Eur Radiol (2007) 17: 449–466DOI 10.1007/s00330-006-0399-7               CHESTCatherine Beigelman-AubryCatherine Hill     ...
450benign. In recent publications on CT screening for lung               Table 1 Causes of incidentally discovered solid p...
451nodules. “Solid nodules” are seen most frequently and are               raises several possibilities. This could repres...
452Fig. 2 Round shaped non-solid nodules with regularmargins in two differentpatients. Primary adenocarcino-mas. a 46-year...
453Fig. 5 Mixed nodule containing bubble like lucencies in the left    examination 2 months later (right). The presumed di...
454Fig. 7 58-year-old man pre-senting a spherical (10-mm)nodule with regular and well-defined contours in the upperpart of...
455                                                                   Fig. 10 25-mm solid nodule containing in the periphe...
456Fig. 11 Entirely calcified nod-ule of the upper part of the leftupper lobe. Diffuse and intensecalcification of the nod...
457Table 4 Criteria defining an indeterminate nodule               investigation of thoracic and extra-thoracic extension ...
458mixed nodules persistent after 1 month of antibiotic          operators. This variation in measurement is above thether...
459Fig. 13 The same patient as inFig. 12. The three-dimensionalreconstructions of the nodule onthe initial CT scan (left) ...
460these nodules must remain within 20 mm of the visceral           Probability of malignancyperipheral or fissural pleura...
461    and life expectancy diminishes. So an indeterminate           pulmonary fibrosis, or immunodeficiency were fol-    ...
462Table 5 Fleischner Society recommendations for the surveillance           years or more (modified from McMahon et al. R...
463 8. Yang ZG, Sone S, Takashima S, Li F,        19. Asamura H, Suzuki K, Watanabe S,           29. Nambu A, Araki T, Tag...
46441. Swensen SJ, Morin RL, Schueler BA,        51. Erasmus JJ, McAdams HP, Patz EF, Jr.,      62. Hasegawa M, Sone S, Ta...
46572. Gaeta M, Pandolfo I, Volta S, Russi EG,      83. Plunkett MB, Peterson MS,                   95. Quint LE, Park CH,...
466107. Risch HA, Howe GR, Jain M, Burch        110. Mayne ST, Buenconsejo J, Janerich DT      113. Swensen SJ, Jett JR, H...
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  1. 1. Eur Radiol (2007) 17: 449–466DOI 10.1007/s00330-006-0399-7 CHESTCatherine Beigelman-AubryCatherine Hill Management of an incidentally discoveredPhilippe A. Grenier pulmonary noduleReceived: 28 February 2006 Abstract The incidental finding of a and limitations of complementaryRevised: 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) toPublished 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 providedC. Beigelman-Aubry . C. Hill . indicated without delay. However, by the Fleischner Society for theP. A. Grenier (*) invasive diagnostic procedures should management of small indeterminateService de Radiologie Polyvalente,Diagnostique et Interventionnelle, be avoided in the case of a benign pulmonary nodules, according to theirHôpital Pitié-Salpêtrière-Assistance lesion. The objectives of this review prior probability of malignancy.Publique-Hôpitaux de Paris, article are: (1) to analyze the CT47-83 boulevard de l’Hôpital, criteria defining benign nodules, nod- Keywords Pulmonary nodule .75651 Paris cedex 13, Francee-mail: philippe.grenier@psl.aphp.fr ules of high suspicion of malignancy Nodule characterization . PulmonaryTel.: +33-1-42178225 and indeterminate nodules, (2) to adenocarcinoma . BronchioloalveolarFax: +33-1-42178224 analyze the diagnostic performances cell carcinoma . Non-solid noduleIntroduction 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 andrays or, more recently, on computed tomography (CT) is multidetector row CT in the late 1990s, the detection ofbecoming an increasingly frequent event. When discovered nodules as small as 1–2 mm in diameter has becomeon 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, particularlyprocedures should be avoided in the case of a benign in the central lung [4]. Computed-aided detection systemslesion. Similarly, it is necessary to avoid excessive patient have shown to improve the performances of radiologists inirradiation through an infinite number of follow-up CT detecting small nodules on CT scans with higher sensitivityexaminations. 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 smallmalignant tumour who would benefit from potentially nodules differs substantially from that of larger nodulescurative surgical treatment, whilst avoiding needle biopsy detected on chest radiographs, in that the vast majority are
  2. 2. 450benign. In recent publications on CT screening for lung Table 1 Causes of incidentally discovered solid pulmonary nodulescancer, the positive relationship of lesion size to likelihood Aetiological classificationof malignancy has been clearly demonstrated [6, 7]. Duringthe past 5-years, new information regarding prevalence, Neoplastic Primary pulmonary carcinoma (adenocarcino-biologic characteristics, and growth rate of small lung ma, bronchioloalveolar carcinoma, squamouscancers has become available, and new guidelines for cell carcinoma, small cell carcinoma)follow-up and management of small pulmonary nodules Malignant Primary pulmonary lymphomadetected 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- GranulomasA pulmonary nodule is defined as a focal pulmonary lesion flammatory Opportunistic infectionor opacity, round or oval in shape, which measures less Round pneumoniathan 3 cm in diameter. A pulmonary nodule is considered Abscesssmall if its largest diameter is 10 mm or less. Above 3 cm in Focal organising pneumoniasize, the lesion is classified as a mass, and the high Cicatrizing fibrosisprobability of malignancy in this case warrants further Necrobiotic nodule in rheumatoid arthritisinvestigation by biopsy or surgical resection. Wegener’s granulomatosis Today, the classification of a pulmonary nodule has been Vascular Pulmonary artery aneurysmextended to include focal areas of ground glass attenuation Pulmonary varices[8], and all small opacities only a few millimetres in size Pulmonary arteriovenous malformationdiscovered incidentally on CT [9]. In general, linear and Pulmonary infarctband-like opacities are excluded from this definition, where Haematomathe likelihood of malignancy is virtually non-existent. Miscellaneous Intrapulmonary lymph node The classic description of a solitary pulmonary nodule istoo restrictive these days, as patients undergoing CT exam- Rounded atelectasisination often have more than one nodule present. For a given Bronchogenic cystpatient, each pulmonary nodule detected must be investigated Mucoid impactionand 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 greatlyincreases [10]; in this case, the investigation differs totally and along with its relationship to bronchovascular structuresis 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 studycomprising of tumours, infection and inflammatory the content and density of the nodule. The evaluation is ofdisorders, but also vascular and congenital causes. The course completed by an exhaustive helical study of themost common malignant lesions are pulmonary metastases entire thorax to confirm if the nodule is solitary, orand primary bronchopulmonary carcinoma. All histologi- associated with other nodular lesions. This also allowscal 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 thenodules are benign, of which 80% are granulomas or entire thorax with thin collimation, it is possible today tointrapulmonary lymph nodes [11], 10% are hamartomas reconstruct 3 or 5 mm contiguous images for lesionand 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 pulmonaryNodule characterisation by CT nodule with 1 mm slice thickness reconstruction, and then perform a maximum intensity projection with slabs ofCharacterisation is based on analysis of the density and around 3 to 5 mm for an easy and confident detection ofmorphology of the nodule. Spiral CT acquisition must be multiple lung nodules.performed 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 spatial Nodule characterisation according to densityresolution reconstruction filter is recommended for pul-monary windows, enabling precise evaluation of the Nodules are classified into three main categories based oninterface between the nodule and the lung parenchyma, their density, solid, non-solid, and part-solid (mixed)
  3. 3. 451nodules. “Solid nodules” are seen most frequently and are raises several possibilities. This could represent athe 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 pulmonarywhich 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 interstitialappearing as areas of focal ground glass. The outline of pneumonia in a smoker [22]. Finally, although lessvessels in contact with or traversing such lesions is not commonly, it could correspond to pulmonary metastaseseffaced (Fig. 2). Specific management of these nodules is exhibiting a lepidic growth pattern, as described inrequired. 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-solidand/or anti-infectious treatment [16]. If a lesion persists ground glass component within which there exists a solidafter 1 month of treatment, it becomes a persistent or component of soft tissue density [24–26] (Fig. 4). Thesechronic non-solid nodule, which could be neoplastic or mixed, or part-solid, nodules may be due to infectious ornon-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 ania in a smoker or pulmonary fibrosis [18] (Fig. 3). lesion persists after 1-month of treatment, it becomes aNeoplastic causes may be benign, specifically atypical persistent or chronic mixed nodule, which is highlyadenomatous hyperplasia, or malignant, consisting of suspicious of malignancy [16, 17, 24]. This usuallyadenocarcinoma or bronchioloalveolar cell carcinoma. corresponds to a primary adenocarcinoma. The solid tissueMalignant 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 nodulescases, these lesions are small in size, measuring less than measuring less than or equal to 10 mm diameter with a5 mm in diameter. Above this size, the lesion becomes ground glass component were malignant, whereas onlyhighly suspicious for adenocarcinoma. The presence of 30% of nodules of the same size with no ground glassmultiple 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 anby 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 largestthickened in its segment close to the nodule. At surgery, the nodule and smallest cross-sectional diameters of the mostwas due to an invasive adenocarcinoma representative area of the nodule. In ongoing low-dose
  4. 4. 452Fig. 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 adenocarcinomaCT-lung-cancer-screening studies of at risk populations, ing less than 5 mm varies between 0.1–1%. The prevalencethe 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 malignantFig. 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 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 lesionsurgery the nodule was due to a focal area of desquamative contains bubble like lucencies. The pathological diagnosis wasinterstitial pneumonia primary adenocarcinoma
  5. 5. 453Fig. 5 Mixed nodule containing bubble like lucencies in the left examination 2 months later (right). The presumed diagnosis wasupper lobe (left). The lesion decreased in size after 1 month of focal organizing pneumoniaantibiotics (middle) and disappeared entirely on the follow-up CTnodules, but may contribute in the probability of malig- appearance of benign and malignant nodules is directlynancy. Well-defined, smooth and regular margins suggest proportional to the quantity of emphysema around thenodule 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 nodulesparticular 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 ineven 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 upperbetween benignity and malignancy, and the overlap in the lobes. Nodules 3–9 mm in size, triangular or ovoid inFig. 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
  6. 6. 454Fig. 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 lobulationshape, and attached to a fissure are often intrapulmonary strongly suggestive of adenocarcinoma, bronchioloalveolarlymph 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 ascause, 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 ofAnalysis of nodule content imaging. In the case of adenocarcinoma or bronchioloal- veolar cell carcinoma, this sign represents lepidic tumoralAn “air bronchogram and/or pseudocavitation” are more growth which respects the pulmonary architecture andfrequently observed in malignant (30%) than benign (5%) bronchi. An air bronchogram may appear to be slightlylesions. Concerning a malignant nodule, this sign is distorted or dilated. This is seen in particular whenFig. 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)
  7. 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 adenocarcinomaFig. 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). 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 calcificationretractile 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, andbronchogram or pseudocavitation, with or without dilata- therefore the diagnosis of hamartoma. However, thetion, may also be encountered in focal organising pneu- radiological diagnosis of hamartoma requires furthermonia [32, 35] (Fig. 5). Air bronchogram and air criteria to be fulfilled [39]. Conversely, eccentric orcontaining space within a non-solid nodule have also dispersed calcification is highly suggestive of a malignantproven 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 ismay be seen in lung abscesses. Benign cavitating lesions always a formal criterion for benignancy. A densitymore often have distinct, regular internal contours and thin between −40 and −120 HU is strongly suggestive of thewalls, whereas malignant nodules typically have thick and diagnosis of hamartoma (Fig. 7). The CT criteria forirregular 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, andwith 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 contributoryfactor in suggesting malignancy or benignancy. Diffusenodule “calcification” is highly characteristic of an old Complementary investigationsgranulomatous lesion and is sufficient evident alone todefinitively confirm benignancy (Fig. 11). The only Subsequent to the CT study, the nodule may be classifiedexception is a known previous history of osteosarcoma, into one of the following three categories: benign, highly
  8. 8. 456Fig. 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 nodulesuspicious for malignancy or indeterminate. Nodules quantitatively from benign nodules [41–43]. The degree ofconsidered as benign are those showing diffuse calcifica- uptake of iodinated contrast material is directly linked totion, or a specific criterion for benignity outlined in Table 2. the probability of malignancy and nodule vascularisationNo further investigation of these lesions is necessary when [44]. This technique was the subject of a multi-centre studythe nodule is entirely calcified. A simple radiographic which demonstrated that an increased enhancement of 15surveillance until two years of stability is only requested in HU was the most effective threshold [44]. This thresholdother 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 specificitysuspicious of malignancy, outlined in Table 3, must be is related to the fact that numerous benign lesions maysubject to histological confirmation by biopsy or surgical show increased enhancement due to rich vascularisation, inresection. Indeterminate nodules, representing around 70% particular hamartomas and certain infectious lesions. Onof cases, include all other nodules of which criteria are the other hand, the excellent sensitivity leads to a very highsummarised in Table 4. The management of indeterminate negative predictive value. So, a nodule with either no ornodule is variable and is based on complementary very little enhancement following contrast injection can beinvestigations, 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 ofevaluation 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 themalignant pulmonary nodules differs qualitatively and Table 3 Criteria defining a nodule as highly suspicious ofTable 2 Criteria defining a benign nodule malignancy (a single criterion is sufficient)Benign nodule criteria Criteria defining a nodule as highly suspicious of malignancyDiffuse, dense calcification Persistent non-solid (focal) ground glass nodule measuring 10 mmVessels 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 diameterDiagnostic criteria of hamartoma (round shape, smooth, regular Solid nodule with spiculated contours contours, containing fat density, +/– popcorn calcification) Solid nodule containing air bronchogram or pseudocavitationBenign-type calcification (central, target, laminated, concentric) Solid nodule containing eccentric or dispersed calcifications
  9. 9. 457Table 4 Criteria defining an indeterminate nodule investigation of thoracic and extra-thoracic extension withIndeterminate nodule criteria tumour characterisation. When the nodule is less than 1 cm in diameter or of ground glass attenuation on CT, PET isPersistent 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]. WithSolid 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 growthnodule, over a region representing at least 60% of thenodule’s surface area. Given that measurement of the In the course of surveillance, this entails repeated CTdensity is difficult for heterogeneous lesions and those less examinations in order to screen for growth, reduction inthan 1 cm in diameter, in practice this technique only yields size or resolution of the nodule [56, 57]. In order to limitreliable information for homogenous nodules equal to or the number of surveillance CT examinations required, aabove 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 thein 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 doseenhancement of 30 HU or more was the retained criterion using thin collimation, without contrast injection, and iffor 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 calculated97% 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=ViÞstudy, the peak enhancement value within the nodulepositively correlated with both the concentration ofmicrovessels present within the lesion on histological where Vi is the initial volume of the nodule, Vf the finalexamination and the scoring of immunological markers for volume, t the time interval between observations and ln thevascular endothelial growth factor. logarithmic value. This formula is based on an exponential model of nodule growth. The doubling time of most malignant solid nodules isPositron 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 or2-deoxy-D-Glucose (FDG) fixation, which is elevated in CT, over a period greater than 2 years implies a doublingneoplastic lesions [46–49]. Today, the value of this time of at least 730 days, which is generally considered totechnique 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 doublingsensitivity of 90% and a specificity of 83% for diagnosing time of tumours lies between 160 and 180 days, assuming amalignancy [50]. Yet, certain histological types with low constant growth rate. However, all of these studiesmetabolism such as low-grade adenocarcinoma, bronchio- recognise a large variation in the volume doubling timeloalveolar cell carcinoma and carcinoid tumours, may give of nodules detected, and in one study 22% of tumours had arise 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, mayinflammatory 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 smallFDG. 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 fora pulmonary lesion of 10 mm or more does not fix with ground glass nodules. These results therefore suggest theFDG, clinical and radiological surveillance may be need for more prolonged surveillance of ground glassproposed, thereby avoiding surgery. Another interest of nodules than for solid nodules. It is important to rememberthe technique lies also in the possibility of combining that, according to the high probability of malignancy,
  10. 10. 458mixed nodules persistent after 1 month of antibiotic operators. This variation in measurement is above thetherapy should be resected without delay. During increase in diameter expected for a nodule of 5 mm whichsurveillance of ground glass nodules, the appearance of doubles in volume (Fig. 12). In order to avoid thisa soft-tissue component is a highly suspicious sign of limitation, it was proposed that the growth rate of all smallmalignancy, 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 variationsdiameter 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 clearlyassessment of lung tumours measuring less than 3 cm on more reliable than a surface measurement, and moreoverCT serial CT scans with non-volumetric measurements the measurement of diameter [66, 67]. The very goodfrequently disagrees with growth assessment with volu- reproducibility of volume measurements by the same andmetric 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 allof only 26% of its diameter according to the formula modifications of shape, as well as asymmetric growth ofV ¼4 3πr3, where r is the radius. Therefore, it may be the nodule, not visible on CT [67, 68] (Fig. 13). Thedifficult to evaluate an increase or decrease in the axial majority of nodules are correctly segmented by thediameter 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 awhich doubles in volume will only increase in diameter by pulmonary vessel and a nodule may lead to a variable1.25 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 ofdemonstrated that this type of measurement varied by inspiration between two CT examinations and this may1.3 mm for the most reproducible operator, with a variation interfere with the temporal growing calculation andof between −1.73 and +1.73 for three independent doubling time. For this reason, it is always necessary toFig. 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)
  11. 11. 459Fig. 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 wasadenocarcinomacontrol 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 absentangular 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 ininations requires software allowing rapid selection of the biopsy planning by specifying lesion depth and the pointpertinent images, with the best possible correlation to aid of the needle in order to aid the approach, and to avoidcomparison. The reproducibility of volumetric measure- the needle path traversing a bulla or fissure. Evenments for the same nodule between different CT examina- lesions less than 10 mm in diameter may be biopsied intions remains dependent on the acquisition and image this way. Although the minimum size varies accordingreconstruction parameters used (slice thickness, kV, mAs, to the expertise of the radiologist, a diameter of at leastreconstruction filter, and pulmonary volume). It is therefore 7 mm is usually required. The main complications ofrecommended to use the same acquisition and image pneumothorax and haemorrhage are seen in 5–30% ofreconstruction parameters on forced suspended inspiration, cases [74–78]. Fine-needle aspiration biopsy yieldswhen 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 anity of this method of measurement. Goodman et al. have onsite cytopathologist at the time of biopsy, allowingraised 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 onsitebetween scans in vivo is still substantial with wide cytopathologist, the use of coaxial cutting needles isconfidence limits of 13.1% (±26.6%) [70]. For this reason, recommended which yield more voluminous biopsyit 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 specificsignificant 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 thanNodule 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 ontechniques can be useful in directing the choice. If the the whole lesion. The operative mortality of thoracotomy isnodule 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-assisteddetected on CT, then “bronchoscopy targeting” to the thoroscopy” has allowed a decrease in peri-operativeappropriate level is recommended and often diagnostic. morbidity and hospitalisation time [82]. Even very smallIn such a case, the CT examination can optimize the nodules may be sampled using this technique. However,
  12. 12. 460these nodules must remain within 20 mm of the visceral Probability of malignancyperipheral or fissural pleura in order to be visualised orpalpated during the procedure. CT may be used to guide The “probability of malignancy” of an indeterminateand help the surgeon during video-assisted thoroscopy. nodule is dependent on several factors: previous historyAdvanced localisation of lesions to be resected is possible of cancer, patient age, smoking history, nodule size, andusing 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 primaryplacement 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 previousManagement 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 CTnodule [3, 60, 89]. Clinical information such as patient age, examinations reported by Benjamin et al., 334 patientsprevious 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 orsuggesting a diagnosis, and guiding the type of manage- surveyed for over 2 years, 77 were benign and 10ment of the nodule. For example, a newly discovered malignant. Nine of the 10 malignant nodules werepulmonary nodule in a young adult presenting with a discovered in patients with a previous history ofperipheral 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 malignancytumour. 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 werenamed 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 discoverythe best evaluation of malignant probability. It uses the of a small pulmonary nodule measuring less thanlikelihood ratios using clinical and radiological signs in 10 mm, situated in the same lobe as the primary cancerorder 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 141using 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 smallalso been used [92, 93] and artificial neural networks (10 mm) pulmonary nodules. One hundred andappear to be of significant help in differentiating between thirty-two of these nodules (95.7%) were proven to bebenign 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 nodulesment strategies for solitary pulmonary nodules depend on turned out to be benign, 11% were malignant, andthe probability of the nodule being cancerous. Several 19% were indeterminate [101]. A similar result wasstudies, published in the middle of the 1980s, enabled the found in a retrospective analysis of 223 patients withsuggestion that the most pertinent strategy in terms of cost- resectable lung cancer: 75% of all 71 nodules 10 mmeffectiveness 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 ofsurgical resection for those with a high probability of malignancy increases. Conversely, lung cancer is verymalignancy (≥60%) and biopsy for those with a probability unusual in subjects less than 40 years old, and evenof malignancy between 5 and 60% [94]. Unfortunately, rarer in the under 35 s. In elderly subjects, the presencethese 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 outweighPET, in order to produce a better pre-operative stratification those of progression of a small lung cancer [102]. Inof 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. 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. 14. 462Table 5 Fleischner Society recommendations for the surveillance years or more (modified from McMahon et al. Radiology 2005and management pulmonary nodules discovered incidentally on CT [103], with permission)of an indeterminate nodule discovered recently in a patient aged 35Nodule 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 changea Average of largest and smallest axial diameters of the noduleb No smoking history and absence of other risk factorsc Previous or current smoking history, or other risk factorsd Risk of malignancy (0.01%) is substantially lower than for an asymptomatic smokere 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. Incould be secondary to a pulmonary metastasis and must consequence, unless there is a known history of primarytherefore be managed according to a protocol adapted to cancer, multiple control CT scans should be avoided forthe clinical situation. Pertinent factors include the site, cell incidentally discovered small nodules. In such a case, atype and stage of the primary tumour, and the impact of single low-dose CT may be recommended at between 6 anddetection of a pulmonary metastasis on the clinical 12 months. In patients with unexplained fever, certainmanagement of the illness. In such a situation, repeated clinical situations such as a neutropenic patient with asurveillance CT examinations may be indicated to study the fever, the presence of a nodule may indicate activegrowth 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 toReferences 1. Berger WG, Erly WK, Krupinski EA, 4. Gruden JF, Ouanounou S, Tigges S, 6. Midthun DE, Swensen SJ, Jett JR, Standen JR, Stern RG (2001) The Norris SD, Klausner TS (2002) Incre- Hartman TE (2003) Evaluation of nod- solitary pulmonary nodule on chest mental benefit of maximum-intensity- ules detected by screening for lung cancer radiography: can we really tell if the projection images on observer detection with low dose spiral computed tomogra- nodule is calcified? AJR Am J of small pulmonary nodules revealed phy. Lung Cancer 41(suppl 2):S40 Roentgenol 176:201–204 by multidetector CT. AJR Am J 7. Henschke CI, Yankelevitz DF, Naidich 2. Wormanns D, Diederich S (2004) Char- Roentgenol 179:149–157 DP, McCauley DI, McGuinness G, acterization of small pulmonary nodules 5. Rubin GD, Lyo JK, Paik DS, Libby DM, Smith JP, Pasmantier MW, by CT. Eur Radiol 14:1380–1391 Sherbondy AJ, Chow LC, Leung AN, Miettinen OS (2004) CT screening for 3. Swensen SJ, Silverstein MD, Ilstrup Mindelzun R, Schraedley-Desmond lung cancer: suspiciousness of nodules DM, Schleck CD, Edell ES (1997) The PK, Zinck SE, Naidich DP, Napel S according to size on baseline scans. probability of malignancy in solitary (2005) Pulmonary nodules on Radiology 231:164–168 pulmonary nodules: application to multi-detector row CT scans: small radiologically indeterminate performance comparison of radiologists nodules. Arch Intern Med 157:849–855 and computer-aided detection. Radiology 234:274–283
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