Lung cancer and positron emission tomography with fluorodeoxyglucose

Lung Cancer 28 (2000) 187–202

Lung cancer and positron emission tomography withfluorodeoxyglucose

Edith M. Marom *, Jeremy J. Erasmus, Edward F. Patz JrDepartment of Radiology, Duke Uni6ersity Medical Center, P.O. Box 3808, Durham, NC 27710, USA

Received 27 September 1999; received in revised form 20 December 1999; accepted 22 December 1999

Abstract

Over the past years, positron emission tomography (PET) with fluoro-2-deoxy-D-glucose (FDG) has emerged as animportant imaging modality. In the thorax, FDG-PET has been shown to differentiate benign from malignantpulmonary lesions and stage lung cancer. Preliminary studies have shown its usefulness in assessing tumor recurrence,and assisting in radiotherapy planning. FDG-PET is often more accurate than conventional imaging studies, and hasbeen proven to be cost-effective in evaluating lung cancer patients. This review will discuss the current applicationsof FDG-PET as compared with conventional imaging in diagnosing, staging, and following patients with lung cancer.© 2000 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Lung cancer; Positron emission tomography; Diagnosis; Staging; Treatment; Prognosis

www.elsevier.nl/locate/lungcan

1. Introduction

Lung cancer is a significant world-wide healthproblem with approximately 3 000 000 new casesin 1998. In the United States alone, there were181 000 cases diagnosed in 1998, and lung cancernow accounts for more cancer-related deaths inmen and women annually than colon, breast andprostate cancer combined [1]. Conventional imag-ing modalities with chest radiography, computedtomography (CT) and, occasionally, magnetic res-onance imaging (MRI) play an essential role indiagnosing, staging, and assessing response to

treatment in patients with lung cancer. Theseimaging modalities provide exquisite anatomicand morphologic detail, but do not alwaysprovide the requisite information for a definitivediagnosis, and tissue sampling is often required.

More recently, positron emission tomography(PET) with F-18–2-fluoro-2-deoxy-D-glucose(FDG), a D-glucose analog labeled with positron-emitting fluorine-18, has been shown to be anaccurate imaging modality that complements con-ventional studies in evaluating these patients.FDG-PET takes advantage of one characteristicfeature of malignant cells, increased glucose con-sumption [2–7]. Because tumors are metabolicallyhyperactive, FDG is taken up by the cancer cellsin greater amounts than in normal tissue, and

* Corresponding author. Tel.: +1-919-6847367; fax: +1-919-6847123.

E-mail address: [email protected] (E.M. Marom)

0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.

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E.M. Marom et al. / Lung Cancer 28 (2000) 187–202188

then enters the glycolytic pathway. It becomesphosphorylated, however, due to an abnormalhexose�phosphate bond, FDG-6 phosphate can-not be further metabolized, and thus it becomestrapped within the cell. This increased uptake,trapping, and subsequent accumulation permitsdifferentiation between benign and malignant le-sions [8–11]. These principals form the fundamen-tal basis for tumor imaging with FDG-PET.

This review will describe the current applica-tions of FDG-PET imaging in diagnosing, stag-ing, and following patients with lung cancer.

2. Diagnosis

The radiological manifestations of lung cancerare variable. The primary mass typically presentsas a focal pulmonary opacity or solitary pul-monary nodule. Not all pulmonary lesions, how-ever, are malignant, and differentiating a benignfrom malignant abnormality can be difficult.Standard evaluation usually includes comparisonwith prior radiographs or CT to determinegrowth. Absence of growth over a 2-year period,although not diagnostic, is highly suggestive of abenign lesion [12–15]. Further imaging, includingcontrast-enhanced CT, can also be useful in dif-ferentiating benign from malignant nodules [16].If the lesion remains indeterminate after conven-tional radiological evaluation then, according tothe likelihood of malignancy, the lesion can eitherbe observed, biopsied or resected.

More recently, FDG-PET has become an addi-tional option that can be used to evaluate patientswith indeterminate lung lesions. FDG-PET is ac-curate in differentiating benign from malignantlesions as small as 10 mm with an overall sensitiv-ity, specificity and accuracy of 96, 88 and 94%,respectively, shown in prospective [17–20] andretrospective trials [21–23]. These studies havesuggested several important features of FDG-PETimaging in the evaluation of an indeterminatepulmonary abnormality.1. The negative predictive value of a FDG-PET

study is clinically useful [20,24]. Patients with afocal lung lesion without significant FDG up-take can be followed, as this is highly sugges-

tive of a benign abnormality. False negativestudies of the primary lesion (a negative FDG-PET that proves to be a tumor) are unusual,but may be seen with small (B10 mm) lungcancers. This is thought to be due to limita-tions in spatial resolution and the paucity oftumor cells within the abnormality. Other falsenegative studies have been reported with car-cinoid tumors and bronchioloalveolar car-cinomas [25–28]. Because malignancies rarelyhave low FDG uptake, patients with negativeFDG-PET studies should be followed radio-logically for 2 years. The radiological follow-up will eliminate unnecessary surgery forbenign nodules, but will detect those uncom-mon, small, slowly progressing lung cancerssuch as carcnoid and bronchioalveolar car-cinoma that may have been falsely negative byFDG-PET. If a lesion grows during this pe-riod of time, it should be considered malignantand removed. This short delay in these malig-nancies is not considered as a significant risk,and is often the standard of care in the ab-sence of an available PET study.

2. The positive predictive value is also usefulbecause the probability of malignancy with apositive FDG-PET, in most places, is high(90% if the patient is older than 60 years).False positive studies of the primary lesion (apositive FDG-PET that proves to be benign)have been reported with infectious and inflam-matory processes such as tuberculosis, histo-plasmosis and rheumatoid nodules [18,29–32].Lesions with increased FDG uptake, however,should be considered malignant until provenotherwise and managed accordingly.

FDG-PET is currently used to further evaluateabnormalities detected on conventional radiologi-cal imaging studies (Fig. 1). The combination ofCT and FDG-PET imaging is clinically useful andcost-effective in evaluating patients with focal pul-monary lesions [33]. FDG-PET has been shown toreduce the number of patients with indeterminatenodules undergoing unnecessary resection of be-nign lesions by 15% [33]. It has been estimatedthat the combination of FDG-PET and CT toevaluate indeterminate focal pulmonary lesionscan save $1192 per patient ($62.7 million annu-

E.M. Marom et al. / Lung Cancer 28 (2000) 187–202 189

Fig. 1. Sixty-five-year-old male with a new right upper lobe pulmonary nodule on routine chest radiograph. (a) Axial thoracic CTat the level of the aortic arch confirms the indeterminate 1 cm nodule in the posterior segment of the right upper lobe (arrow). (b)Soft tissue windows at the same level demonstrate an enlarged right paratracheal lymph node (arrow). (c) Axial FDG-PETdemonstrates increased FDG uptake in the pulmonary nodule and the right paratracheal node. This proved to be stage IIIA (T1N2)nonsmall-cell lung cancer.


ally) in medical treatment costs compared withthe use of CT alone [33].

3. Staging

Accurate staging of lung cancer is important indetermining patient management and prognosis.The primary goal of radiological staging is todistinguish those patients who are potentially re-sectable (stage I–IIIA) from those who are notresectable (stage IIIB and IV) (Fig. 2). Initialevaluation typically begins with a chest radio-graph and thoracic CT from the lung apicesthrough the adrenal glands, which are useful indetermining the extent of local disease. Thesestudies in combination with clinical and labora-tory findings are then used to determine the neces-sity of additional imaging studies, mostcommonly radionuclide bone scan and brainMRI, in the search for extra-thoracic metastases.Unfortunately, despite careful clinical evaluationand the judicious use of imaging studies, somepatients will be incorrectly staged. Recent studieswith FDG-PET demonstrate an improved accu-racy of lung cancer staging. In prospective andretrospective studies, up to 18% of patients con-sidered to be resectable will have more advanced

disease demonstrated by FDG-PET and becomenonresectable [34–36].

3.1. Primary tumor (T status)

The ‘TNM’ descriptors used to stage tumorswere designed for conventional anatomic assess-ment and are not always applicable to FDG-PETimaging. For instance, T status (size of the pri-mary tumor and extent of local invasion) is sub-optimally assessed by FDG-PET imaging due tolimitations in spatial resolution, i.e. it is often notpossible to determine whether a lesion is com-pletely surrounded by lung parenchyma (T1), orinvading adjacent structures including the pleura,chest wall, diaphragm, and mediastinum (T2–T4).FDG-PET assessment of T status consequentlydiffers from conventional anatomic imaging inthat most lung lesions are interpreted as eitherpositive or negative for malignancy.

3.2. Nodal disease (N status)

Although CT, and occasionally MRI, is used toevaluate hilar and mediastinal nodes, the accuracyof detecting nodal metastases using a short axisdiameter \1 cm as abnormal is 56–82% and50–82% for CT and MR, respectively [37–42].

Fig. 1. (Continued)


Fig. 2. Sixty-year-old male complained of increasing shortness of breath. (a) Axial CT image demonstrates a 4 cm cavitary mass inthe posterior segment of the left upper lobe, scattered atelectasis, and small bilateral effusions. (b) Axial FDG-PET at the same levelshows increased FDG uptake within the periphery of the left upper lobe mass (arrow) and both pleura (curved arrows). The rightpleural effusion was found to contain malignant cells consistent with nonsmall-cell lung cancer.


Normal sized lymph nodes may harbor tumor,and enlarged nodes may be reactive [43,44]. FDG-PET, however, relying on the metabolic propertiesof tumor cells is more sensitive and specific thanCT, with accuracy reported to be 81–100% in aretrospective [45] and prospective trials [18,19,46–50]. In a prospective study, FDG-PET correctlyincreased or decreased nodal staging as deter-mined by CT in 24% of pre-surgical patients [51].A retrospective study found mediastinoscopy un-necessary in patients with CT evidence for stage Idisease and a negative FDG-PET of the regionalnodes [52]. Additionally, increased FDG uptakein hilar and mediastinal lymph nodes was used todirect surgical nodal sampling.

A decision analysis model showed that the useof both CT and FDG-PET to stage intra-thoracicnodal metastases is not only clinically useful, butalso cost-effective [53]. FDG-PET reduces theprobability that a patient with unresectable me-diastinal nodal metastases will undergo an at-tempt at curative resection, and has been shownto save $1154 per patient with a small increase inlife expectancy [53]. Although additional cost sav-ings may be obtained by eliminating the chest CTin staging nodal disease [54], it is unlikely to gainclinical acceptance. As stated previously, theTNM staging system was designed for conven-tional anatomic assessment and is important insurgical planning. FDG-PET does not offer thesame anatomic detail, but compliments conven-tional studies with the metabolic information.

3.3. Distant metastases (M status)

Lung cancer most commonly metastasizes tothe regional lymph nodes, adrenal glands, bones,brain, and liver [37,55]. Up to 44% of patients willhave distant disease at presentation [1,56]; how-ever, routine radiological evaluation for metas-tases in the absence of clinical or laboratoryfindings remains controversial and not clearlydefined [37,57–59].

FDG-PET imaging appears to improve thenon-invasive detection of extra-thoracic disease.Whole-body FDG-PET has the capability to stageboth intra- and extra-thoracic disease in a singleexamination and has an overall greater accuracy

than conventional imaging [34–36,51,60–63].Whole-body FDG-PET alters management in upto 40% of cases [34,35,51].

The adrenal glands are the most commonmetastatic site in nonsmall-cell lung cancer [64–66]. Adrenal metastases are found by autopsy in38% of patients, 1 month following curativesurgery [65]. Adrenal masses are found in up to20% of patients at initial presentation [67–71].They are occasionally difficult to distinguish frombenign abnormalities as up to two-thirds ofadrenal lesions detected by CT in patients withlung cancer are benign [67,61–73]. Consequently,FDG-PET has been advocated to evaluateadrenal masses as the sensitivity and specificity ofFDG-PET for detecting adrenal metastases inlung cancer patients are 100 and 80–100%, re-spectively [36,63,74].

The bones are another common site ofmetastatic disease, and metastases are found in12–19% of patients at presentation [62,75,76]. Atleast 20% are asymptomatic [77,78], and bonescintigraphy using 99m-Tc-MDP has a low spe-cificity (61%) with a modest sensitivity (90%).FDG-PET imaging, however, detects lesions notfound on conventional studies. The accuracy, sen-sitivity, specificity, positive and negative predic-tive values of FDG-PET for bone metastases havebeen reported to be 96, 90, 98, 90 and 98%,respectively [76]. Additional prospective studiesconfirm FDG-PET superiority in detecting lungcancer bone metastases [35,36,61,62,51].

Lung cancer also metastasizes to the brain, andup to 6% of patients with brain metastases areasymptomatic at presentation [79,80]. CT is typi-cally performed, although MRI is slightly moresensitive, particularly for leptomeningeal disease.Since the normal brain has significant glucoseuptake, metastases may be difficult to detect onFDG-PET [81]. Because of this, FDG-PET imag-ing has a low sensitivity (68%) in detecting brainmetastases [82] and should not be used to replaceCT or MRI.

Although lung cancer commonly metastasizesto the liver, it is a very unusual isolated site ofdisease, particularly in the absence of metastaticdisease to regional lymph nodes. Thus, in mostcases, liver metastases do not significantly alter


Fig. 3. Seventy-six-year-old male with nonsmall-cell lung cancer returned for follow-up 18 months after partial left upper loberesection. (a) Posterior-anterior (PA) chest radiograph demonstrates a new lobular lingular mass adjacent to the left heart border(arrow head). (b) Axial CT image at the level of the carina confirms the lingular mass (arrow head) without evidence for hilar ormediastinal lymphadenopathy. (c) Axial FDG-PET shows increased FDG uptake in the primary mass as well as in a subcarinal andright hilar lymph node. Biopsy confirmed recurrent nonsmall-cell lung cancer.


Fig. 3. (Continued)

patient management [83]. Whole-body FDG-PETmay be useful in the evaluation of hepatic lesionsthat are indeterminate by conventional imaging.Preliminary data from studies that evaluated liverlesions discovered, while staging nonsmall celllung cancer, suggested that FDG-PET was morespecific than CT in detecting liver metastases[35,36,61]. Data from a study that evaluated livermetastases from several different primaries hasshown FG-PET’s accuracy, sensitivity, and spe-cificity to be 92, 97 and 88%, respectively, incomparison with 85, 93 and 75% by CT [84], withsimilar findings supported by other workers [85–88]. False positive FDG-PET readings can rarelyoccur with other lesions such as liver abscesses orother malignant primary liver lesions (cholangio-carcinoma and hepatocellular carcinoma [85]).

In summary, the use of FDG-PET for routinestaging of nonsmall-cell lung cancer appears tomarkedly improve lesion detection, with reducedcost and morbidity associated with unnecessarysurgical intervention. If FDG-PET is consideredas an addition to conventional staging, the ratioof saving to cost should be greater than 2:1 [54].With the use of FDG-PET, preliminary data sug-gests bone scintigraphy may be eliminated, al-though brain imaging is still required, if clinicallyindicated.

4. Evaluation of recurrent disease

Once patients have been treated for lung can-cer, anatomic and morphological changes includ-ing airway distortion, focal ground glass opacitiesand soft tissue opacities occur within the thoraxand, occasionally, the chest wall. Depending onthe therapeutic intervention (surgical or irradia-tion), benign abnormalities including post-treat-ment scarring and fibrosis may be impossible todistinguish from tumor on conventional imagingstudies (Figs. 3 and 4).

Unfortunately, once patients have had first-linetherapy, additional therapeutic options are notvery effective and, in many cases, detecting earlyrecurrence does not clearly improve survival [89].If it becomes important to distinguish benignpost-treatment changes from recurrent tumor,FDG-PET has an accuracy of 78–98%, sensitivityof 97–100% and specificity of 62–100% [22,90–94]. False positive studies, however, may occurimmediately following surgery or irradiation (Fig.5). It is therefore recommended that FDG-PETstudies in this situation be obtained approxi-mately 4–5 months after completion of the ther-apy, to allow the inflammatory changes to subsideand to provide a more accurate assessment oftumor viability [90].


Fig. 4. Sixty-seven-year-old male with squamous cell carcinoma presented 1 year following left pneumonectomy with general malaiseand hypercalcemia. (a) Axial CT demonstrates thickening and nodularity of the left pleural space extending into the soft tissues ofthe chest wall (arrows). (b) Coronal whole-body FDG-PET demonstrates increased FDG uptake in the left pleural rind and in theperiphery of the chest wall soft tissue mass. Fine needle biopsy confirmed recurrent nonsmall-cell lung cancer.


Fig. 5. Sixty-eight-year-old male with nonsmall-cell lung cancer returned for follow-up 3 months after completing radiotherapy. (a)Axial CT image at the level of the carina demonstrates bilateral paramediastinal opacities with straight lateral margins suggestiveof radiation changes. (b) Axial FDG-PET scan at the same level demonstrates bilateral paramediastinal uptake with a linearappearance correlating to the radiation port. One-year follow-up showed stable opacities by CT with no evidence of recurrence.

5. Radiotherapy planning

Radiation treatment planning traditionally usesconventional imaging including chest radiographs,CT or MRI for an anatomic description of thetumor. As already stated, this relies on morpho-

logic features, which do not always provide aclear distinction between benign and malignanttissue. FDG-PET is more accurate than theseother imaging studies in making this distinction.

Radiation ports are typically planned to treatthe primary lesion with prophylactic doses to the


mediastinum in order to treat microscopic tumorfoci not identified by conventional imaging studies[95]. It is common to use small margins on CTdefined targets when planning three-dimensionaltreatment, to minimize radiation damage to adja-cent normal tissues. The use of FDG-PET inconjunction with CT when planning radiationports has been shown to influence treatment in26.7–34% [95,96], with the result of enlargingportions of the irradiated margins up to 15 cm.The use of morphologic imaging alone in thesecases would have meant inadequate coverage anda higher chance of local recurrence. In addition,in poorly demarcated tumors, FDG-PET canidentify the neoplastic focus to be smaller thansuspected by conventional imaging [97,98], poten-tially allowing irradiation of smaller portals withless morbidity. Thus, for radiation planning, inte-grating FDG-PET with CT appears to be moreaccurate in defining tumor extent, and futurestudies will show if this indeed is associated withincreased survival and reduced morbidity.

6. Therapeutic response and prognostic potential

Preliminary studies have suggested FDG-PETmay be usefully used as a prognostic marker inpredicting survival and response to therapy[90,92,93,99–101]. Once patients have beentreated for lung cancer, a positive FDG-PET inthe thorax is associated with statistically worsesurvival than those patients with a negative FDG-PET [102]. Two retrospective studies showed thatthe amount of FDG uptake in the primary lesionat the time of diagnosis, independent of stage,correlated with survival [103,104]. Other prospec-tive studies suggest that complete reduction inmetabolic activity of tumor site to backgroundactivity (complete response) is indicative of truelocal remission of the disease with a specificity of100% [94,97,99].

When assessing patient’s operability followinginduction chemotherapy (stage IIIa-N2), a prelim-inary study [101] showed promise for FDG-PETas a non-invasive method for selecting those pa-tients who should proceed with surgical resection.Re-mediastinoscopy in these irradiated patients is

difficult due to fibrosis, and neither the disappear-ance of lymphadenopathy, nor a greater than 50%decrease of the primary tumor diameter on CT,was significantly associated with survival. FDG-PET, on the other hand, showed that patientswith a greater than 50% reduction in FDG uptakein the primary tumor following inductionchemotherapy had a more favorable outcome.

7. Cost and future development

Recent meta-analysis studies have suggestedconventional imaging and FDG-PET to be morecost-effective than conventional modalities alone[53,54] as unnecessary invasive procedures wereeliminated and management changed in a signifi-cant number of cases. Because of these extensiveclinical data, PET studies for the evaluation of thesolitary pulmonary nodule and staging of lungcancer has been approved for reimbursement inthe United States [105,106].

Few studies have addressed changes in treat-ment decisions based on PET findings, and noprospective studies documented changes in out-comes of care or costs of care associated withFDG-PET incorporation into the diagnostic strat-egy in lung cancer. Future large-scale studies willhopefully address the efficacy of PET for otherindications as well, while taking into account pa-tient outcome and reimbursement issues.

The price of a whole-body FDG-PET scanthese days costs approximately $1500–2000 [105].It is assumed that with increasing demand, itsprice will drop. This high cost and the rapidtechnological advances in nuclear medicine, elec-tronics and computer science has lead to thedevelopment of FDG imaging on a variety ofPET scanners and modified gamma cameras. Thealternatives are less expensive but are not equiva-lent to a dedicated PET scanner in terms ofperformance. Comparitive studies assessing FDGimaging on a dedicated PET scanner to amodified gamma camera have shown that gammacamera imaging had lower image contrast thatdeteriorated with decrease in lesion size. Gammacamera was useful in detecting lesions greaterthan 2 cm in diameter [107–109]. In a preliminary


study, the gamma camera depicted only 55% ofthe neoplastic lesions that a dedicated PET scan-ner depicted [110]. If a gamma camera were usedfor staging lung cancer, a wrong therapeutic deci-sion would have been made in 29% of patients[111]. Therefore, modified gamma-camera FDGimaging cannot yet replace dedicated FDG-PETscanning in oncology patients. However, furtherperfection of this imaging modality and computerdevelopments may also lead to its future use withFDG imaging in oncology.

8. Conclusion

Over the past years, a tremendous amount ofinformation concerning FDG-PET imaging andlung cancer has been generated. It has becomeclear that this non-invasive imaging modalitycompliments conventional studies in evaluatingpatients with lung cancer. The current clinicalindications include differentiating a benign frommalignant focal pulmonary abnormality and stag-ing lung cancer. Preliminary studies show promisefor the use of FDG-PET in evaluating for recur-rent disease and radiotherapy planning. FDG-PET has provided a new model for tumorimaging and, with an increased understanding oftumor biology, improvements in detection, char-acterization and staging will hopefully lead to anincrease in survival.

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Lung cancer and positron emission tomography with fluorodeoxyglucose