[medical radiology] pet-ct and pet-mri in oncology || chest

Chest

Rathan M. Subramaniam, J. M. Davison, D. S. Surasi,G. Russo, and P. J. Peller

Contents

1 Introduction ....................................................................... 77

2 Thoracic PET/CT Protocols ............................................ 782.1 Non-Contrast Enhanced PET/CT....................................... 782.2 Contrast-Enhanced Dedicated PET/CT.............................. 78

3 Solitary Pulmonary Nodule ............................................. 79

4 Non-Small Cell Lung Cancer (NSCLC) ........................ 794.1 Diagnosis............................................................................. 804.2 Staging ................................................................................ 814.3 T Stage ................................................................................ 814.4 N Stage................................................................................ 824.5 M Stage............................................................................... 844.6 Staging FDG PET/CT and Patient Management .............. 854.7 Response to Therapy and Surveillance.............................. 864.8 Prognosis ............................................................................. 874.9 Considerations for Specific Histological Subtypes

of NSCLC ........................................................................... 88

5 Small Cell Lung Cancer .................................................. 895.1 Response to Therapy .......................................................... 925.2 Prognosis ............................................................................. 92

6 Pleural Disease .................................................................. 93

6.1 Pleural Effusion .................................................................. 936.2 Malignant Pleural Mesothelioma ....................................... 936.3 T Staging............................................................................. 936.4 N Staging ............................................................................ 946.5 M Staging............................................................................ 946.6 Prognosis ............................................................................. 956.7 Response to Therapy .......................................................... 95

7 Limitations of FDG PET/CTImaging of the Chest ........................................................ 96

8 Conclusion.......................................................................... 96

References .......................................................................... 96

Abstract

FDG PET/CT has become the standard-of care forstaging, therapy assessment and follow-up of patientswith lung cancers. It improves the staging, provides aroad map for selective invasive mediastinal nodalbiopsy and surgical planning (especially contrast-enhanced PET/CT) and accurately identifies distantmetastasis. It improves the tumor delineation forradiation therapy planning by identifying tumorfrom atelectasis and involved mediastinal nodes.The maximum SUV of lung tumor correlates stronglywith patient outcome. It is the modality of choice foridentifying distant metastasis and valuable in loco-regional nodal staging for malignant pleural tumors.

1 Introduction

Worldwide, thoracic malignancies are the most com-mon cause of cancer mortality for both men andwomen with approximately 1.2 million deaths per yearattributable to lung cancer alone (Jemal et al. 2009).Cigarette smoking is the primary risk factor in thedevelopment of cancers within the chest and is

R. M. Subramaniam � J. M. Davison � D. S. SurasiBoston University School of Medicine,Boston, MA 02118, USA

P. J. PellerDepartment of Radiology, Mayo Clinic College of Medicine,200 First Street SW, Rochester, MN 55901, USA

G. RussoDepartment of Radiation Oncology, Boston UniversitySchool of Medicine, 3rd Floor, Boston, MA 02118, USA

R. M. Subramaniam (&)Russell H Morgan Department of Radiology andRadiological Sciences Institutions,The Johns Hopkins Medical,601 N. Caroline Street/ JHOC 3235,Baltimore, MD 21287, USAe-mail: [email protected]

P. Peller et al. (eds.), PET-CT and PET-MRI in Oncology, Medical Radiology. Diagnostic Imaging,DOI: 10.1007/174_2011_421, � Springer-Verlag Berlin Heidelberg 2012

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estimated to account for 90% of all lung cancers (Je-mal et al. 2009). Other risk factors include exposure toasbestos, polycyclic aromatic hydrocarbons, nickel,radon gas, and arsenic. The frequency of lung cancerrose dramatically in the last century, emerging as themost common cause of cancer deaths in men in the1950s (Jemal et al. 2008). As more women began tosmoke, lung cancer death rates in women also began torise, and by 1985 lung cancer had become the leadingcause of cancer deaths in women (Jemal et al. 2008).With decreases in the smoking rate, lung cancer inci-dence rates and death rates have decreased amongmen in all age groups since 1990 (Jemal et al. 2008).The rise in the death rate in women continued after1990, and only recently appears to have reached aplateau (Jemal et al. 2008). Almost 50% of all lungcancer deaths now occur in women (Jemal et al. 2008).

2 Thoracic PET/CT Protocols

2.1 Non-Contrast Enhanced PET/CT

Routine PET/CT scan for evaluation of lung cancer isperformed from skull base to midthigh with arms upand without intravenous contrast. A full inspirationchest CT for detailed evaluation of lung parenchyma

often follows this. PET scans are usually done using 3Dimaging with emission scans that range from 2 to 4 minwith a field of view (FOV) of 50 cm. The CT scans areobtained to match the PET scans’ FOV and slicethickness. The low dose CT scan is only for attenuationcorrection and lesion localization of the PET data.Attenuation correction CT scans use a 512 9 512matrix. The pitch is approximately 1.75 and collima-tion is 10 mm. Slices are reconstructed at 3.75 mmthickness and with 3.27 mm spacing. The X-ray beamis set at 120 kV and the mAs is modulated.

2.2 Contrast-EnhancedDedicated PET/CT

The purpose of a contrast-enhanced dedicated CT isto provide the anatomical details needed for surgicalresection and metabolic information about the lungtumor and staging in the same setting. It has theadvantage of an integrated information flow to thephysicians but requires dual expertise in interpretingcontrast-enhanced CT and fluorodeoxyglucose (FDG)PET (Fig. 1). High dose CT scans are similar to lowdose scans except for the use of oral and intravenouscontrast material and higher X-ray dose. A total of100 cc of Optiray 320 (Covidien, Dublin, Ireland) is

Fig. 1 Dedicated contrast-enhanced PET/CT. Anatomic andmetabolic information is provided by a single dedicatedcontrast-enhanced PET/CT of a 54-year-old man with a

hypermetabolic right upper lobe tumor, mediastinal nodaldisease, and distant skeletal and hepatic metastases. The patientunderwent chemotherapy for stage IV NSCLC

78 R. M. Subramaniam et al.

given by intravenous injection at a rate of 3 cc/s,followed by a saline chase of 30 cc at the same rate.The SmartPrep (GE Healthcare, Milwaukee) is usedto trigger imaging once the celiac trunk reaches adensity of 180–200 Hounsfield units (HU).

3 Solitary Pulmonary Nodule

A solitary pulmonary nodule (SPN) is defined as asingle, well-defined pulmonary opacity with a diameterof \3 cm surrounded by normal lung tissue thatis not associated with atelectasis or adenopathy.Approximately 30–50% of solitary pulmonary nodulesare malignant. Accurate and efficient diagnostic evalu-ation of SPNs facilitates prompt resection of malignanttumors when curative removal is possible. Invasiveprocedures, which allow histologic evaluation of SPNs,include fiber-optic bronchoscopy, transthoracic needle-aspiration biopsy, video-assisted thoracoscopy, video-assisted thorascopic surgery, or thoracotomy. Theseprocedures are associated with high costs and morbidity.SPNs are also evaluated noninvasively with chest radi-ography, CT, MRI, and PET. Observation with serialchest radiographs avoids unnecessary surgery in cases ofbenign disease but can delay diagnosis and treatmentwhen malignancy is present. In most cases, benignlesions meet the following criteria: central, concentriccalcifications, round, or no nodule growth on CT after2 years of observation (Gurney and Swensen 1995).Malignant features of a nodule typically include poorlydemarcated borders, eccentric appearance, spiculatedpattern, and a doubling time of less than 10 months(Gurney and Swensen 1995). CT provides excellentanatomic and morphologic information and can confirmwhether a lesion is truly solitary, but it is frequentlyindeterminate, failing to differentiate benign frommalignant nodules (Swensen et al. 2003).

FDG PET/CT appears to be an accurate, noninva-sive imaging test for the characterization of SPNs(Fig. 2). Due to increased metabolism, malignanttissues typically demonstrate higher FDG uptake thanboth benign lesions and normal tissue. One meta-analysis reported a pooled sensitivity and specificity of96.8 and 77.8% respectively for the characterization ofSPNs (Gould et al. 2001). However, this systematicreview was weakened by including studies with smallsample sizes, incomplete masking, and biased patientselection. To address the limitations of previous

studies, the Solitary Nodule Accuracy Project (SNAP),a prospective study conducted at 10 Veterans Admin-istration hospitals nationwide in the United States,compared the accuracy of PET and CT in the charac-terization of pulmonary nodules ranging in size from 7to 30 mm (Fletcher et al. 2008). In this study, sensi-tivity, and specificity were estimated for each level ofdiagnostic confidence (definitely benign, probablybenign, indeterminate, probably malignant, and defi-nitely malignant) (Fletcher et al. 2008). The authorsfound that PET had a sensitivity of 91.7% in the char-acterization of SPNs, which was similar to CT with95.6% sensitivity (Fletcher et al. 2008). However, PEThad superior specificity when compared to CT, with aspecificity of 82.3% but only 40.2% for CT (Fletcheret al. 2008). Nodules that were described as probably ordefinitely benign were strongly associated with abenign final diagnosis regardless of imaging modality.However, definitely malignant results on PET weremuch more predictive of malignancy than were theseresults on CT. Receiver-operating characteristic (ROC)analysis yielded an area under the curve of 0.93 (95%CI, 0.90–0.95) for PET and 0.82 (95% CI, 0.77–0.86)for CT, confirming that PET is more accurate thanCT (Fletcher et al. 2008). PET demonstrated betterinter- and intra-observer variability than CT (Fletcheret al. 2008).

4 Non-Small Cell LungCancer (NSCLC)

Non-small cell lung cancers (NSCLC) comprise 80%of malignant lung tumors. NSCLCs are a heteroge-neous group of neoplasms including adenocarcinoma,squamous cell carcinoma (SCC), and large cell lungcarcinoma. Twenty percent of lung cancers are smallcell lung cancers (SCLC). Centrally located tumors aregenerally squamous cell carcinomas or small cell car-cinomas and most commonly present with cough,dyspnea, atelectasis, postobstructive pneumonia,wheezing, and hemoptysis. Peripheral tumors are usu-ally adenocarcinomas or large cell carcinomas and inaddition to cough and dyspnea, can cause pleuraleffusion and severe pleuritic chest pain due to infiltra-tion of the parietal pleura and chest wall. Adenocarci-nomas tend to develop peripherally and may not besymptomatic until extrathoracic metastases havedeveloped. In this setting, they may present with signs

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of osteolytic bone lesions or intracranial metastaticdisease.

4.1 Diagnosis

CT plays a limited but important role in the initialevaluation of patients with pulmonary lesions.It provides morphologic information regarding the

extent of disease, but it is not very good at differen-tiating benign from malignant lesions at the primarysite or in the lymph nodes. Compared to conventionalimaging, whole-body FDG PET has a higher rate ofdetection of mediastinal lymph node metastases andof extrathoracic metastases (Dwamena et al. 1999;Pieterman et al. 2000; Steinert et al. 1997; Al-Sugairand Coleman 1998). Furthermore, integrated PET/CThas better diagnostic accuracy than CT alone, PET

Fig. 2 Evaluation of a pulmonary nodule. Maximum intensityprojection a and transaxial CT b, PET c, and fused images d.This patient is a 53-year-old woman with a history of smokingfor 15 years, with a CT showing the interval increase in the sizeof a right lower lobe pulmonary nodule to 1.3 cm. PET/CTimages demonstrate increased FDG uptake in the nodule with

an SUVmax of 5.7. Pathology at biopsy was consistent withnon-small cell lung carcinoma. Since she was a poor surgicalcandidate, she received Cyberknife stereotactic radiosurgery-56 Gy in 4 fractions. There was a dramatic reduction in themetabolic activity and size of the tumor within a monthfollowing completion of treatment


alone, or visual correlation of PET and CT (Lardinoiset al. 2003). Integrated PET-CT also has a high levelof reliability in identifying hilar lymph nodes, medi-astinal lymph nodes, and supraclavicular lymphnodes, and providing precise information on chestwall or mediastinal invasion (Lardinois et al. 2003).Pulmonary malignancies generally are differentiatedfrom benign lesions by greater metabolic activity thanthe mediastinum (Patz et al. 1993). For solidpulmonary lesions with low uptake, semiquantitativeapproaches (using a maximum standardized uptakevalue (SUV) cutoff of 2.5) do not improve the accu-racy of FDG PET over visual analysis (Hashimotoet al. 2006). Hashimoto et al. (2006) found that usingfaint visual uptake as the cutoff for positive FDG PETresults, receiver-operating-characteristic (ROC) anal-ysis yielded a sensitivity of 100% and specificity of63%. When an SUVmax of 1.59 was used as thethreshold for positive results, FDG PET had 81%sensitivity and 85% specificity according to ROCanalysis. Thus, lack of visible uptake in pulmonarylesions indicates that the probability of malignancy isvery low.

4.2 Staging

Tumor, node, and metastasis (TNM) staging plays animportant role in determining prognosis and choosing atreatment strategy. Multimodality treatment of NSCLCis common, with surgery, chemotherapy, and radio-therapy alone, concurrently, or in an adjuvant orneoadjuvant setting (Chansky et al. 2009; Nestle et al.2006). Complete surgical resection offers the bestopportunity for long-term survival and cure in patientswith early stage NSCLC, assuming that the patients arefit to undergo such a procedure. The standard-of-care forpatients with stage I and II cancers is a lobectomy orpneumonectomy, with some patients receiving addi-tional neoadjuvant or adjuvant chemotherapy and/orradiation therapy depending on risk factors and charac-teristics of the cancer. Patients who are not fit for sur-gery—usually due to poor pulmonary reserve—are oftentreated with alternative therapies such as radiofrequencyablation, stereotactic body radiation therapy, or suban-atomic surgical resection (e.g. wedge resection or ana-tomic segmentectomy). Patients with stage III diseaseoften are not considered appropriate candidates for sur-gery and are treated primarily with chemoradiotherapy.

Some patients with stage IIIA disease may be treatedwith neoadjuvant chemoradiotherapy followed bysurgical resection.

Chansky et al. (2009) assessed the prognosticimpact of pathologic stage, age, gender, and specifichistologic cell type on surgically managed stageI-IIIA NSCLC cases from the international stagingdatabase of the International Association for theStudy of Lung Cancer. This study confirmed that ageand gender are important prognostic factors in surgi-cally resected NSCLC (Chansky et al. 2009). Patho-logic TNM category is the most important prognosticfactor (Chansky et al. 2009).

4.3 T Stage

Tumor designation (T) is based on tumor size,involvement of contiguous structures, and the pres-ence or absence of satellite nodules (Goldstraw et al.2007). While T1–T3 tumors are potentially resect-able, many T4 tumors are considered inoperable(Goldstraw et al. 2007). Primary tumor extension withNSCLC is usually evaluated with thoracic CT. MRI iscommonly used to evaluate tumors extending to thesuperior sulcus; involvement of the brachial plexushelps determines resectability. MRI is also used withcentrally located tumors (e.g. paramediastinal tumor)where the relationship with the heart or large vesselsis of importance (Schrevens et al. 2004). Theirsuperior anatomic detail makes CT and MRI veryuseful for evaluating the proximity of the tumor tolocal structures. Precise anatomic localization islimited with PET, due to the lower resolution, and itoffers little extra benefit (Schrevens et al. 2004).However, CT and MRI are limited by their reliancesolely on morphology for detection of malignancy.

Hybrid FDG PET/CT is becoming the preferredmethod for noninvasive staging of NSCLC. FDGPET/CT (Fig. 3) can more accurately determine Tdesignation than either PET or CT alone (Lardinoiset al. 2003). One meta-analysis found that PET/CTaccurately predicted the T stage in patients withNSCLC in 82% of cases compared with 55% for PETalone and 68% for CT alone (De Wever et al. 2007).PET/CT can readily differentiate central tumors frompost-obstructive atelectasis because a tumor is morehypermetabolic than an atelectatic lung (De Weveret al. 2007). PET/CT also improves detection of subtle

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areas of invasion into adjacent structures that may notbe apparent on CT alone (Halpern et al. 2005).

4.4 N Stage

A principal advantage of FDG PET lies in improvedmediastinal staging of NSCLC. In the absence of distantmetastases, locoregional lymph node spread will

determine therapy and prognosis. While evaluation withCT has been the method of choice in pre-therapeuticlymph node staging of NSCLC (Quint and Francis1999), use of this modality assumes a correlationbetween node size and metastatic infiltration. A lymphnode with a short-axis diameter[1 cm on conventionalimaging methods is considered enlarged and predictiveof metastasis. However, diagnosing nodal metastasesbased on morphological characteristics has limitations

Fig. 3 Non-small cell lung carcinoma tumor staging. Maxi-mum intensity projection a and transaxial CT b, PET c, andfused images d. This patient is a 64-year-old woman withsevere emphysema being followed for nodular scarring in theright upper lobe apex. A recent CT showed a spiculated nodulemeasuring 1.5 9 1.4 in the right upper lobe. PET and PET/CTimages show hypermetabolism in the right upper lobe lesion

abutting the pleura with an SUVmax of 8.7, but no evidence ofmetastasis. A CT-guided biopsy was positive for adenocarci-noma and the patient underwent right upper lobectomy,mediastinal lymph node dissection and chest wall resectionwhich proved to be a Stage IIB (T3N0) moderately differen-tiated adenocarcinoma. Due to the chest wall involvement, shewas given four cycles of adjuvant chemotherapy


as infectious or inflammatory causes can result in lymphnode enlargement. Furthermore, small- or normal-sizednodes, even with a fatty hilum, can contain metastaticdeposits leading to misdiagnosis and inaccurate stagingwith CT (Arita et al. 1996). No statistically significantrelationship has been found between the size of thelymph nodes and the likelihood of malignancy (Kerret al. 1992). Because of the moderate accuracy ofCT in detecting metastatic lymph node involvement(Prenzel et al. 2003), invasive staging bronchoscopy oresophageal endoscopy with ultrasound-guided biopsiesor mediastinoscopy are often used to assess locore-gional lymph node spread (Schrevens et al. 2004).

FDG PET is an effective, noninvasive method forstaging thoracic lymph nodes in patients with NSCLCand is superior to CT in the evaluation of hilar andmediastinal nodal metastases (Birim et al. 2005;

Graeter et al. 2003; Gould et al. 2003; Halter et al.2004). FDG PET can also differentiate betweenpatients with N1/N2 disease and those with unresec-table N3 disease (Halter et al. 2004). By combiningfunctional and anatomic data, integrated PET/CTsignificantly increases the number of patients with cor-rectly staged NSCLC and is the best noninvasive methodfor the detection of nodal metastases (Antoch et al. 2003;Cerfolio et al. 2004) (Fig. 4). Integrated PET/CT hasbeen shown to improve diagnostic accuracy in theassessment of locoregional lymph nodes when com-pared to contrast-enhanced CT (Yang et al. 2008).Furthermore, integrated PET/CT is more accurate forthe detection of total N2 nodes and for total N1 nodesthan dedicated PET, more sensitive at the mediastinalstations 4R, 5, 7, 10L, and 11, and more accurate at the7 and 11 lymph node stations (Cerfolio et al. 2004).

Fig. 4 Non-small cell lung carcinoma with mediastinal nodalstaging. Maximum intensity projection a and transaxial CT b,PET c and fused images d. This 82-year-old woman with 60-year smoking history presented with chest congestion andhemoptysis. On CT, she had a 5.5 cm mass in the lingula of theleft upper lobe abutting the mediastinum with gross nodaldisease in the left hilar region and the anterior mediastinum.

PET/CT images demonstrate an intensely hypermetabolic mass(SUVmax of 17.7) within the lingula and more than 3 cmcontact of the tumor to the chest wall suggestive of chest wallinvasion. There is FDG uptake in station 4L (left paratracheal),5 (aortopulmonary window), and 10L (left hilar) nodes typicalfor metastatic disease. The left pleural effusion demonstrated nosignificant FDG uptake

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One retrospective study found that, compared to sur-gical resection, the overall sensitivity, specificity,positive and negative predictive values, and accuracyof PET/CT for detecting metastatic lymph nodes were54.2, 91.9, 74.3, 82.3, and 80.5% when evaluated on aper-patient basis, and 57.7, 98.5, 74.5, 96.8, and95.6% on per-nodal-station basis (Bille et al. 2009).The high negative predictive value of PET in medi-astinal lymph node staging may allow PET-negativepatients to be staged without invasive procedures andto proceed directly to thoracotomy (Graeter et al.2003; Vansteenkiste et al. 1997), especially patientswith T1 disease. Many centers will perform medias-tinoscopy immediately prior to thoracotomy, inpatients with T2 disease or above.

False-positive findings in regional lymph nodescan be a problem with FDG PET (Cerfolio et al. 2003;Nakamura et al. 2008), particularly in cases ofanthracosilicosis, infection, or granulomatous disease(Schrevens et al. 2004; Bille et al. 2009) found thatthe sensitivity of PET/CT in detecting malignantinvolvement was 32.4% in nodes less than 10 mm,and 85.3% in nodes greater than or equal to 10 mm.Thus, mediastinoscopy may be necessary to confirmN2 or N3 disease to ensure that no patient withresectable N0 or N1 disease is denied the chance ofcurative surgery (Schrevens et al. 2004; Nakamuraet al. 2008).

Meyers et al. (2006), analyzed the cost-effectivenessof routine mediastinoscopy in patients with stage I lungcancer staged with CT and PET and concluded thatsuch patients benefit little from mediastinoscopy.However, for patients with stage II and III disease,mediastinoscopy is necessary as false positives dooccur with PET/CT. Thus, PET/CT does not neces-sarily obviate the need for mediastinoscopy but canprovide anatomical guidance prior to biopsy.

4.5 M Stage

Detection of distant metastases in patients withNSCLC has major implications on management andprognosis. Forty percent of patients with NSCLChave distant metastases at presentation, most com-monly in the adrenal glands, bones, liver, or brain(Quint et al. 1996). On initial staging, CT alone canshow definitive evidence of metastatic disease in11–36% of patients (Quint et al. 1996).

4.5.1 Adrenal MetastasesNearly 10% of NSCLC patients initially present withenlarged adrenal glands as visualized on CT, approx-imately two-thirds of which are non-malignant(Ettinghausen and Burt 1991). Thus, in a patient withotherwise operable NSCLC, treatment decisionsshould not be made in the presence of an isolatedadrenal mass without pathologic proof of metastaticdisease. PET has a high sensitivity (100%) and spec-ificity (80–100%) for the detection of malignantadrenal metastases (Fig. 5) (Erasmus et al. 1997;Marom et al. 1999), which can reduce the number ofunnecessary adrenal biopsies. Careful interpretation ofPET is required for lesions less than 1 cm, as experi-ence with smaller adrenal lesions is limited (Schrevenset al. 2004). Recently, Brady et al. (2009) developedan algorithm to maximize the diagnostic yield of PET/CT in the identification of adrenal metastases inpatients who underwent PET/CT for known or sus-pected lung cancer. The authors found that a value forthe SUV ratio (nodule SUVmax/liver SUVmean) of[2.5 allowed correct identification of 22 of 37 meta-static lesions and exclusion of all FDG-avid benignnodules (Brady et al. 2009). Alternatively, a meanattenuation [10 HU and SUVmax [3.1 had 97.3%sensitivity and 86.2% specificity in correctly identi-fying adrenal metastases (Brady et al. 2009).

4.5.2 Bone MetastasesFor patients with NSCLC, bone involvement previ-ously was assessed by bone scintigraphy, with asensitivity of 90% (Bury et al. 1998). The specificityof bone scanning is only 60% as false-positive find-ings occur with non-selective uptake of the radionu-clide tracer in any area of increased bone turnover(Bury et al. 1998). Confirmatory imaging by boneX-ray, CT, or MRI is often required. PET has beenfound to have similar sensitivity to bone scintigraphybut a higher specificity of approximately 98%(Marom et al. 1999; Bury et al. 1998).

FDG PET detection of unexpected metastaticspread is particularly valuable (Fig. 6). Unknownmetastases are found with FDG PET in 8–24%of patients with negative conventional imaging(MacManus et al. 2001). The incidence of occultmetastatic lesions increases with advancing stagefrom 8% in stage I, to 18% in stage II, to 24% in stageIII (MacManus et al. 2001). If only a single metastaticlesion is detected with FDG PET additional imaging


or pathological confirmation is warranted, to avoid afalse-positive FDG PET result from preventing sur-gery with curative intent (MacManus et al. 2001).

4.6 Staging FDG PET/CT and PatientManagement

As a single, noninvasive examination, FDG PET/CTfrom orbits to thighs is an attractive staging tool,due to its overall greater diagnostic accuracy whencompared to conventional imaging procedures(Pieterman et al. 2000; Antoch et al. 2003; Hicks et al.2001a; Brink et al. 2004). Clinical staging is oftenaltered by PET/CT results in patients with NSCLC(Hicks et al. 2001a; Hoekstra et al. 2003; Schmuckinget al. 2003). Upstaging is more frequent than downstaging and is generally due to the detection ofunexpected distant metastases by FDG PET (Brink

et al. 2004). PET/CT findings that will alter man-agement occur in 25–52% of NSCLC patients, (Buryet al. 1998; Hicks et al. 2001a; Schmucking et al.2003; Hoekstra et al. 2002; Saunders et al. 1999).

Van Tinteren et al. (2002) reported a randomizedcontrol trial to assess the role of FDG PET in themanagement of patients in routine clinical practice. Inthe PET in Lung Cancer Staging study, better knownas the PLUS study, patients were evaluated preoper-atively with either conventional workup or conven-tional workup plus PET. The primary outcomemeasure was futile thoracotomy, defined as thora-cotomy in a patient with benign disease, explorativethoracotomy, pathological stage IIIA-N2/IIIB, orpostoperative relapse or death within 12 months ofrandomization. In one out of five patients with sus-pected NSCLC, adding PET to conventional workupprevented futile thoracotomies (van Tinteren et al.2002). In a recent randomized study by Fischer et al.

Fig. 5 Non-small cell lung carcinoma with adrenal metastasis.Maximum intensity projection a and transaxial CT b, PET c,and fused images d. This is an 80-year-old man who initiallypresented with chest discomfort. On CT, a heterogeneouslyenhancing 5.4 9 4.7 9 8.2 cm right perihilar mass was noted.PET and PET/CT images demonstrate a large hypermetaboliclung lesion with an SUVmax of 50. A focal region of abnormal

radiotracer uptake was noted within the left adrenal gland withan SUVmax of 3.4 which was highly concerning for metastaticdisease. Fine needle aspiration of the lung mass confirmedsquamous cell carcinoma. Surgery and chemotherapy were notoptions due to his medical comorbidities, and therefore thepatient was treated with radiation therapy

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(2009), the clinical effect of combined PET/CT onpreoperative staging of NSCLC was compared toconventional staging alone (medical history, physicalexamination, blood test, contrast-enhanced CT scanof the chest and upper abdomen, and bronchoscopy).The authors found that while the number of justifiedthoracotomies after staging was similar in bothgroups, the use of PET/CT for preoperative staging ofNSCLC reduced both the total number of thoracoto-mies and the number of futile thoracotomies (Fischeret al. 2009).

4.7 Response to Therapyand Surveillance

NSCLC commonly presents with advanced stage dis-ease and chemotherapy is often integral to treatment.Despite chemotherapy, tumor progression occurs inup to one-third of patients. Early determination of

therapeutic failure allows prompt discontinuation ofineffective treatment and initiation of alternative ther-apies. Image-based serial measurements of tumor sizebefore and after treatment based on recommendationsof the World Health Organization (WHO) or ResponseEvaluation Criteria in Solid Tumors (RECIST) arecommonly used to determine response (Wahl et al.2009). Morphologic alterations on CT do not correlatewith pathologic response and tumor viability. Treat-ment protocols that target tumor biology includingtumor cell proliferation and invasion, angiogenesis,and metastasis further complicate objective assess-ment of response using morphological parameters.The antitumor effect in these regimens can be cytostaticand therefore may not result in a reduction in tumorsize. Early and sensitive assessment of anticancerregimen effectiveness may be achieved with PET asFDG uptake is not only a function of proliferativeactivity but is also related to viable tumor cell num-ber (Duhaylongsod et al. 1995; Higashi et al. 1993).

Fig. 6 Non-small cell lung carcinoma with skeletal metastasis.Maximum intensity projection a and transaxial CT b, PET c,and fused images d. This is a 50-year-old woman with anincidentally discovered right upper lobe nodule during a chestpain workup. The CT, PET, and PET/CT images demonstrate a3.2 cm mass in the right upper lobe, which is intenselyhypermetabolic with an SUVmax of 18.5. A focus of moderate

activity was also noted in the posterior left 10th rib with anSUVmax of 4.1 compatible with metastatic disease. A CT-guided core biopsy of the right upper lobe (RUL) lung lesionconfirmed adenocarcinoma. Brain MRI revealed four enhanc-ing lesions consistent with metastasis. Stereotactic radiosurgerywas planned


Recommendations by the European Organization forResearch and Treatment of Cancer (EORTC) PETStudy Group include patient preparation, timing ofscans, and methods to measure FDG uptake, as well asdefinitions of tumor response (Young et al. 1999). Morerecently, Positron Emission Response Evaluation Cri-teria in Solid Tumors (PERCIST) has been proposedfor use in clinical trials (Wahl et al. 2009).

Post-therapy assessment with CT or MRI may becomplicated by the inability to distinguish persistent orrecurrent tumor from necrosis, post-treatment scarringor fibrosis (Frank et al. 1995). FDG PET can detectlocal tumor recurrence after definitive treatment withsurgery, chemotherapy, or radiotherapy with a sensi-tivity of 98–100% and specificity of 62–92% (Ryu et al.2002; Inoue et al. 1995; Hicks et al. 2001b; Bury et al.1999; Hellwig et al. 2006) and months earlier thanconventional imaging. In particular, 3D conformalradiotherapy frequently produces opacities on CT,which are difficult to distinguish from tumor recur-rence. The inflammatory changes associated withradiation can also result in increased FDG uptake andpotential false positives on PET. However, in a study byHicks et al. (2004), when patients with NSCLC weretreated with radical radiotherapy and reevaluated withFDG PET at a median of 70 days after therapy com-pletion, the ability of FDG PET to assess therapeuticresponse was not confounded by radiation-inducedinflammatory changes. In addition, in a pilot study byKong et al. (2007) a significant reduction in tumor FDGuptake in patients with NSCLC was observed duringthe course of treatment with fractionated radiotherapywithout a significant confounding effect in the sur-rounding irradiated lung. In this study, radiation-induced hypermetabolism secondary to pneumonitisdid not occur during treatment but rather was observedafter completion of radiotherapy. This suggests thatobtaining an FDG PET scan during treatment withradiotherapy may allow identification of targets forindividualized adaptive therapy (Kong et al. 2007).

Determining a favorable response to chemotherapyearly in the course of treatment also allows continuationwith greater confidence in patients with NCSLC.Prospective studies have shown that, in patients withstage IIIB or IV unresectable NSCLC, restaging FDGPET scans could predict progressive disease after justone cycle of chemotherapy (Lee et al. 2009a, b; Weberet al. 2003). In one study, a fall in the primary tumorSUVmax of [20% was an independent predictor of

long-term survival (Weber et al. 2003). Response onFDG PET had a tight correlation with the best responseto therapy as determined on serial CT scans accordingto RECIST and was associated with a higher overallsurvival (Weber et al. 2003). In a prospective study, arestaging FDG PET showing a decrease in FDG uptake[35% after 1 cycle of induction chemotherapy corre-lated with increased overall and disease-free survival inpatients with locally advanced but potentially resect-able stage IIIA N2 NSCLC receiving neoadjuvantchemotherapy (Hoekstra et al. 2005). In this study,FDG PET was better than CT in monitoring response totherapy and enabled a prediction of survival early intherapy (Hoekstra et al. 2005). A currently ongoingmulticenter study, ACRIN 6678 (American College ofRadiology Imaging Network), is evaluating the valueof FDG PET/CT in therapy assessment of stages IIIBand IV NSCLC.

4.8 Prognosis

Several studies suggest PET has a role as a prognosticmarker in NSCLC patients. The degree of FDG uptakein the primary lesion at the time of diagnosis isinversely related to survival rate (Ahuja et al. 1998;Higashi et al. 2002; Jeong et al. 2002; Vansteenkisteet al. 1999). Threshold pretreatment FDG PET maxi-mum SUV prognosis used for univariate analysis inthe literature range from 3.3 to 20. These cut-off val-ues used to predict prognosis are significantly associ-ated with histological subtype (Casali et al. 2009).Casali et al. determined that patient outcome could bemost accurately predicted with a threshold SUVmaxof 5 for adenocarcinoma and 10.7 for other non-ade-nocarcinoma NSCLC subtypes. In one study by Hig-ashi et al. (2002), patients with an SUVmax\5 had abetter disease-free survival than did patients with anSUVmax [5. In patients with pathologic stage I theexpected 5-year disease-free survival rate was 88% ifthe SUVmax was\5 and 17% if the SUVmax was[5(Higashi et al. 2002). Multivariate analysis identifiedthe SUVmax as a more significant independent factorfor disease-free survival than pathologic stage(Higashi et al. 2002). Nair et al. (2010), found that, inpatients with surgically treated clinical stage IANSCLC, high pretreatment FDG uptake (defined asSUVmax[5) identified individuals at increased risk ofdeath due to disease following surgery.

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Post-therapy FDG uptake is also of prognosticsignificance for NSCLC. One prospective studyevaluated the utility of FDG PET in determiningprognosis after completion of definitive radiotherapyor chemoradiotherapy in patients with unresectableNSCLC (Mac Manus et al. 2003). There was a sig-nificant association between qualitative decreasein FDG uptake within the primary tumor and medi-astinal lymph nodes and patient survival(Mac Manus et al. 2003). Furthermore, a single earlypost-treatment PET scan was found to be a betterpredictor of survival than CT response, stage, orpretreatment performance status (Mac Manus et al.2003). For patients with locally advanced but poten-tially resectable NSCLC who have completed neo-adjuvant therapy, FDG PET is also of value. FDGPET can identify patients who have had a pathologicresponse to treatment and may benefit from furtherlocoregional therapy (Vansteenkiste et al. 1998; DeLeyn et al. 2006; Eschmann et al. 2007; Cerfolio et al.2006). In a prospective study by Cerfolio et al. (2006),integrated FDG PET/CT was superior to CT in eval-uating patients with NSCLC and biopsy-proven stageIIIA N2 disease after induction chemoradiation ther-apy. The authors found that a decrease of 75% ormore in primary tumor SUVmax after therapy indi-cates a high likelihood of a complete response, and adecrease of more than 50% in the N2 lymph nodeSUVmax is indicative of a high likelihood of noresidual metastatic disease (Cerfolio et al. 2006).The authors did recommend nodal biopsies in thesetting of a persistently high SUVmax, as this did notreliably equate with residual nodal metastatic disease(Cerfolio et al. 2006). In patients with advancedNSCLC, the difference between initial FDG uptakeand uptake after induction chemotherapy was foundto be highly predictive for long-term survival. Patientswith a 60% or more decrease in SUVmax had a sig-nificantly longer survival than those below thisthreshold (Eschmann et al. 2007).

4.9 Considerations for SpecificHistological Subtypes of NSCLC

4.9.1 Bronchioloalveolar CarcinomaBronchioloalveolar carcinoma (BAC) is a peripheral,well-differentiated adenocarcinoma, usually arisingbeyond a recognizable bronchus and demonstrating a

growth pattern along intact alveolar septa (Higashiet al. 1998; Kim et al. 1998). BACs, particularly thefocal form, typically show only mild FDG uptakewhich can lead to false-negative interpretations formalignancy (Higashi et al. 1998; Kim et al. 1998).This may be due to the low metabolic activity of thisgenerally slow-growing tumor or to the presence of arelatively small number of metabolically activemalignant cells with abundant mucin (Higashi et al.1998; Kim et al. 1998). Awareness of the radiologicappearance of BAC (ground glass opacities with orwithout a solid component on CT, solitary, or multi-ple pulmonary nodules) in the setting of low FDGuptake is important to prevent misinterpretation(Truong et al. 2006) (Fig. 7). Compared to CT alone,PET/CT may be more accurate for the diagnosis ofBAC as the characteristic appearance of BAC on CTcan be integrated with metabolic parameters(Goudarzi et al. 2008). Many BACs have low valuesfor SUVmax, generally less than 2.0, but properidentification is facilitated by their low HU on CT(Goudarzi et al. 2008). Goudarzi et al. (2008) foundthat integrated PET/CT can help differentiate betweenpure BAC and adenocarcinoma with a BAC compo-nent by using tumor size, CT density, and metabolicactivity. They found that pure BAC exhibits smallersize, lower FDG uptake, and lower tumor density thanadenocarcinoma with BAC. In the presence of mul-tifocal BAC, however, FDG PET appears to be highlysensitive (Heyneman and Patz 2002).

4.9.2 Carcinoid TumorsCarcinoid tumors of the respiratory tract are rare neo-plasms of neuroendocrine origin that account for only2–3% of primary pulmonary malignancies (Davilaet al. 1993). Typical carcinoid tumors are comprised ofsmall, regularly arranged polygonal cells with abun-dant eosinophilic cytoplasm (de Rosado Christensonet al. 1999). Typical carcinoid tumors generally havefew mitoses and lack marked nuclear pleomorphism.Atypical carcinoid tumors demonstrate more irregulararchitecture, increased mitoses, nuclear pleomorphism,and areas of necrosis. Typical carcinoid tumors accountfor 85–90% of carcinoid tumors, and are diagnosed atan earlier age than atypical carcinoid tumors (mean35–50 years vs. 55–60 years) (de Rosado Christensonet al. 1999). They are generally small, centrally located,and rarely spread beyond the thorax (de RosadoChristenson et al. 1999). Atypical carcinoid tumors are


larger, located centrally and peripherally with equalfrequency, more aggressive and commonly metastasizeto regional nodes, liver, and bone (de RosadoChristenson et al. 1999).

The sensitivity of FDG PET in the diagnosis ofpulmonary carcinoid is generally considered to belimited due to slow growth and therefore low meta-bolic activity of these tumors (de Rosado Christensonet al. 1999; Erasmus et al. 1998). In one retrospectivestudy, only one of the seven carcinoid tumors thatwere evaluated demonstrated FDG uptake greaterthan background mediastinal activity and was cor-rectly classified as positive for malignancy on PETscan (Erasmus et al. 1998). However, a more recentretrospective study evaluated pretreatment FDG PETscans from 16 patients with pulmonary carcinoid andfound that, while overall metabolic activity of carci-noid tumors was lower and is generally observed inother histological subtypes of lung neoplasms, PET

had a sensitivity of 75% for detecting malignancy inthis cohort (Daniels et al. 2007). PET sensitivity wassomewhat higher for atypical carcinoid tumors (80%)than for typical carcinoid tumors (72.7%) (Danielset al. 2007). Thus, carcinoid tumors may not be uni-versally PET-negative malignancies (Fig. 8).

5 Small Cell Lung Cancer

Small cell lung carcinomas (SCLC) account fornearly 20% of all lung cancers and are almost uni-versally associated with smoking (Govindan et al.2006). According to the National Institute of HealthSEER database, the incidence of SCLC decreased inthe United States between 1986 and 2002, possiblydue to the decrease in smoking and the change to low-tar filter cigarettes (Govindan et al. 2006). Modestimprovements in survival have been seen over the last

Fig. 7 BrochioloalveolarCarcinoma. Maximumintensity projection a andtransaxial PET b, CT c, andfused images d. This is a 68-year-old woman with ahistory of breast cancer whodeveloped a ground glassdensity in the right mid lung.The lung lesion slowlybecame denser over18 months. PET/CTdemonstrated a 2.5 cm nodulewith mild FDG uptake(SUVmax = 2.3). No nodalor distant metastases wereidentified. CT-guided biopsyshowed bronchioloalveolarcarcinoma and the patientunderwent a segmentalresection with negative nodes

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30 years, although despite this trend, the outcomeremains very poor. SCLCs are generally centrallylocated neoplasms arising from neuroendocrine cellprecursors. SCLC is more clinically aggressive thanNSCLC, with a rapid doubling time and propensityfor widespread metastatic disease at presentation(Govindan et al. 2006). SCLC is sensitive to radiationtherapy and chemotherapy, and generally surgery hasno role in management. Though a large percentage ofpatients demonstrate an initial response to chemo-therapy, there is a high rate of local and systemicrecurrence.

In the staging of SCLC, TNM stages convention-ally have been collapsed into a simple binary classi-fication: limited disease (LD) and extensive disease(ED) (Schumacher et al. 2001). LD is defined asdisease confined to the ipsilateral hemithorax that canbe encompassed by a single radiotherapy port; ED is

defined as disease beyond the ipsilateral hemithorax(Lally et al. 2007). Recent data suggests that clinicalstaging of SCLC should be based on TNM staging(Shepherd et al. 2007). Shepherd et al. (2007), usingthe International Association for the Study of LungCancer database, performed survival analyses for8,088 patients with SCLC for which TNM stagingwas available. Survival was directly correlated to bothtumor and node stage, with differences more pro-nounced in patients without mediastinal or supracla-vicular nodal involvement. Stage grouping accordingto the sixth edition of the American Joint Committeeon Cancer’s staging manual also differentiated sur-vival except between IA and IB (Shepherd et al.2007). Thus, while LD and ED are still commonlyreferred to in the literature, TNM staging has replacedclassification according to LD and ED in the currentevaluation of SCLC.

Fig. 8 Carcinoid Tumor.Maximum intensity projectiona and transaxial PET b, CT c,and fused images d. This is a62-year-old woman with anincidentally discovered rightlower lobe nodule. PET/CTdemonstrates a 2.0 cm nodulewith minor FDG uptake(SUVmax = 1.3). CT-guidedbiopsy showed carcinoidhistology. A wedge resectionwas performed withoutrecurrence


Studies have shown that FDG PET when comparedto conventional imaging procedures allows faster,more accurate differentiation between LD and ED,sparing the need for additional invasive diagnosticstudies (Schumacher et al. 2001; Shen et al. 2002;Hauber et al. 2001) (Fig. 9). In a retrospective study,Vinjamuri et al. (2008) found that FDG PET was moreaccurate in the initial staging of SCLC than CT. In thisstudy, the PET results from 8 of 51 patients (16%)resulted in a change in disease management. PETresults accurately down staged 6 of 51 patients (12%)allowing these patients to be treated with radiation(Vinjamuri et al. 2008). Thus PET can ensure that overstaging by CT scan does not deny potentially curativetreatment for limited-stage SCLC. In patients withSCLC, FDG PET appears to be more sensitive for the

detection of metastatic mediastinal and hilar lymphnodes as well as distant metastases (Schumacher et al.2001; Shen et al. 2002). FDG PET is particularlyeffective in the identification of unsuspected regionalnodal metastases, which can have a significant impacton therapy planning (Bradley et al. 2004). PET hasbeen shown to identify occult adrenal metastases andmetastases to supraclavicular lymph nodes missed byCT (Vinjamuri et al. 2008). Whole-body FDG PETmay be useful as a simplified staging tool for small celllung cancer (Schumacher et al. 2001). Evidence sug-gests that whole-body FDG PET may be able toreplace the combination of conventional imagingmodalities for staging SCLC in a cost-effective mannereven when CT or MRI is included to rule out brainmetastases (Chin et al. 2002).

Fig. 9 PET/CT Small cell lung carcinoma staging. Maximumintensity projection a, transaxial CT b, and fused images c. Thisis an 87-year-old man with a positive tuberculin skin test. Achest X-ray revealed a right lower lobe mass. On CT, a rightlower lobe spiculated mass with significant mediastinal andhilar lymphadenopathy was noted. A CT-guided lung biopsywas consistent with undifferentiated small cell carcinoma. PET/

CT images demonstrate a hypermetabolic mass in the rightlower lobe with an SUVmax of 14. Multiple hypermetaboliclymph nodes were identified particularly in the pretrachealregion (SUVmax: 17.8), AP window (SUVmax = 17.1), sub-carinal region (SUVmax = 17), and in the right hilum (SUV-max = 10). The patient refused chemotherapy and was beingfollowed in hospice

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5.1 Response to Therapy

FDG PET is an accurate method for restaging aftertherapy for SCLC as it can correctly identify patientsin total remission, those with residual disease, andpatients with progressive disease (Kamel et al. 2003)(Fig. 10). In predicting residual disease, FDG PEThas been shown to be more effective than CT (Onitiloet al. 2008). With SCLC, dissolution and shrinkage ofresidual tumor mass after therapy may occur, evenafter all viable tumor cells have been eradicated.

5.2 Prognosis

In a prospective study, Lee et al. (2009a, b) found thatpretreatment of tumor metabolic activity as assessedby FDG PET is a significant prognostic factor forSCLC and could identify subgroups of patientsat higher risk of death in both LD and ED SCLC.

For patients with both LD and ED, a high SUVmaxdefined as a value [8.7 was associated with signifi-cantly poorer survival outcomes as compared to thelow SUVmax group. Additionally, post-therapy PETfindings may be of prognostic value in patients withSCLC (Pandit et al. 2003). Patients with positive PETscans after completion of treatment have significantlyworse survival profiles than patients with negativestudies (Onitilo et al. 2008; Pandit et al. 2003) andPET-negative patients have significantly longer pro-gression-free survival times compared to PET-positive patients with SCLC (Onitilo et al. 2008).A good correlation between lesion SUVmax andpatient survival has also been observed, with highmaximum SUVs associated with poor survival (Panditet al. 2003). In patients receiving treatment, a per-sistently high SUVmax may indicate a poor response,indicating a need for a change in treatment, while alow SUVmax suggests a good response to therapy(Pandit et al. 2003).

Fig. 10 Therapy assessment of small cell lung carcinoma byPET/CT. Pretherapy maximum intensity projection a and post-therapy MIP and transaxial CT, fused images b and c. This 62-year-old man with a 40-year smoking history presented withsyndrome of inappropriate secretion of antidiuretic hormone.He was found to have a left upper lobe nodule with hilar andmediastinal lymphadenopathy. The staging PET/CT demon-strated a hypermetabolic lingular mass with an SUVmax of 3.9

and multiple hypermetabolic lymph nodes. Bronchoscopicbiopsy of the station 4L and level 7 mediastinal lymph nodeswas positive for poorly differentiated small cell carcinoma. Hewas treated with concurrent chemoradiation (six cycles ofchemotherapy and 66 Gy in 33 fractions radiotherapy). Arestaging PET/CT 3 months after treatment showed completemetabolic response and diffuse esophageal thickening withincreased uptake consistent with the esophagitis


6 Pleural Disease

6.1 Pleural Effusion

Pleural involvement is relatively common in patientswith lung cancer and differentiation between benignand malignant effusion is important in determiningresectability and use of radiotherapy. Pleural thick-ening or nodularity on CT may indicate the presenceof metastases in the pleural cavity, but CT is oftenunable to distinguish between benign or malignantpleural disease. Similarly, MRI has failed to show highaccuracy in differentiating benign from malignantpleural effusions. FDG PET may be better at evalu-ating pleural effusions than conventional imaging. Inone study, 35 patients with lung cancer and abnormalpleural findings on CT underwent PET (Gupta et al.2002). Sensitivity, specificity, and accuracy of FDGPET were 89, 94, and 91%, respectively. The highnegative predictive value of PET in pleural effusionsmay be of help in reducing the number of repeat tho-racocenteses or thoracoscopic biopsies in patients withnegative PET findings and benign effusion.

6.2 Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a neoplasmarising from the mesothelial cells of the pleural cavities.In the United States, approximately 2500–3000 cases ofMPM are diagnosed per year. The incidence of meso-thelioma in the United States peaked around the year2000, after which a decline has been observed secondaryto control of exposure to asbestos (Teta et al. 2008).Mesothelioma is almost always fatal with a mediansurvival of 11 months. Asbestos is the principal carcin-ogen implicated in the pathogenesis, with 80% ofpatients in the United States reporting history of asbestosexposure. There is a long latency period (30–40 years)from the time of asbestos exposure to the development ofclinically apparent mesothelioma. Malignant mesothe-lioma usually begins as discrete plaques and nodules,which subsequently coalesce to produce a sheet-likeneoplasm. Tumor growth most often begins at the lowerpart of the chest and may invade the diaphragm andencase the surface of the lung and interlobar fissures.

Early identification of the extent of the disease isessential for treatment planning and prognosis. CT was

considered the standard diagnostic study for stagingMPM and is the primary modality in assessing localextent and identifying nodal and distant metastases(Heelan et al. 1999). MRI can be used to complementCT in the evaluation of patients with mesotheliomawhen resection is being considered as a treatmentoption. MRI is superior to CT in the differentiation ofmalignant from benign pleural disease and in revealingsolitary foci of chest wall invasion, endothoracic fasciainvolvement, and diaphragmatic muscle invasion(Heelan et al. 1999). CT and MRI are, however, limitedin that diffuse pleural thickening can represent eithermalignancy or a benign process caused by asbestosexposure, hemorrhagic effusion, or infectious pro-cesses such as tuberculosis or empyema (Ho et al.2001). Benign pleural plaques caused by asbestosexposure can also complicate evaluation based onanatomic parameters alone (Haberkorn 2004). Thus,the accuracy of CT in predicting the malignant nature ofdiffuse pleural lesions is not optimal (Haberkorn 2004).Thoracoscopy has a high sensitivity ([90%) with amortality rate of less than 0.1%, but non-fatal compli-cations occur in up to 10% of patients. Despite this highmorbidity, thoracoscopy remains the primary diag-nostic modality for mesothelioma, but it is invasive andcannot always accurately stage the mediastinal nodesor transdiaphragmatic extension (Haberkorn 2004).

Imaging with FDG PET/CT is noninvasive and canaccurately and reliably differentiate MPM frombenign pleural disease (Yildirim et al. 2009; Duysinxet al. 2004). FDG PET/CT can make this distinctionwith high sensitivity and specificity as the FDGuptake of pleural malignancies is significantly greaterthan that of benign processes (Yildirim et al. 2009).

6.3 T Staging

MPM is typically detected by PET as moderate to highFDG uptake in areas of pleural thickening observedon anatomic imaging modalities (Subramaniamet al. 2009). Early stage tumors usually have focal orlinear patterns of uptake, while diffuse and heteroge-neous patterns are indicative of advanced disease,regardless of histological type or grade (Gerbaudo2003) (Fig. 9). However, due to the poor spatial reso-lution of PET alone, FDG uptake in the parietal pleuracannot be differentiated from hypermetabolism in thevisceral pleura in the absence of a pleural effusion

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(Erasmus et al. 2005). It is also difficult to determine theextent of local invasion into the chest wall, diaphragm,or pericardium (Erasmus et al. 2005). The use of inte-grated PET/CT substantially improves primary tumorstaging (Fig. 11).

6.4 N Staging

MPM metastasizes to intrathoracic lymph nodes in22–50% of patients (Sugarbaker et al. 1999; Ruschand Venkatraman 1996). Metastasis to N2 nodes isassociated with a far worse prognosis than N1 disease(Sugarbaker et al. 1999). Supraclavicular nodalinvolvement has the worst prognosis (Subramaniamet al. 2009). While the accuracy of MRI and CTin differentiating between N1 and N2 disease isapproximately 50% (Marom et al. 2002), the sensi-tivity of FDG PET for staging the mediastinum in

patients with malignant mesothelioma ranges from83 to 88% with a specificity between 75 and 82%(Duysinx et al. 2004; Marom et al. 2002).

6.5 M Staging

Systemic metastases are common with MPM and canoccur in the contralateral lung, liver, adrenal glands,kidneys, bone, anterior and posterior abdominalwall, peritoneum, brain, and leptomeninges (Benardet al. 1998; Duysinx et al. 2004; Kramer et al. 2004).The detection of distant metastases is important indirecting the course of management, as these patientsare not considered candidates for surgery (Erasmuset al. 2005). FDG PET may be superior to routineclinical and conventional radiological evaluation incorrectly identifying distant metastases (Erasmuset al. 2005; Schneider et al. 2000).

Fig. 11 PleuralMesothelioma. Maximumintensity projection a andtransaxial PET b, CT c, andfused images d. This is an 86-year-old man with a remotehistory of asbestos exposurewho presented with shortnessof breath. Pleural thickeningin the left hemithoraxprompted a PET/CT. ThePET/CT demonstrates diffuse,intense hypermetabolismthroughout the thickenedpleura (SUVmax = 17.8).The hypermetabolic pleuralthickening involves the majorfissure, which is a hallmark ofmesothelioma. Anextrapleural pneumonectomywas successfully performed.Left chest wall recurrence wasdetected 3 years after surgery


6.6 Prognosis

FDG PET may be useful for determining the prog-nosis in patients with MPM. In one study, mediansurvivals were significantly lower in patients withlesion maximum SUV[10 compared to patients withan SUVmax of\10 (Flores et al. 2006). In this study,low SUVmax (\10) and epithelial histology had thebest prognosis, whereas high SUVmax ([10) andnon-epithelial histology resulted in the worst survivalprognosis (Flores et al. 2006). In another study, theintensity of tumor uptake correlated poorly with his-tological grade but correlated well with surgical stage(Gerbaudo et al. 2003). Lesion FDG uptake increasedover time at a higher rate in patients with moreadvanced disease and the increment of FDG lesionuptake over time was a better predictor of diseaseaggressiveness than the histological grade (Gerbaudoet al. 2003).

6.7 Response to Therapy

Measuring response with CT is challenging inpatients with MPM due to the circumferential patternof tumor growth. There is growing evidence that

therapy-induced changes in tumor FDG uptake maypredict response and patient outcome early in thecourse of treatment (Ceresoli et al. 2006). In oneprospective study, patients were evaluated by bothFDG PET and CT at baseline and after two cycles of apemetrexed-based regimen of palliative chemother-apy (Ceresoli et al. 2006). A decrease of 25% or morein tumor FDG uptake as measured by the maximumSUV was defined as a metabolic response (Ceresoliet al. 2006). Early metabolic response was signifi-cantly correlated to median time-to-tumor progressionwhile no correlation was found between time-to-tumor progression and radiologic response evaluatedby CT (Ceresoli et al. 2006). Patients with a metabolicresponse also had a trend toward longer overall sur-vival (Ceresoli et al. 2006). In another recent study, astatistically significant relationship was observedbetween a fall in total glycolytic volume of the tumorafter one cycle of chemotherapy and improved patientsurvival (Francis et al. 2007) while neither a reductionin the maximum SUV nor CT demonstrated a statis-tically significant association with patient survival(Francis et al. 2007). Thus, metabolic imaging canimprove the care of patients receiving chemotherapyfor mesothelioma through the early identification offavorable response to therapy.

Fig. 12 Granulomatousdisease. a CT and b PET/CTdemonstrate multiplemediastinal and hilar FDGhypermetabolic lymph nodes.Mediastinoscopy-directedbiopsy proved sarcoidosisrather than metastatic lymphnodes. c and d demonstrateFDG hypermetabolic righthilar and subcarinal lymphnodes which biopsy provento be tuberculosis

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7 Limitations of FDG PET/CT Imagingof the Chest

When evaluating the chest, the interpreter must bemindful of potential artifacts and pitfalls (see PET/CTPitfalls and Artifacts). Inflammatory false positives onFDG PET are not uncommon and can occur withanthracosilicosis, infection, granulomatous disease(Fig. 10) (Schrevens et al. 2004), or reactive hyper-plasia in the mediastinal lymph nodes (Pieterman et al.2000). In patients with malignancies of the lung, false-positive interpretations can occur due to hypermetab-olism from inflammation secondary to obstructingendobronchial tumors (Pieterman et al. 2000). False-negative interpretations can occur due to microscopictumor residue or due to the inability to distinguishbetween a paramediastinal primary tumor and medi-astinal lymph nodes (Pieterman et al. 2000). Imagingcannot detect microscopic lymph node metastases(Lardinois et al. 2003) (Fig. 12).

8 Conclusion

Over the last decade, FDG PET/CT has become thestandard-of care for staging, therapy assessment andfollow-up of patients with thoracic malignancies.It improves the staging, provides a road map forselective invasive mediastinal biopsy and surgicalplanning (especially contrast-enhanced PET/CT) andaccurately identifies distant metastasis. The maximumSUV correlates strongly with patient survival. PET/CTallows accurate assessment of therapy response forpatients with cancer within the chest. PET/CT detectsearly recurrence and identifies the extent of the recur-rent disease. Further research is ongoing to determinethe effects on outcomes, but PET/CT is currently thebest imaging modality for thoracic malignancies.

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