- Email: [email protected]
Computerized Tomography for the Gastroenterologist and Hepatologist
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:20 –26
CLINICAL IMAGING Positron Emission Tomography/Computerized Tomography for the Gastroenterologist and Hepatologist CARMEL G. CRONIN, MICHAEL MOORE, and MICHAEL A. BLAKE Department of Abdominal and Interventional Radiology, Massachusetts General Hospital, Boston, Massachusetts
C
ombined positron emission tomography/computerized tomography (PET/CT) imaging with fluorine 18 fluorodeoxyglucose (FDG) allows fusion of structural and attenuation information provided by CT with functional imaging derived from PET, improving the radiologic assessment of normal anatomic structures and pathologic lesions. PET/CT allows accurate location of hypermetabolic foci identified at PET with its morphologic structure on CT, reducing the incidence of falsepositive and false-negative imaging findings with PET alone. CT, because of its lack of metabolic information, is unable to distinguish fibrotic tissue; a common finding after chemoradiotherapy and/or surgery from residual neoplastic disease and thus may fail in posttreatment assessment. The ability and role of PET/CT in distinguishing active from inactive disease has revolutionized the assessment of gastrointestinal and hepatobiliary malignancies.
Technical Considerations PET/CT is a hybrid device, combining the physical alignment of independent diagnostic PET and CT scanners. Functional and morphologic information are acquired in a single examination allowing accurate alignment. One of the many advantages of PET/CT over stand-alone PET is the use of CT-based attenuation correction for the PET component, resulting in much faster than traditional transmission methods and almost noise-free information, resulting in a total PET/CT scanning times of only 20 to 30 minutes.
Patient Preparation Patients must fast (no caloric intake) for a minimum of 4 hours before imaging. Because FDG is a glucose analogue, its uptake and distribution in tissues is affected by serum glucose and insulin levels such that low levels of both is desirable. As well as fasting, patients with diabetes should not receive regular insulin within the same 4-hour period before the study. The serum glucose level is measured and should be less than 200 mg/dL. If the serum glucose level is higher than 200 mg/dL, options available include gentle exercise (walking) and then a recheck, administration of subcutaneous insulin and rechecking the serum glucose in approximately 3 hours, or rescheduling the examination. Patients consume 1350 mL of low-attenuating oral contrast (VoLumen; E-Z-EM, Inc, Lake Success, NY) over 45 minutes after receiving the FDG intravenous injection. While waiting the 60 minutes between FDG administration and subsequent imaging, patients are encouraged to rest and activities including talking, chewing, and walking are restricted.
Positron Emission Tomography/Computerized Tomography Protocol PET/CT protocols vary between institutions. Traditionally, the standard PET/CT protocol in most institutions was to perform a low radiation dose, unenhanced CT primarily to provide attenuation correction followed by acquisition of PET data. There is ongoing debate as to what the most appropriate CT scanning parameters are as well as regarding the use of oral and intravenous contrast material and the optimal respiratory phase to scan.1–3 In our institution we first perform a lowradiation-dose (3– 4 mSv), unenhanced CT primarily to provide attenuation correction. Thereafter, the PET data are obtained, followed immediately by a fully diagnostic, standard radiation dose, intravenous, contrast-enhanced CT (ceCT) (15–20 mSv) with the previously administered water-attenuation oral contrast outlining the gastrointestinal tract. Undoubtedly, PET/CT has numerous advantages in improved patient management and outcome, however, this is at the cost of radiation exposure from PET/CT imaging, thus radiologists and clinicians alike should strictly adhere to the as low as reasonably achievable principle of using a radiation dose that is as low as possible and performing PET/CT only when clinically necessary.
Physiologic Nonneoplastic Fluorodeoxyglucose Uptake Physiologic FDG uptake in the gastrointestinal and hepatobiliary system is variable. Bowel FDG uptake typically is isolated rather than diffuse, but intense uptake can occur, particularly in the right colon and anal region. The liver typically shows mild FDG activity with a uniform mottled appearance at standard imaging 1 hour after injection of FDG.
False-Positive and False-Negative Results False-positive and false-negative PET/CT results have a negative impact on patient management. The following causes Abbreviations used in this paper: ceCT, contrast-enhanced computerized tomography; CT, computerized tomography; EUS, endoscopic ultrasound; FDG, fluorodeoxyglucose; PET, positron emission tomography. © 2009 by the AGA Institute 1542-3565/09/$36.00 doi:10.1016/j.cgh.2008.10.033
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of potential false-positive and false-negative results highlight the value of clinician understanding of the technique, as well as the importance of physician and radiologist communication to minimize the likelihood of erroneous PET/CT interpretation. First, FDG activity may be observed at the site of surgery in the postoperative period. This typically is owing to postsurgical inflammation or granulation tissue and can masquerade as tumor recurrence on PET/CT. Although normal posttreatment hypermetabolic activity has been seen for up to 6 months to a year, the current literature is deficient in relation to the exact time interval in which normal posttreatment hypermetabolic activity occurs and recommendations in regards to the appropriate time interval between surgery and PET/CT imaging to reduce false-positive results. With this in mind, follow-up response assessment examinations should be postponed for at least 6 weeks after such treatment to limit false-positive interpretation of persistent posttreatment FDG activity and in equivocal cases either biopsy or follow-up PET/CT may be required. Second, intense splenic uptake is seen in patients undergoing treatment with granulocyte-stimulating factor, a process that also may cause diffuse intense FDG uptake in the bone marrow.4 Third, PET/CT has limited spatial resolution and lesions less than 5 to 8 mm may not be identified on PET, leading to a false-negative micrometastasis result. Fourth, because PET scanners differ in how they acquire, reconstruct, and analyze images, serial scans obtained in the same patient on different scanners can yield inconsistent results.5 Fifth, any process associated with increased glycolysis including inflammation, infection, granulomatous disease, and brown fat can result in false-positive FDG results.
Neoplastic FDG Uptake Gastrointestinal Tract In the United States, the Centers for Medicare and Medicaid have approved Medicare coverage for FDG PET, and thus PET/CT, in the diagnosis, staging, and restaging of patients with colorectal and esophageal cancer. PET and PET/CT have been used in the evaluation of a wide variety of other malignancies associated with the gastrointestinal tract and abdominal organs. Although many of these are not currently covered by the Centers for Medicare and Medicaid in the United States, the advent of The National Oncologic PET Registry has enabled their use for such diseases and with time many of these malignancies may gain full coverage.6
Esophageal Diagnosis. The role of PET/CT in the primary diagnosis of esophageal cancer has not been well investigated; in studies of patients with known esophageal cancer, PET appears to be accurate for detection of the primary lesion. However, benign causes of FDG uptake, which may lead to false-positive results, include infectious esophagitis, Barrett’s esophagus without malignancy, inflammatory esophagitis caused by reflux disease, and postprocedural changes.7–9 Staging. Although most esophageal carcinomas appear FDG avid at PET/CT, the insufficient spatial and contrast resolution of PET/CT limits visualization of the anatomic ex-
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tent of the primary mass and precludes evaluation of the depth of local tumor invasion (T stage). Thus, endoscopic ultrasound (EUS) is currently the modality of choice for evaluating depth of local invasion through the esophageal wall. The N stage determines nodal metastases. Previously, FDG PET alone was shown to have a low sensitivity and specificity of 51% and 84%, respectively, for the detection of locoregional lymph node metastases.10 A more recent study showed that FDG PET alone has a similar sensitivity but lower specificity and accuracy for the detection of locoregional lymph node metastases than the combination of PET/CT imaging (sensitivity, 96% vs 96%; specificity, 59% vs 81%; and accuracy, 90% vs 83%, respectively),1 owing to difficulties in differentiating uptake in periesophageal lymph nodes from that of the lesion itself. PET/CT has a higher specificity than either CT or endoscopic US for lymph node metastases, and the presence of discrete focal metabolic activity in periesophageal or regional lymph nodes is highly indicative of nodal metastasis. The M stage denotes lymphadenopathy that is just beyond locoregional lymph nodes as M1a disease and distant organ metastases as M1b. This distinction is important because regional lymphadenopathy adjacent to the esophagus or stomach does not preclude curative surgery, whereas distant metastases are contraindications to radical surgery. PET detects M1a nodal disease significantly better than locoregional nodal disease. In a comparison study, PET was found to be 86% accurate in the evaluation of M1a nodal metastases with a specificity of 90%, whereas the accuracy and specificity for combined CT and EUS assessment were 62% and 69%, respectively.2 PET has been shown to accurately show sites of distant metastatic disease, with the sensitivity and specificity of PET for M1b disease higher than those for CT and EUS (Figure 1).2,3,11–14 Thus, in clinical practice, disease staging should be determined using a multimodality approach including information from EUS, PET, and CT. Restaging and response assessment. PET/CT appears to have an important role in response assessment. In a prospective trial evaluating CT, EUS, and PET/CT in the assessment of disease response to neoadjuvant chemoradiation, complete response was predicted accurately by EUS in 67% and better by PET/CT in 89%.15 Similar findings were found by Weber et al,16 who indicated that PET could differentiate responding from nonresponding tumors early in the course of therapy and thus potentially avoid ineffectual and harmful treatment. However, care is required because specificity in posttreatment response is limited by increased FDG uptake secondary to radiation therapy and balloon dilatation of benign anastomotic strictures. Disease recurrence. PET/CT has a high sensitivity, specificity, and accuracy of 93%, 76%, and 87%, respectively, for the detection of recurrence at all sites in patients with treated esophageal carcinoma.17
Colorectal Carcinoma Diagnosis and staging. Currently, the main role of PET/CT is in detecting nodal and organ metastasis, and evaluating postoperative changes/residual tissue. T stage. Similar to esophageal cancer, PET scanners lack the resolution required to evaluate the depth of tumor penetration through the bowel wall. CT gives more precise
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Figure 1. (A) Axial and coronal ceCT, fused PET/CT, and PET images through the thorax of a 60-year-old woman with metastatic esophageal cancer. CT and fused PET/CT images show a FDG-avid thickened esophagus (straight white arrow), right pretracheal lymphadenopathy (curved white arrow), and left supraclavicular lymphadenopathy (curved black arrow). (B) Diffuse uptake in the mediastinum secondary to esophageal (straight white arrow), periesophageal (arrowheads), mediastinal adenopathy (arrowheads), and abdominal lymphadenopathy (curved white arrow). Supraclavicular lymphadenopathy also is seen (straight black arrow). There is normal physiologic FDG uptake in the brain, kidneys, and bladder.
structural information but cannot delineate the different bowel-wall layers. N stage. The limited spatial resolution of PET renders FDG uptake within pericolonic lymph nodes anatomically close to the primary tumor difficult to differentiate from uptake within the lesion itself. Furthermore, microscopic disease not detected by PET may be revealed only pathologically. M stage. Imaging to detect nodal or organ metastases is important in directing the general therapeutic approach (ie, palliation vs curative tumor resection). Despite the superiority of surgery and histopathology at T and local N stages, PET/CT has an advantage at M stage assessment (Figure 2). Contrast-enhanced multidetector CT is the established primary imaging modality for the detection, localization, and characterization of focal liver lesions,18 with equivocal liver lesions characterized further with contrast-enhanced magnetic resonance imaging in the preoperative setting. Chua et al19 recently compared PET/CT with standard ceCT for the evaluation of patients with hepatic metastases and found PET/CT had 94% sensitivity and 75% specificity compared with lower values of 91% and 25%, respectively, for ceCT. PET/CT imaging also may be particularly useful in patients with hypodense or hypo-enhancing liver lesions that are not characterized clearly by CT alone and in patients in whom standard CT fails to detect metastases in the setting of an increasing carcinoembryonic antigen level. In these cases, PET/CT has the ability to directly affect patient management by guiding biopsies or directing surgical resections of liver metastases. Although PET has high sensitivity for the detection of a number of abdominal cancerous lesions (colorectal, esophageal, sarcoma, melanoma, lymphoma), there are a number of neoplasms that are not hypermetabolic and thus are not FDG avid.
These cancers include certain colonic mucinous adenocarcinomas, carcinoid tumors, neuroendocrine tumors, prostate carcinomas, renal cell cancers, and certain low-grade lymphomas.20 Residual disease assessment and problem solving. The differentiation of the sequelae of prior therapy is particularly problematic with distal tumors, in which presacral scarring and pelvic changes are common. With conventional imaging, serial examinations frequently are required before slowly developing changes can be appreciated. With PET performed 6 months postsurgery, a time when postsurgical change is not hypermetabolic unless there is a leak with persistent inflammation, the presence of metabolic activity in the presacral space generally is indicative of tumor recurrence.6,21 Accurate clinical information regarding postoperative complications is essential to prevent an incorrect diagnosis in this setting. Recurrence detection. FDG-PET was found to be more accurate than CT and carcinoembryonic antigen for the detection of recurrent colorectal cancer.22 Wiering et al,23 in a meta-analysis assessing the diagnostic accuracy of FDG PET in comparison with CT in patients with recurrent colorectal carcinoma, reported pooled sensitivity and specificity of 88% and 96%, respectively, for FDG-PET in the detection of hepatic metastases compared with lower values of 83% and 84%, respectively, for CT. With regard to extrahepatic disease, pooled sensitivity and specificity for PET was 92% and 95%, respectively, in comparison with 61% and 91%, respectively, for CT. PET findings resulted in the alteration of clinical management in 32% of patients. PET/CT has a higher reported sensitivity, specificity, and overall accuracy than PET for the detection of intra-abdominal extrahepatic recurrence24 and for extra-abdominal and/or hepatic recurrence.25
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Figure 2. (A) Axial and coronal ceCT, fused PET/CT, and PET images through the liver and upper abdomen of a 48-year-old man with metastatic colorectal cancer. Images show multiple hypodense FDG-avid liver metastases distributed throughout the right lobe of the liver (straight white arrow, segment 5 lesions; curved white arrow, segment 7/8). (B) Axial and coronal ceCT, fused PET/CT, and PET images of the same 48-year-old patient. Further images through the spine show a minimally expanded sclerotic lesion in the left pedicle (straight white arrow) of T 10, which is FDG avid on the PET and fused PET/CT images (curved white arrows), which precludes surgical management for the liver masses. FDG-avid hepatic lesions also are seen in the upper right lobe of the liver (straight black arrow).
Gastric Cancer PET/CT has not been proven to be highly accurate in the local staging of disease,26,27 thus T staging of gastric carcinoma typically is assessed with endoscopic ultrasound. Currently, MDCT has become standard for N and M staging. However, it generally is expected that PET/CT may play a valuable role in the detection of distant metastases.28 FDG PET
also may be helpful in the follow-up evaluation of patients undergoing chemotherapy, allowing for the identification of early response to treatment.29
Small Intestine There are limited data to date on the use of PET/CT in the assessment of small intestinal malignancy, a reflection of its
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Figure 3. Axial and coronal ceCT, fused PET/CT, and PET images through the thorax of a 62-year-old woman with metastatic pancreatic cancer. Images show a distal FDG-avid pancreatic mass (curved white arrow) with a segment 5, low-attenuation, FDG-avid mass consistent with a liver metastasis.
rare occurrence. PET/CT successfully has imaged duodenal adenocarcinomas, small intestinal sarcomas, and readily identifies melanoma and breast metastases.
Gastrointestinal Stromal Tumor The role of PET in gastrointestinal stromal tumor (GIST) is not defined clearly because there appears to be variable FDG uptake by the primary lesion, most likely a reflection of the varied nature of the tumor, and studies have shown higher sensitivity of ceCT for lesion detection in comparison with PET. Surgical resection is the best chance of cure; Imatinib is the current treatment of choice for local and distant metastatic disease. There is current interest in the documented success of PET/CT for response assessment to Imatinib, and also for providing prognostic information.30 –33
Hepatobiliary Tumors Metastatic disease. PET has been shown to be superior to abdominal ultrasound and CT but not magnetic resonance imaging in the evaluation of both primary and secondary hepatic malignancies.34 Furthermore, PET detected extrahepatic findings in 64% of patients with significantly better sensitivity and specificity than the other modalities. More recently, PET/CT was found to be superior to ceCT for the detection of hepatic metastases from multiple primary malignancies.35 Hepatocellular carcinoma. FDG PET has low sensitivity (sensitivity of 55% vs 90% with CECT) for the detection of hepatocellular carcinoma.36 Well-differentiated and low-grade hepatocellular carcinoma tumors show lower FDG activity than higher-grade tumors and thus PET may help assess tumor grade.
Conversely, PET may be better than CT at detecting extrahepatic disease and a recent study highlighted the use of PET at detecting extrahepatic hepatocellular carcinoma recurrence.37
Gallbladder Carcinoma Previous studies found sensitivities in the region of 80% for PET for the preoperative detection of gallbladder carcinoma38,39 and postoperative evaluation for residual or recurrent gallbladder carcinoma.40 A recent study evaluated PET/CT in patients with gallbladder carcinoma and reported 100% sensitivity for primary lesion and distant metastases detection.41
Cholangiocarcinoma PET/CT and ceCT were found to have comparable accuracy for the detection of primary intrahepatic and extrahepatic cholangiocarcinomas.42 However, in relation to metastasis, PET/CT is superior with a sensitivity of 100% for distant metastasis whereas ceCT has a sensitivity of 25%. The addition of PET and PET/CT to the imaging algorithm for patients with cholangiocarcinoma or gallbladder carcinoma frequently results in alteration in patient management in 17% to 30% of cases.40,41
Pancreatic Cancer To date, there have been relatively few studies assessing the role and usefulness of PET, and more specifically PET/CT, in the diagnosis and staging of patients with pancreatic carcinoma. The sensitivity and specificity results of PET and PET/CT for the evaluation of pancreatic cancer are somewhat varied. Bang et al43 found FDG PET to have a diagnostic accuracy of 95% in the diagnosis and staging of patients with suspected pancreatic carcinoma as compared
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with 77% accuracy for CT. They also found PET to be superior to CT in the detection of hepatic metastases. Heinrich et al44 compared PET/CT imaging with conventional staging (abdominal CT, chest radiograph, and carbohydrate antigen 19-9 measurement) for the preoperative staging of patients with suspected pancreatic carcinoma. They found PET/CT had 89% sensitivity and 69% specificity for the detection of malignancy as compared with 93% and 21%, respectively, for ceCT. In a meta-analysis of all available data, PET and PET/CT had a sensitivity between 90% and 95% with a specificity between 82% and 100%45 for pancreatic cancer diagnosis and had a wider sensitivity between 61% and 100% with specificity between 67% and 100% for overall pancreatic staging. They concluded that PET and PET/CT are best at diagnosing and staging pancreatic cancer but are relatively inefficient in the detection of local nodal disease and that further evidence is required before PET/CT could be considered as a first-line imaging modality (Figure 3).43
Future Developments PET/CT has a growing role in patient response assessment to better tailor treatment regimens, identify responders and nonresponders, and offer prognostic information. Combined PET/CT colonography offers promising results, showing this modality to be at least equivalent to PET plus CT for the staging of colorectal cancer,46 as well as proving effective at detecting premalignant lesions.47 There is growing interest in PET imaging with new radiotracers to increase lesion conspicuity and specificity. Herrmann et al48 reported on a comparison of 3-deoxy-3 18F-fluorothymidine with FDG for the detection of gastric cancer and reported 100% sensitivity for 3-deoxy-3 18F-fluorothymidine and 69% sensitivity for FDG in their study population. 18F-fluorocholine and 11choline-acetate recently have shown higher sensitivity for the detection of primary and recurrent hepatocellular carcinoma. PET imaging of neuroendocrine tumors with novel radiotracers has been reported with positive reports from the use of 18F-FDG, 6-fluoro-L-dopa, and 68Ga-DOTA-D phe(1)-Tyr(3)octreotide.49,50 Nonneoplastic disease assessment. PET/CT has been used recently to assess disease activity in inflammatory bowel disease and other inflammatory conditions of the abdomen including retroperitoneal fibrosis.51–53
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Conclusions PET/CT confers undoubted benefits in the imaging of many gastrointestinal malignancies and already has become a premier oncologic imaging modality. Simultaneous combined PET/CT scanning allows superior image co-registration and better diagnostic accuracy compared with PET and CT alone. The development of new radiotracers may help to further improve and expand the applications of PET/CT in clinical practice. References 1. Bar-Shalom R, Guralnik L, Tsalic M, et al. The additional value of PET/CT over PET in FDG imaging of oesophageal cancer. Eur J Nucl Med Mol Imaging 2005;32:918 –924. 2. Lerut T, Flamen P, Ectors N, et al. Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esopha-
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Address requests for reprints to: Carmel Cronin, MRCPI, FFR(RCSI), Department of Abdominal and Interventional Radiology, White 270, 55 Fruit Street, Massachusetts General Hospital, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617) 7264891. The authors disclose no conflicts.
CLINICAL IMAGING Positron Emission Tomography/Computerized Tomography for the Gastroenterologist and Hepatologist CARMEL G. CRONIN, MICHAEL MOORE, and MICHAEL A. BLAKE Department of Abdominal and Interventional Radiology, Massachusetts General Hospital, Boston, Massachusetts
C
ombined positron emission tomography/computerized tomography (PET/CT) imaging with fluorine 18 fluorodeoxyglucose (FDG) allows fusion of structural and attenuation information provided by CT with functional imaging derived from PET, improving the radiologic assessment of normal anatomic structures and pathologic lesions. PET/CT allows accurate location of hypermetabolic foci identified at PET with its morphologic structure on CT, reducing the incidence of falsepositive and false-negative imaging findings with PET alone. CT, because of its lack of metabolic information, is unable to distinguish fibrotic tissue; a common finding after chemoradiotherapy and/or surgery from residual neoplastic disease and thus may fail in posttreatment assessment. The ability and role of PET/CT in distinguishing active from inactive disease has revolutionized the assessment of gastrointestinal and hepatobiliary malignancies.
Technical Considerations PET/CT is a hybrid device, combining the physical alignment of independent diagnostic PET and CT scanners. Functional and morphologic information are acquired in a single examination allowing accurate alignment. One of the many advantages of PET/CT over stand-alone PET is the use of CT-based attenuation correction for the PET component, resulting in much faster than traditional transmission methods and almost noise-free information, resulting in a total PET/CT scanning times of only 20 to 30 minutes.
Patient Preparation Patients must fast (no caloric intake) for a minimum of 4 hours before imaging. Because FDG is a glucose analogue, its uptake and distribution in tissues is affected by serum glucose and insulin levels such that low levels of both is desirable. As well as fasting, patients with diabetes should not receive regular insulin within the same 4-hour period before the study. The serum glucose level is measured and should be less than 200 mg/dL. If the serum glucose level is higher than 200 mg/dL, options available include gentle exercise (walking) and then a recheck, administration of subcutaneous insulin and rechecking the serum glucose in approximately 3 hours, or rescheduling the examination. Patients consume 1350 mL of low-attenuating oral contrast (VoLumen; E-Z-EM, Inc, Lake Success, NY) over 45 minutes after receiving the FDG intravenous injection. While waiting the 60 minutes between FDG administration and subsequent imaging, patients are encouraged to rest and activities including talking, chewing, and walking are restricted.
Positron Emission Tomography/Computerized Tomography Protocol PET/CT protocols vary between institutions. Traditionally, the standard PET/CT protocol in most institutions was to perform a low radiation dose, unenhanced CT primarily to provide attenuation correction followed by acquisition of PET data. There is ongoing debate as to what the most appropriate CT scanning parameters are as well as regarding the use of oral and intravenous contrast material and the optimal respiratory phase to scan.1–3 In our institution we first perform a lowradiation-dose (3– 4 mSv), unenhanced CT primarily to provide attenuation correction. Thereafter, the PET data are obtained, followed immediately by a fully diagnostic, standard radiation dose, intravenous, contrast-enhanced CT (ceCT) (15–20 mSv) with the previously administered water-attenuation oral contrast outlining the gastrointestinal tract. Undoubtedly, PET/CT has numerous advantages in improved patient management and outcome, however, this is at the cost of radiation exposure from PET/CT imaging, thus radiologists and clinicians alike should strictly adhere to the as low as reasonably achievable principle of using a radiation dose that is as low as possible and performing PET/CT only when clinically necessary.
Physiologic Nonneoplastic Fluorodeoxyglucose Uptake Physiologic FDG uptake in the gastrointestinal and hepatobiliary system is variable. Bowel FDG uptake typically is isolated rather than diffuse, but intense uptake can occur, particularly in the right colon and anal region. The liver typically shows mild FDG activity with a uniform mottled appearance at standard imaging 1 hour after injection of FDG.
False-Positive and False-Negative Results False-positive and false-negative PET/CT results have a negative impact on patient management. The following causes Abbreviations used in this paper: ceCT, contrast-enhanced computerized tomography; CT, computerized tomography; EUS, endoscopic ultrasound; FDG, fluorodeoxyglucose; PET, positron emission tomography. © 2009 by the AGA Institute 1542-3565/09/$36.00 doi:10.1016/j.cgh.2008.10.033
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of potential false-positive and false-negative results highlight the value of clinician understanding of the technique, as well as the importance of physician and radiologist communication to minimize the likelihood of erroneous PET/CT interpretation. First, FDG activity may be observed at the site of surgery in the postoperative period. This typically is owing to postsurgical inflammation or granulation tissue and can masquerade as tumor recurrence on PET/CT. Although normal posttreatment hypermetabolic activity has been seen for up to 6 months to a year, the current literature is deficient in relation to the exact time interval in which normal posttreatment hypermetabolic activity occurs and recommendations in regards to the appropriate time interval between surgery and PET/CT imaging to reduce false-positive results. With this in mind, follow-up response assessment examinations should be postponed for at least 6 weeks after such treatment to limit false-positive interpretation of persistent posttreatment FDG activity and in equivocal cases either biopsy or follow-up PET/CT may be required. Second, intense splenic uptake is seen in patients undergoing treatment with granulocyte-stimulating factor, a process that also may cause diffuse intense FDG uptake in the bone marrow.4 Third, PET/CT has limited spatial resolution and lesions less than 5 to 8 mm may not be identified on PET, leading to a false-negative micrometastasis result. Fourth, because PET scanners differ in how they acquire, reconstruct, and analyze images, serial scans obtained in the same patient on different scanners can yield inconsistent results.5 Fifth, any process associated with increased glycolysis including inflammation, infection, granulomatous disease, and brown fat can result in false-positive FDG results.
Neoplastic FDG Uptake Gastrointestinal Tract In the United States, the Centers for Medicare and Medicaid have approved Medicare coverage for FDG PET, and thus PET/CT, in the diagnosis, staging, and restaging of patients with colorectal and esophageal cancer. PET and PET/CT have been used in the evaluation of a wide variety of other malignancies associated with the gastrointestinal tract and abdominal organs. Although many of these are not currently covered by the Centers for Medicare and Medicaid in the United States, the advent of The National Oncologic PET Registry has enabled their use for such diseases and with time many of these malignancies may gain full coverage.6
Esophageal Diagnosis. The role of PET/CT in the primary diagnosis of esophageal cancer has not been well investigated; in studies of patients with known esophageal cancer, PET appears to be accurate for detection of the primary lesion. However, benign causes of FDG uptake, which may lead to false-positive results, include infectious esophagitis, Barrett’s esophagus without malignancy, inflammatory esophagitis caused by reflux disease, and postprocedural changes.7–9 Staging. Although most esophageal carcinomas appear FDG avid at PET/CT, the insufficient spatial and contrast resolution of PET/CT limits visualization of the anatomic ex-
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tent of the primary mass and precludes evaluation of the depth of local tumor invasion (T stage). Thus, endoscopic ultrasound (EUS) is currently the modality of choice for evaluating depth of local invasion through the esophageal wall. The N stage determines nodal metastases. Previously, FDG PET alone was shown to have a low sensitivity and specificity of 51% and 84%, respectively, for the detection of locoregional lymph node metastases.10 A more recent study showed that FDG PET alone has a similar sensitivity but lower specificity and accuracy for the detection of locoregional lymph node metastases than the combination of PET/CT imaging (sensitivity, 96% vs 96%; specificity, 59% vs 81%; and accuracy, 90% vs 83%, respectively),1 owing to difficulties in differentiating uptake in periesophageal lymph nodes from that of the lesion itself. PET/CT has a higher specificity than either CT or endoscopic US for lymph node metastases, and the presence of discrete focal metabolic activity in periesophageal or regional lymph nodes is highly indicative of nodal metastasis. The M stage denotes lymphadenopathy that is just beyond locoregional lymph nodes as M1a disease and distant organ metastases as M1b. This distinction is important because regional lymphadenopathy adjacent to the esophagus or stomach does not preclude curative surgery, whereas distant metastases are contraindications to radical surgery. PET detects M1a nodal disease significantly better than locoregional nodal disease. In a comparison study, PET was found to be 86% accurate in the evaluation of M1a nodal metastases with a specificity of 90%, whereas the accuracy and specificity for combined CT and EUS assessment were 62% and 69%, respectively.2 PET has been shown to accurately show sites of distant metastatic disease, with the sensitivity and specificity of PET for M1b disease higher than those for CT and EUS (Figure 1).2,3,11–14 Thus, in clinical practice, disease staging should be determined using a multimodality approach including information from EUS, PET, and CT. Restaging and response assessment. PET/CT appears to have an important role in response assessment. In a prospective trial evaluating CT, EUS, and PET/CT in the assessment of disease response to neoadjuvant chemoradiation, complete response was predicted accurately by EUS in 67% and better by PET/CT in 89%.15 Similar findings were found by Weber et al,16 who indicated that PET could differentiate responding from nonresponding tumors early in the course of therapy and thus potentially avoid ineffectual and harmful treatment. However, care is required because specificity in posttreatment response is limited by increased FDG uptake secondary to radiation therapy and balloon dilatation of benign anastomotic strictures. Disease recurrence. PET/CT has a high sensitivity, specificity, and accuracy of 93%, 76%, and 87%, respectively, for the detection of recurrence at all sites in patients with treated esophageal carcinoma.17
Colorectal Carcinoma Diagnosis and staging. Currently, the main role of PET/CT is in detecting nodal and organ metastasis, and evaluating postoperative changes/residual tissue. T stage. Similar to esophageal cancer, PET scanners lack the resolution required to evaluate the depth of tumor penetration through the bowel wall. CT gives more precise
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Figure 1. (A) Axial and coronal ceCT, fused PET/CT, and PET images through the thorax of a 60-year-old woman with metastatic esophageal cancer. CT and fused PET/CT images show a FDG-avid thickened esophagus (straight white arrow), right pretracheal lymphadenopathy (curved white arrow), and left supraclavicular lymphadenopathy (curved black arrow). (B) Diffuse uptake in the mediastinum secondary to esophageal (straight white arrow), periesophageal (arrowheads), mediastinal adenopathy (arrowheads), and abdominal lymphadenopathy (curved white arrow). Supraclavicular lymphadenopathy also is seen (straight black arrow). There is normal physiologic FDG uptake in the brain, kidneys, and bladder.
structural information but cannot delineate the different bowel-wall layers. N stage. The limited spatial resolution of PET renders FDG uptake within pericolonic lymph nodes anatomically close to the primary tumor difficult to differentiate from uptake within the lesion itself. Furthermore, microscopic disease not detected by PET may be revealed only pathologically. M stage. Imaging to detect nodal or organ metastases is important in directing the general therapeutic approach (ie, palliation vs curative tumor resection). Despite the superiority of surgery and histopathology at T and local N stages, PET/CT has an advantage at M stage assessment (Figure 2). Contrast-enhanced multidetector CT is the established primary imaging modality for the detection, localization, and characterization of focal liver lesions,18 with equivocal liver lesions characterized further with contrast-enhanced magnetic resonance imaging in the preoperative setting. Chua et al19 recently compared PET/CT with standard ceCT for the evaluation of patients with hepatic metastases and found PET/CT had 94% sensitivity and 75% specificity compared with lower values of 91% and 25%, respectively, for ceCT. PET/CT imaging also may be particularly useful in patients with hypodense or hypo-enhancing liver lesions that are not characterized clearly by CT alone and in patients in whom standard CT fails to detect metastases in the setting of an increasing carcinoembryonic antigen level. In these cases, PET/CT has the ability to directly affect patient management by guiding biopsies or directing surgical resections of liver metastases. Although PET has high sensitivity for the detection of a number of abdominal cancerous lesions (colorectal, esophageal, sarcoma, melanoma, lymphoma), there are a number of neoplasms that are not hypermetabolic and thus are not FDG avid.
These cancers include certain colonic mucinous adenocarcinomas, carcinoid tumors, neuroendocrine tumors, prostate carcinomas, renal cell cancers, and certain low-grade lymphomas.20 Residual disease assessment and problem solving. The differentiation of the sequelae of prior therapy is particularly problematic with distal tumors, in which presacral scarring and pelvic changes are common. With conventional imaging, serial examinations frequently are required before slowly developing changes can be appreciated. With PET performed 6 months postsurgery, a time when postsurgical change is not hypermetabolic unless there is a leak with persistent inflammation, the presence of metabolic activity in the presacral space generally is indicative of tumor recurrence.6,21 Accurate clinical information regarding postoperative complications is essential to prevent an incorrect diagnosis in this setting. Recurrence detection. FDG-PET was found to be more accurate than CT and carcinoembryonic antigen for the detection of recurrent colorectal cancer.22 Wiering et al,23 in a meta-analysis assessing the diagnostic accuracy of FDG PET in comparison with CT in patients with recurrent colorectal carcinoma, reported pooled sensitivity and specificity of 88% and 96%, respectively, for FDG-PET in the detection of hepatic metastases compared with lower values of 83% and 84%, respectively, for CT. With regard to extrahepatic disease, pooled sensitivity and specificity for PET was 92% and 95%, respectively, in comparison with 61% and 91%, respectively, for CT. PET findings resulted in the alteration of clinical management in 32% of patients. PET/CT has a higher reported sensitivity, specificity, and overall accuracy than PET for the detection of intra-abdominal extrahepatic recurrence24 and for extra-abdominal and/or hepatic recurrence.25
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Figure 2. (A) Axial and coronal ceCT, fused PET/CT, and PET images through the liver and upper abdomen of a 48-year-old man with metastatic colorectal cancer. Images show multiple hypodense FDG-avid liver metastases distributed throughout the right lobe of the liver (straight white arrow, segment 5 lesions; curved white arrow, segment 7/8). (B) Axial and coronal ceCT, fused PET/CT, and PET images of the same 48-year-old patient. Further images through the spine show a minimally expanded sclerotic lesion in the left pedicle (straight white arrow) of T 10, which is FDG avid on the PET and fused PET/CT images (curved white arrows), which precludes surgical management for the liver masses. FDG-avid hepatic lesions also are seen in the upper right lobe of the liver (straight black arrow).
Gastric Cancer PET/CT has not been proven to be highly accurate in the local staging of disease,26,27 thus T staging of gastric carcinoma typically is assessed with endoscopic ultrasound. Currently, MDCT has become standard for N and M staging. However, it generally is expected that PET/CT may play a valuable role in the detection of distant metastases.28 FDG PET
also may be helpful in the follow-up evaluation of patients undergoing chemotherapy, allowing for the identification of early response to treatment.29
Small Intestine There are limited data to date on the use of PET/CT in the assessment of small intestinal malignancy, a reflection of its
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Figure 3. Axial and coronal ceCT, fused PET/CT, and PET images through the thorax of a 62-year-old woman with metastatic pancreatic cancer. Images show a distal FDG-avid pancreatic mass (curved white arrow) with a segment 5, low-attenuation, FDG-avid mass consistent with a liver metastasis.
rare occurrence. PET/CT successfully has imaged duodenal adenocarcinomas, small intestinal sarcomas, and readily identifies melanoma and breast metastases.
Gastrointestinal Stromal Tumor The role of PET in gastrointestinal stromal tumor (GIST) is not defined clearly because there appears to be variable FDG uptake by the primary lesion, most likely a reflection of the varied nature of the tumor, and studies have shown higher sensitivity of ceCT for lesion detection in comparison with PET. Surgical resection is the best chance of cure; Imatinib is the current treatment of choice for local and distant metastatic disease. There is current interest in the documented success of PET/CT for response assessment to Imatinib, and also for providing prognostic information.30 –33
Hepatobiliary Tumors Metastatic disease. PET has been shown to be superior to abdominal ultrasound and CT but not magnetic resonance imaging in the evaluation of both primary and secondary hepatic malignancies.34 Furthermore, PET detected extrahepatic findings in 64% of patients with significantly better sensitivity and specificity than the other modalities. More recently, PET/CT was found to be superior to ceCT for the detection of hepatic metastases from multiple primary malignancies.35 Hepatocellular carcinoma. FDG PET has low sensitivity (sensitivity of 55% vs 90% with CECT) for the detection of hepatocellular carcinoma.36 Well-differentiated and low-grade hepatocellular carcinoma tumors show lower FDG activity than higher-grade tumors and thus PET may help assess tumor grade.
Conversely, PET may be better than CT at detecting extrahepatic disease and a recent study highlighted the use of PET at detecting extrahepatic hepatocellular carcinoma recurrence.37
Gallbladder Carcinoma Previous studies found sensitivities in the region of 80% for PET for the preoperative detection of gallbladder carcinoma38,39 and postoperative evaluation for residual or recurrent gallbladder carcinoma.40 A recent study evaluated PET/CT in patients with gallbladder carcinoma and reported 100% sensitivity for primary lesion and distant metastases detection.41
Cholangiocarcinoma PET/CT and ceCT were found to have comparable accuracy for the detection of primary intrahepatic and extrahepatic cholangiocarcinomas.42 However, in relation to metastasis, PET/CT is superior with a sensitivity of 100% for distant metastasis whereas ceCT has a sensitivity of 25%. The addition of PET and PET/CT to the imaging algorithm for patients with cholangiocarcinoma or gallbladder carcinoma frequently results in alteration in patient management in 17% to 30% of cases.40,41
Pancreatic Cancer To date, there have been relatively few studies assessing the role and usefulness of PET, and more specifically PET/CT, in the diagnosis and staging of patients with pancreatic carcinoma. The sensitivity and specificity results of PET and PET/CT for the evaluation of pancreatic cancer are somewhat varied. Bang et al43 found FDG PET to have a diagnostic accuracy of 95% in the diagnosis and staging of patients with suspected pancreatic carcinoma as compared
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with 77% accuracy for CT. They also found PET to be superior to CT in the detection of hepatic metastases. Heinrich et al44 compared PET/CT imaging with conventional staging (abdominal CT, chest radiograph, and carbohydrate antigen 19-9 measurement) for the preoperative staging of patients with suspected pancreatic carcinoma. They found PET/CT had 89% sensitivity and 69% specificity for the detection of malignancy as compared with 93% and 21%, respectively, for ceCT. In a meta-analysis of all available data, PET and PET/CT had a sensitivity between 90% and 95% with a specificity between 82% and 100%45 for pancreatic cancer diagnosis and had a wider sensitivity between 61% and 100% with specificity between 67% and 100% for overall pancreatic staging. They concluded that PET and PET/CT are best at diagnosing and staging pancreatic cancer but are relatively inefficient in the detection of local nodal disease and that further evidence is required before PET/CT could be considered as a first-line imaging modality (Figure 3).43
Future Developments PET/CT has a growing role in patient response assessment to better tailor treatment regimens, identify responders and nonresponders, and offer prognostic information. Combined PET/CT colonography offers promising results, showing this modality to be at least equivalent to PET plus CT for the staging of colorectal cancer,46 as well as proving effective at detecting premalignant lesions.47 There is growing interest in PET imaging with new radiotracers to increase lesion conspicuity and specificity. Herrmann et al48 reported on a comparison of 3-deoxy-3 18F-fluorothymidine with FDG for the detection of gastric cancer and reported 100% sensitivity for 3-deoxy-3 18F-fluorothymidine and 69% sensitivity for FDG in their study population. 18F-fluorocholine and 11choline-acetate recently have shown higher sensitivity for the detection of primary and recurrent hepatocellular carcinoma. PET imaging of neuroendocrine tumors with novel radiotracers has been reported with positive reports from the use of 18F-FDG, 6-fluoro-L-dopa, and 68Ga-DOTA-D phe(1)-Tyr(3)octreotide.49,50 Nonneoplastic disease assessment. PET/CT has been used recently to assess disease activity in inflammatory bowel disease and other inflammatory conditions of the abdomen including retroperitoneal fibrosis.51–53
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Conclusions PET/CT confers undoubted benefits in the imaging of many gastrointestinal malignancies and already has become a premier oncologic imaging modality. Simultaneous combined PET/CT scanning allows superior image co-registration and better diagnostic accuracy compared with PET and CT alone. The development of new radiotracers may help to further improve and expand the applications of PET/CT in clinical practice. References 1. Bar-Shalom R, Guralnik L, Tsalic M, et al. The additional value of PET/CT over PET in FDG imaging of oesophageal cancer. Eur J Nucl Med Mol Imaging 2005;32:918 –924. 2. Lerut T, Flamen P, Ectors N, et al. Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esopha-
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Address requests for reprints to: Carmel Cronin, MRCPI, FFR(RCSI), Department of Abdominal and Interventional Radiology, White 270, 55 Fruit Street, Massachusetts General Hospital, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617) 7264891. The authors disclose no conflicts.