21
HIGH-RESOLUTION CT OF THE LUNG II 0033–8389/02 $15.00 .00 THE SOLITARY PULMONARY NODULE Johnsey L. Leef III, MD, and Jeffrey S. Klein, MD The evaluation of a solitary pulmonary nodule (SPN) is a common diagnostic di- lemma that has become more prevalent with the increasing use of helical CT. 21 The ultimate goal of imaging in the evaluation of SPNs is to accurately distinguish benign from poten- tially malignant lesions. This has practical im- portance because the ultimate goal of imaging is to avoid referring a patient with a benign SPN for unnecessary surgical resection, while being certain not to characterize a small ma- lignant SPN incorrectly that may represent resectable (i.e., curable) early stage lung can- cer as benign. Although most SPNs prove to be benign, the distinction of benign from malignant le- sions can be difficult. One of the most im- portant but understated aspects of SPN evalu- ation is to be certain that a focal opacity detected radiographically actually represents a solitary intrapulmonary lung nodule. Once this has been determined, demographic fea- tures including patient age, smoking history, history of prior malignancy, and environmen- tal exposures are important in guiding evalu- ation because these factors influence the post- test probability of malignancy independent of imaging characteristics of the lesion in ques- tion. An important characteristic of the lesion that can often be discerned from a review of prior radiographs is an assessment of growth rate that helps determine the likelihood of From the Department of Radiology, Fletcher Allen Health Care, and University of Vermont College of Medicine, Burlington, Vermont RADIOLOGIC CLINICS OF NORTH AMERICA VOLUME 40 NUMBER 1 JANUARY 2002 123 malignancy. Following this preliminary as- sessment, assuming the risk of malignancy remains significant, most patients undergo thin-section CT for detailed analysis of size, internal density, and morphologic features of the SPN. 28 Adhering to strict criteria for de- fining benign SPNs leaves most lesions inde- terminate. These patients require more detailed nodule evaluation with contrast-enhanced CT or positron emission tomography (PET); some ultimately require biopsy or resection for de- finitive diagnosis. DEFINITION An SPN is defined as a single round intra- parenchymal opacity, at least moderately well-marginated and no greater than 3 cm in maximum diameter. This size limitation is based on the fact that most solitary lung le- sions larger than 3 cm in diameter (termed masses) are malignant, whereas most lesions less than 3 cm are benign. In addition, the detection of benign patterns of calcification in a solitary lung lesion allows the confident diagnosis of a benign lesion only when it is less than 3 cm. 12 It is important when considering a radio- graphically detected SPN to be certain that the density in question is truly solitary, lies within the lung, and represents a nodule. As

THE SOLITARY PULMONARY NODULE pulmonary disease/The Solitary...THE SOLITARY PULMONARY NODULE 125 chial wall is seen sometimes. Other presumed SPNs are found to represent linear parenchy-mal

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HIGH-RESOLUTION CT OF THE LUNG II 0033–8389/02 $15.00 � .00

THE SOLITARY PULMONARYNODULE

Johnsey L. Leef III, MD, and Jeffrey S. Klein, MD

The evaluation of a solitary pulmonarynodule (SPN) is a common diagnostic di-lemma that has become more prevalent withthe increasing use of helical CT.21 The ultimategoal of imaging in the evaluation of SPNs isto accurately distinguish benign from poten-tially malignant lesions. This has practical im-portance because the ultimate goal of imagingis to avoid referring a patient with a benignSPN for unnecessary surgical resection, whilebeing certain not to characterize a small ma-lignant SPN incorrectly that may representresectable (i.e., curable) early stage lung can-cer as benign.

Although most SPNs prove to be benign,the distinction of benign from malignant le-sions can be difficult. One of the most im-portant but understated aspects of SPN evalu-ation is to be certain that a focal opacitydetected radiographically actually representsa solitary intrapulmonary lung nodule. Oncethis has been determined, demographic fea-tures including patient age, smoking history,history of prior malignancy, and environmen-tal exposures are important in guiding evalu-ation because these factors influence the post-test probability of malignancy independent ofimaging characteristics of the lesion in ques-tion. An important characteristic of the lesionthat can often be discerned from a review ofprior radiographs is an assessment of growthrate that helps determine the likelihood of

From the Department of Radiology, Fletcher Allen Health Care, and University of Vermont College of Medicine,Burlington, Vermont

RADIOLOGIC CLINICS OF NORTH AMERICA

VOLUME 40 • NUMBER 1 • JANUARY 2002 123

malignancy. Following this preliminary as-sessment, assuming the risk of malignancyremains significant, most patients undergothin-section CT for detailed analysis of size,internal density, and morphologic features ofthe SPN.28 Adhering to strict criteria for de-fining benign SPNs leaves most lesions inde-terminate. These patients require more detailednodule evaluation with contrast-enhanced CTor positron emission tomography (PET); someultimately require biopsy or resection for de-finitive diagnosis.

DEFINITION

An SPN is defined as a single round intra-parenchymal opacity, at least moderatelywell-marginated and no greater than 3 cmin maximum diameter. This size limitation isbased on the fact that most solitary lung le-sions larger than 3 cm in diameter (termedmasses) are malignant, whereas most lesionsless than 3 cm are benign. In addition, thedetection of benign patterns of calcification ina solitary lung lesion allows the confidentdiagnosis of a benign lesion only when it isless than 3 cm.12

It is important when considering a radio-graphically detected SPN to be certain thatthe density in question is truly solitary, lieswithin the lung, and represents a nodule. As

124 LEEF & KLEIN

many as 50% of patients with suspected SPNsdetected radiographically actually prove tohave multiple nodules on CT evaluation.6

This is particularly important because thepresence of multiple lung nodules is sugges-tive of metastatic or granulomatous diseaseand requires a different approach than theSPN. Even when an SPN is detected as anincidental finding on helical CT or in thecourse of screening for lung cancer, a detailedanalysis of both lungs, particularly with thin-section collimation (i.e., � 5 mm) and over-lapping reconstructions viewed on a worksta-tion, can allow detection of multiple lesionsthat may alter the diagnostic evaluation.25

The intrapulmonary localization of a nodu-lar opacity seen on only a single radiographicprojection can likewise be difficult. For a le-sion to be considered intrapulmonary on con-ventional radiographs it must be a discreteopacity completely circumscribed by aeratedlung on orthogonal projections. Pseudonod-ules caused by EKG pads or other devices onthe patient’s skin surface can mimic intrapul-monary lesions on frontal radiographs. Cuta-neous lesions including moles, nipple shad-ows, hemangiomas, neurofibromas, andlipomas that protrude from the patient’s skinand are surrounded by atmospheric air alsomay appear intrapulmonary on a single ra-diographic projection (Fig. 1). Careful exami-nation of the skin surface usually readilyidentifies these lesions; if necessary these can

Figure 1. Skin lesion mimicking intrapulmonary nodule. A, Frontal chest radiograph demonstrates avague nodular opacity overlying the right midlung. B, Lateral radiograph shows that the densityrepresents a cutaneous lesion projecting from the posterior chest wall. Physical examination con-firmed the presence of a cutaneous hemangioma.

be confirmed easily by repeat frontal andoblique radiographs or limited chest fluoros-copy following placement of localizing metal-lic markers. Other lesions that may mimic aSPN include sclerotic bone lesions, such asbone islands; healing rib fractures; and spinalosteophytes. Although these usually are eas-ily recognized after review of prior radio-graphs, detailed views of the area in question,chest fluoroscopy, or CT may be necessaryin selected cases. Likewise, mediastinal andpleural lesions that are pedunculated andproject into the lung (i.e., pleural plaques)can appear as SPNs when viewed en face. Atangential view of the region of contact be-tween the lesion and the mediastinum orpleura, however, usually shows an indistinctborder that forms obtuse angles.

Many apparent focal nodular opacities seenradiographically actually represent vascularstructures that are tortuous, seen en face, orare superimposed on other vascular struc-tures that lie in the same sagittal plane. Theseusually can be identified by review of priorradiographs taken at slightly different obliq-uities or by performing chest fluoroscopy; CTshould be reserved for equivocal cases. Occa-sionally, a mucocele within a dilated bron-chus appears as a SPN. This diagnosis is usu-ally readily apparent by detailed review ofthin-section CT images that show a tubularor branching lesion of water attenuation; re-sidual air between the mucocele and bron-

THE SOLITARY PULMONARY NODULE 125

chial wall is seen sometimes. Other presumedSPNs are found to represent linear parenchy-mal scars seen en face. Unless this is easilyrecognized on current or prior radiographicstudies, thin-section CT is often necessary todisplay the two-dimensional linear nature ofthe opacity and help distinguish this lesionfrom a spherical nodule.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of a SPN is exten-sive and includes neoplastic, infectious, in-flammatory, vascular, traumatic, and congeni-tal conditions (Table 1). Most benign SPNs aregranulomas, hamartomas, or intrapulmonarylymph nodes, whereas bronchogenic carcino-mas represent most malignant SPNs.

CLINICAL DATA

Once a SPN has been definitively identi-fied, a detailed investigation almost invari-ably ensues. Specific clinical features affectthe likelihood of benignancy or malignancy,however, and in conjunction with the imagingcharacteristics of the lesion can impact boththe diagnostic approach and choice of thera-peutic options. Bayesian analysis allows for a

Table 1. DIFFERENTIAL DIAGNOSIS OF A SOLITARY PULMONARY NODULE

Neoplasm Benign HamartomaInflammatory pseudotumor

Malignant Bronchogenic carcinomaCarcinoid tumorLymphoma (Non-Hodgkin’s)Metastasis

Infection Granuloma MycobacteriaFungi

Septic embolusAbscess Bacteria (anaerobes, Staphylococcus,

gram-negative)Nocardia

Round pneumonia PneumococcusParasitic Echinococcus

Dirofilaria (dog heartworm)Inflammatory Connective tissue Wegener’s granulomatosis

Rheumatoid (necrobiotic) noduleSarcoidosis (rare)

Vascular Arteriovenous malformationHematomaPulmonary infarctPulmonary artery aneurysmPulmonary venous varix

Airway Congenital lesion Bronchogenic cystBronchial atresia

MucoceleInfected bulla

more precise determination of the likelihoodof malignancy by combining radiographicfindings with clinical information (specificallyage, smoking history, and symptoms) to cal-culate mathematically the probability of ma-lignancy of a specific SPN. Bayes’ theoremuses an odds-ratio formula where the oddsof malignancy are divided by the odds ofmalignancy plus one. The equation for de-termining the overall odds of malignancy iscalculated by multiplying the patients’ priorodds of malignancy by the radiographic like-lihood ratio of malignancy by the clinical like-lihood ratio of malignancy. In this equation,the prior odds of malignancy are the preva-lence of malignancy for a given populationdivided by the prevalence of benign diseaseof that population.14 The likelihood of malig-nancy ratios are intuitive measures of diag-nostic information provided by radiographictest results or clinical findings.1, 14 Clinical in-formation or radiographic test results strong-ly suggestive of malignancy have a likelihoodratio much greater than one, whereas thosefindings suggestive of benignity have a likeli-hood ratio close to zero, and information ortest results that are considered to contain nodiagnostic information have a likelihood ratioof one.14

The clinical factors to consider in evalu-ating the likelihood of malignancy include

126 LEEF & KLEIN

patient age; smoking history; symptoms;comorbid conditions (particularly severe em-physema); history and type of prior malig-nancy; and environmental exposures. For ex-ample, a 30-year-old nonsmoking patientwithout a history of malignancy found tohave a smooth round SPN has a high likeli-hood of a benign lesion and radiologic followupto ensure stability is a reasonable and cost-effective approach. Conversely, one could ar-gue that a spiculated SPN in a 50-year-oldcigarette smoker should proceed to immedi-ate resection because the likelihood of lungcancer is so high that the results of diagnosticstudies are unlikely to impact the patient’smanagement.33 As in many areas of clinicalpractice, semiquantitative techniques, such asbayesian analysis of SPNs, have not gainedwidespread use because of the large numberof variables to be estimated and differencesin local practice, particularly the availabilityand expertise with advanced imaging tech-niques, such as PET.

CHARACTERISTICS OF SOLITARYPULMONARY NODULES

Size

There is no size criterion that reliably dis-tinguishes benign from malignant SPNs. In

Figure 2. Small solitary pulmonary nodule (SPN) represents non–small cell lung carcinoma. A, ProneCT scan through lower lobes shows a 12-mm irregular nodule in the superior segment of the rightlower lobe. B, Scan during needle placement for biopsy shows needle approaching edge of lesionwith a small pneumothorax. Biopsy yielded adenocarcinoma.

general, smaller nodules are more likely to bebenign and larger lesions, particularly thoseexceeding 3 cm in diameter, are more likelyto be malignant. Although 80% of benignSPNs are less than 2 cm in diameter, smallsize is not necessarily reliable evidence of be-nignity because 15% of malignant nodulesare less than 1 cm in diameter (Fig. 2) andapproximately 42% are less than 2 cm in di-ameter.9 As shown in the prevalence datafrom the Early Lung Cancer Screening Proj-ect, a growing number of smaller malignantSPNs will likely be detected if lung cancerscreening with low-dose helical CT gainswidespread acceptance.15 For these reasons,SPN size is helpful information but does notallow definitive distinction of benign frommalignant SPNs.

Growth

The absence of growth over at least a 2-yearperiod is a reliable indicator of benignity.23

To establish firmly the absence of growth,sequential films obtained with comparable ra-diographic technique are necessary. Limitedthin-section CT should be performed for moreaccurate lesion measurement if there is anyquestion whether a SPN has increased in size.The use of doubling time, which for sphericallesions is defined as a 25% increase in diame-ter, is based on the observation that benign

THE SOLITARY PULMONARY NODULE 127

lesions have doubling times of less than 30days or greater than 450 days. SPNs withdoubling times between 30 and 450 days re-quire further evaluation.

The use of helical CT for evaluating SPNgrowth rates, particularly for small lesions,has recently received greater attention givenadvances in scanner technology, the ability toobtain nodule volumes using helical acquisi-tion techniques and computer-aided evalua-tion of data sets, and the increasing numberof small lesions detected on CT performedfor other indications or to screen for lungcancer presenting as a SPN. A recent paperdescribes the use of a software program thatsegments SPNs and calculates nodule volumeto within a 3% accuracy. In a small series of

Figure 3. CT-derived volumetric analysis of SPN growth. A, Scan shows a small left upper lobenodule. Boxes at right show detailed sequential axial reconstructions through nodule. B, Repeat thin-section CT scan with sequential reconstructions shows questionable interval change in nodule shape.

Illustration continued on following page

patients with SPNs and a definitive diagnosis,the doubling time as determined by changein nodule volume on repeat CT scans wasless than 177 days for all malignant nodulesand greater than 396 days for all benign le-sions (Fig. 3).34 It is likely that computer-aidedanalysis of nodule volume will become animportant part of the evaluation of smallSPNs by helping to determine growth ratesthat allow distinction of benign from malig-nant SPNs. The technique may prove usefulfor irregularly shaped small lesions and le-sions that grow in a cephalocaudal fashionthat is difficult to discern on review of axialimages given differences in scan planes andpatient positioning on follow-up CT examina-tions.

128 LEEF & KLEIN

Figure 3 (Continued). Three-dimensional shaded surface displays of nodule obtained from volumetricacquisition in various projections from June (C) and October (D) with nodule volume calculatedshows an interval increase in nodule volume. Biopsy revealed adenocarcinoma. (From Henschke CI,Yankelevitz DF: CT screening for lung cancer. Radiol Clin North Am 383:487–495, 2000; withpermission.)

Density and Internal Characteristics

Calcification

The presence of a specific pattern of macro-scopic calcification within a SPN as seen onconventional radiographs or CT is indicativeof a benign lesion. These patterns include cen-tral, laminated, diffuse, or popcorn calcifica-tion (Fig. 4).30 Central, solid (Fig. 5), and lami-nated forms of calcification (Fig. 6) are foundin association with prior granulomatous in-fection, most commonly histoplasmosis or tu-berculosis. Popcorn calcification usually rep-resents the chondroid calcification in apulmonary hamartoma. Eccentric or amor-phous calcification can represent a calcifiedgranuloma engulfed by a malignancy or dys-

trophic malignant calcification, respectively,and should not be taken as evidence of be-nignancy (Fig. 7).20 Although the presenceand pattern of calcification can sometimes bedetermined on conventional radiographs, ap-proximately one third of noncalcified SPNshave calcification on CT.35 For this reason,definitive identification of calcium usually re-quires thin-section CT using 1- to 3-mm colli-mated scans reconstructed with a high spatialfrequency algorithm. In lesions where calcifi-cation is not visible on thin-section CT scans,quantitative CT densitometry can be per-formed to determine the attenuation value ofthe nodule. Quantitative CT densitometry canbe performed by comparing the CT densityof the SPN with that of a microscopicallycalcified prosthetic reference nodule placed

THE SOLITARY PULMONARY NODULE 129

Figure 4. Benign patterns of calcification within SPNs.(From Klein JS, Wand A: Pulmonary neoplasms. In BrantWE, Helms CA (eds): Fundamentals of Diagnostic Radiol-ogy, ed 2. Baltimore, Williams and Wilkins, 1999; with per-mission.)

within a chest phantom model.22 Most tho-racic radiologists no longer use a referenceCT phantom for this purpose and insteadcalculate the average attenuation valuethrough the central portion of the nodule. Avalue of 200 H or greater from at least 10%of the central pixels or throughout the noduleis reliable evidence of microscopic calcifica-tion and indicates benignity.17

The absence of calcium is of little value indistinguishing benign from malignant SPNsbecause 38% to 63% of benign nodules, twothirds (67%) of carcinoid tumors, and as manyas 94% of all lung cancers do not containappreciable calcium.9

Fat

The identification of fat within a SPN withsmooth or lobulated margins is indicative ofbenignity. A pulmonary hamartoma, the third

most common cause of a SPN, is a benignneoplasm composed of disorganized epithe-lial and mesenchymal elements normallyfound in the bronchus or lung. Up to 50% ofhamartomas have fat that can be detected onthin-section CT (Fig. 8), with 30% showingcalcification or ossification that is often pop-corn in appearance.27 These lesions typicallydevelop in middle-aged adults and demon-strate slow growth. In patients with character-istic findings on thin-section CT, pathologicconfirmation is usually unnecessary and ra-diographic follow-up to confirm stability overa 2-year period is recommended, althoughtransthoracic needle biopsy can be performedif a definitive diagnosis is deemed necessary.

Cavitation

Although cavitation can occur in necroticmalignant SPNs, particularly squamous cell

130 LEEF & KLEIN

Figure 5. Calcified SPN from tuberculosis. A, Frontal chest radiograph shows aperipheral right upper lobe nodule. B, Thin-section CT scan shows a completelycalcified nodule representing prior tuberculosis.

THE SOLITARY PULMONARY NODULE 131

Figure 6. Laminated calcification in histoplasmoma. A, Scout view from CT scanshows a sharply marginated peripheral right upper lobe nodule. B, Thin-sectionCT scan shows laminated calcification. The patient had a history of prior his-toplasma infection.

132 LEEF & KLEIN

Figure 7. Dystrophic calcification in lung cancer. A, Frontal chest radiographshows a large left lower lobe mass. B, Unenhanced thin-section CT scan showseccentric punctate calcifications. Biopsy revealed adenocarcinoma.

THE SOLITARY PULMONARY NODULE 133

Figure 8. Fat within pulmonary hamartoma. A, Detailed view of a thin-section CT scan through theright middle lobe shows a smooth, sharply defined 15-mm oval nodule. B, Scan at mediastinalwindows shows scattered fat attenuation within the nodule characteristic of a hamartoma.

carcinoma, inflammatory lesions, such as ab-scesses, infectious granulomatous lesions,Wegener’s granulomatosis, and pulmonaryinfarcts, can also cavitate. The thickness of thecavity wall can be helpful in distinguishingbenign from malignant lesions. Cavities witha greatest wall thickness less than 5 mm arealmost always benign, whereas most of thosewith a maximal wall thickness greater than15 mm are malignant (Fig. 9).31, 32

Figure 9. Cavitatary lung cancer. CT scan through the upper lobes shows aright upper lobe mass with central cavitation. The thickest portion of the cavitywall measures 22 mm. Transthoracic biopsy showed squamous cell carcinoma.

Air Bronchograms or Bubbly (Cystic)Lucencies

The assessment of the internal density of anoncalcified SPN as evaluated with thin-sec-tion CT can provide useful information. Ho-mogeneous nodule attenuation is observedmore frequently in benign (55%) than malig-nant lesions (20%).36 Internal inhomogeneity,particularly the presence of air bronchograms

134 LEEF & KLEIN

or cystic or ‘‘bubbly’’ lucencies within a SPN,is highly suggestive of an adenocarcinoma,particularly the localized form of bronchio-loalveolar cell carcinoma (Fig. 10). Other ma-lignancies, however, such as lymphoma andbenign lesions including organizing pneumo-nia, pulmonary infarcts, and mass-like sar-coidosis, can produce a similar appearance.

Margins

A detailed assessment of the margins of aSPN as depicted on thin-section CT can pro-vide useful information. Although smooth,well-defined margins most often indicate abenign nodule (Figs. 8 and 11), 21% of malig-nant nodules have a smooth well-definedmargin.26, 35 Alternatively, a lobulated marginmay reflect uneven growth of a SPN and canindicate malignancy (Fig. 12), although 25%of benign nodules, particularly hamartomas,are lobulated.36 A nodule that has an ill-de-fined margin and demonstrates an irregularor spiculated contour most often represents amalignancy. Spiculated margins result fromcicatrization (scarring) of the lung intersti-tium surrounding a lesion (Fig. 13). It is im-portant to recognize, however, that whereas aspiculated margin is highly suspicious forlung cancer, cicatrization producing a spicu-lated nodule can also be seen in benign in-flammatory processes, such as lipoid pneu-

Figure 10. Cystic lucencies in bronchioloalveolar cell carcinoma. Thin-section CT scanthrough left upper lobe shows an irregularly marginated nodule containing small cysticlucencies. Biopsy revealed bronchioloalveolar cell carcinoma.

monia, organizing pneumonia, tuberculoma,and the mass-like lesions of progressive mas-sive fibrosis seen in complicated silicosis.

There are several other features of the mar-gins of SPNs as depicted on thin-section CTthat are of diagnostic value. The presence ofsmall satellite nodules surrounding the pe-riphery of a smooth dominant nodule isstrongly suggestive of a granulomatous infec-tion (Fig. 14).4 The pleural tail is a linearopacity seen extending from the edge of aperipherally situated SPN to indent thepleura. Although this finding can be associ-ated with lung cancer (see Fig. 13), in particu-lar bronchioloalveolar cell carcinoma, it isalso seen with peripheral granulomas and itspresence is of limited diagnostic value.35 Thehalo sign refers to the presence of ground-glass opacity surrounding a nodule or mass.When seen in a neutropenic patient, thisfinding is highly suggestive of an angioinva-sive opportunistic infection, particularly as-pergillosis.3 The detection of feeding anddraining vessels entering the hilar aspect of around or lobulated SPN is diagnostic of apulmonary arteriovenous malformation,which is seen more commonly in patientswith hereditary hemorrhagic telangiectasia(Rendu-Osler-Weber syndrome).

CT NODULE ENHANCEMENT

The technique of contrast enhancement ofSPNs on CT has developed as an extension

THE SOLITARY PULMONARY NODULE 135

Figure 11. Smoothly marginated benign SPN. A, Coned-down view of right lung shows a nodule atthe right base. B, Thin-section CT scan shows a smoothly marginated middle lobe nodule. Biopsyrevealed a granuloma caused by Cocciodioides immitis infection.

Figure 12. Lobulated margin in malignant SPN. Coned-down view of rightupper lobe shows a 20-mm nodule with a lobulated margin. Biopsy re-vealed adenocarcinoma.

136 LEEF & KLEIN

Figure 13. Spiculated margin in malignant SPN. CT scan at the levelof the aortic arch shows a spiculated right upper lobe nodule with apleural tail extending posteriorly to distort the major fissure. Biopsyshowed adenocarcinoma.

of the observation that malignant lung tu-mors are relatively hypervascular comparedwith benign lesions. CT nodule enhancementafter intravenous contrast administration isnow accomplished easily with the use ofpower injectors and rapid-scan acquisitionwith helical CT. The technique involves thin-collimated (3 mm) spiral acquisitions througha SPN between 6 and 30 mm in diameterbefore and after intravenous contrast injec-tion. Scans obtained each minute for 4 min-utes after contrast injection are comparedwith baseline unenhanced scans. An enhance-

Figure 14. Satellite nodules in granulomatous SPN. Prone CT scan beforetransthoracic biopsy of a radiographically detected SPN shows a cluster ofsmall nodules in the posterior segment of the right upper lobe with a largercentral nodule (arrow). Biopsy revealed granulomatous inflammation with aspecific organism identified.

ment value is then determined by calculatingthe mean attenuation value through the cen-ter of the nodule at peak contrast enhance-ment and subtracting the baseline value. Arecent prospective multicenter study hasshown that an enhancement value of less than15 H is virtually diagnostic of a benign lesion(i.e., the test has a high sensitivity for malig-nancy) (Fig. 15).29 The rare false-negativestudy is usually caused by central necrosis ora mucin-producing malignant neoplasm, suchas a bronchioloalveolar cell carcinoma (Fig.16). An enhancement value exceeding 15 H is

THE SOLITARY PULMONARY NODULE 137

Figure 15. Benign nodule by contrast-enhanced SPN on CT scan. Frontal (A) and lateral (B) chestradiographs in a 54-year-old man show a subtle right lower lobe nodule seen best on the lateral film.C, Sequential contrast-enhanced scans obtained at baseline (upper left) and every minute aftercontrast injection (upper left, lower left, lower right, respectively) show enhancement of 5 H frombaseline. Biopsy revealed a granuloma.

138 LEEF & KLEIN

Figure 16. False-negative contrast-enhanced CT nodule study. Sequential contrast-enhancedscans obtained at baseline (upper left) and every minute after contrast injection (upper right,lower left, lower right, respectively) shows virtually no enhancement of right upper lobe nodule.Biopsy and surgical resection revealed mucinous subtype of bronchioloalveolar cell carcinoma.

nonspecific because both inflammatory le-sions and malignancies can enhance (Fig. 17);this limits the positive predictive value of thetest to 68%.

Because of the rapid image acquisition withspiral CT, CT nodule enhancement can beperformed following routine scanning of thechest without need for additional contrast ad-ministration and little additional scan timeand radiation dose. The technique requiresmeticulous attention to detail, however, andmay be less accurate in larger SPNs (i.e., those� 2 cm) because these lesions are more oftennecrotic and may produce false-negative ex-aminations. The technique may prove to bemost useful for the evaluation of probablybenign SPNs when transthoracic needle bi-opsy is unavailable, cannot be performed, oris nondiagnostic and the patient is a poorsurgical candidate.

POSITRON EMISSIONTOMOGRAPHY

There is a growing experience in the use ofPET using the radiopharmaceutical fluoro-2-deoxy-D-glucose (FDG) in the evaluation offocal lung lesions including SPNs. FDG up-

take in focal lesions is measured semiquanti-tatively by calculating a standardized uptakeratio. When assessing lesions greater than 10mm in diameter, FDG-PET has a sensitivityof 94% to 96% and a specificity of 87% to 88%for the evaluation of SPNs (Fig. 18).7, 9, 10 Thelow false-negative rate of PET makes this auseful adjunct to thin-section CT in excludingmalignancy and allows clinical follow-up ofprobably benign lesions. As with CT noduleenhancement, false-positive cases are usuallyseen in granulomas with active inflammation.The limited availability and high expense ofFDG-PET are the main obstacles to wide-spread use in the evaluation of SPNs. Giventhe increasing availability of mobile PET scan-ners and the reimbursement for solitary nod-ule evaluation and lung cancer staging cur-rently supported by Medicare, it is likely thatthe use of thoracic and whole-body PET willexpand well beyond academic research cen-ters and become a mainstay of solitary noduleevaluation and lung cancer staging.

TECHNETIUM 99m DEPREOTIDESCINTIGRAPHY

The affinity of malignant neoplasms includ-ing both small cell and non–small cell lung

THE SOLITARY PULMONARY NODULE 139

Figure 17. Positive contrast-enhanced CT nodule study. A, Coned-down view of CT scan throughright upper lobe shows an SPN with a lobulated and spiculated margin. B, Sequential contrast-enhanced scans obtained at baseline (upper left) and every minute after contrast injection (upperleft, lower left, lower right, respectively) shows enhancement of 41 H from baseline. Biopsyrevealed adenocarcinoma.

140 LEEF & KLEIN

Figure 18. Positron emission tomography (PET) of SPN. A, Frontal chest radiograph shows a roundright lower lung mass. B, Unenhanced CT scan shows a middle lobe mass with an irregular marginperipherally. C, Axial PET image shows intense uptake. Biopsy proved bronchogenic carcinoma.(Courtesy of Edward F. Patz, MD, Department of Radiology, Duke University Medical Center, Dur-ham, NC.)

cancer for peptide analogues of somatostatinhas led to at least two studies investigatingthe use of this agent in the noninvasive evalu-ation of SPNs. In a recent multicenter studyusing this agent commercially available asNeotect (Diatide, Londonderry, NH), 96.6% ofmalignant SPNs and masses were correctlyidentified (Fig. 19), although the specificityof the agent for distinguishing benign frommalignant lesions was only 73%.2 Because theavailability of single photon emission CT iscurrently greater than that of FDG-PET, thisagent may have some clinical use in selectedpatients, most typically nonsurgical candi-dates with irregularly shaped lesions that arenot amenable to CT nodule enhancement orpercutaneous biopsy.

PATHOLOGIC DIAGNOSIS OFSOLITARY PULMONARY NODULES

Transthoracic Needle Biopsy

Image-guided transthoracic needle biopsyhas become the semi-invasive procedure ofchoice for definitive characterization of pe-ripheral SPNs. The procedure is most oftenperformed under CT guidance and has beenshown to have a sensitivity of over 90% formalignancy in most series, particularly whenexpert cytopathology is used (see Fig. 2).16, 18

The ability of transthoracic needle biopsy toobtain a specific benign diagnosis for focallung lesions is limited by difficulty in aspirat-ing diagnostic material from sclerotic granu-

THE SOLITARY PULMONARY NODULE 141

Figure 19. Positive technetium medronate (Tc99m) depreotide scintigramof lung. A, CT scan through upper lobes shows irregular mass peripher-ally in the right upper lobe. B, Axial single photon emission computedtomography (SPECT) scan at the same level as A shows increaseduptake in the lesion. Biopsy proved non–small cell carcinoma.

lomas. Recently, the use of small-gauge (� 20-gauge) cutting biopsy needles has providedhistologic material from SPNs and can sig-nificantly improve the yield for benign lesionsto 80% or greater.11

Bronchoscopy

In a patient with a SPN and findings sug-gesting central airway involvement (i.e., he-moptysis or bronchus entering hilar aspectof nodule on thin-section CT), bronchoscopywith brushings, washings, and endobronchialor transbronchial biopsy or transbronchialneedle aspiration is the initial diagnostic pro-cedure of choice, and in such situations canobtain a diagnosis in up to 80% of lesions.5

The diagnostic yield from bronchoscopy dif-

fers significantly with the size and location ofthe lesion and the experience of the broncho-scopist, however, with yields as low as 28%in one series.24 A cooperative bronchoscopicand transthoracic approach has been shownto be effective for peripheral nodules,13 andconventional or CT fluoroscopy helps guideaccurate placement of transbronchoscopicbrushes and needles to improve diagnosticyield.

Video-Assisted ThoracoscopicSurgery

This technique, usually performed by sur-geons in the operating room under generalanesthesia with single lung ventilation, canbe used as both a diagnostic and therapeutic

142 LEEF & KLEIN

procedure for SPNs. The indications forvideo-assisted thoracoscopic surgery resec-tion of SPNs differ considerably between in-stitutions, but it has been shown to have highdiagnostic accuracy with less morbidity thanthoracotomy.19

Thoracotomy

Thoracotomy for resection of SPNs is usu-ally limited to lesions with a high likelihoodof malignancy when lobectomy and nodal re-section are necessary for definitive lung can-cer staging and treatment.8 Additional indica-tions include a deeply situated nodule orother lesion not amenable to thoracoscopiclocalization and resection or when limitedpulmonary reserve necessitates limited lungresection to preserve pulmonary function.

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Jeffrey S. Klein, MDDepartment of Radiology

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