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The Solitary Pulmonary Nodule 1 Helen T. Winer-Muram, MD The imaging evaluation of a solitary pulmonary nodule is complex. Management decisions are based on clinical his- tory, size and appearance of the nodule, and feasibility of obtaining a tissue diagnosis. The most reliable imaging features are those that are indicative of benignancy, such as a benign pattern of calcification and periodic follow-up with computed tomography for 2 years showing no growth. Fine-needle aspiration biopsy and core biopsy are important procedures that may obviate surgery if there is a specific benign diagnosis from the procedure. In using the various imaging and diagnostic modalities described in this review, one should strive to not only identify small malig- nant tumors—where resection results in high survival rates— but also spare patients with benign disease from undergoing unnecessary surgery. RSNA, 2006 1 From the Department of Radiology, Indiana University, Indianapolis, Ind. Received February 28, 2005; revision requested April 22; revision received April 28; accepted June 13; final version accepted August 11; final review and update by the author October 31. Address corre- spondence to the author, 11224 Clarkston Rd, Zionsville, IN 46077 (e-mail: [email protected]). RSNA, 2006 REVIEWS AND COMMENTARY REVIEW FOR RESIDENTS 34 Radiology: Volume 239: Number 1—April 2006 Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.

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Page 1: The Solitary Pulmonary Nodule - University of North ...msrads.web.unc.edu/files/2018/08/Solitary-Pulmonary-Nodule.pdf · The Solitary Pulmonary Nodule1 HelenT.Winer-Muram,MD The imaging

The Solitary Pulmonary Nodule1

Helen T. Winer-Muram, MDThe imaging evaluation of a solitary pulmonary nodule iscomplex. Management decisions are based on clinical his-tory, size and appearance of the nodule, and feasibility ofobtaining a tissue diagnosis. The most reliable imagingfeatures are those that are indicative of benignancy, suchas a benign pattern of calcification and periodic follow-upwith computed tomography for 2 years showing nogrowth. Fine-needle aspiration biopsy and core biopsy areimportant procedures that may obviate surgery if there is aspecific benign diagnosis from the procedure. In using thevarious imaging and diagnostic modalities described in thisreview, one should strive to not only identify small malig-nant tumors—where resection results in high survivalrates—but also spare patients with benign disease fromundergoing unnecessary surgery.

� RSNA, 2006

1 From the Department of Radiology, Indiana University,Indianapolis, Ind. Received February 28, 2005; revisionrequested April 22; revision received April 28; acceptedJune 13; final version accepted August 11; final reviewand update by the author October 31. Address corre-spondence to the author, 11224 Clarkston Rd, Zionsville,IN 46077 (e-mail: [email protected]).

� RSNA, 2006

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34 Radiology: Volume 239: Number 1—April 2006

Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.

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A solitary pulmonary nodule (SPN)is a round or oval opacity smallerthan 3 cm in diameter that is com-

pletely surrounded by pulmonary pa-renchyma and is not associated withlymphadenopathy, atelectasis, or pneu-monia (1) (Fig 1a). Larger lesions arenot included in this definition becausemany of these lesions are malignant (2–4). An SPN is noted on up to 0.2% ofchest radiographs (5,6) (Fig 2a). Whilethe differential diagnosis for SPN is ex-tensive (Figs 3, 4), most lesions arefound to be granulomas, lung cancers,or hamartomas (7,8) (Fig 5). Detectionand work-up of SPNs are critical be-cause SPNs may be malignant and lungcancer has an overall mortality rate ofup to 85% (3,9). Early detection ofsmall nodules may potentially reducelung cancer–specific mortality; in time,data from the National Lung ScreeningTrial may be used to prove this hypoth-esis.

While one may not be able to estab-lish a diagnosis based solely on the im-

aging features, the radiologist oftenplays a major role in the care of patientswith SPNs. In this article, some of theclinical and radiographic features thatare important to consider when deter-mining the likelihood of malignancy ofan SPN will be reviewed, and an algo-rithm will be proposed for the care ofpatients with indeterminate nodules.

Risk of SPN Malignancy

To understand the rationale underlyingclinical and imaging work-up when anSPN is discovered, one must first recog-nize the clinical factors that make lungcancer a more likely cause of SPN (Ta-ble). The likelihood of lung cancer in-creases if a patient has a smoking his-tory, and it is directly proportional tothe number of pack-years as a smoker(12). While many physicians have be-lieved that smoking cessation producesa progressive reduction in lung cancerincidence, this concept has been chal-lenged (13). The incidence of lung can-cer does not increase after smoking ces-sation, but it never equals that for indi-viduals who have never smoked.Consequently, one commonly sees pa-tients with newly diagnosed lung cancerwho stopped smoking years or even de-cades earlier (14).

Lung cancer risk also increases ifthe patient has a history of primary pul-monary or extrapulmonary cancer orpulmonary fibrosis (eg, idiopathic fibro-sis or fibrosis due to asbestos exposure,collagen vascular disease, adult respira-tory distress syndrome, or radiation)(10,15) (Fig 6). An SPN is unlikely to bea metastasis in the absence of a knownprior malignancy, and a routine searchfor an extrathoracic primary tumor isnot cost-effective (16) (Fig 7). In pa-tients with melanoma, sarcoma, or tes-ticular carcinoma, a malignant SPN is2.5 times more likely to be a metastasisthan a primary lung cancer; however, inpatients with head and neck squamouscell carcinoma, a malignant SPN is eighttimes more likely to be a primary lungcancer (17).

Onset of lung cancer before the ageof 40 years is rare; however, its inci-dence increases steadily between 40

and 80 years of age (18). Patients withthe human immunodeficiency virus havean increased risk for lung cancer andmay develop cancer at a younger age(19). Lung cancer was once far morecommon in men than women, but in-creased smoking rates among womenduring the 1960s and 1970s have led toan increased incidence of lung cancer inwomen (20). The American Cancer So-ciety estimated that there would beabout 172 570 new cases of lung cancerin 2005 (93 010 in men and 79 560 inwomen). The chance of developing lungcancer is one in 13 in men and one in 18in women. This incidence includes allpeople, and it does not take into ac-count whether they smoke (21).

SPN Size

At chest radiography, an SPN is seldomevident until it is at least 9 mm in diam-eter (22). Moreover, even larger nod-ules may be missed with radiography,unless prior chest radiographs are avail-able for comparison. SPNs are fre-quently detected because they are ei-ther absent on previously obtainedradiographs or present and not recog-nized until the current radiographsshow enlargement. Nearly 90% ofnewly discovered SPNs on chest radio-graphs may be visible in retrospect onprior radiographs (23). Failure to detectan SPN is directly related to obscurationof the nodule by overlying structures,failure to compare the current radio-graph with prior radiographs, or use ofa faulty search pattern (24). Prior chestradiographs are also needed because anodule that is unchanged on chest radio-graphs for 2 years is almost certainlybenign and requires no further imaging.

Published online10.1148/radiol.2391050343

Radiology 2006; 239:34–49

Abbreviations:FDG � fluorine 18 fluorodeoxyglucoseFNAB � fine-needle aspiration biopsySPN � solitary pulmonary nodule

Essentials

� While the differential diagnosisfor SPN is extensive, most SPNsare found to be granulomas, lungcancers, or hamartomas.

� Benign nodules can be confidentlydiagnosed if the lesion is smallerthan 3 cm in diameter and exhib-its one of the following patterns ofcalcification: central nidus, lami-nated, popcorn, or diffuse.

� The probability of malignancy ishigh (90% if the patient is olderthan 60 years) with positive FDGPET findings and low (�5%) withnegative FDG PET findings.

� Nodules with low likelihood formalignancy that are at least 5 mmand smaller than 10 mm can beobserved with CT for a 2-yearperiod, while nodules with inter-mediate or high likelihood for ma-lignancy can be sampled withFNAB or resected.

� A new persistent nodule that de-velops during observation is wor-risome for malignancy and war-rants intervention.

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Key PointAlways compare current radiographswith previous radiographs (if available).

The size of the SPN is not a reliablepredictor of benignity (4); however, the

larger the nodule (approaching 3 cm indiameter), the more likely it is to bemalignant. More than 90% of nodulesthat are smaller than 2 cm in diameterare benign (10,25).

The prevalence of cancer in SPNssmaller than 1 cm in diameter is un-known. Of noncalcified nodules smallerthan 1 cm, 42%–92% have been found tobe benign (3,4,26). The large variabilityreflects selection bias, and reports fromsurgical series tend to show higher preva-lence of malignant lesions than do reports

Figure 1

Figure 1: Chest CT scans (5-mm section width) in a female 48-year-old former smoker (9 pack-years) with ahistory of remote purified protein derivative conversion. (a) Transverse cardiac screening scan shows a 10-mmsolid nodule (arrow) in the right lower lobe. (b) Transverse thin-section (1.25-mm section width) scan shows irregu-lar margins and central lucency. (c) Thin-section scan shows central lucency (�208 HU), which indicates air bron-chiolograms or early cavitation. (d) Three-dimensional CT scan obtained with volume rendering shows the nodulevolume to be 531 mm3. FNAB was performed, and atypical cells were seen. Because of the nonspecific diagnosis,repeat FNAB was performed, and no malignant cells were seen. The nodule will be observed with serial CT duringthe next 24 months. If the nodule remains stable for 24 months, no further intervention will be performed.

Figure 2

Figure 2: (a) Chest radiograph shows an inci-dental small nodule (arrow) at the left costophrenicangle. (b) Thin-section CT scan shows central fatattenuation (�43 HU) in the nodule. Hamartomawas diagnosed.

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from screening studies. In 64 patientswith SPNs 1 cm or smaller in diameterwho were referred for video-assisted tho-racoscopic surgery, 58% of SPNs, includ-ing six that were smaller than 5 mm indiameter, were malignant (27). Other se-ries have found a similar frequency of ma-lignancy (26–29). In comparison, theEarly Lung Cancer Action Project screen-ing study showed that only 8% of lesions

smaller than 1 cm in diameter were ma-lignant (26).

Key PointNodules approaching 3 cm in diameterare more likely to be malignant, whilenodules smaller than 1 cm in diameterare more likely to be benign.

SPN Location

Lung cancer is 1.5 times more likely tooccur in the right lung than in the left lung(30). Studies have shown that 70% oflung cancers are located in the upperlobes and occur most frequently in theright lung (31,32). Thus, one should care-fully scrutinize the upper lobes when re-

viewing chest images, as most missedlung cancers are located in the right up-per lobe (24). As benign nodules areequally distributed throughout the upperand lower lobes, location alone cannot beused as an independent predictor of ma-lignancy (16). In patients with idiopathicpulmonary fibrosis, lung cancers morecommonly involve the periphery of thelower lobe, a site in which fibrosis is mostlikely to occur (15). Approximately half ofprimary pulmonary adenocarcinomasmanifest as isolated peripheral SPNs,while squamous cell carcinomas thatmanifest as SPNs are more likely to becentrally located (33).

Increasing use of low-tar and filteredcigarettes in the United States has been

Figure 3

Figure 3: CT scan shows a markedly enhanc-ing right lower lobe nodule with a feeding arteryand draining vein (not shown). Pulmonary arterio-venous malformation was diagnosed.

Figure 4

Figure 4: CT scan in a 90-year-old woman withchronic congestive heart failure shows a tiny nod-ule adjacent to the right major fissure that is likelyto represent a congested intrapulmonary lymphnode (arrow). Follow-up CT was not performedbecause of the patient’s advanced age.

Figure 5

Figure 5: Chart shows differential diagnosis of SPN.

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associated with changes in the histologictype and anatomic distribution of lungcancer, such as decreasing incidence ofsmall-cell carcinoma (the cell type mostclosely associated with cigarette smoking)and increasing incidence of adenocarci-noma (34). Adenocarcinomas are fre-quently peripheral lung tumors ratherthan central lung tumors because peoplewho smoke low-tar filtered cigarettes in-hale deeply and distribute smoke to thelung periphery. People who smoke high-tar unfiltered cigarettes do not inhale asdeeply and are more likely to develop tu-mors associated with central lesions, suchas squamous cell carcinomas (34).

Key PointThe right upper lobe is the most com-mon location of lung cancer.

SPN Internal AttenuationCharacteristics

CalcificationThe most important imaging featurethat can be used to distinguish benign

SPNs from malignant SPNs is calcifica-tion. Benign nodules can be diagnosedconfidently if the lesion is smaller than 3cm in diameter and exhibits one of thefollowing patterns of calcification: cen-tral nidus, laminated, popcorn, or dif-fuse. When one of these patterns isseen, the likelihood of benignity ap-proaches 100% (3,4). Popcorn calcifica-tions are observed in one-third ofhamartomas (7), and the other patternsare seen with histoplasmosis and tuber-culosis (Fig 8).

SPNs smaller than 9 mm in diame-ter are rarely visible on chest radio-graphs; therefore, a nodule of that size

that is clearly seen is likely to be dif-fusely calcified and benign. For largerSPNs, however, detection of calcifica-tion with radiography is less certain. Ina study where the mean SPN diameterwas 13 mm, sensitivity and specificity ofradiography in the detection of calcifica-tion were 50% and 87%, respectively(35) (Fig 9). When computed tomogra-phy (CT) was used, 7% of these defi-nitely calcified nodules were not calci-fied and were, therefore, potentiallymalignant.

While low-voltage radiography and

Figure 6

Figure 6: Transverse CT scan in a 75-year-oldman with idiopathic pulmonary fibrosis shows asolid left lower lobe nodule (arrow). FNAB of thenodule revealed squamous cell carcinoma.

Figure 7

Figure 7: Transverse CT scan of the chestshows a solitary right lower lobe nodule. FNABof the nodule revealed renal cell carcinomametastasis.

Figure 8

Figure 8: Transverse CT scan shows a 1-cm-diameter left lower lobe nodule with central niduscalcification. This finding is indicative of benigndisease.

Hierarchy of Likelihood Ratios forMalignancy

CharacteristicLikelihoodRatio

Cavity wall thickness (mm)�16 37.97�4–16 0.72�4 0.07

Size (cm)�3.0 5.232.1–3.0 3.671.1–2.0 0.74�1.0 0.52

PET standardized uptake value�2.5 4.30�2.5 0.04

Age (y)�70 4.1650–70 1.9030–39 0.2420–29 0.05

Growth rate (d)�465 0.017–465 3.40�7 0

Enhancement (HU)�15 2.32�15 0.04

Irregular spiculated edge 5.54History of malignancy 4.95Current smoker 2.27Never smoked 0.19Indeterminate calcification at CT 2.20Upper and/or middle lobe location 1.22Smooth nodule at CT 0.30Benign calcification at CT 0.01

Source.—References 10 and 11.

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dual-energy computed radiography(and perhaps in the future, tomosynthe-sis) can be used to show calcificationwithin SPNs (36,37), CT has largely re-placed radiography for this purpose.Assessing calcification with CT requiresthe use of sequential thin “cuts” through

the nodule, with standard soft-tissue re-construction. If a benign pattern of cal-cification involving more than 10% ofthe cross-sectional area of the nodule ispresent, malignancy is unlikely and ob-servation is appropriate (38).

While CT studies have shown thatup to 13% of lung cancers have somecalcification (4,39,40), this is true ofonly 2% of lung cancers smaller than 3cm in diameter (39). Eccentric calcifica-tion should not be considered a benignfinding. It may represent a benign lesionthat has calcified in an eccentric fashionor a malignant lesion that has dystro-phic calcification or has engulfed a be-

nign calcified lesion (4) (Fig 10). Fur-thermore, central calcification in a spic-ulated SPN should prompt concern formalignancy, as most benign SPNs havesmooth or minimally lobulated margins.

Calcification in lung cancers may ap-pear amorphous, stippled, or diffuse(40). Some lung cancers can have densefoci of calcification or be entirely calcified,with a pattern resembling that of benigndisease. Both of these patterns can beseen in carcinoids, metastatic osteosarco-mas, and chondrosarcomas (Figs 11, 12).A stippled appearance or psammomatouscalcification can be seen in SPNs that aremetastases from mucin-secreting tumors,such as colon or ovarian cancers. In pa-tients with a history of these tumors and abenign-appearing SPN, CT cannot beused to reliably determine benignity andbiopsy may be necessary.

Unfortunately, calcification is oftennot useful, as about 45% of benign nod-ules are not calcified (4); thus, otherimaging features associated with benig-nity must be sought.

Key PointWith the exception of SPNs in patientswith a history of bone malignancy, SPNswith a benign pattern of calcification areindeed benign.

FatDemonstration of fat may be difficult ifthe nodule is small, as partial volumeinclusion of the lung may interfere withattenuation measurements. However, ifone can determine that fat is present,hamartoma or lipoma (albeit less likely)become the most likely causes (Fig 2b).Some malignancies, such as a metasta-sis from liposarcoma or renal cell carci-noma, may occasionally contain fat(41). In patients without prior malig-nancy, focal fat attenuation (�40 to�120 HU) is a reliable indicator of ahamartoma and is seen in over 50% ofhamartomas at thin-section CT (42). Ina series of 47 patients with hamarto-mas, both fat and calcium were seen in10 and fat alone was seen in 18 (42).

Key PointDemonstration of fat in an SPN in pa-tients without a history of liposarcoma

Figure 9

Figure 9: (a) Chest radiograph shows a rightupper lobe nodule with central calcification. Themargins are irregular. (b) CT scan shows a rightupper lobe nodule with irregular margins thatrepresents pulmonary carcinoma (black arrow).The calcification seen on the radiograph is causedby a calcified granuloma anterior to the tumor(white arrow).

Figure 10

Figure 10: CT scan in an 80-year-old manshows a 2.2-cm-diameter nodule in the left upperlobe with eccentric calcification. FNAB of the nod-ule revealed adenocarcinoma.

Figure 11

Figure 11: CT scan shows eccentric densecalcification in a right lower lobe carcinoid tumor.(Image courtesy of J. W. Gurney, MD, University ofNebraska, Omaha, Neb.)

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or renal cell carcinoma suggests that theSPN is benign.

Nodule AttenuationThe advent of CT has led to improvedrecognition of the frequency with whichnodules are nonsolid, partly solid, andsolid. Aerated lung parenchyma is visi-ble through a nonsolid (ground-glass)nodule, while a partly solid nodule con-tains solid regions that mask an aeratedlung.

Approximately 34% of nonsolidnodules are due to malignancy (43). Therisk of malignancy increases if the diam-eter of the SPN exceeds 1.5 cm or thenodule is round (43,44). Malignanciessuch as bronchioloalveolar carcinomasor invasive adenocarcinomas with bron-chioloalveolar cell features may appearto be nonsolid nodules (Fig 13). Non-solid nodules are often caused by benignconditions, such as inflammatory dis-ease, and may contain premalignant le-sions, such as atypical adenomatous hy-perplasia or bronchoalveolar hyperpla-sia (45). Precursors of adenocarcinomaare believed to begin in regions of bron-choalveolar hyperplasia (46). Noguchiet al (47) devised a histopathologic clas-sification system in which nodules arestratified according to their malignantpotential and propensity for local andregional metastases.

Partly solid nodules are more likelyto be malignant than nonsolid nodules(Fig 14). Between 40% and 50% ofpartly solid nodules smaller than 1.5 cmin diameter are cancerous, and the riskof cancer increases with increasing nod-ule size, particularly if the solid compo-nent is in the center of the nodule(43,44). This solid component oftencontains invasive adenocarcinoma.

Although solid nodules are the mostcommon type of nodule, they are lesslikely to be malignant than are partlysolid or nonsolid nodules. Inflammatorydiseases of the lung, particularly tuber-culosis and mycoses, usually producesolid nodules that may eventually calcifyand permit the designation of benigndisease. Only 15% of solid nodulessmaller than 1 cm in diameter containmalignant foci, but the proportion ofnodules that contain such foci increases

with increasing diameter (48). Whilesolid nodules are usually noncancerous(granulomas), most lung cancers arefound in solid nodules (Fig 6). Histologictypes of cancerous solid nodules includeadenocarcinomas and squamous cell,large-cell anaplastic, neuroendocrine,carcinoid, and (rarely) small-cell carci-nomas (48). In addition, most meta-static nodules are solid in appearance,with a partly solid appearance occurringless frequently.

Key PointWhile most cancerous nodules aresolid, partly solid nodules are mostlikely to be malignant.

Air BronchogramsAir bronchograms and bronchiologramsare seen more commonly in pulmonarycarcinomas than in benign nodules (42)(Figs 1b, 1c, 15b). In one review, airbronchograms were seen in approxi-mately 30% of malignant nodules but inonly 6% of benign nodules (49). Airbronchiolograms, also referred to asbubble-like lucencies or pseudocavita-tion, may simulate cavities and are seenin up to 55% of bronchioloalveolar cell

Figure 12

Figure 12: CT scan shows calcified right lowerlobe nodule that resembles a benign granuloma(arrow). The patient had a history of osteosarcoma.Open lung biopsy revealed metastatic disease.

Figure 13

Figure 13: CT scan in a 64-year-old manshows an oval 2.1-cm left lower lobe nonsolidnodule (arrow). FNAB revealed adenocarcinoma.

Figure 14

Figure 14: CT scan in an 81-year-old manshows a 2.8-cm irregular, partly solid left upperlobe nodule with pleural tags. FNAB revealedbronchioloalveolar cell carcinoma.

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carcinomas (42). This appearance iscaused by a desmoplastic reaction to thetumor that distorts the airways (50,51).

MarginEdge characteristics indicative of malig-nancy include irregularity, spiculation,and lobulation (10) (Fig 1b). Edge irregu-larity and spiculation are associated withthe radial extension ofmalignant cells alonginterlobular septa, lymphatics, small air-ways, or blood vessels and have been lik-ened to the spokes of a wheel (52).

In a study with thin-section CT, allnodules with a halo margin—97% withdensely spiculated margins, 93% withragged margins, and 82% with lobulatedmargins—were malignant (53). Nodulehalos (peripheral nonsolid component)should not be confused with the coronaradiata, which is a radiolucent halo asso-ciated with paracicatricial emphysema(52,54). The presence of spiculation has apredictive value for malignancy of ap-proximately 90% and should promptan aggressive work-up (3,4,10,42,55).While an irregular margin is indicative of

malignancy, it can occasionally be seen ingranulomatous disease, lipoid pneumo-nia, organizing pneumonia, and progres-sive massive fibrosis (4,56). A smoothmargin does not indicate benignity, as upto one-third of malignant lesions havesmooth margins and many of these tu-mors are metastatic (7,9,54) (Figs 7, 16).

A lobulated margin indicates that thenodule has uneven rates of growth (Fig16). In a series by Siegelman et al (3),approximately 40% of smooth-edged lob-ulated nodules were malignant. However,close inspection of any nodule that ap-pears to be lobulated is necessary. Adja-cent tiny nodules, called satellite nodules,may mimic the appearance of a lobulatedmargin, and the presence of these nod-ules is strongly associated with benignity(Fig 17). Even so, the presence of satellitenodules does not allow confident diagno-sis of benignity, as 10% of dominant nod-ules with satellite nodules will be malig-nant (4,52). When cancerous, satellitenodules are usually the result of periph-eral foci of tumor or skip metastatic le-sions (52).

CavitationBoth benign and malignant nodules canform a cavity. Up to 15% of lung cancersform a cavity, but most are larger than 3cm in diameter (57). However, cavitationmay be seen in SPNs as small as 7 mm indiameter. SPNs with irregular-walled cav-ities thicker than 16 mm tend to be malig-nant (84%–95% of SPNs), while benigncavitated lesions usually have thinnersmoother walls; approximately 95% of le-sions with cavity walls thinner than 4 mmare benign (58–60). However, becausethere is much overlap, cavity wall charac-teristics cannot be used to confidently dif-ferentiate benign and malignant SPNs(Figs 18, 19).

Key PointSeveral imaging features (nodule atten-uation, presence of air bronchograms,edge characteristics, and cavity wallthickness) must be considered when as-sessing the likelihood of malignancy;however, there is considerable overlapin the appearance of benign and malig-nant lesions.

CT Examination

In any patient with a newly discoveredSPN, a standard CT examination with-out contrast material enhancement maybe performed in the chest. This exami-nation will ensure there are no otherfindings, such as additional nodules,lymphadenopathy, pleural effusion, chestwall involvement, or adrenal mass. Be-cause of concerns about radiation doseto the patient, subsequent follow-up CTmay be limited to the nodule location.Thin-section CT scans obtained throughthe nodule provide information regard-ing nodule size (by using diameters fromthe largest cross-sectional area or vol-ume measurement), attenuation, edgecharacteristics, and the presence ofcalcification, cavitation, or fat (42) (Fig1b, 1c). Sequential thin-section CT (1–3-mm section width) performedthrough the entire nodule with a singlebreath hold and without contrast mate-rial enhancement should allow thesefeatures to be analyzed. Demonstrationof certain findings, such as fat or a be-nign pattern of calcification, may be all

Figure 15

Figure 15: (a) Transverse CT scan in a 75-year-old man shows a 2.0-cm-diameter nonsolid left upper lobenodule. FNAB revealed no malignant cells; thus, no specific diagnosis was made. (b) The lesion was followedup with serial CT; 25 months later, the nodule was slightly increased in size and had converted to a partly solidattenuation lesion with air bronchograms. Volumetric measurement showed the doubling time of the opacityto be 1375 days. Repeat FNAB showed bronchioloalveolar cell carcinoma.

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that is required to ascertain that thenodule is benign (42) (Figs 2b, 8).

The cause of many SPNs, however,will remain undetermined after the ini-tial and thin-section CT examinations. Ifthe nodule is at least 10 mm in diame-ter, a contrast material–enhanced ex-amination may be performed. The useof contrast material may be especiallyhelpful in regions where granulomatousdisease is endemic. Contrast enhance-ment is directly related to the vascular-ity of the nodule, and blood flow is usu-ally greater in malignant nodules than inbenign nodules (61,62). To perform thestudy, the nodule is examined with3-mm collimation before and after ad-ministration of a weight-related dose ofintravenous contrast material. Con-trast-enhanced examinations are per-formed at 1-minute intervals up to 4minutes after injection of contrast mate-rial. Nodule enhancement is determinedby subtracting baseline attenuationfrom peak mean attenuation during thecontrast-enhanced examinations (31).The use of multi–detector row CT facil-itates performance of this examinationbecause the nodule is likely to be in theexamined volume, despite varyingbreath holds.

Nodule enhancement of less than15 HU after administration of contrastmaterial is strongly indicative of be-nignity (positive predictive value, ap-proximately 99%). Rare false-negativefindings are associated with centralnoncavitating necrosis and adenocar-cinomas (especially bronchioloalveo-lar cell carcinoma), which may be re-lated to mucin production (31,63,64).Although enhancement of more than15 HU is more likely to represent ma-lignancy, only 58% of nodules are ma-lignant; the remainder represent en-hancing lesions due to active inflam-matory disease that have increasedblood flow, such as granulomas or or-ganizing pneumonias (31,63,65). En-hancing nodules should still be consid-ered indeterminate and require fur-ther work-up. In summary, nodulebehavior after contrast material ad-ministration is sensitive but not spe-cific for malignancy. Contrast-en-hanced CT examinations should not be

performed in nodules smaller than 10mm in diameter, cavitary lesions, orlesions with central necrosis.

Key PointWhen performing contrast-enhancedCT, enhancement of less than 15 HUindicates benignity.

Positron Emission Tomography

Positron emission tomography (PET)is rapidly becoming a front-line modal-ity in the evaluation of SPNs. Its diag-nostic ability is based on increasedglucose consumption of malignantcells. The radiopharmeutical fluorine18 fluorodeoxyglucose (FDG) is aglucose analogue that is injected intra-venously, transported through thecell membrane, and phosphorylatedthrough normal glycolytic pathways,remaining unmetabolized in the cell(66). For solid pulmonary nodules 1–3cm in diameter, sensitivity and speci-ficity are approximately 94% and

Figure 16

Figure 16: CT scan in a 56-year-old manshows a 2.9-cm smooth lobulated central rightmiddle lobe nodule (arrow). FNAB revealed squa-mous cell carcinoma.

Figure 17

Figure 17: CT scan shows a right lower lobesubcentimeter nodule with adjacent tiny satellitenodules (arrow). The larger nodule was calcified(not shown). The appearance is that of benigngranulomatous disease.

Figure 18

Figure 18: CT scan in an 83-year-old manshows a 2.3-cm left upper lobe cavitary nodule.The wall is variable and the cavity wall is asthick as 8 mm. FNAB revealed squamous cellcarcinoma.

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83%, respectively (11). Demonstra-tion of a hypermetabolic state, espe-cially in smaller lesions, is of concernfor malignancy and necessitates eitherintervention or close scrutiny. Theprobability of malignancy in associa-tion with positive FDG PET findings ishigh (90% if the patient is older than60 years); likewise, the probability ofmalignancy in association with nega-tive FDG PET findings is low (�5%)(67,68) (Fig 20). Once lung cancer hasbeen diagnosed in a solid nodule, par-ticularly if FDG uptake is high, PETmay be helpful in the detection of me-diastinal lymph node metastases, evenwhen the nodes are not enlarged onCT scans (69). Occult extrathoracicmetastases and synchronous extratho-racic primary malignancies also maybe detected with PET.

False-positive PET findings are asso-ciated with focal infections, inflamma-tion, and nonneoplastic diseases (eg, tu-berculosis, sarcoidosis, and rheumatoiddisease) and are more frequent in re-gions with endemic fungal diseases suchas Histoplasma and Coccidioides infec-tions. The high negative predictive valueof PET in low-risk populations supports

the strategy of observing nodules thatare negative at PET. However, certainneoplasms, such as carcinoid and bron-chioloalveolar cell carcinoma, have alow metabolic rate that may result infalse-negative examinations. Further-more, sensitivity and specificity are notas high for nodules that are smaller than1 cm in diameter (69).

Key PointFDG PET examination of an SPN largerthan 1 cm in diameter is the best test todetermine if a lesion is malignant or be-nign.

Bayesian Analysis

Bayesian analysis can be useful in theevaluation of SPN. Bayesian analysis in-volves the use of likelihood ratios of nu-merous imaging findings and clinicalfeatures associated with SPNs to estab-lish the probability of malignancy(10,70) (Table). In addition to imagingfindings, age and smoking history arefactors that are included in the Bayesiananalysis. A general principle in Bayesianmodels is that each characteristic used

in the development of the model is con-ditionally independent of all others.

Investigators in one study analyzedmany of the characteristics used in themodel and found that three clinical (age,smoking history, and history of previousmalignancy) and three radiographic (di-ameter, spiculation, and upper lobe lo-cation) features are independent pre-dictors of malignancy (16). Investiga-tors in another study compared theassessment made with the clinical pre-diction model with that made by theclinicians. Receiver operating charac-teristic analysis showed no differencebetween the assessments. However,physicians overestimated the probabil-ity of a malignant lesion in patients withlow risk of malignant disease. The au-thors concluded that the logistic modelcould be used to improve the care ofpatients with SPNs that are likely to bebenign (6).

Not all Bayesian models are effec-tive: Comparison of a Bayesian ap-proach with FDG PET alone revealedthat FDG PET outperformed the model(68). A standard uptake value of morethan 2.5 with PET yields a likelihoodratio of 4.30 for malignancy, whereas anegative PET examination has a likeli-hood ratio of 0.04. Bayesian analysis isequivalent or slightly superior to evalua-tion by an experienced radiologist in thestratification of benign and malignantpulmonary nodules (69). An explana-tion of the mathematics of Bayesianmodeling is beyond the scope of thisarticle; however, for a particular pa-tient, one can easily determine theprobability that an SPN is cancerous atthe following Web site: http://www.chestx-ray.com.

Key PointA Bayesian analysis that includes PETfindings is an effective method that canbe used to calculate the probability ofmalignancy.

Growth Rate Measured from SerialStudies

The notion that an SPN exhibiting nogrowth for at least 2 years is benign iswidely accepted and is the standard of

Figure 19

Figure 19: CT scan in an 80-year-old manshows a right upper lobe 2.9-cm cavitary nodulewith a smooth, uniform 2.5-mm-thick cavity wall.FNAB revealed non–small cell lung cancer.

Figure 20

Figure 20: FDG PET scan shows a lingularnodule (arrow) with a standardized uptake value ofmore than 2.5. FNAB revealed carcinoid tumor.(Image courtesy of Dr E. Long, Goshen GeneralHospital, Goshen, Ind.)

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care (71,72). Yankelevitz and Henschke(73) have challenged the basis of 2-yearstability as a reliable indicator thatSPNs are benign. They used no growthas the predictor of benignity and calcu-lated the predictive value as 65%, thesensitivity as 40%, and the specificity as72%. The 2-year rule is still being used;however, one should exercise cautionand attempt to obtain radiographs andCT scans older than 2 years becauseeven a substantial increase in volumemay be missed in small nodules (73).

The time for a nodule to double involume is referred to as the doublingtime. For radiographic measurement,the nodule diameter is measured in atleast two dimensions and averaged ontwo serial images. Doubling time (Td) iscalculated with the following equation:Td � Ti � log 2/3 � log(Di/Do), where Ti �interval time, Di � initial diameter, andDo � final diameter. For example, a di-ameter increase of 26% corresponds toa volume increase of 100%. Diametersmeasured with electronic calipers arepreferable to diameters measured man-ually; however, it is difficult to reliablyshow changes in size that are smallerthan 2 mm (74). As new software be-comes more widely available, auto-mated volume measurement algorithmswill likely become more important inthe evaluation of indeterminate nodules(75) (Fig 1d). Automated measurementwith multi–detector row CT (whichspeeds up image acquisition, thus de-creasing motion and partial volume ef-fects) may enable growth to be detectedwith serial CT examinations performedas little as 4 weeks apart (48).

A limitation of nodule measurementis that adjacent inflammatory change,atelectasis, or scars may inadvertentlybe included in the measurement, thusmaking the lesion appear larger than itis. Tumors may undergo necrosis, hem-orrhage, or cavitation, any of whichwould alter their size. The partial vol-ume effect may lead to substantial over-estimation of lesion size, particularly ifthin CT sections are not used. Even withthin CT sections, volume measurementsin very small nodules may show sub-stantial variability and be inaccurate,especially if the diameter of the nodule

is close to the CT section width(32,74,76). Another limitation of theautomated volumetric assessment is thepotential to not include in the measure-ment the ground-glass component of apartly solid nodule, which has a highfrequency of malignancy.

An early study showed that all nod-ules doubling in size in less than 7 daysand almost all nodules doubling in sizein more than 465 days were benign(77). Some benign lesions, such as gran-ulomas and hamartomas, grow slowly;therefore, growth in and of itself cannotbe used to predict malignancy (78).Many investigators have estimated thegrowth rates of various types of lungcancer with chest radiography (79–84).The volume-doubling time for most lungcancers was reported to be between 1and 18 months. Few CT studies havebeen reported, but they have shownthat lung cancer doubling times have awider range than anticipated on the ba-sis of the previously reported chest radi-ography literature. CT-derived doublingtimes have been reported to range from32 days to virtually no detectablegrowth (32,85,86) (Figs 15, 21). It hasbeen speculated that the wider range ofgrowth rates may be related to the useof a more sensitive modality in noduledetection and measurement. The ma-jority of lung cancers have rapid ormoderately rapid growth rates; how-ever, CT may preferentially depict slow-growing adenocarcinomas that are notdepicted with radiography (86). Tu-mors with doubling times of more than730 days will appear stable during a2-year observation period (87) (Fig 15).Growth rate is an independent and im-portant prognostic factor in patientswith lung cancer, so one can expectlonger survival in patients with slow-growing tumors (88).

Key PointCancerous tumors with doubling times ofmore than 730 days may appear stableduring the 2-year observation period.

SPN Biopsy

For nodules that have clinical and imag-ing features of malignancy, a tissue sam-

Figure 21

Figure 21: (a) CT scan in an 80-year-old manshows a 2.5-cm right upper lobe nodule at theposterior segment. (b) Repeat CT scan obtainedprior to treatment performed 2 months later showsrapid interval enlargement. The volumetric dou-bling time was 26 days. FNAB revealed mixedsmall cell and non–small cell carcinoma.

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ple is required. There are many meth-ods of obtaining tissue from an SPN,such as video-assisted thoracoscopic oropen surgical biopsy; however, themethod radiologists are frequentlyasked to perform is fine-needle aspira-tion biopsy (FNAB). CT-guided FNABhas been a great advancement in thediagnosis of small pulmonary noduleslarger than 5 mm in diameter. In pa-tients who are not candidates for sur-gery because of comorbidities, FNABcan be used to diagnose malignancy anddetermine the histologic type of malig-nancy. In patients who are candidatesfor surgery, FNAB may be used to diag-nose benign disease, thus obviating sur-gery (89–91) (Fig 1). Contraindicationsto FNAB include inability of the patientto cooperate (eg, inability to reproducebreath holds, lie immobile on the CTtable for more than 30 minutes, or with-hold coughing). Other relative contrain-dications include bleeding diathesis,previous pneumonectomy, severe em-physema, severe hypoxemia, pulmo-nary artery hypertension, or nodules inwhich successful biopsy cannot be per-

formed because of their small size orlocation.

FNAB has a sensitivity of 86.0% anda specificity of 98.8% in the diagnosis ofmalignancy (92); however, in nodules5–7 mm in diameter, sensitivity is only50% (93). Sensitivity of FNAB is alsosubstantially lower (12%) in patientswith lymphoma, and core biopsy (sensi-tivity, 62%) is recommended when pa-tients are suspected of having lym-phoma (94). The skills and experienceof the cytopathologist are critical in theinterpretation of biopsy specimens. Im-mediate cytologic interpretation in-creases the yield and accuracy of FNAB(95).

FNAB may be performed with fluo-roscopic, CT, or ultrasonographic (US)guidance. With fluoroscopy, FNAB canbe performed quickly and with the pa-tient in a seated position, if necessary.CT allows localization of smaller nod-ules and enables planning of the needlepath to avoid blebs and fissures. US maybe useful when the lesion abuts thepleura. Most malignant lesions can bediagnosed with FNAB and with use of a

coaxial technique. FNAB is optimallyused in peripheral nodules, although bi-opsies can be performed in more cen-tral lesions. Nodules that are in thelower lobes or adjacent to the heart maybe difficult to access because of varyingbreath holds and diaphragmatic andcardiac motion. Core-needle biopsy canbe reserved for cases where FNAB failsto provide a specific diagnosis, espe-cially for cases of benign disease.

Interpretation of the FNAB speci-mens falls into one of three categories:malignant, specific benign, or nonspe-cific benign. When the FNAB sample isinterpreted as malignant or if a specificbenign condition is diagnosed, furtherdecisions regarding care are dictated bythe diagnosis. On the other hand, whena nonspecific benign condition is diag-nosed, further evaluation is required.The lesion may be malignant, but thesample was obtained outside the noduleor from a necrotic area, thus precludingthe pathologist from establishing a diag-nosis. Core-needle biopsy is more likelythan FNAB to provide a specific benignresult. In a group of patients with be-nign nodules, a specific benign diagnosiswas made in 69% of patients with coreneedle biopsy and in 31% of patientswith FNAB (96).

A nonspecific benign diagnosis re-quires careful clinical and radiographicfollow-up. Diagnoses such as atypicalbronchioloalveolar hyperplasia or in-flammation without organisms on asmear or a culture are considered non-specific. If further growth occurs after anonspecific benign diagnosis is obtainedwith FNAB, repeat biopsy or resectionis indicated.

The most common complications ofFNAB are pneumothorax and hemor-rhage (87,89). Pneumothorax occurs inapproximately 25% of patients, but it isoften not clinically important. Onlyabout 7% of patients with a pneumotho-rax will eventually require a chest tube(92). The use of an autologous bloodpatch (injecting the patient’s own bloodalong the needle track while withdraw-ing the needle) has shown mixed resultsin reducing the rate of pneumothoraxafter FNAB (97). Presence of emphy-sema, deep lesion location, a lengthy

Figure 22

Figure 22: Flowchart for evaluation of the solitary indeterminate nodule for patients with intermediate andintermediate risk for malignancy. FNA � FNAB.

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procedure, many pleural punctures,and traverse of the fissure all increasethe risk for pneumothorax (98,99). Asurgent intervention may be required,radiologists who perform lung biopsyprocedures must be competent at aspi-ration of pleural air and insertion of achest tube. Hemorrhage is almost al-ways self-limiting, although it can occa-sionally be life-threatening (100). Bleed-ing complications are more likely to oc-cur in patients with bleeding diathesesor pulmonary artery hypertension.

Air embolism is a rare complication;patients can present with symptoms re-sembling thoseof stroke, transient ische-mic attack, seizure, or cardiopulmonarycollapse. Treatment includes placing thepatient in the left lateral decubitus posi-tion or Trendelenburg position and ad-ministering 100% oxygen. Hyperbaricoxygen therapy is recommended. A di-agnosis may be established by perform-ing immediate brain or cardiac CT tosearch for intravascular air bubbles(101).

Key PointFNAB results other than a specific ma-lignant or benign diagnosis should beviewed with caution.

Imaging Management of IndeterminateNodules

There is no uniform approach for themanagement of an indeterminate nod-ule. In patients with a high or intermedi-ate likelihood for malignancy, early in-tervention with FNAB or surgery is agood approach. In patients with a lowlikelihood for malignancy, close obser-vation with serial CT might be pre-ferred. In patients with a very low likeli-hood for malignancy (eg, a healthy non-smoker younger than 30 years with awell-defined noncalcified nodule), onemight consider observation with radiog-raphy if the nodule is visible on thechest radiograph.

The flowchart presented in Figure22 is a guide proposed by the author forthe care of patients with an SPN of in-termediate or high likelihood for malig-nancy. Note that nodules smaller than 5mm in diameter are often benign, and

their growth is difficult to detect. Thus,thin-section CT examinations per-formed to show stability at 12 and 24months are acceptable (102,103). Nod-ules shown to be stable at 2-year fol-low-up are considered benign and areno longer followed with CT. It is possi-ble that as volumetric measurementsbecome routine, the current follow-upCT protocol (3-, 6-, 12-, and 24-monthfollow-up) will become compressed(73).

Nodules with low likelihood for ma-lignancy that are at least 5 mm in diam-eter but smaller than 10 mm in diame-ter can be observed with CT for a 2-yearperiod, while nodules with intermediateor high likelihood for malignancy maybe sampled with FNAB or resected(104). Demonstration of nodule growthshould prompt intervention with eitherFNAB or surgery. A new persistent nod-ule that develops during observation isworrisome for malignancy and warrantsintervention (104).

For a nodule at least 10 mm in diam-eter, PET and contrast-enhanced CTmay be helpful in deciding between ob-servation or intervention. Patients withnegative PET findings and enhancementof less than 15 HU on contrast-en-hanced CT scans may be observed,while intervention and tissue diagnosisare indicated in patients with positivePET findings.

Summary

In general, SPNs can be considered be-nign if they exhibit a pattern of benigncalcification and/or show no growth for2 years. When the imaging features in-dicate that the probability of malignancyis high, tissue samples should be ob-tained for diagnosis.

In using the various imaging and diag-nostic modalities described in this review,one should strive to not only identify smallmalignant tumors—where resection re-sults in high survival rates—but alsospare patients with benign disease fromundergoing unnecessary surgery.

Acknowledgment: Many thanks to S. GregoryJennings, MD, for his assistance in editing thismanuscript.

References1. Midthun DE, Swensen SJ, Jett JR. Ap-

proach to the solitary pulmonary nodule.Mayo Clin Proc 1993;68:378–385.

2. Swensen SJ, Morin RL, Schueler BA, et al.Solitary pulmonary nodule: CT evaluationof enhancement with iodinated contrastmaterial—a preliminary report. Radiology1992;182(2):343–347.

3. Siegelman SS, Khouri NF, Leo FP, FishmanEK, Braverman RM, Zerhouni EA. Solitarypulmonary nodules: CT assessment. Radi-ology 1986;160(2):307–312.

4. Zerhouni EA, Stitik FP, Siegelman SS, et al.CT of the pulmonary nodule: a cooperativestudy. Radiology 1986;160(2):319–327.

5. Holin SM, Dwork RE, Glaser S, Rikli AE,Stocklen JB. Solitary pulmonary nodulesfound in a community-wide chest roentgen-ographic survey. Am Rev Tuberc 1959;79:427–439.

6. Swensen SJ, Silverstein MD, Edell ES, et al.Solitary pulmonary nodules: clinical predic-tion model versus physicians. Mayo ClinProc 1999;74:319–329.

7. Bateson EM. An analysis of 155 solitarylung lesions illustrating the differential diag-nosis of mixed tumors of the lung. Clin Ra-diol 1965;16:51–65.

8. Murthy SC, Rice TW. The solitary pulmo-nary nodule: a primer on differential diag-nosis. Semin Thorac Cardiovasc Surg 2002;14:239–249.

9. Siegelman SS, Zerhouni EA, Leo FP,Khouri NF, Stitik FP. CT of the solitarypulmonary nodule. AJR Am J Roentgenol1980;135:1–13.

10. Gurney JW. Determining the likelihood ofmalignancy in solitary pulmonary noduleswith Bayesian analysis. I. Theory. Radiol-ogy 1993;186:405–413.

11. Gould MK, Maclean CC, Kuschner WG,Rydzak CE, Owens DK. Accuracy ofpositron emission tomography for diagno-sis of pulmonary nodules and mass lesions:a meta-analysis. JAMA 2001;285:914–924.

12. Wynder EL, Graham EA. Tobacco smokingas a possible etiologic factor in bronchio-genic carcinoma: a study of 684 provedcases. J Am Med Assoc 1950;143:329–336.

13. Hrubec Z, McLaughlin JK. Former ciga-rette smoking and mortality among USveterans: a 26-year followup, 1954–1980.In: Burns D, Garfinkel L, Samet J, eds.Changes in cigarette-related disease risksand their implication for prevention andcontrol. Bethesda, Md: U.S. GovernmentPrinting Office, 1997; 501–530.

REVIEW FOR RESIDENTS: The Solitary Pulmonary Nodule Winer-Muram

46 Radiology: Volume 239: Number 1—April 2006

Page 14: The Solitary Pulmonary Nodule - University of North ...msrads.web.unc.edu/files/2018/08/Solitary-Pulmonary-Nodule.pdf · The Solitary Pulmonary Nodule1 HelenT.Winer-Muram,MD The imaging

14. Tong L, Spitz MR, Fueger JJ, Amos CA.Lung carcinoma in former smokers. Cancer1996;78:1004–1010.

15. Lee HJ, Im JG, Ahn JM, Yeon KM. Lungcancer in patients with idiopathic pulmo-nary fibrosis: CT findings. J Comput AssistTomogr 1996;20:979–982.

16. Swensen SJ, Silverstein MD, Ilstrup DM,Schleck CD, Edell ES. The probability ofmalignancy in solitary pulmonary nodules:application to small radiologically indeter-minate nodules. Arch Intern Med 1997;157:849–855.

17. Quint LE, Park CH, Iannettoni MD. Solitarypulmonary nodules in patients with ex-trapulmonary neoplasms. Radiology 2000;217:257–261.

18. Jemal A, Chu KC, Tarone RE. Recenttrends in lung cancer mortality in theUnited States. J Natl Cancer Inst 2001;93:277–283.

19. Parker MS, Leveno DM, Campbell TJ,Worrell JA, Carozza SE. AIDS-relatedbronchogenic carcinoma: fact or fiction?Chest 1998;113:154–161.

20. Travis WD, Lubin J, Ries L, Devesa S.United States lung carcinoma incidencetrends: declining for most histologic typesamong males, increasing among females.Cancer 1996;77:2464–2470.

21. American Cancer Society. What are thekey statistics for lung cancer? AmericanCancer Society detailed guide: lung can-cer—2005. www.cancer.org. AccessedApril 2005.

22. Kundel HL. Predictive value and thresholddetectability of lung tumors. Radiology1981;139(1):25–29.

23. Muhm JR, Miller WE, Fontana RS, Sander-son DR, Uhlenhopp MA. Lung cancer de-tected during a screening program using4-month chest radiographs. Radiology1983;148:609–615.

24. Austin JH, Romney BM, Godsmith LS.Missed bronchogenic carcinoma: radiologicfindings in 27 patients with a potentiallyrespectable lesion evident in retrospect.Radiology 1992;182:115–122.

25. Swensen SJ, Jett JR, Hartman TE, et al. CTscreening for lung cancer: 5-year prospec-tive experience. Radiology 2005;235(1):259–265.

26. Henschke CI, McCauley DI, YankelevitzDF, et al. Early lung cancer action project:overall design and findings from baselinescreening. Lancet 1999;354:99–105.

27. Munden RF, Pugatch RD, Liptay MJ, Sugar-baker DJ, Linh UL. Small pulmonary lesions

detected at CT: clinical importance. Radiol-ogy 1997;202:105–110.

28. Zerhouni EA, Spivey JF, Morgan RH, LeoFP, Stitik FP, Siegelman SS. Factors influ-encing quantitative CT measurements ofsolitary pulmonary nodules. J Comput As-sist Tomogr 1982;6:1075–1087.

29. Proto AV, Thomas SP. Pulmonary nodulesstudied by computed tomography. Radiol-ogy 1985;156:149–153.

30. Garland LH. Bronchial carcinomas: lobardistribution of lesions in 250 cases. CalifMed 1961;94:7–8.

31. Swensen SJ, Viggiano RW, Midthun DE, etal. Lung nodule enhancement at CT: multi-center study. Radiology 2000;214:73–80.

32. Winer-Muram HT, Jennings SG, TarverRD, et al. Volumetric growth rate of stage Ilung cancer prior to treatment: serial CTscanning. Radiology 2002;223:798–805.

33. Quinn D. Gianlupi A, Broste S. The chang-ing radiographic presentation of broncho-genic carcinoma with reference to celltypes. Chest 1996;110:1474–1479.

34. Thun MJ, Lally CA, Flannery JT, Calle EE,Flanders WD, Heath CW Jr. Cigarettesmoking and changes in the histopathologyof lung cancer. J Natl Cancer Inst 1997;89:1580–1586.

35. Berger WG, Erly WK, Krupinski EA,Standen JR, Stern RG. The solitary pulmo-nary nodule on chest radiography: can wereally tell if the nodule is calcified? AJRAm J Roentgenol 2001;176:201–204.

36. Kelcz F, Zink FE, Peppler WW, KrugerDG, Ergun DL, Mistretta CA. Conventionalchest radiography vs dual-energy computedradiography in the detection and character-ization of pulmonary nodules. AJR Am JRoentgenol 1994;162:271–278.

37. Sone S, Kasuga T, Sakai F, et al. Digitaltomosynthesis imaging of the lung. RadiatMed 1996;14:53–63.

38. Colice GL. Chest CT for known or sus-pected lung cancer. Chest 1994;106:1538–1550.

39. Grewal RG, Austin JH. CT demonstrationof calcification in carcinoma of the lung.J Comput Assist Tomogr 1994;18:867–871.

40. Mahoney MC, Shipley RT, Corcoran HL,Dickson BA. CT demonstration of calcifica-tion in carcinoma of the lung. AJR Am JRoentgenol 1990;154:255–258.

41. Muram TM, Aisen A. Fatty metastatic le-sions in 2 patients with renal clear-cell car-cinoma. J Comput Assist Tomogr 2003;27:869–870.

42. Zwirewich CV, Vedal S, Miller RR, MullerNL. Solitary pulmonary nodule: high-reso-lution CT and radiologic-pathologic correla-tion. Radiology 1991;179:469–476.

43. Henschke CI, Yankelevitz DF, Mirtcheva R,et al. CT screening for lung cancer: fre-quency and significance of part solid andnon-solid nodules. AJR Am J Roentgenol2002;178:1053–1057.

44. Li F, Sone S, Abe H, MacMahon H, Doi K.Malignant versus benign nodules at CTscreening for lung cancer: comparison ofthin section CT findings. Radiology 2004;233:793–798.

45. Vazquez M, Flieder D, Travis W, et al.Early lung cancer action project pathologyprotocol [letter]. Lung Cancer 2003;39:231–232.

46. Kerr KM. Pulmonary preinvasive neopla-sia. J Clin Pathol 2001;54:257–271.

47. Noguchi M, Morikawa A, Kawasaki M, etal. Small adenocarcinoma of the lung. Can-cer 1995;75:2844–2852.

48. Libby DM, Smith JP, Altorki NK, Pasman-tier MW, Yankelevitz D, Henschke CI.Managing the small pulmonary nodule dis-covered by CT. Chest 2004;125:1522–1529.

49. Kui M, Templeton PA, White CS, Cai ZL,Bai YX, Cai YQ. Evaluation of the air bron-chogram sign on CT in solitary pulmonarylesions. J Comput Assist Tomogr 1996;20:983–986.

50. Weisbrod GL, Towers MJ, ChamberlainDW, Herman SJ, Matzinger FR. Thin-walled cystic lesions in bronchioalveolarcarcinoma. Radiology 1992;185:401–405.

51. Lee KS, Kim Y, Han J, Ko EJ, Park CK,Primack SL. Bronchioloalveolar carcinoma:clinical, histopathologic, and radiologicfindings. RadioGraphics 1997;17:1345–1357.

52. Heitzman ER, Markarian B, Raasch BN,Carsky EW, Lane EJ, Berlow ME. Path-ways of tumor spread through the lung:radiologic correlations with anatomy andpathology. Radiology 1982;144:3–14.

53. Furuya K, Murayama S, Soeda H, et al.New classification of small pulmonary nod-ules by margin characteristics on high-reso-lution CT. Acta Radiol 1999;40:496–504.

54. Seemann MD, Seeman O, Luboldt W, et al.Differentiation of malignant from benignsolitary pulmonary lesions using chest radi-ography, spiral CT and HRCT. Lung Cancer2000;29:105–124.

55. Khan A, Herman PG, Vorwerk P, StevensP, Rojas KA, Graver M. Solitary pulmonary

REVIEW FOR RESIDENTS: The Solitary Pulmonary Nodule Winer-Muram

Radiology: Volume 239: Number 1—April 2006 47

Page 15: The Solitary Pulmonary Nodule - University of North ...msrads.web.unc.edu/files/2018/08/Solitary-Pulmonary-Nodule.pdf · The Solitary Pulmonary Nodule1 HelenT.Winer-Muram,MD The imaging

nodules: comparison of classification withstandard, thin-section, and reference phan-tom CT. Radiology 1991;179:477–481.

56. Huston J 3rd, Muhm JR. Solitary pulmo-nary opacities: plain tomography. Radiol-ogy 1987;163:481–485.

57. Chaudhuri MR. Primary pulmonary cavitat-ing carcinomas. Thorax 1973;28:354–366.

58. Theros EG. Varying manifestations of pe-ripheral pulmonary neoplasms: a radiology-pathologic correlative survey. AJR Am JRoentgenol 1977;128:893–914.

59. Woodring JH, Fried AM, Chaung VP. Soli-tary cavities of the lung: diagnostic implica-tions of cavity wall thickness. AJR Am JRoentgenol 1980;135:1269–1271.

60. Woodring JH, Fried AM. Significance ofwall thickness in solitary cavities of thelung: a follow up study. AJR Am J Roentge-nol 1983;140:473–474.

61. Swensen SJ, Brown LR, Colby TV, WeaverAL. Pulmonary nodules: CT evaluation ofenhancement with iodinated contrast mate-rial. Radiology 1995;194:393–398.

62. Swensen SJ, Brown LR, Colby TV, WeaverAL, Midthun DE. Lung nodule enhance-ment at CT: prospective findings. Radiology1996;201:447–455.

63. Zhang M, Kono M. Solitary pulmonarynodules: evaluation of blood flow patternswith dynamic CT. Radiology 1997;205:471–478.

64. Yamashita K, Matsunobe S, Tsuda T, et al.Intratumoral necrosis of lung carcinoma: apotential diagnostic pitfall in incrementaldynamic computed tomography analysis ofsolitary pulmonary nodules? J Thorac Im-aging 1997;12(3):181–187.

65. Yamashita K, Matsunobe S, Tsuda T, et al.Solitary pulmonary nodule: preliminarystudy of evaluation with incremental dy-namic CT. Radiology 1995;194:399–405.

66. Erasmus JJ, McAdams HP, Patz EF Jr.Non-small cell lung cancer: FDG-PET imag-ing. J Thorac Imaging 1999;14:247–256.

67. Gupta NC, Maloof J, Gunel E. Probability ofmalignancy in solitary pulmonary nodulesusing fluorine-18-FDG and PET. J Nucl Med1996;37:943–948.

68. Dewan NA, Shehan CJ, Reeb SD, GobarLS, Scott WJ, Ryschon K. Likelihood ofmalignancy in a solitary pulmonary nodule:comparison of Bayesian analysis and resultsof FDG-PET scan. Chest 1997;112:416–422.

69. Goldsmith SJ, Kostakoglu L. Nuclear medi-cine imaging of lung cancer. Radiol ClinNorth Am 2000;38:511–524.

70. Black WC, Armstrong P. Communicatingthe significance of radiologic test results:the likelihood ratio. AJR Am J Roentgenol1986;147:1313–1318.

71. Gurney JW, Lyddon DM, McKay JA. De-termining the likelihood of malignancy insolitary pulmonary nodules with Bayesiananalysis. II. Application. Radiology 1993;186:415–422.

72. Tan BB, Flaherty KR, Kazerooni EA, Ian-nettoni MD; American College of ChestPhysicians. The solitary pulmonary nodule.Chest 2003;123(1 suppl):89S–96S.

73. Yankelevitz DF, Henschke CI. Does 2-yearstability imply that pulmonary nodules arebenign? AJR Am J Roentgenol 1997;168:325–328.

74. Jennings SG, Winer-Muram HT, TarverRD, Farber MO. Lung tumor growth: as-sessment with CT—comparison of diame-ter and cross-sectional area with volumemeasurements. Radiology 2004;231:866–871.

75. Yankelevitz DF, Reeves AP, Kostis WJ,Zhao B, Henschke CI. Small pulmonarynodules: volumetrically determined growthrates based on CT evaluation. Radiology2000;217:251–256.

76. Winer-Muram HT, Jennings SG, MeyerCA, et al. Effect of varying CT section widthon volumetric measurement of lung tumorsand application of compensatory equations.Radiology 2003;229:184–194.

77. Nathan MH, Collins VP, Adams RA. Differ-entiation of benign and malignant pulmo-nary nodules by growth rate. Radiology1962;79:221–232.

78. Jensen KG, Schiodt T. Growth conditionsof hamartoma of the lung: a study based on22 cases operated on after radiographic ob-servation for from one to 18 years. Thorax1958;13:233–237.

79. Steele JD, Buell P. Asymptomatic solitarypulmonary nodules: host survival, tumorsize, and growth rate. J Thorac CardiovascSurg 1973;65:140–151.

80. Weiss W, Boucot KR, Cooper DA. Growthrate in the detection and prognosis of bron-chogenic carcinoma. JAMA 1966;198:1246–1252.

81. Weiss W. Tumor doubling time and sur-vival of men with bronchogenic carcinoma.Chest 1974;65:3–8.

82. Garland LH, Coulson W, Wollin E. The rateof growth and apparent duration of un-treated primary bronchial carcinoma. Can-cer 1963;16:694–707.

83. Garland LH. The rate of growth and natural

duration of primary bronchial cancer. Am JRoentgenol Radium Ther Nucl Med 1966;96:604–611.

84. Weiss W. Peripheral measurable broncho-genic carcinoma: growth rate and period ofrisk after therapy. Am Rev Respir Dis 1971;103:198–208.

85. Aoki T, Nakata H, Watanabe H, et al. Evo-lution of peripheral lung adenocarcinomas:CT findings correlated with histology andtumor doubling time. AJR Am J Roentgenol2000;174:763–768.

86. Hasegawa M, Sone S, Takashima S, et al.Growth rate of small lung cancers detectedon mass CT screening. Br J Radiol 2000;73:1252–1259.

87. Lillington GA. Management of solitary pul-monary nodules. Dis Mon 1991;37:271–318.

88. Usuda K, Saito Y, Sagawa M, et al. Tumordoubling time and prognostic assessment ofpatients with primary lung cancer. Cancer1994;74:2239–2244.

89. Westcott JL, Rao N, Colley DP. Transtho-racic needle biopsy of small pulmonary nod-ules. Radiology 1997;202:97–103.

90. Li H, Boiselle PM, Shepard JO, Trotman-Dickenson B, McLoud TC. Diagnostic accu-racy and safety of CT-guided percutaneousneedle aspiration biopsy of the lung: com-parison of small and large pulmonary nod-ules. AJR Am J Roentgenol 1996;167:105–109.

91. Moore EH. Needle-aspiration lung biopsy: acomprehensive approach to complicationreduction. J Thorac Imaging 1997;12:259–271.

92. Lacasse Y, Wong E, Guyatt GH, et al.Transthoracic needle aspiration biopsy forthe diagnosis of localized pulmonarylesions: a meta-analysis. Thorax 1999;54:884–893.

93. Wallace MJ, Krishnamurthy S, BroemelingLD, et al. CT-guided percutaneous fine-nee-dle aspiration biopsy of small (�1-cm) pul-monary lesions. Radiology 2002;225:823–828.

94. Goralnik CH, O’Connell DM, el Yousef SJ,Haaga JR. CT-guided cutting-needle biop-sies of selected chest lesions. AJR Am JRoentgenol 1988;151:903–907.

95. Austin JH, Cohen MB. Value of having acytopathologist present during percutane-ous fine-needle aspiration biopsy of lung:report of 55 cancer patients and metaanaly-sis of the literature. AJR Am J Roentgenol1993;160:175–177.

96. Boiselle PM, Shepard JO, Mark EJ. Routine

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addition of an automated biopsy device tofine needle aspiration of the lung: a pro-spective assessment. AJR Am J Roentgenol1997;169:661–666.

97. Lang EK, Ghavami R, Schreiner VC, et al.Autologous blood clot seal to prevent pneu-mothorax at CT guided lung biopsy. Radiol-ogy 2000;216:93–96.

98. Laurent F, Michel P, Latrabe V, Tunon deLara M, Marthan R. Pneumothoraces andchest tube placement after CT-guidedtransthoracic lung biopsy using a coaxialtechnique: incidence and risk factors. AJRAm J Roentgenol 1999;172:1049–1053.

99. Kazerooni EA, Lim FT, Mikhail A, et al.Risk of pneumothorax in CT-guided trans-thoracic needle aspiration biopsy of thelung. Radiology 1996;198:371–375.

100. Milner LB, Ryan K, Gullo J. Fatal intratho-racic hemorrhage after percutaneous aspi-ration lung biopsy. AJR Am J Roentgenol1979;132:280–281.

101. Kodama F, Ogawa T, Hashimoto M, et al.Fatal air embolism as a complication of CTguided needle biopsy of the lung. J ComputAssist Tomogr 1999;23:949–951.

102. Henschke CI, Yankelevitz DF, Naidich DP,et al. CT screening for lung cancer: suspi-

ciousness of nodules according to size onbaseline scans. Radiology 2004;231:164–168.

103. Macmahon H, Austin JH, Gamsu G, et al.Guidelines for management of small pulmo-nary nodules detected on CT scans: a state-ment from the Fleischner Society. Radiol-ogy 2005;237(2):395–400.

104. Henschke CI, Naidich DP, Yankelevitz DF,et al. Early Lung Cancer Action Project:initial findings on repeat screenings. Cancer2001;92:153–159.

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