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POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX
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POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX Jeremy J. Erasmus, MD, and Edward F. Patz, Jr, MD
Positron emission tomography (PET) is emerging as a powerful tool that complements conventional radiologic assessment (chest radiographs, CT scans, MR imaging) of thoracic abnormalities. PET is a physiologic imaging technique that uses radiopharmaceuticals produced by labeling metabolic markers such as amino acids or glucose with the positron-emitting radionuclides fluorine-18, carbon-11, or oxygen-15. The radiopharmaceutical is typically imaged by coincidence detection of the two 511-KeV photons that are produced by annihilation of the emitted positrons. In the thorax, PET has been used to evaluate cardiac abnormalities, including myocardial viability, but most research has focused on its application in tumor imaging. The radiopharmaceutical, 18F-2-deoxy-D-glucose (FDG), a D-glucose analog labeled with fluorine-18, is ideally suited for tumor imaging. PET performed with this agent exploits the differences in glucose metabolism between normal and neoplastic cells. After intravenous administration, FDG preferentially accumulates within neoplastic cells, allowing accurate, noninvasive differentiation of benign versus malignant abnormalities by PET imaging. This article focuses on the current applications of FDG-PET in the thorax and reviews the evaluation of focal pulmonary opacities, lung cancer staging, tumor recurrence, treatment response, and prognosis.
EVALUATION OF FOCAL PULMONARY ABNORMALITIES
Focal pulmonary abnormalities, including solitary pulmonary nodules (SPNs), are common radiologic abnormalities that are often detected incidentally. These lesions are produced by a wide spectrum of disorders, including infections, inflammatory processes, collagen vascular diseases, and tumors. Although most focal pulmonary opacities are benign and usually caused by prior infection (tuberculoma, histoplasmoma, or coccidioidomycoma), some are malignant (lung cancer or metastasis).lg,27, 28, 53 In fact, an SPN is the initial radiographic finding in 20% to 30% of patients with lung cancer.84Because the prognosis of lung cancer depends on a number of factors, including stage at presentation, there is an emphasis on early diagnosis. This means indeterminate focal pulmonary opacities are often evaluated extensively. The most cost-effective initial step in evaluation is a review of prior radiologic studies to determine whether the focal pulmonary opacity has changed in size. The absence of visible growth over a 2-year period, although not diagnostic, is considered to be reliable in determining a benign status.2o,21, 45 If stability cannot be determined (no old radiologic studies available or if pre-existing imaging studies cover less than a 2-year period), then charac-
From the Department of Radiology, Duke University Medical Center, Durham, North Carolina
CLINICS IN CHEST MEDICINE
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VOLUME 20 NUMBER 4 DECEMBER 1999
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terization of the abnormality by CT scan is recommended. Certain morphologic features may suggest a malignancy, but none is uniformly 42 Generally, the larger a nodule, the specific.41, less likely it is to be benign (80% of benign nodules are < 2 cm in diameter).25,27* 92 Small size, however, cannot be used to exclude lung cancer, because 15% of resected malignant lesions are less than 1 cm in diameter and approximately 42% are less than 2 cm in diameter.73, 84, 91 The majority of nodules with smooth, sharp edges are benign, but 21% of malignant nodules have a similar a ~ p e a r a n c eA . ~lobu~ lated contour implies uneven growth, a characteristic associated with malignancy.25Lobulation, however, is seen in approximately 25% of benign nodules.92 Irregular, spiculated edges with distortion of adjacent vessels, often described as sunburst or corona radiata appearance, are typical of a malignant lesion, although this finding can occur with benign lesions.25, 72, 80,91,92 There is also considerable overlap in the internal characteristics of benign and malignant nodules. Cavitation occurs in both benign and malignant lesions, but benign nodules generally have smooth, thin walls, whereas malignant nodules typically have thick, irregular walls.8o,92 Ninety-seven percent of nodules with a wall thickness greater than 5 mm are malignant. Conversely, if the wall thickness is less than 4 mm, 93% of nodules are benign.87,88 Contrast-enhanced CT may accurately differentiate benign from malignant nodules. It has been suggested that blood flow in malignant pulmonary nodules is qualitatively and quantitatively different from that in benign nodules.79,90 Enhancement of a nodule up to 15 Hounsfield units (HU) following contrast administration is strongly predictive of a benign lesion; nodules that enhance greater than 15 HU are more likely to be malignant.79 Unfortunately, many benign and malignant lesions have similar morphologic features on conventional imaging studies and remain indeterminate after extensive radiologic evaluation. Depending on the clinical history and likelihood of malignancy, indeterminate focal pulmonary lesions can then either be observed, biopsied (transthoracic or transbronchial needle aspiration), or resected. Not uncommonly, biopsy results are nondiagnostic, particularly if the lesions are benign.36Furthermore, because the decision to resect an
indeterminate nodule is usually subjective (depending on the perceived probability that the nodule is malignant), up to 60% of resected nodules are benign.10,44, 46 Improvement in characterization of focal pulmonary opacities could reduce the cost and morbidity of resecting benign lesions. FDG-PET is a newer, noninvasive modality used to evaluate focal pulmonary lesions that are indeterminate by conventional studies. FDG uptake can be assessed visually on PET images by comparing the activity of the lesion with that of the background or by semiquantitative analysis using calculated standardized uptake ratios (SUR=mean ROI activity [mCi / mL] /injected dose [mCi]/body wt [kg]).A standardized uptake ratio of less than 2.5 is generally considered to be indicative of a benign lesion.4*,49 FDG-PET is accurate in differentiating benign from malignant lesions as small as 10 mm with an overall sensitivity, specificity, and accuracy of 96%, 8870, and 94%, respectively, in the detection of malignancy7,23, 24, 31, 70 (Fig. 1). The use of FDG-PET as a single test has been reported to be a better predictor of malignancy than standard clinical and morphologic criteria used in Bayesian 24 Because the probability of maliganaly~is.~, nancy is high (goyo if the patient is more than 60 years old) with a positive FDG-PET study and low with a negative study (less than 5% probability of malignancy), FDG-PET is clinically more useful than Bayesian analysis in directing clinical management of a focal pul24 monary ~pacity.~, The high specificity of PET imaging for benign lesions has important clinical use. Lesions with low FDG uptake can be considered benign. These lesions should be followed radiologically because: (1)rarely, false-negative studies can occur with primary pulmonary malignancies (carcinoid tumors and bronchioloalveolar carcinoma can have lower FDG uptake than expected for malignant tumors)", 26, 49 and (2) poor spatial resolution of PET can result in false-negative studies when lesions .~~ smaller than 10 mm are e ~ a l u a t e dLesions with increased FDG uptake should be considered malignant, although false-positive studies have been reported with infectious and inflammatory processes such as active tuberculosis, histoplasmosis, and rheumatoid nodules.8, 39, 62, 65, 78 PET imaging is currently used as a complementary study to thoracic CT. Decision-analysis models indicate that the use of CT and
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Figure 1. A 77-year-old asymptomatic man with a long history of smoking had questionable new focal opacity detected on routine chest radiograph (not shown). A, Axial chest CT confirms right upper lobe poorly marginated, noncalcified nodule (arrow). Note diffuse emphysema. B, Axial 2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) shows marked uptake (hypermetabolism) in lesion (arrow). Surgical resection confirmed non-small cell lung cancer (NSCLC).
FDG-PET imaging for evaluating focal pulmonary lesions is the most cost-effective and useful strategy in determining patient management when there is an intermediate pretest likelihood (0.12-0.69) that the lesion is malignant. With a low (up to 0.12) or high (above 0.9) pretest likelihood of malignancy, the most cost-effective strategy is observation and resection, respectively.16In the management of a focal pulmonary lesion within the pretest likelihood of 0.1 to 0.7, an estimated 15% fewer patients will undergo resection if FDG-PET imaging is included in the assessment. Although FDG-PET imaging is more expensive than other imaging modalities, its high accuracy and minimal risk make it cost effective. It has been estimated that the combination of FDG-PET and CT to evaluate a focal pulmonary lesion in the pretest likelihood of 0.1 to 0.7 range will save $1192 per patient ($62.7 million annually) in medical treatment costs compared with CT a1one.I6
The limited availability and expense of PET imaging currently restricts its widespread application. Less expensive and more readily available single photon emission CT (SPECT) cameras to image positron-emitting radionuclides are being developed and, despite limitations in spatial resolution, they may have potential clinical u s e f u l n e s ~ . ~ ~ STAGING OF NON-SMALL CELL LUNG CANCER
Staging establishes the extent of lung cancer so that appropriate treatment options and prognostic information can be detem~ined.5~. 56 A lung cancer stage is assigned to each patient at presentation using TNM descriptorsprimary tumor (T), lymph nodes status (N), and metastases (M).55 The clinical stage (cstage) is determined by history, physical examination, and radiologic imaging? 6, 65, 71, 77 whereas a pathologic stage (pstage) results
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from histologic confirmation. Despite extensive preoperative evaluation, patients considered surgical candidates according to their cstage can have lesions that are unresectable at With the addition of FDG-PET, the accuracy of clinical staging has improved, and this strategy is more cost-effective than conventional imaging a10ne.I~PET has been reported to change management in 41% of patients with lung cancer by detecting unsuspected metastases or by indicating that abnormalities on conventional studies may not be malignant. In several studies, up to 18% of patients considered to have resectable malignancy have more advanced disease demon86 strated by PET and are n~nresectable.~~, CT is usually used in the evaluation of the primary tumor to determine the size, anatomic location, and extent of local invasion (T The poor spatial and contrast resolution of PET prevents accurate anatomic assessment of T status-that is, it is often not possible to determine whether the lesion is completely surrounded by lung parenchyma (Tl), or invading adjacent structures, includ-
ing the pleura, chest wall, diaphragm, and mediastinum (T2-T4). Accurate lymph node staging and determination of the N status is essential in predicting resectability. Conventional imaging evaluation is based exclusively on size because nodal morphology and MR signal characteristics are not useful.18,65 A short axis nodal diameter of 1 cm is considered the upper limit of n0rma1.l~Although CT and MR can clearly demonstrate hilar and mediastinal nodes, the specificity is too low for them to be more than adjuncts to invasive (mediastinoscopy, bronchoscopy) In several studies, FDG-PET has consistently been shown to be more accurate than CT in determining nodal status (81%-100% and 52%85%).ZZ,23, 62, 63, 69,76, 83. 85 FDG-PET is more sensitive and specific than CT in detecting metastatic disease in normal-sized nodes and in differentiating enlarged benign nodes from enlarged nodal met a ~ t a s e s82, ~ ~83,, (Fig. 2). PET has been reported to correctly increase or decrease the nodal staging as determined by CT in 21% of
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Figure 2. A 61-year-old woman with NSCLC. A, Posteroanterior chest radiograph shows a right hilar mass (arrow) with right paratracheal adenopathy. The lungs are hyperinflated and emphysematous. B, Axial chest CT confirmed the hilar mass (arrow) and paratracheal adenopathy (arrowhead). C, Axial PET image shows increased FDG uptake in the right hilum (arrow) and paratracheal region (arrowhead). Mediastinal biopsy in this area confirmed NSCLC.
POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX
presurgical patients.8I The combined use of CT and FDG-PET to stage intrathoracic nodal metastases is clinically useful and cost-effective.15It reduces the probability that a patient with unresectable mediastinal nodal metastases will undergo an attempt at curative resection and it has been shown to save $1154 per patient with a small increase in life expectancy.I5 Invasive nodal sampling will be required until noninvasive imaging can reliably improve its specificity to greater than 90h. 0 50, 81 This is the value required for noninvasive imaging to have the same predicted outcome as invasive staging of the mediastinum. Combined FDG-PET and CT assessment of mediastinal nodal metastases has a higher negative predictive value (92%-100%) than mediastinoscopy and could reduce the need for invasive staging.76,81-83, 85 It has been suggested that invasive mediastinal staging could be omitted when the PET study is normal. Although PET has a high positive predictive value, false-positive results can occur with infection, active inflammation, hyperplasia, sarcoidosis, and anthracotic nodes.22,43,81 Invasive mediastinal staging should still be performed if there is increased nodal uptake in
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the mediastinum to prevent denial of a potentially curative resection. It has been estimated that the use of this strategy in the staging of mediastinal nodes would dramatically reduce invasive mediastinal staging.82,83 The prevalence of distant metastatic disease in lung cancer at presentation ranges from 11%to 36%.51,66 Common sites of metastases are the liver, adrenal glands, bones, and brain.37,66 Staging performed on the basis of symptomatology, abnormal laboratory indices, and conventional radiologic imaging will incorrectly stage some patients with M1 disease.'j8rs6Whole-body PET imaging has the capability to stage intra and extrathoracic disease in a single study and has a greater sensitivity and specificity than CT in the detection of metastases in the liver, adrenals, and extrathoracic lymph nodes.'*fi 67, 86 FDG-PET has been shown to detect occult extrathoracic metastases in 11%to 14% of patients selected for curative resection and alters management in up to 40% of The ability of PET to detect unsuspected extrathoracic metastases with few false-positive results makes it an ideal screening method, limited only by lack of availability and high cost (Figs. 3, 4). Adrenal metastases are present in as many
Figure 3. A 53-year-old woman presented with low back pain. A, Axial CT coned to the lumbar spine shows a lytic lesion of the fourth lumbar vertebra (arrows). B, Coronal whole-body PET image reveals a focal area of increased FDG uptake in the lumbar spine (arrow). There is also marked FDG uptake in the large left upper lobe primary lung cancer (arrowheads). Vertebral body biopsy confirmed metastatic NSCLC.
Figure 4. A 51-year-old woman presenting with history of headache and confusion. A, Posteroanteriorchest radiograph shows a small nodule in the right upper lobe (arrow). There is no hilar or mediastinal adenopathy. 13,Axial chest CT confirmed the nodule (arrow) and absence of intrathoracic adenopathy. C,Coronal wholebody PET image revealed increased FDG uptake in the right upper lobe nodule (arrow). Hilar and mediastinal activity was normal. Note normal renal excretion and accumulation of FDG in the bladder. 0,Axial CT image of the brain revealed a focal cystic left parietal lesion (arrow) consistent with a space-occupyinglesion. €, Axial PET image of the brain shows a photopenic left parietal mass (arrow) consistent with a space-occupying lesion consistent with metastatic NSCLC.
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as 20% of patients with lung cancer at initial ~resentation.3~. 5740 Clinical examination and laboratory findings are generally not useful in detecting adrenal metastases. The adrenal glands are usually evaluated by CT or MR. An isolated adrenal mass in patients with lung cancer, however, may not represent metastatic disease.'J 58 In more than 60% of patients without extrathoracic metastases, a 3cm or smaller adrenal mass is more likely to be benign.37,58 Most adrenal masses that are indeterminate on conventional imaging, in patients with potentially resectable disease, are biopsied percutaneously. Percutaneous biopsy, however, although accurate (83%loo%), can be falsely negative and is associated with potential morbidity and m~rtality.~, 4, 59 FDG-PET imaging is a noninvasive alternative that can accurately assess adrenal masses. The sensitivity and specificity for detecting metastatic disease to the adrenal gland from lung cancer with PET imaging is 100% and 80%, respectively.'2 If FDG-PET scan of the adrenals is normal in a patient with nonsmall cell lung cancer, curative surgical resection should be considered without further evaluation. Patients with non-small cell lung cancer and an isolated adrenal mass with increased FDG uptake should have the adrenal lesion biopsied before being denied surgical resection. Because conventional radiologic screening (radiographs, radionuclide 99Tc-99mmethylene diphosphate) for occult skeletal metastases has a low (4%) detection rate and a high false-positive rate, evaluation for metastases is usually performed only if the patient has focal bone pain or elevated serum alkaline ph~sphatase.~~,In a recent study evaluating the detection of extrathoracic metastases in lung cancer using whole-body PET, however, skeletal metastases were detected in 13% of the patients, approximately 75% of whom were asymptomatic.86 Isolated metastases to the central nervous system (CNS) have been reported to be a rare occurrence in patients with non-small cell lung cancer and, when present, are frequently associated with an abnormal neurologic e x a m i n a t i ~ n .37 ~ ~Although , asymptomatic CNS metastases occur in 2.7% to 9.6% of patients with non-small cell lung cancer, routine CT or MR imaging of the CNS is controver~ial.2~. 54,64, Whole-body FDG-PET can detect occult CNS metastases but the specificity and sensitivity are unknown.
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EVALUATION OF RECURRENT LUNG CANCER
Chest radiographs, CT, or MR images are often unable to distinguish persistent or recurrent tumor from necrotic tumor, posttreatment scarring, or fib~0sis.I~ PET imaging may have an important role in guiding patient care after surgery or radiation therapy because it is more accurate than conventional studies in detecting recurrent tumor (accuracy of 78%98%, sensitivity of 97%-loo%, and specificity of 62%-100%).7,14, 30, 32, 33, 35, 40, 61 False-positive studies can be caused by postirradiation inflammatory changes and it therefore is recommended that PET studies not be obtained until 4 to 5 months after irradiati~n.'~ Monitoring patients with serial FDG-PET studies can detect local recurrence before conventional imaging and can allow earlier treatment with external irradiati~n'~ (Fig. 5). Reliance on patient symptomatology to determine local recurrence can delay diagnosis and compromise retreatment with external irradiation. Although retreatment of asymtomatic patients with local recurrence results in decreased or absent FDG uptake in the tumor, the effects on survival and prognosis need to be determined.14
THERAPEUTIC RESPONSE AND PROGNOSTIC POTENTIAL
Preliminary studies suggest a possible role for PET as a prognostic marker. Patients with significantly increased FDG uptake in the primary lesion have a poorer survival rate than those with modest FDG activity? Other studies suggest a role in the assessment of therapeutic response after radiation and chemotherapy.', 38, 40 A decrease in FDG uptake before and after one or two cycles of chemotherapy may predict outcome, with improved survival directly related to the magnitude of decreased uptake.', 75 FDG uptake has been reported to return to normal in patients judged clinically to have had a complete response to radiotherapy or chemotherapy and remain high in those with only a partial response.' In patients with normal FDG uptake after treatment, disease-free periods are significantly longer than those in whom FDGPET uptake remains high.l
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Figure 5. An 81-year-old asymptomatic man with remote history of resected NSCLC. A, Posteroanterior chest radiograph shows a nodular opacity in the midaspect of the right lung (arrows), adjacent to surgical sutures from prior partial pulmonary resection. B, Coronal PET image shows increased FDG uptake within this nodular opacity consistent with recurrent lung cancer.
SUMMARY Positron emission tomography imaging has proven valuable in the evaluation and management of thoracic abnormalities. It is more accurate than CT or MR imaging in characterizing indeterminate focal abnormal pulmonary opacities, staging lung cancer, and assessing the therapeutic response. PET imaging in lung cancer also appears to be cost-effective, particularly with whole-body studies. The metabolic and physiologic abnormalities used in FDG-PET imaging, rather than conventional anatomic or morphologic characteristics, provide an invaluable model for the future of tumor imaging.
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77. Stitik FP: Staging of lung cancer. Radiology Clin North Am 28:619430, 1990 78. Strauss LG, Conti PS: The applications of PET in clinical oncology. J Nucl Med 32623-648, 1991 79. Swensen SJ, Brown LR, Colby TV, et al: Lung nodules enhancement at CT Prospective findings. Radiology 201:447455, 1996 80. Theros EG: Varying manifestations of peripheral pulmonary neoplasms: A radiologic-pathologic correlative study. AJR 1282393-914, 1977 81. Valk PE, Pounds TR, Hopkins DM, et al: Staging non-small cell lung cancer by whole-body positron emission tomographic imaging. Ann Thorac Surg 601573-1582, 1995 82. Vansteenkiste JF, Stroobants SG, De Lelyn PR, et al: Mediastinal lymph node staging with FDG-PET scan in patients with potentially operable non-small cell lung cancer. Chest 112:1480-1486, 1997 83. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al: Lymph node staging in non-small-cell lung cancer with FDG-PET scan: A prospective study on 690 lymph node stations from 68 patients. J Clin Oncol 16:2142-2149, 1998 84. Viggiano RW, Swensen SJ, Rosenow EC III: Evaluation and management of solitary and multiple pulmonary nodules. Clin Chest Med 13:83-95, 1992 85. Wahl RL, Quint LE, Greenough RL, et al: Staging of mediastinal non-small cell lung cancer with FDG PET, CT, and fusion images: Preliminary prospective evaluation. Radiology 191:371-377, 1994 86. Weder W, Schmid RA, Bruchhaus H, et al: Detection of extrathoracic metastases by positron emission tomography in lung cancer. Ann Thorac Surg 66886893, 1998 87. Woodring JH,Fried AM: Significance of wall thickness in solitary cavities of the lung: A follow-up study. AJR 140:473474, 1983 88. Woodring JH, Fried AM, Chuang VP: Solitary cavities of the lung: Diagnostic implications of cavity wall thickness. AJR 135:1269-1271, 1980 89. Worsley DF, Celler A, Adam MJ, et al: Pulmonary nodules: Differential diagnosis using 18F-fluorodeoxyglucose single-photon emission computed tomography. AJR 168:771-774, 1997 90. Yamashita K, Matsunobe S, Tsuda T, et al: Solitary pulmonary nodule: Preliminary study of evaluation with incremental dynamic CT. Radiology 194:399405, 1995 91. Zerhouni EA, Stitik FP, Siegelman SS, et al: CT of the pulmonary nodule: A cooperative study. Radiology 160:319-327, 1986 92. Zwirewich CV, Veda1 S, Miller RR, et al: Solitary pulmonary nodule: High-resolution CT and radiologic-pathologic correlation. Radiology 179:469476, 1991 Address reprint requests to: Edward F. Patz, Jr, MD Department of Radiology Box 3808 Duke University Medical Center Durham, NC 27710
e-mail: [email protected]
IMAGING
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POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX Jeremy J. Erasmus, MD, and Edward F. Patz, Jr, MD
Positron emission tomography (PET) is emerging as a powerful tool that complements conventional radiologic assessment (chest radiographs, CT scans, MR imaging) of thoracic abnormalities. PET is a physiologic imaging technique that uses radiopharmaceuticals produced by labeling metabolic markers such as amino acids or glucose with the positron-emitting radionuclides fluorine-18, carbon-11, or oxygen-15. The radiopharmaceutical is typically imaged by coincidence detection of the two 511-KeV photons that are produced by annihilation of the emitted positrons. In the thorax, PET has been used to evaluate cardiac abnormalities, including myocardial viability, but most research has focused on its application in tumor imaging. The radiopharmaceutical, 18F-2-deoxy-D-glucose (FDG), a D-glucose analog labeled with fluorine-18, is ideally suited for tumor imaging. PET performed with this agent exploits the differences in glucose metabolism between normal and neoplastic cells. After intravenous administration, FDG preferentially accumulates within neoplastic cells, allowing accurate, noninvasive differentiation of benign versus malignant abnormalities by PET imaging. This article focuses on the current applications of FDG-PET in the thorax and reviews the evaluation of focal pulmonary opacities, lung cancer staging, tumor recurrence, treatment response, and prognosis.
EVALUATION OF FOCAL PULMONARY ABNORMALITIES
Focal pulmonary abnormalities, including solitary pulmonary nodules (SPNs), are common radiologic abnormalities that are often detected incidentally. These lesions are produced by a wide spectrum of disorders, including infections, inflammatory processes, collagen vascular diseases, and tumors. Although most focal pulmonary opacities are benign and usually caused by prior infection (tuberculoma, histoplasmoma, or coccidioidomycoma), some are malignant (lung cancer or metastasis).lg,27, 28, 53 In fact, an SPN is the initial radiographic finding in 20% to 30% of patients with lung cancer.84Because the prognosis of lung cancer depends on a number of factors, including stage at presentation, there is an emphasis on early diagnosis. This means indeterminate focal pulmonary opacities are often evaluated extensively. The most cost-effective initial step in evaluation is a review of prior radiologic studies to determine whether the focal pulmonary opacity has changed in size. The absence of visible growth over a 2-year period, although not diagnostic, is considered to be reliable in determining a benign status.2o,21, 45 If stability cannot be determined (no old radiologic studies available or if pre-existing imaging studies cover less than a 2-year period), then charac-
From the Department of Radiology, Duke University Medical Center, Durham, North Carolina
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terization of the abnormality by CT scan is recommended. Certain morphologic features may suggest a malignancy, but none is uniformly 42 Generally, the larger a nodule, the specific.41, less likely it is to be benign (80% of benign nodules are < 2 cm in diameter).25,27* 92 Small size, however, cannot be used to exclude lung cancer, because 15% of resected malignant lesions are less than 1 cm in diameter and approximately 42% are less than 2 cm in diameter.73, 84, 91 The majority of nodules with smooth, sharp edges are benign, but 21% of malignant nodules have a similar a ~ p e a r a n c eA . ~lobu~ lated contour implies uneven growth, a characteristic associated with malignancy.25Lobulation, however, is seen in approximately 25% of benign nodules.92 Irregular, spiculated edges with distortion of adjacent vessels, often described as sunburst or corona radiata appearance, are typical of a malignant lesion, although this finding can occur with benign lesions.25, 72, 80,91,92 There is also considerable overlap in the internal characteristics of benign and malignant nodules. Cavitation occurs in both benign and malignant lesions, but benign nodules generally have smooth, thin walls, whereas malignant nodules typically have thick, irregular walls.8o,92 Ninety-seven percent of nodules with a wall thickness greater than 5 mm are malignant. Conversely, if the wall thickness is less than 4 mm, 93% of nodules are benign.87,88 Contrast-enhanced CT may accurately differentiate benign from malignant nodules. It has been suggested that blood flow in malignant pulmonary nodules is qualitatively and quantitatively different from that in benign nodules.79,90 Enhancement of a nodule up to 15 Hounsfield units (HU) following contrast administration is strongly predictive of a benign lesion; nodules that enhance greater than 15 HU are more likely to be malignant.79 Unfortunately, many benign and malignant lesions have similar morphologic features on conventional imaging studies and remain indeterminate after extensive radiologic evaluation. Depending on the clinical history and likelihood of malignancy, indeterminate focal pulmonary lesions can then either be observed, biopsied (transthoracic or transbronchial needle aspiration), or resected. Not uncommonly, biopsy results are nondiagnostic, particularly if the lesions are benign.36Furthermore, because the decision to resect an
indeterminate nodule is usually subjective (depending on the perceived probability that the nodule is malignant), up to 60% of resected nodules are benign.10,44, 46 Improvement in characterization of focal pulmonary opacities could reduce the cost and morbidity of resecting benign lesions. FDG-PET is a newer, noninvasive modality used to evaluate focal pulmonary lesions that are indeterminate by conventional studies. FDG uptake can be assessed visually on PET images by comparing the activity of the lesion with that of the background or by semiquantitative analysis using calculated standardized uptake ratios (SUR=mean ROI activity [mCi / mL] /injected dose [mCi]/body wt [kg]).A standardized uptake ratio of less than 2.5 is generally considered to be indicative of a benign lesion.4*,49 FDG-PET is accurate in differentiating benign from malignant lesions as small as 10 mm with an overall sensitivity, specificity, and accuracy of 96%, 8870, and 94%, respectively, in the detection of malignancy7,23, 24, 31, 70 (Fig. 1). The use of FDG-PET as a single test has been reported to be a better predictor of malignancy than standard clinical and morphologic criteria used in Bayesian 24 Because the probability of maliganaly~is.~, nancy is high (goyo if the patient is more than 60 years old) with a positive FDG-PET study and low with a negative study (less than 5% probability of malignancy), FDG-PET is clinically more useful than Bayesian analysis in directing clinical management of a focal pul24 monary ~pacity.~, The high specificity of PET imaging for benign lesions has important clinical use. Lesions with low FDG uptake can be considered benign. These lesions should be followed radiologically because: (1)rarely, false-negative studies can occur with primary pulmonary malignancies (carcinoid tumors and bronchioloalveolar carcinoma can have lower FDG uptake than expected for malignant tumors)", 26, 49 and (2) poor spatial resolution of PET can result in false-negative studies when lesions .~~ smaller than 10 mm are e ~ a l u a t e dLesions with increased FDG uptake should be considered malignant, although false-positive studies have been reported with infectious and inflammatory processes such as active tuberculosis, histoplasmosis, and rheumatoid nodules.8, 39, 62, 65, 78 PET imaging is currently used as a complementary study to thoracic CT. Decision-analysis models indicate that the use of CT and
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Figure 1. A 77-year-old asymptomatic man with a long history of smoking had questionable new focal opacity detected on routine chest radiograph (not shown). A, Axial chest CT confirms right upper lobe poorly marginated, noncalcified nodule (arrow). Note diffuse emphysema. B, Axial 2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) shows marked uptake (hypermetabolism) in lesion (arrow). Surgical resection confirmed non-small cell lung cancer (NSCLC).
FDG-PET imaging for evaluating focal pulmonary lesions is the most cost-effective and useful strategy in determining patient management when there is an intermediate pretest likelihood (0.12-0.69) that the lesion is malignant. With a low (up to 0.12) or high (above 0.9) pretest likelihood of malignancy, the most cost-effective strategy is observation and resection, respectively.16In the management of a focal pulmonary lesion within the pretest likelihood of 0.1 to 0.7, an estimated 15% fewer patients will undergo resection if FDG-PET imaging is included in the assessment. Although FDG-PET imaging is more expensive than other imaging modalities, its high accuracy and minimal risk make it cost effective. It has been estimated that the combination of FDG-PET and CT to evaluate a focal pulmonary lesion in the pretest likelihood of 0.1 to 0.7 range will save $1192 per patient ($62.7 million annually) in medical treatment costs compared with CT a1one.I6
The limited availability and expense of PET imaging currently restricts its widespread application. Less expensive and more readily available single photon emission CT (SPECT) cameras to image positron-emitting radionuclides are being developed and, despite limitations in spatial resolution, they may have potential clinical u s e f u l n e s ~ . ~ ~ STAGING OF NON-SMALL CELL LUNG CANCER
Staging establishes the extent of lung cancer so that appropriate treatment options and prognostic information can be detem~ined.5~. 56 A lung cancer stage is assigned to each patient at presentation using TNM descriptorsprimary tumor (T), lymph nodes status (N), and metastases (M).55 The clinical stage (cstage) is determined by history, physical examination, and radiologic imaging? 6, 65, 71, 77 whereas a pathologic stage (pstage) results
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from histologic confirmation. Despite extensive preoperative evaluation, patients considered surgical candidates according to their cstage can have lesions that are unresectable at With the addition of FDG-PET, the accuracy of clinical staging has improved, and this strategy is more cost-effective than conventional imaging a10ne.I~PET has been reported to change management in 41% of patients with lung cancer by detecting unsuspected metastases or by indicating that abnormalities on conventional studies may not be malignant. In several studies, up to 18% of patients considered to have resectable malignancy have more advanced disease demon86 strated by PET and are n~nresectable.~~, CT is usually used in the evaluation of the primary tumor to determine the size, anatomic location, and extent of local invasion (T The poor spatial and contrast resolution of PET prevents accurate anatomic assessment of T status-that is, it is often not possible to determine whether the lesion is completely surrounded by lung parenchyma (Tl), or invading adjacent structures, includ-
ing the pleura, chest wall, diaphragm, and mediastinum (T2-T4). Accurate lymph node staging and determination of the N status is essential in predicting resectability. Conventional imaging evaluation is based exclusively on size because nodal morphology and MR signal characteristics are not useful.18,65 A short axis nodal diameter of 1 cm is considered the upper limit of n0rma1.l~Although CT and MR can clearly demonstrate hilar and mediastinal nodes, the specificity is too low for them to be more than adjuncts to invasive (mediastinoscopy, bronchoscopy) In several studies, FDG-PET has consistently been shown to be more accurate than CT in determining nodal status (81%-100% and 52%85%).ZZ,23, 62, 63, 69,76, 83. 85 FDG-PET is more sensitive and specific than CT in detecting metastatic disease in normal-sized nodes and in differentiating enlarged benign nodes from enlarged nodal met a ~ t a s e s82, ~ ~83,, (Fig. 2). PET has been reported to correctly increase or decrease the nodal staging as determined by CT in 21% of
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Figure 2. A 61-year-old woman with NSCLC. A, Posteroanterior chest radiograph shows a right hilar mass (arrow) with right paratracheal adenopathy. The lungs are hyperinflated and emphysematous. B, Axial chest CT confirmed the hilar mass (arrow) and paratracheal adenopathy (arrowhead). C, Axial PET image shows increased FDG uptake in the right hilum (arrow) and paratracheal region (arrowhead). Mediastinal biopsy in this area confirmed NSCLC.
POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX
presurgical patients.8I The combined use of CT and FDG-PET to stage intrathoracic nodal metastases is clinically useful and cost-effective.15It reduces the probability that a patient with unresectable mediastinal nodal metastases will undergo an attempt at curative resection and it has been shown to save $1154 per patient with a small increase in life expectancy.I5 Invasive nodal sampling will be required until noninvasive imaging can reliably improve its specificity to greater than 90h. 0 50, 81 This is the value required for noninvasive imaging to have the same predicted outcome as invasive staging of the mediastinum. Combined FDG-PET and CT assessment of mediastinal nodal metastases has a higher negative predictive value (92%-100%) than mediastinoscopy and could reduce the need for invasive staging.76,81-83, 85 It has been suggested that invasive mediastinal staging could be omitted when the PET study is normal. Although PET has a high positive predictive value, false-positive results can occur with infection, active inflammation, hyperplasia, sarcoidosis, and anthracotic nodes.22,43,81 Invasive mediastinal staging should still be performed if there is increased nodal uptake in
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the mediastinum to prevent denial of a potentially curative resection. It has been estimated that the use of this strategy in the staging of mediastinal nodes would dramatically reduce invasive mediastinal staging.82,83 The prevalence of distant metastatic disease in lung cancer at presentation ranges from 11%to 36%.51,66 Common sites of metastases are the liver, adrenal glands, bones, and brain.37,66 Staging performed on the basis of symptomatology, abnormal laboratory indices, and conventional radiologic imaging will incorrectly stage some patients with M1 disease.'j8rs6Whole-body PET imaging has the capability to stage intra and extrathoracic disease in a single study and has a greater sensitivity and specificity than CT in the detection of metastases in the liver, adrenals, and extrathoracic lymph nodes.'*fi 67, 86 FDG-PET has been shown to detect occult extrathoracic metastases in 11%to 14% of patients selected for curative resection and alters management in up to 40% of The ability of PET to detect unsuspected extrathoracic metastases with few false-positive results makes it an ideal screening method, limited only by lack of availability and high cost (Figs. 3, 4). Adrenal metastases are present in as many
Figure 3. A 53-year-old woman presented with low back pain. A, Axial CT coned to the lumbar spine shows a lytic lesion of the fourth lumbar vertebra (arrows). B, Coronal whole-body PET image reveals a focal area of increased FDG uptake in the lumbar spine (arrow). There is also marked FDG uptake in the large left upper lobe primary lung cancer (arrowheads). Vertebral body biopsy confirmed metastatic NSCLC.
Figure 4. A 51-year-old woman presenting with history of headache and confusion. A, Posteroanteriorchest radiograph shows a small nodule in the right upper lobe (arrow). There is no hilar or mediastinal adenopathy. 13,Axial chest CT confirmed the nodule (arrow) and absence of intrathoracic adenopathy. C,Coronal wholebody PET image revealed increased FDG uptake in the right upper lobe nodule (arrow). Hilar and mediastinal activity was normal. Note normal renal excretion and accumulation of FDG in the bladder. 0,Axial CT image of the brain revealed a focal cystic left parietal lesion (arrow) consistent with a space-occupyinglesion. €, Axial PET image of the brain shows a photopenic left parietal mass (arrow) consistent with a space-occupying lesion consistent with metastatic NSCLC.
POSITRON EMISSION TOMOGRAPHY IMAGING IN THE THORAX
as 20% of patients with lung cancer at initial ~resentation.3~. 5740 Clinical examination and laboratory findings are generally not useful in detecting adrenal metastases. The adrenal glands are usually evaluated by CT or MR. An isolated adrenal mass in patients with lung cancer, however, may not represent metastatic disease.'J 58 In more than 60% of patients without extrathoracic metastases, a 3cm or smaller adrenal mass is more likely to be benign.37,58 Most adrenal masses that are indeterminate on conventional imaging, in patients with potentially resectable disease, are biopsied percutaneously. Percutaneous biopsy, however, although accurate (83%loo%), can be falsely negative and is associated with potential morbidity and m~rtality.~, 4, 59 FDG-PET imaging is a noninvasive alternative that can accurately assess adrenal masses. The sensitivity and specificity for detecting metastatic disease to the adrenal gland from lung cancer with PET imaging is 100% and 80%, respectively.'2 If FDG-PET scan of the adrenals is normal in a patient with nonsmall cell lung cancer, curative surgical resection should be considered without further evaluation. Patients with non-small cell lung cancer and an isolated adrenal mass with increased FDG uptake should have the adrenal lesion biopsied before being denied surgical resection. Because conventional radiologic screening (radiographs, radionuclide 99Tc-99mmethylene diphosphate) for occult skeletal metastases has a low (4%) detection rate and a high false-positive rate, evaluation for metastases is usually performed only if the patient has focal bone pain or elevated serum alkaline ph~sphatase.~~,In a recent study evaluating the detection of extrathoracic metastases in lung cancer using whole-body PET, however, skeletal metastases were detected in 13% of the patients, approximately 75% of whom were asymptomatic.86 Isolated metastases to the central nervous system (CNS) have been reported to be a rare occurrence in patients with non-small cell lung cancer and, when present, are frequently associated with an abnormal neurologic e x a m i n a t i ~ n .37 ~ ~Although , asymptomatic CNS metastases occur in 2.7% to 9.6% of patients with non-small cell lung cancer, routine CT or MR imaging of the CNS is controver~ial.2~. 54,64, Whole-body FDG-PET can detect occult CNS metastases but the specificity and sensitivity are unknown.
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EVALUATION OF RECURRENT LUNG CANCER
Chest radiographs, CT, or MR images are often unable to distinguish persistent or recurrent tumor from necrotic tumor, posttreatment scarring, or fib~0sis.I~ PET imaging may have an important role in guiding patient care after surgery or radiation therapy because it is more accurate than conventional studies in detecting recurrent tumor (accuracy of 78%98%, sensitivity of 97%-loo%, and specificity of 62%-100%).7,14, 30, 32, 33, 35, 40, 61 False-positive studies can be caused by postirradiation inflammatory changes and it therefore is recommended that PET studies not be obtained until 4 to 5 months after irradiati~n.'~ Monitoring patients with serial FDG-PET studies can detect local recurrence before conventional imaging and can allow earlier treatment with external irradiati~n'~ (Fig. 5). Reliance on patient symptomatology to determine local recurrence can delay diagnosis and compromise retreatment with external irradiation. Although retreatment of asymtomatic patients with local recurrence results in decreased or absent FDG uptake in the tumor, the effects on survival and prognosis need to be determined.14
THERAPEUTIC RESPONSE AND PROGNOSTIC POTENTIAL
Preliminary studies suggest a possible role for PET as a prognostic marker. Patients with significantly increased FDG uptake in the primary lesion have a poorer survival rate than those with modest FDG activity? Other studies suggest a role in the assessment of therapeutic response after radiation and chemotherapy.', 38, 40 A decrease in FDG uptake before and after one or two cycles of chemotherapy may predict outcome, with improved survival directly related to the magnitude of decreased uptake.', 75 FDG uptake has been reported to return to normal in patients judged clinically to have had a complete response to radiotherapy or chemotherapy and remain high in those with only a partial response.' In patients with normal FDG uptake after treatment, disease-free periods are significantly longer than those in whom FDGPET uptake remains high.l
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Figure 5. An 81-year-old asymptomatic man with remote history of resected NSCLC. A, Posteroanterior chest radiograph shows a nodular opacity in the midaspect of the right lung (arrows), adjacent to surgical sutures from prior partial pulmonary resection. B, Coronal PET image shows increased FDG uptake within this nodular opacity consistent with recurrent lung cancer.
SUMMARY Positron emission tomography imaging has proven valuable in the evaluation and management of thoracic abnormalities. It is more accurate than CT or MR imaging in characterizing indeterminate focal abnormal pulmonary opacities, staging lung cancer, and assessing the therapeutic response. PET imaging in lung cancer also appears to be cost-effective, particularly with whole-body studies. The metabolic and physiologic abnormalities used in FDG-PET imaging, rather than conventional anatomic or morphologic characteristics, provide an invaluable model for the future of tumor imaging.
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