada S, Saeki H,Takashima S, Mogami H, Teramoto N,Eguchi K (2003) Prospective study ofthoracoscopic limited resection forground-glass opacity selected by com-puted tomography. Ann Thorac Surg75:1601–1605; discussion 1605–1606

21. Kawakami S, Sone S, Takashima S, LiF, Yang ZG, Maruyama Y, Honda T,Hasegawa M, Wang JC (2001) Atypicaladenomatous hyperplasia of the lung:correlation between high-resolution CTfindings and histopathologic features.Eur Radiol 11:811–814

22. Kishi K, Homma S, Kurosaki A,Tanaka S, Matsushita H, Nakata K(2002) Multiple atypical adenomatoushyperplasia with synchronous multipleprimary bronchioloalveolar carcino-mas. Intern Med 41:474–477

23. Okita R, Yamashita M, Nakata M,Teramoto N, Bessho A, Mogami H(2005) Multiple ground-glass opacity inmetastasis of malignant melanoma di-agnosed by lung biopsy. Ann ThoracSurg 79:1–2

24. Gaeta M, Blandino A, Scribano E,Minutoli F, Volta S, Pandolfo I (1999)Computed tomography halo sign inpulmonary nodules: frequency and di-agnostic value. J Thorac Imaging14:109–113

25. Nakazono T, Sakao Y, Yamaguchi K,Imai S, Kumazoe H, Kudo S (2005)Subtypes of peripheral adenocarcinomaof the lung: differentiation by thin-section CT. Eur Radiol 15:1563–1568

26. Wang JC, Sone S, Feng L, Yang ZG,Takashima S, Maruyama Y, HasegawaM, Kawakami S, Honda T, Yamanda T(2000) Rapidly growing small periph-eral lung cancers detected by screeningCT: correlation between radiologicalappearance and pathological features.Br J Radiol 73:930–937

27. Yoon HE, Fukuhara K, Michiura T,Takada M, Imakita M, Nonaka K, IwaseK (2005) Pulmonary nodules 10 mm orless in diameter with ground-glass opac-ity component detected by high-resolu-tion computed tomography have a highpossibility of malignancy. Jpn J ThoracCardiovasc Surg 53:22–28

28. Takashima S, Sone S, Li F, Maruyama Y,HasegawaM,Matsushita T, Takayama F,Kadoya M (2003) Small solitary pulmo-nary nodules (<or = 1 cm) detected atpopulation-based CT screening for lungcancer: reliable high-resolution CT fea-tures of benign lesions. AJR Am JRoentgenol 180:955–964

29. Nambu A, Araki T, Taguchi Y, OzawaK, Miyata K, Miyazawa M, Hiejima Y,Saito A (2005) Focal area of ground-glass opacity and ground-glass opacitypredominance on thin-section CT: dis-crimination between neoplastic andnon-neoplastic lesions. Clin Radiol60:1006–1017

30. Aberle DR, Gamsu G, Henschke CI,Naidich DP, Swensen SJ (2001) Aconsensus statement of the Society ofThoracic Radiology: screening for lungcancer with helical computed tomogra-phy. J Thorac Imaging 16:65–68

31. Ost D, Fein A (2000) Evaluation andmanagement of the solitary pulmonarynodule. Am J Respir Crit Care Med162:782–787

32. Kohno N, Ikezoe J, Johkoh T, TakeuchiN, Tomiyama N, Kido S, Kondoh H,Arisawa J, Kozuka T (1993) Focalorganizing pneumonia: CT appearance.Radiology 189:119–123

33. Matsuoka S, Kurihara Y, Yagihashi K,Niimi H, Nakajima Y (2005) Peripheralsolitary pulmonary nodule: CT findingsin patients with pulmonary emphyse-ma. Radiology 235:266–273

34. Oshiro Y, Kusumoto M, Moriyama N,Kaneko M, Suzuki K, Asamura H,Kondo H, Tsuchiya R, Murayama S(2002) Intrapulmonary lymph nodes:thin-section CT features of 19 nodules.J Comput Assist Tomogr 26:553–557

35. Kui M, Templeton PA, White CS, CaiZL, Bai YX, Cai YQ (1996) Evaluationof the air bronchogram sign on CT insolitary pulmonary lesions. J ComputAssist Tomogr 20:983–986

36. Kuriyama K, Tateishi R, Doi O,Higashiyama M, Kodama K, Inoue E,Narumi Y, Fujita M, Kuroda C (1991)Prevalence of air bronchograms insmall peripheral carcinomas of the lungon thin-section CT: comparison withbenign tumors. AJR Am J Roentgenol156:921–924

37. Lee KS, Kim Y, Han J, Ko EJ, ParkCK, Primack SL (1997) Bronchioloal-veolar carcinoma: clinical, histopatho-logic, and radiologic findings.Radiographics 17:1345–1357

38. Woodring JH, Fried AM (1983) Sig-nificance of wall thickness in solitarycavities of the lung: a follow-up study.AJR Am J Roentgenol 140:473–474

39. Siegelman SS, Khouri NF, Scott WW,Jr., Leo FP, Hamper UM, Fishman EK,Zerhouni EA (1986) Pulmonaryhamartoma: CT findings. Radiology160:313–317

40. Stewart JG, MacMahon H, VybornyCJ, Pollak ER (1987) Dystrophic cal-cification in carcinoma of the lung:demonstration by CT. AJR Am JRoentgenol 148:29–30

463

41. Swensen SJ, Morin RL, Schueler BA,Brown LR, Cortese DA, Pairolero PC,Brutinel WM (1992) Solitary pulmo-nary nodule: CT evaluation of en-hancement with iodinated contrastmaterial: a preliminary report.Radiology 182:343–347

42. Yamashita K, Matsunobe S, TakahashiR, Tsuda T, Matsumoto K, Miki H,Oyanagi H, Konishi J (1995) Smallperipheral lung carcinoma evaluatedwith incremental dynamic CT: radio-logic-pathologic correlation. Radiology196:401–408

43. Yamashita K, Matsunobe S, Tsuda T,Nemoto T, Matsumoto K, Miki H,Konishi J (1995) Solitary pulmonarynodule: preliminary study of evaluationwith incremental dynamic CT.Radiology 194:399–405

44. Swensen SJ, Viggiano RW, MidthunDE, Muller NL, Sherrick A, YamashitaK, Naidich DP, Patz EF, Hartman TE,Muhm JR, Weaver AL (2000) Lungnodule enhancement at CT: multicenterstudy. Radiology 214:73–80

45. Yi CA, Lee KS, Kim EA, Han J, KimH, Kwon OJ, Jeong YJ, Kim S (2004)Solitary pulmonary nodules: dynamicenhanced multi-detector row CT studyand comparison with vascular endo-thelial growth factor and microvesseldensity. Radiology 233:191–199

46. Gupta NC, Frank AR, Dewan NA,Redepenning LS, Rothberg ML,Mailliard JA, Phalen JJ, Sunderland JJ,Frick MP (1992) Solitary pulmonarynodules: detection of malignancy withPET with 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 184:441–444

47. Gupta NC, Maloof J, Gunel E (1996)Probability of malignancy in solitarypulmonary nodules using fluorine-18-FDG and PET. J Nucl Med 37:943–948

48. Lowe VJ, Fletcher JW, Gobar L,Lawson M, Kirchner P, Valk P, Karis J,Hubner K, Delbeke D, Heiberg EV,Patz EF, Coleman RE (1998) Prospec-tive investigation of positron emissiontomography in lung nodules. J ClinOncol 16:1075–1084

49. Patz EF, Jr., Lowe VJ, Hoffman JM,Paine SS, Burrowes P, Coleman RE,Goodman PC (1993) Focal pulmonaryabnormalities: evaluation with F-18fluorodeoxyglucose PET scanning.Radiology 188:487–490

50. Rohren EM, Turkington TG, ColemanRE (2004) Clinical applications of PETin oncology. Radiology 231:305–332

51. Erasmus JJ, McAdams HP, Patz EF, Jr.,Coleman RE, Ahuja V, Goodman PC(1998) Evaluation of primary pulmo-nary carcinoid tumors using FDG PET.AJR Am J Roentgenol 170:1369–1373

52. Higashi K, Ueda Y, Seki H, Yuasa K,Oguchi M, Noguchi T, Taniguchi M,Tonami H, Okimura T, Yamamoto I(1998) Fluorine-18-FDG PET imagingis negative in bronchioloalveolar lungcarcinoma. J Nucl Med 39:1016–1020

53. Kim BT, Kim Y, Lee KS, Yoon SB,Cheon EM, Kwon OJ, Rhee CH, Han J,Shin MH (1998) Localized form ofbronchioloalveolar carcinoma: FDGPET findings. AJR Am J Roentgenol170:935–939

54. Nomori H, Watanabe K, Ohtsuka T,Naruke T, Suemasu K, Uno K (2004)Evaluation of F-18 fluorodeoxyglucose(FDG) PET scanning for pulmonarynodules less than 3 cm in diameter,with special reference to the CT im-ages. Lung Cancer 45:19–27

55. Steinert HC, Kamel EM, de Juan R(2003) PET and PET/CT of tumors ofthe chest. In: von Schulthess GK (ed)Clinical molecular anatomic imaging,Lippincot, Philadelphia, PA, p 291–305

56. Yankelevitz DF, Henschke CI (1997)Does 2-year stability imply that pul-monary nodules are benign? AJR Am JRoentgenol 168:325–328

57. Takashima S, Sone S, Li F, MaruyamaY, Hasegawa M, Kadoya M (2003)Indeterminate solitary pulmonary nod-ules revealed at population-based CTscreening of the lung: using firstfollow-up diagnostic CT to differentiatebenign and malignant lesions. AJR AmJ Roentgenol 180:1255–1263

58. Usuda K, Saito Y, Sagawa M, Sato M,Kanma K, Takahashi S, Endo C, ChenY, Sakurada A, Fujimura S (1994)Tumor doubling time and prognosticassessment of patients with primarylung cancer. Cancer 74:2239–2244

59. Winer-Muram HT, Jennings SG, TarverRD, Aisen AM, Tann M, Conces DJ,Meyer CA (2002) Volumetric growthrate of stage I lung cancer prior totreatment: serial CT scanning.Radiology 223:798–805

60. Erasmus JJ, McAdams HP, ConnollyJE (2000) Solitary pulmonary nodules.Part II. Evaluation of the indeterminatenodule. Radiographics 20:59–66

61. Aoki T, Nakata H, Watanabe H,Nakamura K, Kasai T, Hashimoto H,Yasumoto K, Kido M (2000) Evolutionof peripheral lung adenocarcinomas:CT findings correlated with histologyand tumor doubling time. AJR Am JRoentgenol 174:763–768

62. Hasegawa M, Sone S, Takashima S, LiF, Yang ZG, Maruyama Y, Watanabe T(2000) Growth rate of small lungcancers detected on mass CT screening.Br J Radiol 73:1252–1259

63. Kakinuma R, Ohmatsu H, Kaneko M,Kusumoto M, Yoshida J, Nagai K,Nishiwaki Y, Kobayashi T, Tsuchiya R,Nishiyama H, Matsui E, Eguchi K,Moriyama N (2004) Progression offocal pure ground-glass opacity de-tected by low-dose helical computedtomography screening for lung cancer.J Comput Assist Tomogr 28:17–23

64. Jennings SG, Winer-Muram HT, TarverRD, Farber MO (2004) Lung tumorgrowth: assessment with CT-compari-son of diameter and cross-sectional areawith volume measurements. Radiology231:866–871

65. Revel MP, Bissery A, Bienvenu M,Aycard L, Lefort C, Frija G (2004) Aretwo-dimensional CT measurements ofsmall noncalcified pulmonary nodulesreliable? Radiology 231:453–458

66. Kostis WJ, Yankelevitz DF, Reeves AP,Fluture SC, Henschke CI (2004) Smallpulmonary nodules: reproducibility ofthree-dimensional volumetric measure-ment and estimation of time to follow-up CT. Radiology 231:446–452

67. Yankelevitz DF, Reeves AP, Kostis WJ,Zhao B, Henschke CI (2000) Smallpulmonary nodules: volumetrically de-termined growth rates based on CTevaluation. Radiology 217:251–256

68. Revel MP, Lefort C, Bissery A, BienvenuM, Aycard L, Chatellier G, Frija G (2004)Pulmonary nodules: preliminary experi-ence with three-dimensional evaluation.Radiology 231:459–466

69. Wormanns D, Kohl G, Klotz E,Marheine A, Beyer F, Heindel W,Diederich S (2004) Volumetric mea-surements of pulmonary nodules atmulti-row detector CT: in vivo repro-ducibility. Eur Radiol 14:86–92

70. Goodman LR, Gulsun M, WashingtonL, Nagy PG, Piacsek KL (2006) In-herent variability of CT lung nodulemeasurements in vivo using semiauto-mated volumetric measurements. AJRAm J Roentgenol 186:989–994

71. Gaeta M, Barone M, Russi EG, Volta S,Casablanca G, Romeo P, La Spada F,Minutoli A (1993) Carcinomatous soli-tary pulmonary nodules: evaluation ofthe tumor-bronchi relationship with thin-section CT. Radiology 187:535–539

464

72. Gaeta M, Pandolfo I, Volta S, Russi EG,Bartiromo G, Girone G, La Spada F,Barone M, Casablanca G, Minutoli A(1991)Bronchus sign onCTin peripheralcarcinoma of the lung: value in predictingresults of transbronchial biopsy. AJR AmJ Roentgenol 157:1181–1185

73. Wang KP, Haponik EF, Britt EJ, KhouriN, Erozan Y (1984) Transbronchialneedle aspiration of peripheral pulmo-nary nodules. Chest 86:819–823

74. Greene R, Szyfelbein WM, Isler RJ,Stark P, Janstsch H (1985) Supplemen-tary tissue-core histology from fine-nee-dle transthoracic aspiration biopsy. AJRAm J Roentgenol 144:787–792

75. Klein JS, Zarka MA (1997) Transtho-racic needle biopsy: an overview.J Thorac Imaging 12:232–249

76. Moore EH (1997) Needle-aspirationlung biopsy: a comprehensive approachto complication reduction. J ThoracImaging 12:259–271

77. Wallace JM, Deutsch AL (1982) Flex-ible fiberoptic bronchoscopy and per-cutaneous needle lung aspiration forevaluating the solitary pulmonary nod-ule. Chest 81:665–671

78. Westcott JL (1980) Direct percutaneousneedle aspiration of localized pulmo-nary lesions: result in 422 patients.Radiology 137:31–35

79. Yamagami T, Iida S, Kato T, Tanaka O,Nishimura T (2003) Combining fine-needle aspiration and core biopsy underCT fluoroscopy guidance: a better wayto treat patients with lung nodules?AJR Am J Roentgenol 180:811–815

80. Lucidarme O, Howarth N, Finet JF,Grenier PA (1998) Intrapulmonary le-sions: percutaneous automated biopsywith a detachable, 18-gauge, coaxialcutting needle. Radiology 207:759–765

81. Daly BD, Faling LJ, Diehl JT, BankoffMS, Gale ME (1991) Computedtomography-guided minithoracotomyfor the resection of small peripheralpulmonary nodules. Ann Thorac Surg51:465–469

82. Suzuki K, Nagai K, Yoshida J,Ohmatsu H, Takahashi K, NishimuraM, Nishiwaki Y (1999) Video-assistedthoracoscopic surgery for small inde-terminate pulmonary nodules: indica-tions for preoperative marking. Chest115:563–568

83. Plunkett MB, Peterson MS,Landreneau RJ, Ferson PF, Posner MC(1992) Peripheral pulmonary nodules:preoperative percutaneous needle lo-calization with CT guidance. Radiology185:274–276

84. Templeton PA, Krasna M (1993) Lo-calization of pulmonary nodules forthoracoscopic resection: use of needle/wire breast-biopsy system. AJR Am JRoentgenol 160:761–762

85. Tsuchida M, Yamato Y, Aoki T,Watanabe T, Koizumi N, Emura I,Hayashi J (1999) CT-guided agarmarking for localization of nonpalpableperipheral pulmonary lesions. Chest116:139–143

86. Lenglinger FX, Schwarz CD, ArtmannW (1994) Localization of pulmonarynodules before thoracoscopic surgery:value of percutaneous staining withmethylene blue. AJR Am J Roentgenol163:297–300

87. Vandoni RE, Cuttat JF, Wicky S, SuterM (1998) CT-guided methylene-bluelabelling before thoracoscopic resectionof pulmonary nodules. Eur JCardiothorac Surg 14:265–270

88. Shah RM, Spirn PW, Salazar AM,Steiner RM, Cohn HE, Solit RW,Wechsler RJ, Erdman S (1993) Local-ization of peripheral pulmonary nod-ules for thoracoscopic excision: valueof CT-guided wire placement. AJR AmJ Roentgenol 161:279–283

89. Tan BB, Flaherty KR, Kazerooni EA,Iannettoni MD (2003) The solitarypulmonary nodule. Chest 123:89S–96S

90. Gurney JW (1993) Determining thelikelihood of malignancy in solitarypulmonary nodules with Bayesiananalysis. Part I. Theory. Radiology186:405–413

91. Gurney JW, Lyddon DM, McKay JA(1993) Determining the likelihood ofmalignancy in solitary pulmonary nod-ules with Bayesian analysis. Part II.Application. Radiology 186:415–422

92. Gurney JW, Swensen SJ (1995) Soli-tary pulmonary nodules: determiningthe likelihood of malignancy withneural network analysis. Radiology196:823–829

93. Matsuki Y, Nakamura K, Watanabe H,Aoki T, Nakata H, Katsuragawa S, DoiK (2002) Usefulness of an artificialneural network for differentiating be-nign from malignant pulmonary nod-ules on high-resolution CT: evaluationwith receiver operating characteristicanalysis. AJR Am J Roentgenol178:657–663

94. Cummings SR, Lillington GA, RichardRJ (1986) Estimating the probability ofmalignancy in solitary pulmonary nod-ules: aBayesian approach. Am RevRespir Dis 134:449–452

95. Quint LE, Park CH, Iannettoni MD(2000) Solitary pulmonary nodules inpatients with extrapulmonary neo-plasms. Radiology 217:257–261

96. Ginsberg MS, Griff SK, Go BD, YooHH, Schwartz LH, Panicek DM (1999)Pulmonary nodules resected at video-assisted thoracoscopic surgery: etiologyin 426 patients. Radiology 213:277–282

97. Benjamin MS, Drucker EA, McLoudTC, Shepard JA (2003) Small pulmo-nary nodules: detection at chest CT andoutcome. Radiology 226:489–493

98. Grampp S, Bankier AA, Zoubek A,Wiesbauer P, Schroth B, Henk CB,Grois N, Mostbeck GH (2000) SpiralCT of the lung in children with malig-nant extra-thoracic tumors: distributionof benign vs. malignant pulmonarynodules. Eur Radiol 10:1318–1322

99. Yuan Y, Matsumoto T, Hiyama A, MiuraG, Tanaka N, Emoto T, Kawamura T,Matsunaga N (2003) The probability ofmalignancy in small pulmonary nodulescoexisting with potentially operable lungcancer detected by CT. Eur Radiol13:2447–2453

100. Kim YH, Lee KS, Primack SL, Kim H,Kwon OJ, Kim TS, Kim EA, Kim J,Shim YM (2002) Small pulmonarynodules on CT accompanying surgi-cally resectable lung cancer: likelihoodof malignancy. J Thorac Imaging17:40–46

101. Keogan MT, Tung KT, Kaplan DK,Goldstraw PJ, Hansell DM (1993) Thesignificance of pulmonary nodulesdetected on CT staging for lung cancer.Clin Radiol 48:94–96

102. Read WL, Tierney RM, Page NC,Costas I, Govindan R, Spitznagel EL,Piccirillo JF (2004) Differential prog-nostic impact of comorbidity. J ClinOncol 22:3099–3103

103. MacMahon H, Austin JH, Gamsu G,Herold CJ, Jett JR, Naidich DP, PatzEF, Jr., Swensen SJ (2005) Guidelinesfor management of small pulmonarynodules detected on CT scans: astatement from the Fleischner Society.Radiology 237:395–400

104. Bach PB, Kattan MW, ThornquistMD, Kris MG, Tate RC, Barnett MJ,Hsieh LJ, Begg CB (2003) Variationsin lung cancer risk among smokers.J Natl Cancer Inst 95:470–478

105. Bain C, Feskanich D, Speizer FE,Thun M, Hertzmark E, Rosner BA,Colditz GA (2004) Lung cancer ratesin men and women with comparablehistories of smoking. J Natl CancerInst 96:826–834

106. Blot WJ, McLaughlin JK (2004) Arewomen more susceptible to lung can-cer? J Natl Cancer Inst 96:812–813

465

107. Risch HA, Howe GR, Jain M, BurchJD, Holowaty EJ, Miller AB (1993)Are female smokers at higher risk forlung cancer than male smokers? Acase-control analysis by histologictype. Am J Epidemiol 138:281–293

108. Field RW, Steck DJ, Smith BJ, BrusCP, Fisher EL, Neuberger JS, PlatzCE, Robinson RA, Woolson RF,Lynch CF (2000) Residential radongas exposure and lung cancer: theIowa Radon Lung Cancer Study. Am JEpidemiol 151:1091–1102

109. Gottlieb LS, Husen LA (1982) Lungcancer among Navajo uranium miners.Chest 81:449–452

110. Mayne ST, Buenconsejo J, Janerich DT(1999) Familial cancer history and lungcancer risk in United States nonsmokingmen and women. Cancer EpidemiolBiomarkers Prev 8:1065–1069

111. Bailey-Wilson JE, Amos CI, PinneySM, Petersen GM, de Andrade M,Wiest JS, Fain P, Schwartz AG, YouM, Franklin W, Klein C, Gazdar A,Rothschild H, Mandal D, Coons T,Slusser J, Lee J, Gaba C, Kupert E,Perez A, Zhou X, Zeng D, Liu Q,Zhang Q, Seminara D, Minna J,Anderson MW (2004) A major lungcancer susceptibility locus maps tochromosome 6q23-25. Am J HumGenet 75:460–474

112. Lee PN (2001) Relation between ex-posure to asbestos and smoking jointlyand the risk of lung cancer. OccupEnviron Med 58:145–153

113. Swensen SJ, Jett JR, Hartman TE,Midthun DE, Sloan JA, Sykes AM,Aughenbaugh GL, Clemens MA(2003) Lung cancer screening withCT: Mayo Clinic experience.Radiology 226:756–761

114. Swensen SJ, Jett JR, Hartman TE,Midthun DE, Mandrekar SJ, HillmanSL, Sykes AM, Aughenbaugh GL,Bungum AO, Allen KL (2005) CTscreening for lung cancer: five-yearprospective experience. Radiology235:259–265

115. Piyavisetpat N, Aquino SL, Hahn PF,Halpern EF, Thrall JH (2005) Smallincidental pulmonary nodules: Howuseful is short-term interval CT fol-low-up? J Thorac Imaging 20:5–9

466