CT): Improving Therapeutic Decisions

Hybrid Imaging (SPECT/CT and PET/CT): Improving Therapeutic Decisions Dominique Delbeke, MD, PhD,* Heiko Schöder, MD,† William H. Martin, MD,* and Richard L. Wahl, MD‡ The incremental diagnostic value of integrated positron emission tomography– computed tomography (PET/CT) or single-photon emission computed tomography (SPECT)/CT images compared with PET or SPECT alone, or PET or SPECT correlated with a CT obtained at a different time includes the following: (1) improvement in lesion detection on both CT and PET or SPECT images, (2) improvement in the localization of foci of uptake resulting in better differentiation of physiological from pathologic uptake, (3) precise localization of the malignant foci, for example, in the skeleton vs soft tissue or liver vs adjacent bowel or node (4) characterization of serendipitous lesions, and (5) confirmation of small, subtle, or unusual lesions. The use of these techniques can occur at the time of initial diagnosis, in assessing the early response of disease to treatment, at the conclusion of treatment, and in continuing follow-up of patients. PET/CT and SPECT/CT fusion images affect the clinical management in a significant proportion of patients with a wide range of diseases by (1) guiding further procedures, (2) excluding the need of further procedures, (3) changing both inter- and intramodality therapy, including soon after treatment has been initiated, and (4) by providing prognostic information. PET/CT fusion images have the potential to provide important information to guide the biopsy of a mass to active regions of the tumor and to provide better maps than CT alone to modulate field and dose of radiation therapy. It is expected that the role of PET/CT and SPECT/CT in changing management will continue to evolve in the future and that these tools will be fundamental components of the truly “personalized medicine” we are striving to deliver. Semin Nucl Med 39:308-340 © 2009 Elsevier Inc. All rights reserved.

M

orphologic imaging, most typically with computed tomography (CT), has been the conventional imaging modality for detection and localization of abnormalities and neoplasms. In oncology, limitations of anatomic imaging with CT are well known and related to size criteria to differentiate benign from malignant lymph nodes and other masses, difficulty differentiating post-therapy changes from tumor recurrence, difficulty differentiating nonopacified loops of bowel from metastases in the abdomen and pelvis, and poor sensitivity for detecting disease in the bone marrow.

*Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN. †Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. ‡Division of Nuclear Medicine, Department of Radiology and Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD. Address reprint requests to: Dominique Delbeke, MD, PhD, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, 21st Avenue South and Garland, Nashville, TN 37232-2675. E-mail: [email protected]

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0001-2998/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2009.03.002

Functional and metabolic imaging using radiopharmaceuticals labeled with single photon and positron emitters may detect disease earlier in its course because metabolic changes antedate morphologic changes. However, functional and metabolic imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have limitations, including the limited spatial resolution of the images, difficulty precisely localizing lesions because of the lack of anatomical landmarks and physiological variations in biodistribution, leading to foci of uptake unrelated to the underlying disease. Numerous studies have shown that the sensitivity and specificity of 18F-fluorodeoxyglucose (FDG) PET imaging are superior to those of CT in many clinical settings, as published in a 2001 summary of literature regarding the performance of FDG-PET in a wide variety of malignancies.1 However, the inability of FDG imaging to provide anatomic localization remains a significant limitation in maximizing its clinical utility. In addition, because FDG uptake is not limited to malignant tissue, the interpreter must be familiar with the normal

Hybrid imaging to improve therapeutic decisions pattern and physiological variations in FDG distribution and with pertinent clinical data to avoid misinterpretations. Close correlation of FDG studies with a near contemporaneous conventional CT scans helps minimize these difficulties. Interpretation was conventionally accomplished by visually comparing corresponding FDG and CT images. The interpreting physician visually integrated the 2 image sets to approximate the location of a focus of increased uptake. Viewing PET images coregistered with CT images has proved superior to visual analysis of separate datasets and interpretation of fused images has supplanted PET-only acquisitions. Efforts at software fusion of separately acquired PET with CT or MRI to produce “anatomometabolic” images have been shown feasible in the whole body but have been supplanted by integrated PET/CT systems and SPECT/CT systems.2 Fusion of SPECT and CT by software can also be useful in dosimetric calculations.3

Integrated PET/CT and SPECT/CT Imaging The fusion of anatomic and molecular images obtained with integrated PET/CT or SPECT/CT systems, sequentially in time but without moving the patient from the imaging table, allows optimal coregistration of anatomic and molecular images, leading to accurate attenuation correction and precise anatomic localization of lesions with increased uptake. The fusion images provided by these systems allow the most accurate interpretation of both PET/CT and SPECT/CT studies in oncology. FDG-PET/CT imaging is also a promising tool for optimizing radiation therapy planning and for infection/ inflammation imaging. SPECT/CT and PET/CT have major and growing roles in assessing nonmalignant central nervous system disease as well, but these are beyond the scope of the current review. Cardiac applications of this technology are reviewed in a separate chapter in this edition of the Seminars. As addressed in another article in this issue, integrated SPECT/CT and PET/CT systems can include different PET and CT systems with different performance. For example, the first SPECT/CT system developed (VG Millenium/Hawkeye, GE Healthcare, Waukesha, WI) has a very low-mA (2.5 mA) CT system mounted on the gantry of the dual-head gamma camera providing low-resolution CT images that can be used for attenuation correction and anatomic localization, but the quality of the CT images are far from a state-of-the-art diagnostic CT study. However, hybrid imaging systems equipped with a low-dose CT may be used as a bridge to diagnostic high-resolution, contrast-enhanced CT or MRI of a specific area of interest. State-of-the-art PET/CT and SPECT/CT systems are now available with multidetector CT (MDCT) up to 64 or more slices. As summarized in this article and in Table 1,4-39 PET/CT and SPECT/CT fusion images have an incremental diagnostic value and affect clinical management, including guiding biopsy and radiation therapy planning.40 Technical issues regarding optimal protocols as well as technical and clinical expertise regarding performance and

309 interpretation of PET/CT and SPECT/CT imaging have been discussed.41,42 Procedure guidelines for tumor imaging using FDG-PET/CT and for SPECT/CT imaging have also been published and list numerous sources of false-positive and false-negative findings.43,44 This new powerful technology provides more accurate interpretation of both CT and PET or SPECT images and, therefore, a more nearly optimal patient care.

Role of PET/CT in Radiotherapy Treatment Planning: General Considerations FDG-PET and PET/CT have been used for delineation of the metabolically active tumor volume for radiation therapy planning. Three-dimensional radiotherapy and intensitymodulated radiation therapy are the principal modalities because they allow accurate delivery of high doses of radiation leading to improved local control and reduced morbidity. The advantages of PET- and PET/CT-based radiation treatment planning are the following: (1) more accurate staging to better identify patients that will benefit from radical radiation therapy; (2) more accurate delivery of radiation to the appropriate target volume leading to less damage to normal tissue; and (3) accurate target volume delineation allowing delivery of higher doses to malignant tissue, which should lead to improved tumor control rates. In addition, PET or PET/CT leads to a significant reduction in interobserver variability during target volume delineation. However, the question remains as to whether the above improvements translate into improvements in patient outcome after radiation therapy. Most studies have reported changes in gross tumor volume (GTV), which is defined as (according to ICRU Report 50) all known areas of gross disease as determined by physical examination, imaging, and endoscopy. The clinical target volume (CTV) is the GTV plus areas suspected to contain potential microscopic disease. Typically, this will be the GTV plus a 1-2 cm expansion in 3 dimensions, depending on the targets proximity to critical structures. The planning target volume (PTV) is the CTV plus a margin to account for variability in patient immobilization/localization, internal organ motion, and other potential daily set-up variations, typically a 5-mm three-dimensional expansion of the CTV. Although microscopic nodal disease will be underestimated by FDGPET, it may be covered by the safety margins of the PTV. Despite the advantage of PET and complementarity to CT for radiotherapy treatment planning, PET imaging suffers from a number of well-known technical limitations, mainly spatial resolution, misregistration caused by target motion and tumor edge definition. Integrated PET/CT imaging provides the most optimal coregistration and image fusion compared with visual or software fusion. PET/CT images should be obtained in the treatment position with the appropriate immobilization devices. Because radiation treatments are typically given on a flat table, a flat PET table should be used for optimal planning purposes as opposed to the commonly used curved table.

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Table 1 Hybrid Imaging: Impact on Management

Disease Process

Author al4

Year

No. Patients

Modality

204 173 22,975

FDG-PET/CT FDG-PET/CT FDG-PET (16%) and PET/CT (84%) Sentinel LN SPECT/CT Sentinel LN SPECT/CT FDG-PET/CT FDG-PET/CT FDG-PET/CT FDG-PET/CT

Bar-Shalom et Roman et al5 Hillner et al6 (NOPR)

2003 2005 2008

Head and neck cancer Head and neck cancer Head and neck cancer Head and neck cancer Nasopharyngeal cancer Nasopharyngeal cancer

Even-Sapir et al7 Khafif et al8 Schoder et al9 Fleming et al10 Gordin et al11 Gordin et al12

2003 2006 2004 2007 2007 2007

6 20 68 123 untreated 107 45

Breast Breast Breast Breast Breast

Lerman et al13 Vander Ploeg et al14 Lerman et al15 Radan et al16 Heron et al17

2006 2007 2007 2006 2006

157 31 49 overweight 47

2005 2008

41 48

FDG-PET/CT FDG-PET/CT

Colorectal cancer

Bar-Shalom et al18 Wong and Chambers19 Soyka et al20

2008

54

Anorectal cancer

Anderson et al21

2007

23

FDG-PET/CT FDG-PET/contrasted CT FDG-PET/CT

Cholangiocarcinoma

Kim et al22

2008

123

Endometrial cancer Endometrial cancer Ovarian cancer

Park et al23 Chung et al24 Simcock et al25

2008 2008 2006

Ovarian cancer

Mangili et al26

2007

Ovarian cancer Ovarian cancer Ovarian cancer

Chung et al27 Soussan et al28 Kitajama et al29

2007 2008 2008

Thyroid cancer Thyroid cancer Parathyroid adenoma

Tharp et al30 Ruf et al31 Serra et al32

2004 2004 2006

71 25 16

Parathyroid adenoma

Krausz et al33

2006

36

cancer cancer cancer Cancer cancer

Esophageal cancer Esophageal cancer

88 31 55 for surveillance or suspicion of relapse 32 with suspicion of relapse 77 29 132

Sentinel LN SPECT/CT Sentinel LN SPECT/CT Sentinel LN SPECT/CT FDG-PET/CT FDG-PET/CT

FDGF PET/CT primary Lymph nodes Distant metastases FDG-PET or PET/CT FDG-PET/CT FDG-PET/CT

Specificity

Accuracy

PPV

NPV

PET alone PET alone Referring Physician Questionnaire Planar Planar PET alone

87%

89% 92%

90%

84%

95% 90%

90%

71%

83%

81%

90%

79%

93% 76% 88%

87% 94% 90%

60%

90% 91%

83%

FDG-PET/CT FDG-PET/CT FDG-PET/CT FDG-PET/contrastenhanced CT Radioiodine SPECT/CT Radioiodine SPECT/CT 99mTc-sestamibi SPECT/CT 99mTc-sestamibi SPECT/CT

93% 79%

Comparison

97% 91%

94% 85%

98%

PET alone Conventional imaging Planar Planar Planar Contrasted CT Radiation therapy planning PET alone PET and CT side by side Contrasted CT FDG-PET/CT Radiation management CT and MRI/MRCP CT CT

14% 12.5% 36.5% 33% 30% 18% 31% 56% 58% 13% 5% 59% 51% 50% 10% 17% 10% 42%

25%

Prospective

16% 22% 23% 58%

CT

44%

Questionnaire CT

25% 33% 39%

Planar Planar Planar

41% 25% 19%

91%

39%

D. Delbeke et al

Mixed tumors Mixed tumors Mixed tumors

Sensitivity

Modification of Management

14%

28%

24%

25% 14% 36%

SPECT and CT

SPECT and CT

SPECT

CT Conventional Planar and SPECT

Hybrid imaging to improve therapeutic decisions

311 PET acquisitions take several minutes with the patient free breathing resulting in tumor motion, especially if the tumor is located near the diaphragm. Cardiac motion particularly affects lesions in the lingula. Various methods are being investigated to correct for respiratory motion, such as respiratory gating or deep-inspiration breath-hold during the acquisition of the images. Tumor edge definition has been the subject of debate in the literature. Different approaches have been explored for target volume definition, such as visual inspection, thresholding using standard uptake values (SUV) or target-to-background ratio, and automated mathematical algorithms. Automatic contouring can be used as a first approximation but cannot replace clinical expertise to differentiate malignant from benign sources of uptake.45

106 117 28 2006 2007 2006 Raanani et al37 Tateishi et al38 Filipi and Schillaci39 Lymphoma Sarcoma Infection

2006 Hillel et al36 Neuroendocrine tumors

29

2003 Pfannenberg et al35 Neuroendocrine tumors

54

SPECT/CT 111In-pentetreotide or 123I-MIBG SPECT/CT 111In-pentetreotide SPECT/CT FDG-PET/CT FDG-PET/CT 99mTc-HMPAO-WBC SPECT/CT

2003 Krausz et al34 Neuroendocrine tumors

72

111In-pentetreotide

PET/CT and SPECT/CT Radiopharmaceuticals The incremental value of PET/CT and SPECT/CT has been demonstrated for many radiopharmaceuticals. For PET, the most commonly used radiopharmaceutical is FDG but other PET radiopharmaceuticals have been investigated with PET/ CT, such as 18F-fluoride, radiolabeled choline tracers (18Ffluorocholine and 11C-choline), 11C-acetate, 11C-methionine, 124I, 18F-FDOPA, and 18F-fluoro-deoxy-thymidine. For PET and SPECT, somatostatin receptor (SSR)-binding peptides with chelator molecules capable of binding 111In, 68Ga, 90Y, and 177Lu are in use. SPECT/CT can additionally be performed with any of the standard single photon emitters, including 99mTc-sestamibi, 99mTc-diphosphonates, 99mTc-red blood cells (RBC), 99mTc-sulfur colloid, 99mTc renal agents, as well as 123I-iodine. The superiority of SPECT/CT over planar imaging or SPECT alone has been demonstrated in bone scintigraphy, SSR scintigraphy, adrenal gland scintigraphy, parathyroid scintigraphy, thyroid scintigraphy, and rates of detection of sentinel lymph nodes, among others. For most PET and SPECT radiopharmaceuticals, there are physiological variation in biodistribution and overlap of uptake between malignant and benign processes. An additional challenge can be the very high target to background ratios achieved with some of these tracers, making the anatomic data provided by hybrid PET/CT or SPECT/CT to allow for better characterization of foci of uptake by precise localization of these foci and better characterization of lesions seen on CT with the metabolic/molecular component.

Effect on Management of PET/ CT and SPECT/CT in Oncology Many publications have reported a change in patient management related to PET findings compared with conventional work-up (usually CT). A tabulated summary of the FDG-PET literature was published in 2001, including a wide range of change in management for various types of cancer.1 After 2001, integrated PET/CT instruments became available and

312 have progressively replaced stand-alone PET. The diagnostic performance and change of management related to PET/CT in various malignancies have been reported usually compared with contrast-enhanced CT. Few studies have investigated the incremental diagnostic performance and incremental change in management related to PET/CT compared with CT alone, PET alone, and PET and CT interpreted side by side. The same applies for SPECT/CT. In addition, the CT portion of the integrated studies can be performed with various acquisition protocols and with or without oral and intravenous contrast. Therefore, comparison between and among studies is difficult.

Mixed Patient Population In 2003, a study of 204 patients from Rambam Medical Center4 concluded that FDG-PET/CT improved the diagnostic accuracy in approximately 50% of patients as compared with PET stand-alone. Fusion images improved characterization of equivocal lesions as either definitely benign in 10% or definitely malignant in 5% of sites. It precisely defined the anatomic location of malignant FDG uptake in 6% and led to retrospective lesion detection on PET or CT in 8%. The results of PET/CT images affected management in 14% of patients by obviating the need for further evaluation in 5 patients, guiding further diagnostic procedures in 7 patients and assisting in treatment planning for 16 patients. Similar conclusions were found in a study of 173 patients performed at Vanderbilt University,5 with an incremental diagnostic value of FDG-PET/CT imaging in 27% of patients and an incremental impact on management in 12.5% of patients. The impact on management included retrospective detection of lesions on either CT or PET, guiding biopsies, detection of local recurrence of colon cancer, guiding surgery, detection of recurrent or metastatic disease leading to chemotherapy and/or radiation therapy, and exclusion of metastatic disease leading to avoidance of additional therapy. Recently, initial results from the National Oncologic PET Registry (NOPR) became available and concluded that overall, physicians changed their intended management in 36.5% of cases after PET or PET/CT.6 The cohort included data from 22,975 FDG-PET studies from 1178 PET centers of which 84% were PET/CT acquisitions. Patients diagnosed with a wide variety of cancer types were included and the numbers of referrals for diagnosis, initial staging, restaging, and suspected recurrence were approximately equal. Data were collected from questionnaires completed by referring physicians on intended management before and after PET. In patients with planned biopsy before PET, biopsy was avoided in 70%. If the pre-PET strategy was treatment, the post-PET strategy involved a major change in the type of treatment in 8.7% and goal of therapy in 5.6%.

Brain Tumors Brain tumors have been imaged with various SPECT radiopharmaceuticals, including 201Tl chloride, 99mTc-sestamibi, 99mTc-tetrofosmin and 111In-DTPA-octreotide46 in addition to FDG-PET and other PET radiopharmaceuti-

D. Delbeke et al cals. Although clearly inferior to both contrast-enhanced CT and MRI, these SPECT and PET radiopharmaceuticals can demonstrate primary or metastatic lesions of the brain. Correlation with MRI or CT is critical for interpretation of the metabolic images, especially when there is physiological distribution in the cerebral cortex, such as with FDG. The low-dose CT often performed with PET/CT and SPECT/CT commonly demonstrates a hypodense or hyperdense lesion or allows correlation with the appropriate slice of an optimized MRI or CT with intravenous contrast. The major limitation of CT and MRI is for detection of recurrent tumor after radiation therapy because the findings of radiation necrosis and tumor recurrence are similar. Metabolic imaging with SPECT or PET is critical to identify recurrent tumor. SPECT/CT and PET/CT fusion imaging can help in evaluating lesions near sites of physiological uptake and in exactly localizing the presence of viable tumor tissue after surgery and/or radiotherapy, within areas of altered anatomy. SPECT/CT and PET/CT can be useful in the evaluation of cerebral tumors by providing guidance for stereotactic biopsy. Some cerebral gliomas may be well differentiated in some regions and yet contain less differentiated cells in others. Using FDG-PET/CT to target the site of maximum activity increases the accuracy of the procedure by decreasing the biopsy sampling error. FDG-PET/CT guidance for biopsy is particularly helpful when access to the lesion is difficult. The use of PET/CT to guide stereotactic cerebral biopsy has increased the diagnostic yield and accuracy using both FDG and 11C-methionine PET.47 One of the advantages of imaging with 11C-methionine is the relative absence of background uptake in the normal cerebral cortex. Therefore, both lowgrade and high-grade gliomas are better delineated on 11Cmethionine than on FDG studies. However, 11C-methionine accumulates in all types of glioma, and therefore does not permit differentiation between low- and high-grade gliomas. Despite this limitation, a correlation between areas of highest 11C-methionine uptake and those with highest FDG uptake has been found in some studies.48 Where available, 11C-methionine, as well as fluorinated amino acids, in combination with MRI, have gained a place in defining neurosurgical strategies that aim at delineating the entire tumor volume for resection under neuronavigation or for radiosurgery.49 In the future, the implementation of integrated PET/MRI instruments may further enhance the contribution of PET to the assessment of cerebral pathology.50 The integration of functional images (SPECT and PET) with CT and MRI in radiotherapy treatment planning allows a more accurate definition of the target volume and thus better sparing of normal tissues, with an improved therapeutic ratio. The anatomometabolic target localization could facilitate precise radiation therapy planning for brain tumors by better delineating the boundary between the tumor, edema, and the normal brain parenchyma and identify more accurately the viable tumor tissue, also permitting dose escalation to the region of interest.

Hybrid imaging to improve therapeutic decisions

Head and Neck Cancer Role of SPECT/CT for SLN Localization and Biopsy Sentinel lymph node localization and biopsy have been advocated for patients with head and neck cancer. Because of the anatomic complexity of the neck, SPECT/CT has been reported useful for precise localization of the sentinel node compared with planar images. In an early report of the incremental value of SPECT/CT for SLN localization, multiple drainage basins were clearly identified in 33% patients with head and neck malignancy.7 In another report, SPECT/CT improved sentinel node identification and/or localization compared with planar images in 30% of patients with oral cavity squamous cell carcinoma (SCC).8 A limitation of all of these studies is the lack of comparison of the imaging findings to the intraoperative findings using a handheld detector probe.

FDG-PET/CT FDG-PET plays an increasing role in the assessment of head and neck cancer, both for initial staging and for restaging patients after treatment, and has been proved to be superior to both CT and MRI in the assessment of cancer of the head and neck.51,52 Precise localization of suspicious foci of FDG uptake is difficult because of the complex anatomy of the neck and physiological variation in FDG biodistribution in lymphoid, muscular, glandular, and brown adipose tissue.53 Paralysis of one of the vocal cords can cause increased uptake in the contralateral cord due to compensatory use. Asymmetric physiological FDG uptake because of strain or excessive use is frequently seen in the mastication muscles, sternocleidomastoid muscle, scalene muscles, and various other neck muscles. The problem is compounded in the post-therapy setting when organs are unilaterally absent or metabolically inactive after radiation. Seventy-eight percent of Warthin’s tumor and pleomorphic adenomas have been reported to accumulate FDG and can be erroneously interpreted as malignancy.54 PET/CT improves the anatomic localization of FDG-avid abnormalities, reduces the number of equivocal interpretations, and also defines the functional significance of structural abnormalities seen on CT or MRI.55 As for other primaries, the performance of PET/CT has been compared with PET alone. PET/CT aids in precisely localizing lesions, decreasing the number of equivocal lesions by 53%, resulting in a higher accuracy than PET alone (96% vs 90%) and a favorable impact on management in 18% of patients.9 FDG-PET/CT has a potential effect on management of patients with N0 neck by clinical examination and conventional imaging modalities because 10%-45% of N0 neck patients have pathologic (N⫹) neck disease at surgery.56 Elective neck dissection is recommended whenever the risk for occult neck metastases of a specific head and neck SCC is above 20% (eg, base of tongue and supraglottic SCC). However, Schoder et al57 concluded that surgical management of the N0 neck should not be based only on PET/CT findings because they

313 demonstrated a suboptimal sensitivity of 67% for PET/CT in detecting cervical node metastases in a group of patients with clinically defined N0 cancer. Patients with advanced stage head and neck cancer may particularly benefit from a pretreatment PET/CT study as detection of distant metastases or a synchronous tumor will change the treatment plan dramatically; these patients have a 25% chance of developing distant metastases and 10% chance of having a synchronous second malignancy.58 Fleming et al10 reported a 15% detection rate of distant metastases, 8% detection rate of synchronous lesions, and a change in management in 31% of patients. Figure 1 illustrates a patient in whom PET/CT detected a second primary carcinoma at the gastroesophageal junction at initial staging of a squamous cell carcinoma of the hypopharynx. FDG-PET is also helpful for detection of the primary lesion of metastatic cancer of unknown primary origin. Unknown primary studies are extremely heterogeneous, use different definitions of what is an unknown primary, and different pretest probability. Some studies only use physical examination prior to PET; other studies use CT and MRI prior to PET. A meta-analysis demonstrated that FDG-PET detects the primary lesion in 43% of patients (range 8%-65%), which approximately doubles the rate of detection compared with conventional diagnostic procedures.59 With FDG-PET/CT, the detection rate with for primary tumors in patients with metastatic neck nodes ranges between 40% and 65%.60,61 PET/CT has been shown to provide data with further clinical impact in up to 60% of patients in this category mainly by improving the localization of tracer uptake foci.60 Hybrid imaging increases sensitivity by decreasing false-positives. Advanced head and neck cancer is commonly treated with a combination of radiation therapy and chemotherapy. PET/CT represents a good modality for identifying patients who show only partial response with residual active disease, and is superior to CT or MRI in detecting postchemoradiation residual disease with a sensitivity of 90%.62,63 A relatively high false-positive rate in FDG-PET assessment of patients after treatment is related to the frequency of inflammatory changes in the region of the head and neck, persisting for longer periods after completion of treatment. However, when PET/CT is performed at 12 weeks after the end of radiotherapy a sensitivity of 93%-100% for detection of residual tumors has been reported.64-66 For example, laryngeal edema can persist after radiation treatment and is difficult to differentiate from tumor recurrence. Laryngeal biopsy under general anesthesia is the gold standard for diagnosis of recurrence but can cause additional edema, and may contribute to chondroradionecrosis and impairment of the airway, leading to tracheotomy. Direct laryngoscopy with biopsy has a low sensitivity and negative predictive value (NPV), with approximately 30% false-negative rate.67 PET/CT was reported to have a sensitivity 92% and specificity of 96% in a group of patients with a suspected recurrent laryngeal carcinoma.11 PET/CT imaging can accurately guide biopsy to the hypermetabolic focus in an edematous larynx. Gordin et al11 reported a change in management in 56% of patients with FDG-PET/CT findings, including elimination of the need of

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D. Delbeke et al

Figure 1 A 59-year-old man underwent FDG-PET/CT for initial staging of SCC of the hypopharynx. The head and neck PET/CT images demonstrate intense FDG uptake in the hypopharyngeal mass extending inferiorly to the level of the hyoid bone consistent with the known primary and in a 20 ⫻ 15-mm, right, level IIA lymph node consistent with a metastasis (A). The body PET/CT images demonstrate intense FDG uptake in a necrotic 16 ⫻ 12 mm left supraclavicular lymph node consistent with a metastasis (B) and focal intense FDG uptake at the gastroesophageal junction worrisome for a second primary carcinoma (C). This latter finding guided endoscopic biopsy of the gastroesophageal junction confirming a moderately differentiated SCC.

Hybrid imaging to improve therapeutic decisions previously planned diagnostic procedures in 26%, induction of a change in the planned therapeutic approach in 23%, and guiding biopsy in 7% of patients. The same group of investigators12,68 reported a change in management related to PET/CT findings in 57% of patients with nasopharyngeal carcinoma. PET/CT eliminated the need of previously planned procedures in 33%, induced a change in the planned therapeutic approach in 14% and guided biopsy to a specific metabolically active area inside an edematous region in 10% of patients.

Role of PET/CT in Radiotherapy Treatment Planning CT and MRI are the modalities used for target volume selection and delineation. Several studies have investigated how the addition of FDG-PET into the planning process affects the delineation of GTVs in the head and neck. As expected, both increases and decreases in GTV have been reported. The more recent studies used combined PET/CT.40,69,70 Although changes in GTV may not always translate into changes in the clinically relevant volume, which is the PTV, the additional information derived from PET may identify unexpected distant disease and thereby change patient management.71 PET/CT may also identify tumor regions that are particularly hypermetabolic for radiation dose escalation. Moreover, PET-based changes in GTV frequently permit sparing of normal tissues, such as the parotid gland. In some studies, planning changes were noted in up to 55% of patients, although the impact on patient outcome remains to be shown. Preliminary clinical follow-up data from 1 institution suggest, however, that implementation of PET/CT-based planning in head and neck cancer is safe and leads to satisfactory levels of disease control.72 The use of FDG imaging for radiation treatment planning has been recommended but is still under evaluation. In both SPECT/CT and PET/CT, close attention to technical quality of the studies is essential so that no motion occurs between the PET and CT images to avoid misregistrations, which could affect image interpretation and treatment plans.

Lung Cancer FDG-PET/CT The American College of Chest Physicians (ACCP) has published guidelines for noninvasive staging of non-small-cell lung cancer (NSCLC) based on a meta-analysis of data from a variety of imaging modalities (CT, PET, PET/CT, bone scintigraphy, and MRI).73 FDG imaging was clearly superior to CT in evaluation of metastatic mediastinal lymphadenopathy with pooled estimates of sensitivity and specificity of 74% and 85%, respectively, and should therefore be considered for any patient in whom treatment with curative intent is contemplated. Importantly, FDG imaging could also detect occult extrathoracic disease not seen by other imaging modalities in 1%-8% of patients thought to have Stage I disease and 7%-18% of patients thought to have Stage II disease. Up to 50% of thoracotomies performed with curative in-

315 tent for NSCLC are “futile” because of the presence of unsuspected advanced disease or occult metastatic spread. If discovered preoperatively, these patients would have been upstaged and categorized as surgically incurable. The effectiveness of FDG-PET in the staging of patients with NSCLC has been shown to change patient management in 19%-41% of cases.1 Of particular importance is the exclusion of surgery by demonstration of unsuspected distant metastases. The multicenter PLUS trial74 included 188 patients from 9 hospitals, who were randomized to conventional work-up (CWU) and CWU ⫹ PET. The end point was futile thoracotomy. This trial demonstrated that PET decreased futile thoracotomies in 50% of patients. There were 41% futile thoracotomies with CWU and only 21% with CWU ⫹ PET. In a prospective study, Lardinois et al75 evaluated the accuracy for TNM staging in 50 patients with proven or suspected NSCLC using CT alone, FDG-PET alone, visually correlated CT with FDGPET, and truly integrated, hybrid FDG-PET/CT. Integrated, hybrid FDG-PET/CT provided additional information in 41% of patients compared with side-by-side correlation of FDG-PET and CT. Integrated FDG-PET/CT had superior diagnostic accuracy compared with CT alone, PET alone, or CT and PET scans interpreted side-by-side. Diagnostic certainly was also greatest for PET/CT as compared with visual assessment of nonfused PET and CT images. PET/CT has also been shown useful in assessing treatment response in lung cancer and mesothelioma, with the greatest declines in FDG uptake typically indicative of the best responses. The area of treatment response and change in management is expected to grow dramatically in the coming years, but space limitations do not allow a full discussion in this review.

Role of PET/CT in Radiotherapy Treatment Planning Among lung cancer cases, 85% are NSCLC histology. Patients with stage IIIA or IIIB at the time of diagnosis and patients with limited disease that are not candidates for surgery due to comorbidities are candidates for radiation therapy. The use of FDG-PET for radiotherapy treatment planning for lung cancer changes the TNM stage in 25%-30% of patients and changes management from curative to palliative in 10%-25% of patients due to detection of unsuspected distant metastases.40,76-79 In addition, FDG PET increases the GTV when FDG-positive lymph nodes are seen on PET and decreases the GTV when FDG-negative nodes or areas of atelectasis are excluded from the treatment field, resulting in a change in the GTV or dose in up to two-third of cases.77,79-82 An example is shown in Figure 2. Importantly, the addition of PET to CT reduces interobserver variability in defining target volumes.40,83-86 PET alone provides only limited structural information, and contours should generally follow anatomic landmarks or borders. Collaboration between nuclear physician with expertise in PET/CT interpretation and radiation oncologists is critical to exclude from contouring foci of physiological uptake, such as in brown adipose tissue, at sites of joint arthritis, in the esophagus, or in the atria or auricles of the heart. PET/CT fusion images are particularly helpful to

D. Delbeke et al

316

Figure 2 A 90-year-old woman underwent PET/CT for initial staging of non-small-cell lung carcinoma and for guiding radiation therapy planning. The CT showed extensive consolidation of the left lower lobe as well as a left hilar mass. The selected image displayed demonstrates that the region with intense FDG uptake is smaller than the area of consolidation on CT consistent with atelectasis surrounding the large left hilar tumor. In this case, delineation of the gross target volume will be smaller using PET/CT than CT alone, and will conform to the contour of FDG uptake sparing the area of atelectasis.

identify these foci as physiological and may be difficult to explain when PET and CT are reviewed separately or even with visual correlation.

Breast Cancer Early Breast Cancer: Role of SPECT/CT for SLN Localization and Biopsy For staging early breast carcinoma, identification and sampling of the sentinel lymph node is the standard of care because the sensitivity of FDG-PET is limited compared with sentinel node biopsy.87 Microscopic lymph node metastases not detected by PET leads to understaging of these patients. If the sentinel lymph node is positive, axillary lymphadenectomy is usually performed as a diagnostic procedure for staging purposes as the presence of nodal metastases is the most important prognostic in patients with breast carcinoma.88 Lerman et al13 examined the added value of SPECT/CT in breast cancer. For 157 consecutive patients, 13% of sentinel nodes were visualized by SPECT/CT but not on planar scintigraphy. Unexpected sites of drainage and non-node-related hot spots were identified for 33 patients, including axillary, internal mammary, interpectoral, and intramammary lymph

node sites. Van der Ploeg et al14 demonstrated that SPECT/CT was superior to SPECT for SLN detection; for 4 of 31 patients, 6 additional SLNs were detected by SPECT/CT, leading to a change in management for 5% of patients because of upstaging in the axilla. SPECT/CT has been shown to be especially useful in overweight patients.15 For 22% of patients, planar images failed to identify a sentinel node. However, SPECT/CT identified 59% of sentinel nodes in these 22% patients. Overall, the sensitivity of SPECT/CT in overweight patients was 89%. SPECT/CT was also superior to blue dye labeling during surgery and identified sentinel nodes in 75% of patients in whom the blue dye technique failed to detect sentinel nodes. Although the current literature does not indicate a major role for SPECT/CT in SLN identification in breast cancer, this modality may be helpful when the standard approach fails to identify the SLN. Data to indicate that SEPCT/CT imaging is superior to intraoperative identification of axillary nodes using a handheld probe have not yet been reported.

FDG-PET/CT Reviews of the role of FDG-PET and PET/CT in breast cancer have been recently published.89,90 For advanced local dis-

Hybrid imaging to improve therapeutic decisions ease, the advantages of FDG-PET imaging are the detection of unsuspected distant metastases,91 and the capability of detecting internal mammary and mediastinal lymph node metastases that are not routinely sampled with the current standard of care.92 FDG-PET imaging is the modality of choice for detecting recurrent disease and restaging. In a meta-analysis, the sensitivity and specificity were 93% and 82%, respectively.93 The impact of FDG-PET on the management of patients with breast cancer varied from 22% to 44%.94,95 The incremental value of PET/CT has also been demonstrated.96 Fueger et al97 assessed the role of FDG-PET/CT in breast cancer patients with suspected recurrence and reported an accuracy of 90% for PET/CT as compared with 79% for PET alone. Tatsumi et al98 reported an 86% accuracy for PET/CT compared with 77% for CT alone. Similar findings with sensitivity, specificity, and accuracy values of 90%, 71%, and 83%, respectively, were reported by Radan et al.16 False-negative findings included subcentimeter lesions and false-positive findings were caused by inflammation. An impact on management occurred in up to 50% of patients with suspected locoregional recurrence being considered for aggressive local therapy in which FDG-PET/CT detects disseminated disease.16 PET/CT and PET can also help in rapid assessment of treatment response. In general, large early declines in FDG uptake are predictive of a good response to chemotherapy. A “flare” in FDG uptake can be seen soon after effective hormonal therapy. More extensive discussions of treatment response in breast cancer are beyond the scope of the current review.

SPECT/CT and PET/CT for Detection of Skeletal Metastases Both 99mTc-diphosphonate skeletal scintigraphy and FDGPET are used to detect skeletal metastases in cancer patients. Skeletal metastases are common in patients with advanced breast cancer, and, whereas most are osteolytic, or cause little early destruction in the marrow, up to 20% are predominantly osteoblastic. Because of their different mechanism of uptake, skeletal scintigraphy is more sensitive for detection of osteoblastic metastases that are poorly detected with FDGPET because of their low cellularity, and FDG-PET is more sensitive for detections of active osteolytic lesions. Overall, the sensitivity of FDG-PET for the detection of skeletal metastases in breast cancer patients ranges from 56% to 100%.99,100 The hybrid PET/CT technology is expected to have an impact on management permitting evaluation of both FDG avidity and anatomic characterization on CT, which helps in detecting osteoblastic metastases and differentiating benign from malignant lesions. After treatment, FDG-negative/CTpositive (usually sclerotic/osteoblastic) lesions are more prevalent and probably represent adequately treated lesions.101 18F-fluoride PET/CT may offer improved detection of skeletal metastases compared with 99mTc-diphosphonate and FDG.102

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Role of PET/CT in Radiotherapy Treatment Planning After breast cancer surgery, several appropriate radiation therapy protocols are applied. Although studies using FDGPET/CT for radiation treatment planning in malignancies, such as head and neck, lung, colon, and gynecologic tumors, report promising results, no clinical data are yet available for breast cancer. However, a simulation study demonstrated that FDG-PET/CT can contribute significantly for radiation therapy planning in patients with suspected recurrent breast cancer, allowing a better delineation of the tumor volume and for an increased precision for radiation therapy delivery in these patients.17

Esophageal and Gastric Cancer Endoscopic ultrasound (EUS), EUS-guided fine-needle aspiration (FNA-EUS), and CT have been the modalities of choice for evaluation of esophageal cancer. FDG-PET and PET/CT imaging are of complementary value for initial staging, evaluation of response to neoadjuvant therapy, detection of recurrence, and differentiating recurrence versus post-treatment changes.19,103 Both CT and PET are limited to T-staging because of their inability to determine the depth of wall invasion; however, EUS is useful in this regard. FDG-PET is as sensitive as CT in detecting regional metastasis but is more sensitive than CT at detecting distant metastasis; approximately 20% of patients with esophageal cancer being considered for surgical therapy have distant metastases.104 Therefore, PET imaging followed by EUS with FNA biopsy of abnormal lymph nodes or metastases provides the most cost-effective strategy for preoperative staging and management of patients with carcinoma of the esophagus.105 FDG-PET has been reported to significantly impact management of 6%-40% patients with newly diagnosed esophageal cancer, mainly by excluding patients from futile surgery.19 The use of hybrid PET/CT improves the diagnosis of clinically significant FDG uptake in the vicinity of the primary FDG-avid tumor or adjacent to physiological sites of increased activity.18,106 In a prospective study comparing presurgical locoregional lymph node staging by PET/CT to sideby-side review of PET and CT, PET/CT had an incremental value over PET interpretation in 22% of sites, improved the specificity and accuracy of stand-alone PET for detecting esophageal cancer from 59% and 83% to 81% and 90%, respectively, and had an effect on management of 10% of patients by detecting nodal metastases that upstaged the disease and excluding disease in sites of benign uptake after surgery.18 Similar data have been reported by another group of investigators who demonstrated that PET/CT has incremental value over side-by-side review of stand-alone PET and CT, resulting in a change in management of an additional 17% of patients.19 Esophageal carcinoma is often treated preoperatively with neoadjuvant chemoradiation therapy, and FDG-PET is useful to assess the response to therapy before surgery. During and

318 for a period after radiation therapy, radiation-induced esophagitis commonly occurs, and these inflammatory changes should not be confused with residual tumor. The uptake in inflammation of the esophagus typically matches the radiation field and corresponds to a normal esophagus on the CT scan. A low performance of FDG-PET/CT has been reported in a recent study assessing response to neoadjuvant therapy in 88 patients planned for surgical resection. PET was unable to predict the presence of residual pathologic disease in the primary tumor or locoregional lymph nodes.107 It should be noted that PET is typically more capable of detecting early response to treatment than the presence of residual viable tumor (as it cannot detect residual microscopic disease). Changing management based on PET scans obtained soon after treatment was started has been proposed as a tool to enhance patient outcomes. However, PET/CT demonstrated new interval metastases in 9% of patients occult by other modalities. Overall, multimodality assessment of esophageal cancer using PET/CT in combination with EUS-FNA has been suggested as the optimal strategy to evaluate treatment response and for directing further clinical decisions.108

Role of PET/CT in Radiotherapy Treatment Planning FDG-PET also defines the longitudinal extent of esophageal cancer more accurately than structural imaging.109,110 In fact, the length of esophageal cancer measured on CT corresponds to the tumor length in the surgical specimen in only 32% of cases.111 Accordingly, CT-based planning may underestimate the true longitudinal extent of esophageal cancer, resulting in geographic misses of GTV. A recent study has shown that tumor length measured on FDG-PET correlates well with macroscopic tumor extent in surgical specimens.110

Gastrointestinal Stromal Tumors Hybrid PET/CT was invaluable in the assessment of 34 patients with gastrointestinal stromal tumors (GIST), mostly after surgery or imatinib (Gleevec) therapy, with CT detecting more lesions than PET, and mainly for delineation of the extent of disease and for directing further surgical procedures.112 The metabolic (FDG) response to imatinib precedes changes seen at CT, also true with the response to sunitinib (Sutent) in patients with imatinib-resistant GIST.113

Colorectal Cancer For colorectal cancer, FDG-PET and PET/CT have been used mainly for detection of recurrent disease. In a meta-analysis, the sensitivity and specificity of FDG-PET for detecting recurrent colorectal cancer were 97% and 76%, respectively.114 However, false-negative FDG-PET findings have been reported with mucinous adenocarcinomas. Hepatic metastases are common in colorectal cancer and other studies have compared the accuracy of FDG-PET and CT for detection of he-

D. Delbeke et al patic metastases. A 2002 meta-analysis performed to compare noninvasive imaging methods (ultrasound, CT, MRI, and FDG-PET) for the detection of hepatic metastases from colorectal, gastric, and esophageal cancers demonstrated that at an equivalent specificity of 85%, FDG-PET had the highest sensitivity of 90% compared with 76% for MRI, 72% for CT, and 55% for ultrasound.115 A subsequent 2005 meta-analysis included MRI studies with gadolinium and superparamagnetic iron oxide particle (SPIO) enhancement.116 SPIO MRI had a 90% sensitivity compared with 76% for FDG-PET for lesions ⬎1 cm. In 1999, Valk et al117 compared the sensitivity and specificity of FDG-PET and CT for specific anatomic locations and found that FDG-PET was more sensitive than CT in all locations except the lung. The largest difference between PET and CT was found in the abdomen, pelvis, and retroperitoneum, where over one-third of PET-positive lesions were negative, as found by CT. With careful examination of a breath-hold CT from PET/CT it is expected that the sensitivity of the combined study for lung lesions would be comparable. FDG-PET imaging changed the management in 29% of patients.114 In a recent prospective study of 51 patients evaluated for resection of hepatic metastases, clinical management decisions based on conventional diagnostic methods were changed in 20% of patients based on the findings on FDG-PET imaging, especially by detecting unsuspected extrahepatic disease.118 The same group of investigators recently reported the 5-year survival after resection of metastasis from colorectal carcinoma. The 5-year survival rate of patients evaluated with conventional diagnostic imaging is in the 30% range and does not appear to have changed with time.119 With the addition of FDG-PET imaging for preoperative restaging of patients with hepatic metastases, the 5-year survival rate improves to 58%, an almost 2-fold improvement. The main contribution is in detecting occult disease, leading to a reduction of futile surgeries. Hybrid fused PET/CT images are especially important in the abdomen and pelvis, to clarify and precisely localize nonspecific FDG uptake to the stomach, small bowel and colon, and the urinary tract. The incremental value of integrated PET/CT over PET alone has also been demonstrated. PET/CT has been reported to increase the interpretation accuracy and certainty of lesion localization, to decrease the frequency of equivocal lesions by 50% as compared with PET alone, with a subsequent increase of 25% in the number of definite locations and in the overall correct staging from 78% to 89% of patients.120 The performance of PET/contrast-enhanced CT has been compared with PET/low-dose CT.20,121 PET/low-dose CT was superior to stand-alone contrast-enhanced CT in 50% of patients due to detection of additional metastases and change in therapy in 10% of patients. PET/contrast-enhanced CT had a further incremental value to PET/low-dose CT in 72% of patients mainly by providing correct segmental localization of hepatic metastases, and thus changing the management in 42% of patients.

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Role of PET/CT in Radiotherapy Treatment Planning For patients with rectal carcinoma, systemic chemotherapy with 5-fluorouracil in combination with radiotherapy has been shown to improve survival. PET/CT fusion images have the potential to provide better dosimetry maps than CT alone for field and dose modulation of radiation therapy, including for patients with colorectal cancer. Small studies suggest that FDG-PET/CT radiation treatment planning influence the size and distribution of the GTV in patients with rectal cancer.122,123 For example, PET/CT altered the PTV significantly in 17% of patients and in 26% it changed the radiation treatment plan.21 For 25% of patients, PET detected distant metastases and changed the overall management.

Hepatobiliary and Pancreatic Malignancies Despite the low sensitivity of 64% of FDG imaging for detection of hepatocellular carcinoma (HCC), FDG-PET had a significant effect on management in 28% of patients due to detection of unsuspected metastases in high-risk patients, including liver transplant candidates, and monitoring response to liver-directed therapy.124 11C-acetate PET has been evaluated in patients with HCC. 11C-acetate and FDG seem to be complementary, and combined FDG and 11C-acetate PET improve the overall sensitivity of PET for detection of HCC as well-differentiated tumors tend to be 11C-acetate-avid, whereas poorly differentiated tumors tend to be FDG-avid. The combination of both radiotracers affects patient management.125 Anderson et al126 reviewed 36 consecutive patients who underwent 18F-FDG-PET for suspected cholangiocarcinoma caused by either a nodular mass ⬎ 1 cm in diameter or for the presence of an infiltrating lesion. The sensitivity of 18F-FDG imaging for nodular morphology was 85% but decreased to only 18% for the infiltrating pattern. Sensitivity for detection of metastases was 65% with false negatives in patients with carcinomatosis and false positives in the presence of primary sclerosing cholangitis with superimposed acute cholangitis. A significant percent of patients had also FDG uptake along the tract of a biliary stent, probably due to a foreign body inflammatory reaction. FDG-PET led to a change in surgical management in 30% of patients, mainly due to detection of unsuspected metastases. The clinical usefulness of FDG imaging in the differential diagnosis of bile duct cancer is also related to the site of primary disease. Although helpful in cases of intrahepatic and common bile duct cancers, FDG imaging is less optimal in perihilar cholangiocarcinoma.127,128 However, 18F-FDG-PET is of definite value in detection of unsuspected distant metastases. A study of 126 patients with biliary cancer confirmed an overall sensitivity of 78% for cholangiocarcinoma and 86% for gallbladder carcinoma.129 Of the 126 study patients, 93 (74%) underwent preoperative staging PET scans, the results of which changed the stage and treatment in 22 patients (24%): 15 of 62 (24%)

319 with cholangiocarcinoma and 7 of 31 (23%) with gallbladder carcinoma. For pancreatic carcinoma, Delbeke et al130 reported a series of 65 patients in whom that the addition of FDG-PET to CT altered the surgical management in 41% of the patients, either by detection of CT-occult pancreatic carcinoma in 27% of patients or by identification of unsuspected distant metastases in 14%. Although PET/CT has been used in the most recent literature addressing the role of FDG-PET in hepatobiliary and pancreatic malignancies, there are little data reporting a change in management specifically related to PET/CT although it is expected to be in the same range as reported for other malignancies. For example, for cholangiocarcinoma, Kim et al22 demonstrated that PET/CT improved the accuracy of preoperative staging in patients with cholangiocarcinoma planning to undergo curative resection. Thus, PET/CT had an important clinical effect on the selection of appropriate treatment and diagnosis of primary tumor, although PET/CT showed no significant difference in detecting mass-forming, periductal-infiltrating, and intraductal-growing types of cholangiocarcinoma. PET/CT revealed significantly higher accuracy over CT in the diagnosis of regional lymph node metastases (75.9% vs 60.9%) and distant metastases (88.3% vs 78.7%). Additional use of PET/CT for assessing resectability correctly showed different results from those determined by conventional imaging in 15 (15.9%) of 94 patients with cholangiocarcinoma. There are data reporting the role of SPECT/CT for characterization of hepatic lesions and as well as a related change in management.131,132 Space-occupying lesions in the liver are often concerning for malignant tumors, especially in patients with a history of cancer. In patients without known malignancies, the most common benign lesions are hepatic cysts, hemangiomas, focal nodular hyperplasia and adenomas. Simple cysts are the most common benign hepatic lesions. None of these benign hepatic masses are FDG-avid. Hemangioma is the second most common benign tumor of the liver. It is characterized by sluggish perfusion and increased activity on delayed blood pool imaging. 99mTc-RBC scintigraphy is commonly used to differentiate cavernous hemangiomas from other lesions. 99mTc-RBC is a blood pool imaging tracer and is helpful to evaluating the vascularity of the lesion, similar to intravenous contrast agents used for CT and MRI. There is progressive visualization of hemangiomas over time and images are typically acquired as long as 2 hours after administration of the radiopharmaceutical. The specificity of 99mTc-RBC for the diagnosis of hepatic hemangioma is extremely high, but the sensitivity is high only for lesions of size ⬎2.5 cm. With SPECT, the sensitivity for smaller lesions improves. SPECT/CT is very helpful in localization of the lesions and correlation with diagnostic CT. It is also of use for evaluation of lesions adjacent to structures with high uptake, such as blood vessels, heart, spleen or renal blood pool. Among the benign hepatic neoplasms, it is important to differentiate an adenoma from focal nodular hyperplasia because an adenoma can rupture with life-threatening hemorrhage, whereas focal nodular hyperplasia does not. Focal

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320 nodular hyperplasia appears typically as a solitary mass detected incidentally in asymptomatic young women. Histologically, the tumor has a thin capsule with a small central fibrous scar and numerous bile ducts. It contains all types of hepatic cells, including Kupffer cells. Focal nodular hyperplasia and adenoma have characteristic CT features related to vascularity, hemorrhage, fat content, and central scar.133 99mTc-sulfur colloid is removed from the circulation by the reticuloendothelial system. Therefore, in the liver, it is a marker for the Kupffer cells. Most space-occupying lesions in the liver, including adenoma and malignancies, do not usually contain Kupffer cells but focal nodular hyperplasia often does. Therefore, 99mTc-sulfur colloid uptake is helpful for characterization of focal nodular hyperplasia. SPECT/CT allows precise identification and localization of the lesion and evaluation of the degree of uptake, especially if it is exophytic and not clearly localized in the liver. Splenic scintigraphy with 99mTc-sulfur colloid or heatdamaged RBC is the most sensitive method to detect active splenic tissue. Moreover, scintigraphy also is useful in cancer patients for distinguishing tumor sites from splenosis, a differential diagnosis that is not so easy to obtain when using anatomical images.134 SPECT/CT in patients who underwent splenectomy is able to accurately detect and localize active splenic tissue due to splenosis, especially intrahepatic, intrapulmonary and pleural implants. Moreover, SPECT/CT can be very useful for the diagnosis of ectopic splenic tissue simulating abdominal tumors that may be observed in cancer patients, as illustrated in Figure 3. Intra-arterial chemotherapy has been used in the regional treatment of hepatic malignancies by delivering high-concentration chemotherapy directly to the tumor and minimizing systemic drug exposure and side effects. Hepatic perfusion scintigraphy with 99mTc-macroaggregated human serum albumin is indicated to confirm that the surgically placed arterial line used for selective hepatic infusion is correctly positioned. Hybrid fused SPECT/CT images display images of the actual distribution of the infused chemotherapeutic agent, which helps not only to monitor adequate drug distribution but also to avoid potential extrahepatic complications in case of blood flow shunting to the lungs, gastrointestinal tract, or other extrahepatic organs.

Gynecological Cancer Cervical and Endometrial Cancer With early detection, the prognosis of preinvasive disease has improved, but the overall 5-year survival of 70% for invasive cervical cancer has remained constant for ⬎20 years. The Fédération Internationale de Gynécologie Obstétrique (FIGO) staging system relies primarily on physical examination and basic tests, and does not include cross-sectional imaging. The pathologic status of pelvic and para-aortic lymph nodes is not included in the FIGO system. However, in a series of 626 patients, the status of para-aortic nodes, determined by surgical staging, was the most significant prognostic factor in cervical cancer patients.135 The detection

of nodal involvement and distant metastases not only impacts therapeutic decisions (surgery vs radiotherapy as well as radiotherapy treatment planning) but also prognosis. Although, no specific data are available for PET/CT, PET has been demonstrated to be more accurate than CT and MRI for detection of metastatic lymph nodes.136 The positive predictive value (PPV) for nodal metastases is 90% for PET and only 64% for MRI.137 Supraclavicular lymph nodes are detected by PET in 8% of patients.138 A meta-analysis showed that FDGPET-pooled sensitivity and specificity were 79% and 99% and 84% and 95% for pelvic and para-aortic lymph node detection, respectively.139 For detection of recurrence, the meta-analysis concluded that FDG-PET detected cervical cancer recurrence with a 96% pooled sensitivity and an 81% pooled specificity. FDGPET can prevent unnecessary therapy by detecting unsuspected metastases and modify therapy in patients with a curative intent. The role of FDG-PET/CT in endometrial cancer is evolving and may be of clinical significance mainly in the post-therapy evaluation of these patients. Park et al23 in a study of 88 patients previously treated for histopathologically diagnosed endometrial adenocarcinoma demonstrated that the clinical decisions on treatment were modified in 14 (21.9%) patients by introducing PET or PET/CT into their conventional posttherapy surveillance program. Chung et al24 found similar conclusions. In their study, the PET/CT results modified the diagnostic or treatment plan in 7 patients (22.6%), resulting in 5 patients (16.1%) undergoing previously unplanned therapeutic procedures and eliminating previously planned diagnostic procedures in 2 patients (6.5%). Patients with negative PET/CT scans showed significantly better progression-free survival than those with positive scans.

Cervical Cancer: The Role of PET/CT in Radiotherapy Treatment Planning Treatment of patients with locally advanced cervical cancer includes a combination of radiotherapy and chemotherapy. FDG-PET/CT is increasingly used to delineate the target volume for radiation treatment planning. Hybrid fused PET/CT images can be used to differentiate tumor from adjacent normal structures more reliably, and thus allow for delivery of higher doses of radiation to the tumor while decreasing radiation dose to normal structures. Lin et al140 recently demonstrated that FDG-PET-based treatment planning allows for improved dose coverage of the tumor without significantly increasing the dose to the bladder and rectum. Dose escalation with intensity-modulation radiation therapy to FDGavid primary tumor and para-aortic lymph nodes have also been reported.141,142

Ovarian Cancer Ovarian cancer spreads initially to local organs, then the retroperitoneum with decreased metastases into the pouch of Douglas, the omentum, and subphrenic space. Lymphatic spread occurs via inguinal, pelvic, and para-aortic lymph

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Figure 3 A 58-year-old man who presented with a 20-mm solid right renal lesion on CT suspicious for renal cell carcinoma and a 15-mm nodule in the tail of the pancreas (A) underwent 99mTc-damaged RBC SPECT/CT scintigraphy to differentiate metastasis from an intrapancreatic splenule (B). The images demonstrate tracer uptake in the pancreatic nodule, confirming the diagnosis of splenule. The patient was then referred for partial right nephrectomy, and pathologic examination demonstrated clear-cell renal carcinoma.

nodes while the patient is still asymptomatic, as well as transdiaphragmatically to internal mammary lymph nodes. Initial evaluation usually includes ultrasonography, tumor markers, peritoneal cytology, and CT. The most accurate diagnosis and staging is performed at the time of surgery (FIGO staging system). The performance of FDG-PET for characterization of adnexal masses is limited compared with ultrasonography and MRI with sensitivity of 58%, specificity of 80%, PPV of 93%, and accuracy of 77%.143 The combination of ultrasonogra-

phy, MRI, and PET improved accuracy for characterizing adnexal masses, but negative MRI or PET did not exclude early-stage ovarian cancer. FDG-PET is mostly useful in detecting and restaging recurrent ovarian cancer, particularly in patients with increasing serum CA-125 and negative or equivocal conventional imaging. There are known limitations in patients with small volume disease, such as miliary carcinomatosis, and it is not recommended as a replacement for second-look laparoscopy. For diagnosis of recurrent ovarian cancer after completion of

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322 therapy, the performance of FDG-PET has an overall sensitivity of 83% and specificity of 83%. In a subgroup of patients with elevated levels of tumor markers or abnormal CT or ultrasonography, the sensitivity of FDG-PET was ⬎90%.144 A meta-analysis showed that PET had a pooled sensitivity and specificity of 90% and 86% in patients with clinical suspicion of recurrence.139 The most recent studies have evaluated integrated PET/CT and have included the effect on patient management. FDGPET and PET/CT may be particularly useful for the selection of patients with late recurrent disease who may benefit from secondary cytoreductive surgery.145 A prospective study of 22 patients with elevated serum CA-125 and negative or equivocal CT findings evaluated the ability of PET to detect macroscopic disease that can potentially be resected surgically. PET/CT patient-based accuracy was 82% for lesions ⬎ 1 cm. The authors suggested that only patients harboring recurrent tumor of size ⬎ 1 cm would benefit from surgical explorations, and thus that FDG-PET/CT could identify these candidates. A 72% complete response rate of secondary cytoreductive surgery was achievable in this series.145 In a subsequent prospective study of 56 patients with a suspicion of recurrent ovarian cancer, FDG-PET/CT changed the management in 58% of patients.25 In addition, FDG-PET/CT identified a subgroup of patients with apparently localized disease or no definite evidence of disease that had an improved survival compared with patients having systemic disease. In a retrospective review of 32 patients, integrated PET/CT had an effect on management in 44% of cases and PET/CT detected tumor relapse in a higher percentage of patients than could CT.26 The effect on management has been confirmed in larger series patients,27 including a questionnaire-based study showing that PET/CT imaging allows a better restaging than CT and induces a change in clinical management in over one-third of patients with suspected ovarian carcinoma recurrence based on increased serum CA-125 levels.28 Figure 4 describes a patient in whom PET/CT detected recurrence in the abdominal wall scar. The performance of PET/contrast-enhanced CT is slightly superior to PET/non-contrast-enhanced CT, and both are significantly superior to contrast-enhanced CT alone.29 The findings of PET/contrast-enhanced CT resulted in a change in management for 39% of patients and affected the management of 12% of patients diagnosed by enhanced CT alone and 2% of patients diagnosed by PET/non-contrast-enhanced CT. In summary, FDG-PET and PET/CT is most helpful in the evaluation of patients with suspected recurrent ovarian carcinoma, especially in case of increasing serum CA-125 levels and normal or equivocal CT. PET and CT are complementary; PET/CT should be used when available. Preliminary data suggest that the addition of FDG-PET/CT to the evaluation of these patients changes the management in approximately one-third of patients and reduces the overall treatment costs by accurately identifying patients who will and will not benefit from surgical procedures.

Genitourinary Cancer In urology, FDG is a considered suboptimal tracer because of its variable uptake in renal and prostate cancers, and because of its accumulation and excretion through the urinary tract, potentially masking kidney, bladder, and prostate tumors. Thus, other PET tracers are being investigated for urologic malignancies. Contrast-enhanced CT is the procedure of choice for the diagnosis and staging of renal cell carcinoma. CT can characterize renal masses as cystic, solid, or mixed, classifying them according to the Bosniak classification,146 and provides evaluation of lymph node and vascular involvement.147 CT is highly accurate in the diagnosis of benign renal angiomyolipoma. The reported experience of FDG-PET imaging in patients with genitourinary neoplasms is limited to studies with small numbers of patients.148 The reported sensitivity of 60% for detection of the primary is relatively low as compared with 92% for CT.149 The sensitivity of PET is also lower than CT or bone scintigraphy for detection of lymph node, lung, and skeletal metastases. This has an important implication for interpretation of PET/CT images; if a complex renal lesion is identified on PET/CT images, relatively low FDG avidity does not exclude a renal cell carcinoma. No data are available regarding the impact of FDG-PET or PET/CT on patient management. A chimeric antibody G250 labeled with 124I (124I-cG250) is a promising PET radiopharmaceutical for preoperative characterization of clear-cell renal carcinoma in patients with renal masses. PET/CT is critical for localization.150

Prostate PET/CT Radiopharmaceuticals FDG-PET has a low tumor uptake in most primary prostate cancer. The probability of a positive FDG study increases with rising PSA. For PSA levels higher than 4 ng/mL, locoregional recurrence is diagnosed in approximately 50% of cases, and FDG-PET has not been found useful in patients with PSA values ⬍2.4 ng/mL.151 Preliminary data suggest that PET imaging using 11C-choline,152 18F-choline,153 11C-acetate,154 and 11C-methionine, which have negligible urinary excretion, are radiopharmaceuticals with improved sensitivity in the evaluation of bladder and prostate malignancies. In that respect, PET/CT has a distinct advantage over PET, allowing a more accurate localization of small foci of mildly increased activity and in dealing with the complex and variable anatomy of the anatomic pelvis. More encouraging results were obtained when using state-of-the-art PET/CT techniques with oral and intravenous contrast enhancement for the CT component. PET/CT provides incremental information regarding the presence of nodal metastases, which is crucial to differentiate between local and regional recurrence, which can lead to changes in patient management. A limited number of studies report on the use of 11C-methionine in recurrent prostate cancer. The sensitivity for soft tissue and skeletal metastases was 70%

Hybrid imaging to improve therapeutic decisions

Figure 4 A 40-year-old woman presented with a history of stage IIIB papillary serous adenocarcinoma of the ovary treated with hysterectomy and bilateral salpingo-oophorectomy followed by chemotherapy 2 years earlier. She was referred for FDG-PET/CT for restaging because of increasing serum CA-125 levels. The FDG-PET/CT images demonstrate moderate FDG uptake in an area of thickening of her abdominal scar (A) and in a 10-mm cutaneous nodule on the posterior aspect of the right shoulder (B). The right shoulder skin nodule corresponded to a small cutaneous abscess on physical examination. FDG uptake in the abdominal scar guided biopsy that confirmed metastastic ovarian carcinoma.

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324 each with 11C-methionine compared with 48% and 34%, respectively, for FDG.155 111In-Capromab

Pentetide (ProstaScint) SPECT/CT Initial results demonstrated ProstaScint (EUSA Pharma, Munich, Germany) scintigraphy to have a sensitivity of 63% and an NPV of 92% for the detection of prostate cancer.9 The use of SPECT/CT allows for better localization of foci of increased tracer uptake and subsequently enables a more confident interpretation of the images. In a study of 800 patients, ProstaScint SPECT/CT had a sensitivity of 79%, a specificity of 80%, and an overall accuracy of 80% for detection of prostate cancer.156 ProstaScint SPECT/CT has been also used to guide focal brachytherapy in patients with prostate cancer, allowing delivery of increased radiation doses to focal areas of increased tracer uptake inside the prostate.157 Other studies have suggested lower prognostic value of this agent in assessing patients with an increasing PSA level,158 but these studies did not include SPECT/CT. SPECT/CT and PET/CT for Detection of Skeletal Metastases More accurate detection of skeletal metastases has an impact on therapy. 18F-fluoride PET/CT is more sensitive and specific than planar and 99mTc-diphosphonate SPECT scintigraphy and than 18F-fluoride PET alone in prostate cancer and a variety of other neoplasms. Even-Sapir et al159 compared planar bone scintigraphy with 99mTc-diphosphonates SPECT, 18F-fluoride PET, and PET/CT in 44 patients with high-risk prostate cancer. The sensitivity, specificity, PPV, and NPV of planar bone scintigraphy were 79%, 57%, 64%, and 55%, respectively. The values for multiple fields-of-view SPECT were better at 92%, 82%, 86%, and 90%, respectively. For 18F-fluoride PET, the values were 100%, 62%, 74%, and 100%, respectively, whereas for 18F-fluoride PET/CT, the values were 100% for all parameters due to a decrease in falsepositive findings.

Testicular Cancer With regard to other malignancies, accurate initial staging has prognostic significance and implications for treatment. At the time of diagnosis, approximately two-third of nonseminomatous germ cell tumors (NSGCT) and one-third of seminomas have nodal involvement. Distant metastases commonly involve the lungs, liver, and brain. For nodal staging, the sensitivity of FDG-PET ranges from 70% to 87% and is superior to CT (⬃60%), which is limited by size criteria for lymph node involvement. The specificity of PET ranges from 94% to 100%, also superior to CT. An effect on management has been demonstrated in 15%-20% of patients.160 FDG-PET also has a role in the evaluation of a residual mass after completion of therapy and in the evaluation of patients presenting with elevated tumor markers and a normal conventional work-up. For patients with seminomas, a residual mass ⬎3 cm have viable tumor in 27%-41% of the cases and surgery is indicated. FDG-PET has a good PPV and NPV to predict viable tumor in the residual mass

and for detection of recurrence when tumor markers are elevated.161For NSGCT, 60%-85% of patients with advanced disease have a residual mass after therapy. FDGPET has a good PPV but a poor NPV because there is overlap of uptake between mature teratoma and malignant tumors.162 In summary, FDG-PET is most valuable in patients with residual or recurrent tumor, leading to changes in patient management, with a high sensitivity and NPV in seminoma and high PPV in NSGCT.163 With regard to other FDG-avid malignancies, it can be assumed that PET/CT will be shown in the future to have an incremental value over separate PET and CT.

Thyroid Cancer Radioiodine SPECT/CT In patients with differentiated thyroid carcinoma, wholebody radioiodine scintigraphy has a sensitivity of 60%-70% for the detection of metastases, in part dependent on the dose (2-5 vs 10 mCi) and type of radioiodine (131I or 123I) used. Post-therapy scans obtained 5-8 days after a ⬎100 mCi 131I dose commonly reveal additional lesions or clarify equivocal abnormalities seen on a diagnostic scan in as many as 35% of patients. The visualization of radioiodine-avid metastases is important to identify patients who will benefit from 131I therapy. Although radioiodine uptake is specific for tissue originating from the thyroid, false-positive findings can occur on planar radioiodine scintigraphy related to benign processes, physiological radioiodine excretion, or contaminations of the skin. Differentiating malignant from physiological uptake or contamination requires accurate localization of radioiodineavid sites that can be provided with SPECT/CT. SPECT/CT is particularly helpful when metastases are small or occur in regions exhibiting distorted anatomy due to previous surgery and surgical resection is indicated. By precise localization of radioiodine uptake, SPECT/CT improves the diagnostic accuracy and has a significant effect on patient management. Several studies assessing the value of SPECT/CT with radioiodine suggest that it is advantageous over planar imaging and SPECT imaging alone.30,31,164 Tharp et al30 demonstrated that SPECT/CT had an incremental diagnostic value for 58% of patients. SPECT/CT improved the characterization of indeterminate findings as definitely benign in 13% of patients and the precise localization of metastases to the skeleton in 17% of patients, as illustrated in Figure 5, and to the lungs vs the mediastinum in 7% of patients. SPECT/CT further optimized the localization of radioiodine uptake to nodal metastases versus remnant thyroid tissue. Overall, additional findings at SPECT/CT had an effect on management for 41% of patients by influencing referral for 131I treatment, tailoring of the administered radioiodine dose, and/or the addition of surgery or external radiation therapy when indicated. Ruf et al31 reported that SPECT/CT correctly classified most radioiodine-avid foci as benign or malignant, provided a superior anatomical localization for 44% of lesions, and modified the therapeutic procedure in 25% of patients.

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Figure 5 A 22-year-old man with a history of papillary thyroid carcinoma metastatic to lymph nodes diagnosed 2 years earlier. He underwent thyroidectomy followed by 2 131I treatments at intervals of 1 year. He was referred for follow-up whole-body 123I scintigraphy. A focus of radiotracer uptake is seen at the base of the right neck on the planar images, and SPECT/CT was performed. The SPECT/CT images allowed localization of the focus of uptake in the right clavicle consistent with a skeletal metastasis. SPECT alone was clearly indeterminant for lesion localization.

In the future, the use of SPECT/CT to derive dosimetric estimates of radioiodine doses for treatment may allow more rationally planned radionuclide therapy in patients with metastatic thyroid cancer.165

FDG-PET/CT As the differentiated thyroid neoplasms are subjected to various therapies, they may dedifferentiate, losing the iodine symporter and/or organification mechanisms, and thus fail to accumulate radioiodine while retaining the ability to express thyroglobulin. Some differentiated thyroid neoplasms as well as less differentiated ones, including Hurthle cell carcinoma, are not routinely radioiodine avid. Anaplastic and medullary carcinoma generally show no radioiodine uptake. These thyroid neoplasms not detected by radioiodine scintigraphy have been successfully imaged using 201Tl-chloride, 99mTcsestamibi, and 99mTc-tetrofosmin; FDG-PET has demonstrated high sensitivity and specificity for the detection of Hurthle cell carcinoma166 as well as poorly differentiated and anaplastic carcinoma. Medullary thyroid carcinoma is a neuroendocrine tumor; detection with FDG-PET is related to volume of disease as evidenced by serum calcitonin levels.167 Medullary thyroid carcinoma can be imaged with high accuracy using the PET tracer 18F-DOPA.168 In all these instances,

imaging with combined PET/CT is critical as metastatic lesions may be small and can occur throughout various organ systems. In an unselected population of patients with thyroid cancer, the sensitivity of FDG-PET ranges between 50% and 75%. The largest study evaluating the use of FDG imaging in differentiated thyroid cancer was a multicenter retrospective analysis that included 222 patients. The overall sensitivity and specificity of FDG for the detection of disease was 75% and 90%, respectively.169 In the subgroup of 166 patients with negative radioiodine scintigraphy, the sensitivity was 85%. Therefore, FDG-PET has proved most useful in the population of thyroid carcinoma patients with elevated serum thyroglobulin and negative whole-body radioiodine scintigraphy with sensitivity in the range of 80%-90%. PET has localized occult metastases in 50%-82% of such patients and altered therapy in approximately 30% of them.170 High FDG uptake indicates a poor prognosis, especially if there is high-volume disease.171 TSH stimulation often enhances FDG uptake by malignant thyroid tumors, so rhTSH or thyroid hormone withdrawal is recommended to improve the sensitivity for detection of recurrent and/or metastatic disease.172 The diagnostic accuracy for detection of differentiated thyroid cancer is higher for PET/CT, that is 93%, as compared

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Figure 6 A 37-year-old woman was referred for FDG-PET/CT for initial staging of locally advanced carcinoma of the cervix. Intense FDG uptake is seen corresponding to the known primary carcinoma of the cervix (A). A focus of intense FDG uptake is also seen in the right thyroid lobe corresponding to a heterogeneous poorly defined nodule (B). Fine-needle aspiration biopsy demonstrated a previously unsuspected primary papillary thyroid carcinoma.

Hybrid imaging to improve therapeutic decisions with 78% for PET alone.173 PET/CT also had an incremental value when compared with the side-by-side interpretation of PET and CT in 48% of patients that have a FDG-positive focus of uptake. Focal FDG uptake localized to the thyroid gland on PET/CT of patients referred for evaluation of another primary cancer is not unusual and is due to thyroid cancer in approximately one-third of lesions that have been biopsied,174,175 as illustrated in Figure 6. Such a finding obviously warrants biopsy in most cases. FDG-PET/CT has been reported to alter therapy in 9%54% of patients with differentiated thyroid cancer.173,176 In patients with known disease in the neck, previously planned surgery may be more or less extensive, and aggressive local treatment may be canceled if distant metastases are found on FDG-PET/CT.

Neuroendocrine Tumors SPECT/CT and PET/CT Imaging of Gastroenteropancreatic Tumors Neuroendocrine tumors express SSR with high density. In general, 111In-DTPA-octreotide scintigraphy is reported to be more sensitive than CT for the detection of metastatic carcinoid and other neuroendocrine tumors and may more accurately represent the extent of disease.177 This is especially true for extrahepatic and extra-abdominal disease. The therapeutic plan is altered in a substantial number of patients due to the superior sensitivity of this technique for detection of extrahepatic disease. Furthermore, tumors detected SSR positive by scintigraphy have often been found to be responsive to systemic somatostatin analog therapy. Carcinoid metastases may be heterogeneous for SSR, some being positive and some negative even in the same patient. When these tumors become more undifferentiated, they may lose their SSR expression and become FDG positive. The sensitivity of 111InDTPA-octreotide scintigraphy is high for the detection of islet cell tumors, such as nonfunctioning tumors, glucagonomas, somatostatinomas, and VIPomas, but is less sensitive in the detection of insulinomas. Several reports have demonstrated the contribution of SPECT/CT as an adjunct to SSR scintigraphy in patients with gastroenteropancreatic tumors, mainly by delineating softtissue tumors, detecting invasion into adjacent bones, identifying previously unknown or changing the location of tumor sites, with further effect on management in about onethird of the patient population.34,164 For example, in one of these studies,34 SPECT/CT affected the diagnostic interpretation in 32% of patients and resulted in changes in management in 14% by altering the surgical approach, sparing unnecessary surgery, and/or modifying the therapeutic modality. In another study,35 therapy was modified in 28% of patients owing to the results of image fusion: in 5 patients tumor could be excluded, in 3 patients the individuals were spared unnecessary surgery due to detection of additional lesions indicating systemic tumor spread, in 4 patients the surgical approach was modified owing to precise tumor localization and minimization of the surgical field, and in 2

327 patients medical and radiopeptide therapy was modified. Other investigators reported an effect on management in 24% of patients for whom the anatomic localization was modified by SPECT/CT. When somatostatin receptor scintigraphy is negative, SPECT/CT may confirm the absence of receptor expression in a tumor visualized on CT. PET/CT using 68Ga-DOTATOC had higher detection rates for neuroendocrine tumors as compared with CT, 111InDOTATOC and 111In-DTPA-octreotide-SPECT.178,179 The newer 68Ga-DOTANOC analog further increased image quality and has been suggested for routine SSR PET/CT studies.180,181 There is limited data comparing FDG to SSR scintigraphy for the detection of carcinoid tumors, but these and other neuroendocrine tumors tend to be less hypermetabolic than the more common carcinomas and may yield false-negative result with FDG-PET.182,183 Therefore, FDG-PET should be reserved for patients who have negative SSR scintigraphy or additional lesions on CT or MRI that are not SSR avid.

SPECT/CT and PET/CT Imaging of Neural Crest Tumors Pheochromocytoma/paraganglioma. The diagnostic modality of choice for metastatic disease is scintigraphy using radiolabeled MIBG, with an overall sensitivity of 86%-88% and specificity of 96%-99%. Spatial resolution of 123I-MIBG scans remains limited even with SPECT, and 123I-MIBG-avid foci require anatomic correlation, using SPECT/CT studies. Hybrid images may contribute to diagnosis when unilateral, asymmetric, low-intensity uptake occurs in the adrenal gland, characterizing areas of normal 123I-MIBG biodistribution or excretion, and also facilitates detection of recurrent or metastatic disease in the vicinity of normal structures with high tracer uptake, such as the myocardium and liver. Furthermore, SPECT/CT can help differentiate between 123IMIBG-avid retroperitoneal recurrence and adrenal gland hyperplasia after contralateral adrenalectomy, and optimize characterization of equivocal findings visualized on non-contrasted CT184 (Fig. 7). MIBG scintigraphy may be useful in the detection, staging, and follow-up of patients with other neuroendocrine tumors. Approximately 80%-90% of paragangliomas, 60% of carcinoid tumors, and ⬍50% of medullary carcinoma of the thyroid concentrate MIBG.177 For neuroendocrine tumors demonstrated to be MIBG-avid, high dose of 131I-MIBG treatment may provide palliation. Neuroblastoma. Neuroblastoma is one of the most common solid extracranial malignancies in children. 123I-MIBG scintigraphy is used for diagnosis of a primary lesion that is inaccessible to biopsy, staging, evaluation of prognosis, radioguided surgery and response to therapy, and for targeted radiotherapy. SPECT/CT improves the delineation of physiological diffuse intraluminal bowel activity, localization of tumor sites, and detection of bone and bone marrow involvement. Similar to pheochromocytoma, SPECT/CT may characterize tumor recurrence adjacent to organs with physiological 123I-MIBG activity. Rozovsky et al184 reported that

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Figure 7 A 14-year-old boy with Von Hippel–Lindau Disease presented with a history of bilateral adrenal pheochromocytomas resected 5 years earlier. A recurrence in the left adrenal bed was resected surgically 1 year earlier. He presented again with increasing plasma catecholamine levels and was referred for 123I-MIBG scintigraphy. The planar images revealed a faint focus of radiotracer uptake in the abdomen. SPECT/CT images localized the focus of uptake to the left adrenal bed (A). There was no evidence of additional metastases. A follow-up CT demonstrated a 1.5-cm enhancing soft-tissue lesion in the left adrenal bed (B). Surgical resection of the lesion revealed metastatic pheochromocytoma.

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Figure 8 A 76-year-old woman presented with hyperparathyroidism and was referred for 99mTc-sestamibi parathyroid scintigraphy. The planar images demonstrated a focus of radiotracer uptake at the base of the right neck vs thoracic inlet. SPECT/CT was performed, which localized the focus of uptake to the region of the inferior pole of the right lobe of the thyroid. A 1.15 g parathyroid adenoma was found on surgical exploration.

SPECT/CT provided additional clinical information in 53% of the cases. SPECT/CT differentiated between bilateral symmetric upper thoracic activity, probably related to physiological muscular or brown fat uptake, and malignant lesions, such as skeletal metastases in the scapula, ribs, or malignant supraclavicular lymphadenopathy. SPECT/CT has also been advocated as a tool for quantification of radiation dose delivered during 131I-MIBG therapy, using CT-based measurements of tumor volume.185 Most neuroblastomas accumulate FDG and PET has been found to be equal or superior to MIBG imaging for identifying soft tissue and extracranial skeletal metastases, for identifying small lesions, and for delineating the extent and localizing sites of disease.186,187 Calvarial metastases may be more difficult to detect with FDG-PET due to the marked physiological cerebral activity.

or SPECT studies.188 SPECT/CT can lead to a modification of the surgical approach in patients with an uncommon location of the parathyroid glands. SPECT/CT provided additional data in 39% of lesions and modified the surgical approach in 19% patients with retrotracheal glands.32 SPECT/CT has a major effect, predominantly in ectopic parathyroid adenomas, as documented in several studies, including patients with primary hyperparathyroidism who subsequently underwent neck or mediastinal exploration.33,164,189 In one of these studies, SPECT/CT contributed to the localization of parathyroid adenomas in patients with primary hyperparathyroidism and to planning the surgical exploration in 39% of patients, predominantly those with ectopic parathyroid adenomas or who had distorted neck anatomy33 (Fig. 8).

SPECT/CT Imaging of Parathyroid Adenoma

Lymphoma

Precise localization of parathyroid adenoma is critical for the success of minimally invasive parathyroidectomy. Early 99mTc-sestamibi SPECT/CT in combination with delayed imaging is significantly superior to single- or dual-phase planar

Lymphomas are classified into 2 main groups, non-Hodgkin lymphomas (NHL) and Hodgkin Lymphoma (HL). NHL is more common compared with HL, representing approximately 85% of lymphomas.

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330 The NHLs can also be divided into 2 prognostic groups: the aggressive lymphomas and the indolent lymphomas.190 Diffuse large B cell lymphoma is the most common aggressive lymphoma representing 30% of NHL; other relatively common aggressive lymphomas include mantle cell lymphoma (MCL) and adult T cell leukemia/lymphoma, each representing 6%-8% of NHL. Indolent NHL types have a relatively good prognosis, with median survival of as long as 10 years, but they usually are not curable in advanced clinical stages. Follicular lymphoma (FL) is the most common type of indolent lymphoma representing 22% of NHL. Marginal zone B cell lymphoma and small lymphocytic lymphoma are other types of indolent lymphoma representing each 6%-8% of NHL. Although there is an overlap of SUV between aggressive and indolent NHL, the mean SUV in aggressive NHL and HL are significantly higher than the values obtained for indolent lymphomas, though a majority of FL are easily identified on PET/CT.191 A majority of lymphoma subtypes are FDG-avid and PET is therefore a valuable tool for evaluation of these patients. FDG-PET more accurate than CT for staging and restaging lymphoma, including extranodal and bone marrow involvement. FDG-PET/CT is superior to either modality alone in evaluating patients with lymphoma, mainly by accurately defining sites of increased tracer uptake unrelated to lymphoma, thus reducing the false-positive rate. The change in stage I/II to III/IV has major therapeutic and prognostic implications. A modification in stage and management has been reported in various studies summarized in a review article.1,192 Although a change in stage due to FDG-PET has been reported in 7%-50% of patients, the major modification in management occurs in a lesser percentage of patients because it occurs only when patients are upstaged from stage I/II to III/IV. With regard to other malignancies, the incremental value of PET/CT has been demonstrated.193 PET/CT is commonly performed without intravenous contrast using a low-dose (40-80 mA) CT component to reduce the exposure of the patient to radiation. When the protocol for the CT component is not specified, the low-dose CT without intravenous contrast is usually applied. However, the CT component can be performed using a diagnostic CT protocol with oral and intravenous contrast when warranted clinically. PET/low-dose CT and contrast-enhanced CT were compared regarding the modification in stage and management in 103 patients referred for initial staging of lymphoma (HD ⫽ 35, NHL ⫽ 68).37 PET/CT changed the stage in 32% of patients with NHL (31% upstaged, 1% downstaged) and 47% of patients with HD (32% upstaged and 15% downstaged). PET/CT changed the management of 25% and 45% of patients with NHL and HD, respectively. PET/low-dose CT and PET/contrast CT were compared in 47 patients with lymphoma. On a region-based analysis, there was no significant difference for detection of lymphoma. PET/contrast CT provided slightly less equivocal sites (2/188) and allowed detection of slightly more extranodal sites (n ⫽ 4/188). For the purpose of staging, there was almost perfect agreement (46/47 patients).194

These 3 studies concluded that PET/low-dose CT is adequate for most patients and that the use of iodinated contrast enhancement provided little, if any, benefit. Contrasted CT is recommended only for selected cases. FDG-PET/CT performed early in the course of treatment can detect nonresponding patients and suggest a change in the therapeutic strategy. Positive FDG-PET/CT studies during or at the end of treatment are associated with a worse prognosis. FDG-PET/CT can distinguish between a residual mass consisting of necrotic and fibrotic tissue and residual active lymphoma, can detect relapse during follow-up often earlier than CT alone, and can identify transformation of lowto high-grade lymphoma. FDG-PET/CT studies provide a metabolic guiding tool and thus optimize the process of selecting a site for biopsy with a subsequent decrease in tissue sampling errors. FDG-PET/CT is an appropriate test in certain clinical settings when lymphoma is suspected, such as finding the most appropriate site for biopsy in patients without obviously accessible nodal sites or with exclusively extranodal disease. In patients with peripheral adenopathy in which needle biopsy rather than excisional biopsy is considered, FDG imaging can improve the yield of biopsy guiding toward the lesion, which is not only most accessible but also has the highest and most homogenous tracer uptake. This may help circumvent sampling errors in large lymph nodes with necrotic tissue or small but benign lymph nodes.

Melanoma Early-Stage Melanoma: Role of SPECT/CT for Sentinel Lymph Node Localization and Biopsy For Stage I and II disease in which there is no clinical evidence of spread and tumor thickness is ⬍4 mm, elective regional lymph node dissection once was routinely recommended because it decreases recurrence rate and probably mortality. However, approximately 75%-80% of these patients do not have nodal metastases at the time of exploration, and therefore could be spared the expense and morbidity of lymphadenectomy. Sentinel node localization and biopsy is therefore useful for detection in patients who are most likely to benefit from lymphadenectomy. Nodal basins identified by lymphoscintigraphy are discordant with the expected drainage pattern in over 60% of patients with head and neck melanoma and one-third of patients with truncal lesions. Trunk lesions can drain to multiple sites, including cervical, supraclavicular, and inguinal lymph nodes. Upper extremity lesions drain to the axillary and epitrochlear lymph nodes, and lower extremity lesions drain to inguinal and popliteal lymph nodes. The results of the multicenter selective lymphadenectomy trial suggest that there is a significantly better 5-year diseasefree survival rate for patients staged with a sentinel lymph node (SLN) procedure compared with patients staged without an SLN procedure.195 The SNM has published a procedure guideline for SLN localization in the management of

Hybrid imaging to improve therapeutic decisions patients with melanoma.196 The radiopharmaceutical procedure is not uncommonly used in conjunction with methylene blue dye injected in the operating room. Blue and radioactive nodes are excised and extensively assessed histopathologically. If the nodes are histologically positive for melanoma, subsequent lymphadenectomy is usually performed. SPECT/CT is not always needed for accurate localization of the SLN, but it is useful in anatomically complex regions and/or in regions where lymphatic drainage can be variable, such as the head and neck or the trunk.7,197 For instance, 50% patients with melanoma of the trunk demonstrated multiple drainage basins by SPECT/CT and SPECT/CT identified hot nodes missed on planar images, including nodes invaded by metastases in 43% cases of primary melanoma located in the head and neck or trunk region. SPECT/CT is usually of no added value in localization of the SLN in patients with melanoma of the extremities. A comparison of the findings from SPECT/CT versus the intraoperative findings using a handheld probe have not yet been reported.

Detection of Recurrence and Restaging with FDG-PET and PET/CT A prospective evaluation of a proposed follow-up strategy for patients with melanoma showed that imaging was of no significant value in routine follow-up of patients with stage I and II melanoma. For stage III disease after regional lymphadenectomy, imaging techniques have been suggested to be used every 6 months for 10 years.198 The use of imaging for effective whole-body melanoma surveillance requires the use of CT, brain MRI, and/or FDG-PET/CT. Of these modalities, FDGPET/CT is the imaging modality of choice for initial staging and restaging of stage III–IV melanoma.199 FDG-PET/CT is superior to CT alone in evaluation of the abdomen and pelvis but inferior to breath-hold CT for evaluation of small pulmonary metastases and to MRI for evaluation of cerebral metastases.197 A meta-analysis on the use of whole-body FDG-PET in management of patients with melanoma reported a sensitivity of 92%, specificity of 90%, and a change in management based on FDG-PET imaging in 22% of patients.200 Baseline FDG-PET in stage III melanoma improves staging accuracy and can prevent unnecessary surgery for presumed limited disease or futile resection of a solitary metastasis when, in fact, other sites of disease are present. In a retrospective analysis of 257 patients, Bastiaannet et al201 found that FDG-PET upstaged 22% of patients from stage III to stage IV disease, modified the treatment in 17% of patients, and found unrelated premalignant or malignant conditions, mainly colorectal tumors, in 4% of patients. Although many melanoma metastases are FDG avid, not all tumor sites accumulate the radiopharmaceutical. However, most metastases that do not accumulate FDG will be visible on the CT portion of the PET/CT examination. In a prospective study of 124 patients with melanoma, Strobel et al202 demonstrated improved accuracy in staging or restaging patients when the CT component was interpreted separately and in addition to the PET/CT study because not all foci of

331 tumor involvement were FDG avid. FDG-PET/CT demonstrated a sensitivity and accuracy of 85% and 91%, respectively, when only areas of increased uptake were considered as possibly representing tumor. When the CT performed for anatomic localization and attenuation correction was interpreted, both separately and in concert with the FDG-PET images, sensitivity and accuracy increased to 98% and 96%, respectively. Most metastases detected only on CT were in the lungs, with other locations, including a small subcutaneous nodule in the gluteal region, an iliac node metastasis, and a muscle metastasis. Similarly, in a retrospective study of 250 patients with metastatic cutaneous melanoma, Reinhardt et al203 reported separate overall N- and M-staging accuracy of FDG-PET/CT of 97% as compared with the PET-only accuracy of 93% and CT-only accuracy of 79%. This study included patients in multiple clinical settings, specifically initial staging, treatment assessment, restaging, and follow-up. In summary, SLN localization and biopsy is the standardof-care for initial staging of early stage melanoma. FDGPET/CT is a well-established imaging modality for staging and restaging high-risk melanoma with the caveat that the CT component must be interpreted methodically for FDG-negative tumor sites. MRI remains superior to other imaging options for evaluation of cerebral metastases or choroidal tumors. A dedicated, breath-hold MDCT is superior for detection of small pulmonary nodules that are easily missed on FDG-PET/CT. A multiphasic MDCT is similarly superior for evaluation of small and/or metabolically quiescent metastases of the liver or spleen. All these available imaging modalities should be considered for complete staging and restaging of the melanoma patient.

Skeletal Primary and Secondary Malignancies and Sarcoma Detection of malignant skeletal involvement is based on either direct visualization of tumor cells or the secondary osteoblastic reaction of the bone to the presence of malignant cells. FDG directly accumulates in tumor cells and may therefore identify malignant skeletal involvement at early stages when confined to the marrow, before the cortical skeletal reaction has occurred. Increased accumulation of 99mTcdiphosphonate or 18F-fluoride depends on the presence of secondary reactive bone remodeling and osteoblastic changes.204 99mTc-Diphosphonate

SPECT/CT

The most common indication for skeletal scintigraphy is screening for skeletal metastases. Most skeletal metastases have increased radiotracer uptake but some appear photopenic. The specificity of skeletal scintigraphy for detection of metastases is limited because many benign skeletal processes demonstrate increased uptake. Anatomic imaging with CT can help differentiate benign from malignant etiologies. This can be accomplished in a single imaging setting using hybrid SPECT/CT or PET/CT systems. Romer et al205 demonstrated that 63% of indeterminate lesions on SPECT could be corre-

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332 lated with benign findings on SPECT-guided CT. These findings involved mostly osteochondrosis, spondylosis, and spondylarthrosis of the spine. Twenty-nine percent of lesions could be correlated with osteolysic or sclerotic metastases on CT. Even after analysis of the SPECT/CT images, 8% of lesions remained indeterminate. Horger et al206 were also able to correctly classify 85% of unclear foci; in comparison, 36% of such foci were correctly classified by SPECT alone. The sensitivity for cancer detection was in a similar range for SPECT/CT and SPECT (⬎90%) but the specificity was much higher for SPECT/CT (81% compared with 19%). In addition, fused images can be used to further guide biopsies of skeletal lesions. Increased diagnostic confidence to differentiate benign from malignant skeletal lesions has been reported in multiple studies207,208 (Fig. 9). 18F-Fluoride

PET/CT

Even-Sapir et al102 have demonstrated that 18F-fluoride PET/CT was more specific than 18F-fluoride PET alone (97% vs 72%, respectively) for differentiating benign from malignant skeletal lesions in a group of patients with cancer. The same group of investigators159 has demonstrated that in patients with high-risk prostate cancer, 18F-fluoride PET/CT is a highly sensitive and specific modality for detection of skeletal metastases. It is more specific than 18F-fluoride PET alone and more sensitive and specific than planar and 99mTcdiphosphonate SPECT scintigraphy. Detection of skeletal metastases is improved by SPECT compared with planar scintigraphy and by 18F-fluoride PET compared with SPECT. The authors concluded that this added value of 18F-fluoride PET/CT may beneficially affect the clinical management of patients with high-risk prostate cancer.

FDG-PET/CT Hybrid imaging with FDG-PET/CT allows accurate localization of abnormal tracer uptake to soft tissue vs skeleton. Detection of skeletal metastases in the vicinity of physiological FDG uptake, such as in the skull, is improved with fusion images.209 Fusion FDG-PET/CT images also improve localization of the precise level of an abnormality in the vertebral column (necessary for biopsy) and detects potential invasion of the epidural space or neural foramen by the tumor. Early detection of such lesions is critical to guide appropriate therapy.210 The most important advantage of FDG imaging is its ability to detect early marrow-based metastases before the appearance of structural abnormalities on CT or osteoblastic activity on skeletal scintigraphy. However, FDG-PET has a limited sensitivity for detection of osteoblastic metastases as demonstrated in patients with breast and prostate cancer.211-213 After successful treatment, normal appearing or lytic bone lesions often become sclerotic. When monitoring response of metastatic skeletal disease to therapy, CT and skeletal scintigraphy are of limited value in differentiating active disease from a reparative process. On FDG-PET/CT imaging successful treatment is reflected by a decrease or even disappearance

of FDG uptake, whereas a treated malignant skeletal lesion may remain abnormal on the CT component of PET/ CT.100,214 In a recent publication by Du et al,100 sequential PET/CT studies were performed in 408 consecutive patients with known or suspected recurrent breast cancer. The CT morphologic changes varied greatly with time. CT performed after treatment actually identified more skeletal lesions than initially. FDG uptake is an indicator of the actual tumor metabolism in skeletal metastases at the time of imaging. The follow-up FDG-PET/CT study showed no FDG uptake in the “new” sclerotic lesions seen on CT, clarifying that sclerosis represents a reparative process rather than active disease, whereas increased FDG uptake at other sites indicates the presence of residual active metastatic disease.

FDG-PET/CT for Staging Primary Skeletal Tumors and Soft Tissue Sarcomas Primary soft tissue and skeletal sarcomas can be variably FDG avid. More aggressive tumors tend to have higher FDG uptake than lower grade tumors. Tateishi et al38 compared the accuracy of tumor-node-metastasis (TNM) staging using conventional imaging, FDG-PET, FDG-PET/CT, and FDGPET/CT plus conventional imaging. The reference standard was histology for T and N staging and radiologic follow-up and/or biopsy for M staging. Interpretations based on combined FDG-PET/CT and conventional imaging findings correctly staged tumors in 87% of patients, overstaged tumors in 12% of patients, and understaged tumors in 1% of patient. Overall staging accuracy of combined PET/CT and conventional imaging was significantly higher than that at PET/CT (83%), PET alone (70%), and conventional imaging alone (77%). Combined PET/CT and conventional imaging resulted in correct N staging in 97% of patients and M staging in 93% of patients. Analysis of PET/CT findings revealed that the tumor had been overstaged in 16% and understaged in 1% of patient, whereas conventional imaging classified the tumor as overstaged in 19% and understaged in 4% of patients. The management was modified from resectable tumor to unresectable tumor for 13% of patients and from unresectable tumor to resectable tumor for 1% of patient, using combined PET/CT and conventional imaging compared with conventional imaging alone. Compared with PET/CT alone, combined PET/CT and conventional imaging helped decrease overstaging in 4% of patients and helped change tumor diagnosis from unresectable to resectable in 2% of patients.

Impact on Management of PET/CT and SPECT/CT in Benign Disease Benign Skeletal Diseases 99mTc-Diphosphonate

SPECT/CT The high sensitivity of skeletal scintigraphy results in a high rate of incidental benign findings and SPECT/CT hybrid systems allow morphologic characterization of scintigraphic le-

Hybrid imaging to improve therapeutic decisions

Figure 9 A 60-year-old man presented with a history of weakness and numbness in the upper extremities and a nonenhancing intramedullary lesion on MRI of the cervical spine extending from C4 to C6. He was referred for 99mTc-MDP scintigraphy. The planar images revealed focal uptake in the right lower C-spine and right shoulder. SPECT/CT was performed, which helped to localize the foci of uptake to degenerative changes in a right facet joint (A) and right shoulder joint (B) excluding metastatic disease. During 2 years of close follow-up, the patient and intramedullary cervical lesion remained stable, consistent with a benign etiology.

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334 sions.215 Depending on the system used, the CT component of the hybrid device may be a single- or multislice low-dose, a reduced-dose, or full-dose spiral CT. McDonald et al216 fused SPECT and CT using software in 37 patients with back pain clinically attributable to facet joint disease. In contrast to SPECT alone, SPECT/CT allowed precise localization to L4/5 vs L5/S1. In patients with solitary lesions, localized anesthetic blockade led to complete, even if temporary, pain resolution. Even-Sapir et al217 assessed the role of SPECT/very lowdose CT in 76 consecutive nononcologic patients with nonspecific scintigraphic findings, which required further correlation with morphologic data. SPECT/CT was of clinical added value in 89% of patients. The morphologic data obtained by the very low-dose multislice CT permitted the final diagnosis to be made in 58% of the patients, thus obviating the need for additional imaging. In an additional 30% of the patients, an optimized diagnostic work-up was based on SPECT/CT findings, which provided guidance toward the use of diagnostic full-dose CT, MRI, or radiolabeled-leukocyte scintigraphy as the most appropriate imaging modality for further assessment. 18F-Fluoride

PET/CT

18F-fluoride

The role of imaging has been evaluated in the assessment of back pain in children and young adults using either PET or PET/CT.218,219 In addition to accurate diagnosis of the cause of back pain, 18F-fluoride imaging had a high NPV. Patients with negative 18F-fluoride imaging did not require medical intervention. Even-Sapir et al220 performed 18F-fluoride PET/CT in 82 patients with suspected non-oncologic skeletal abnormality. 18F-fluoride PET/CT was valuable in identifying clinically relevant skeletal lesions overlooked when CT was interpreted alone.

FDG-PET/CT Highly cellular benign lesions containing histiocytic or giant cells, such as osteoblastoma, brown tumor, aneurysmal bone cyst, sarcoidosis, radionecrosis or skeletal infection, and hibernomas, may also be associated with increased FDG-PET uptake. In patients referred for evaluation of cancer, it is important to differentiate benign from malignant lesions. The clinical history, pattern of FDG uptake, and morphologic characterization on CT are all important to avoid false-positive upstaging of the disease.221

Infection Detecting or excluding the presence of infection affects the management of patients. Localizing the site of infection to soft tissues or bone has an impact on the type of therapy. 99mTc-Diphosphonate

SPECT/CT

Horger et al222 evaluated the contribution of 99mTc-diphosphonate SPECT/CT for diagnosis and localization of skeletal infection. The authors concluded that SPECT/CT improves

the diagnostic performance of 3-phase skeletal scintigraphy for diagnosing osteomyelitis by avoiding false-positive or equivocal interpretations. However, the advantage of SPECT/CT fusion over visual fusion could not be demonstrated. The sensitivity of skeletal scintigraphy and SPECT/CT was similar at 78%, whereas the specificity of SPECT/CT was 86% compared with 50% for skeletal scintigraphy. The limited specificity of skeletal scintigraphy was due mainly to the presence of noninfectious skeletal pathology, such as fracture or previous surgery, which is also associated with increased 99mTc-diphosphonate uptake and difficult to differentiate from infection. 67Ga

Citrate and Labeled-White Blood Cell SPECT/CT Bar-Shalom et al223 have evaluated the role of SPECT/CT for diagnosis or localization of infection using 67Ga or 111Inwhite blood cell (WBC) scintigraphy. SPECT/CT made an incremental contribution in 48% of patients by improving diagnosis, localization, and definition of extent (43%) of disease and by excluding infection in 4 suggestive sites defined as physiological bowel uptake on 67Ga scintigraphy. Filippi et al39 have evaluated SPECT/CT in a group of patients with suspected skeletal and joint infections using 99mTc-hexamethyl propylene amine oxime (HMPAO)-WBC. SPECT/CT accurately detected infection in 64% (true positive) and excluded infection in 36% of patients (true negative). SPECT/CT allowed correct diagnosis of osteomyelitis vs soft-tissue infection in patients with structural alterations after trauma, and identified synovial infection without prosthesis involvement in patients with a knee implant. Clinical effect was observed in 36% of patients, osteomyelitis was excluded in 25% of patients, and the extent of infection was more correctly assessed in 11% of patients. Scintigraphy with 111In- or 99mTc-HMPAO-WBC has been used in patients with inflammatory bowel disease to confirm the diagnosis in patients with high clinical suspicion and to evaluate the extent of the disease. Preliminary data suggest that hybrid SPECT/CT can increase the accuracy of 99mTcHMPAO-WBC scintigraphy in detecting inflammatory lesions, especially within the pelvic floor, due to its improved capability for anatomic localization.132

FDG-PET/CT Data on the role of FDG-PET imaging in the assessment of benign skeletal pathology in patients without cancer are accumulating, mainly for suspected musculoskeletal infection.224,225 Various studies have assessed the role of FDG PET imaging, and recently of FDG PET/CT imaging, in patients with suspected chronic osteomyelitis, in osteomyelitis in immunocompromised patients or after trauma, in patients with a diabetic foot, in infected joint prosthesis or inflammatory joint diseases, and in patients with prosthetic vascular graft infection.215,221,225-228

References 1. Gambhir SS, Czernin J, Schimmer J, et al: A tabulated summary of the FDG PET literature. J Nucl Med 42 (suppl):1S-93S,2001

Hybrid imaging to improve therapeutic decisions 2. Wahl RL, Quint LE, Cieslak RD, et al: Tumor imaging: Fusion of FDG PET with CT or MRI to localize foci of increased activity. J Nucl Med 34:1190-1197, 1993 3. Koral KF, Zasadny KR, Kessler ML, et al: CT-SPECT fusion plus conjugate views for determining dosimetry in iodine-131 monoclonal antibody therapy of lymphoma patients. J Nucl Med 35:1714-1720, 1994 4. Bar-Shalom R, Yefremov N, Guralnik L, et al: Clinical performance of PET/CT in the evaluation of cancer: Additional value for diagnostic imaging and patient management. J Nucl Med 44:1200-1209, 2003 5. Roman CD, Martin WH, Delbeke D: Incremental value of fusion imaging with integrated PET-CT in oncology. Clin Nucl Med 30:470477, 2005 6. Hillner BE, Siegel BA, Liu D, et al: Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: Initial results from the National Oncologic PET Registry. J Clin Oncol 26: 2155-2161, 2008 7. Even-Sapir E, Lerman H, Lievshitz G, et al: Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med 44:1413-1420, 2003 8. Khafif A, Schneebaum S, Fliss DM, et al: Lymphoscintigraphy for sentinel node mapping using a hybrid single photon emission CT (SPECT)/CT system in oral cavity squamous cell carcinoma. Head Neck 28:874-879, 2006 9. Schoder H, Yeung HW, Gonen M, et al: Head and neck cancer: Clinical usefulness and accuracy of PET/CT image fusion. Radiology 231: 65-72, 2004 10. Fleming AJ, Smith SP, Paul CM, et al: Impact of PET/CT on previously untreated head and neck cancer patients. Laryngoscope 117:11731179, 2007 11. Gordin A, Golz A, Keidar Z, et al: The role of FDG-PET/CT imaging in head and neck malignancies—Impact on diagnostic accuracy and patient care. Otolaryngol Head Neck Surg 137:130-137, 2007 12. Gordin A, Golz A, Daitzchman M, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging in patients with carcinoma of the nasopharynx: Diagnostic accuracy and impact on clinical management. Int J Radiat Oncol Biol Phys 68:370-376, 2007 13. Lerman H, Metser U, Lievshitz G, et al: Lymphoscintigraphic sentinel node identification in patients with breast cancer: The role of SPECTCT. Eur J Nucl Med Mol Imaging 33:329-337, 2006 14. van der Ploeg IM, Valdes Olmos RA, Nieweg OE, et al: The additional value of SPECT/CT in lymphatic mapping in breast cancer and melanoma. J Nucl Med 48:1756-1760, 2007 15. Lerman H, Lievshitz G, Zak O, et al: Improved sentinel node identification by SPECT/CT in overweight patients with breast cancer. J Nucl Med 48:201-206, 2007 16. Radan L, Ben-Haim S, Bar-Shalom R, et al: The role of FDG-PET/CT in suspected recurrence of breast cancer. Cancer 107:2545-2551, 2006 17. Heron DE, Beriwal S, Avril N: FDG-PET and PET/CT in radiation therapy simulation and management of patients who have primary and recurrent breast cancer. PET Clin 1:39-49, 2006 18. 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 32:918-924, 2005 19. Wong WL, Chambers RJ: Role of PET/PET CT in the staging and restaging of thoracic oesophageal cancer and gastrooesophageal cancer: A literature review. Abdom Imaging 33:183-190 20. Soyka JD, Veit-Haibach P, Strobel K, et al: Staging pathways in recurrent colorectal carcinoma: Is contrast-enhanced 18F-FDG PET/CT the diagnostic tool of choice? J Nucl Med 49:354-361, 2008 21. Anderson C, Koshy M, Staley C, et al: PET-CT fusion in radiation management of patients with anorectal tumors. Int J Radiat Oncol Biol Phys 69:155-162, 2007 22. Kim JY, Kim MH, Lee TY, et al: Clinical role of 18F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: A prospective study compared with conventional imaging. Am J Gastroenterol 103:1145-1151, 2008

335 23. Park JY, Kim EN, Kim DY, et al: Clinical impact of positron emission tomography or positron emission tomography/computed tomography in the posttherapy surveillance of endometrial carcinoma: Evaluation of 88 patients. Int J Gynecol Cancer 18:1332-1338, 2008 24. Chung HH, Kang WJ, Kim JW, et al: The clinical impact of [18 F]FDG PET/CT for the management of recurrent endometrial cancer: Correlation with clinical and histological findings. Eur J Nucl Med Mol Imaging 35:1081-1088, 2008 25. Simcock B, Neesham D, Quinn M, et al: The impact of PET/CT in the management of recurrent ovarian cancer. Gynecol Oncol 103:271276, 2006 26. Mangili G, Picchio M, Sironi S, et al: Integrated PET/CT as a first-line re-staging modality in patients with suspected recurrence of ovarian cancer. Eur J Nucl Med Mol Imaging 34:658-666, 2007 27. Chung HH, Kang WJ, Kim JW, et al: Role of [18F]FDG PET/CT in the assessment of suspected recurrent ovarian cancer: Correlation with clinical or histological findings. Eur J Nucl Med Mol Imaging 34:480486, 2007 28. Soussan M, Wartski M, Cherel P, et al: Impact of FDG PET-CT imaging on the decision making in the biologic suspicion of ovarian carcinoma recurrence. Gynecol Oncol 108:160-165, 2008 29. Kitajima K, Murakami K, Yamasaki E, et al: Performance of integrated FDG-PET/contrast-enhanced CT in the diagnosis of recurrent ovarian cancer: Comparison with integrated FDG-PET/non-contrast-enhanced CT and enhanced CT. Eur J Nucl Med Mol Imaging 35:14391448, 2008 30. Tharp K, Israel O, Hausmann J, et al: Impact of 131I-SPECT/CT images obtained with an integrated system in the follow-up of patients with thyroid carcinoma. Eur J Nucl Med Mol Imaging 31:1435-1442, 2004 31. Ruf J, Lehmkuhl L, Bertram H, et al: Impact of SPECT and integrated low-dose CT after radioiodine therapy on the management of patients with thyroid carcinoma. Nucl Med Commun 25:1177-1182, 2004 32. Serra A, Bolasco P, Satta L, et al: Role of SPECT/CT in the preoperative assessment of hyperparathyroid patients. Radiol Med 111:999-1008, 2006 33. Krausz Y, Bettman L, Guralnik L, et al: Tc99m-MIBI SPECT/CT in primary hyperparathyroidism. World J Surg 30:76-83, 2006 34. Krausz Y, Keidar Z, Kogan I, et al: SPECT/CT hybrid imaging with In111-pentetreotide in assessment of neuroendocrine tumors. Clin Endocrinol 59:565-573, 2003 35. Pfannenberg AC, Eschmann SM, Horger M, et al: Benefit of anatomical-functional image fusion in the diagnostic work-up of neuroendocrine neoplasms. Eur J Nucl Med Mol Imaging 30:835-843, 2003 36. Hillel PG, van Beek EJ, Taylor C, et al: The clinical impact of a combined gamma camera/CT imaging system on somatostatin receptor imaging of neuroendocrine tumors. Clin Radiol 61:579-587, 2006 37. Raanani P, Shasha Y, Perry C, et al: Is CT scan still necessary for staging in Hodgkin and non-Hodgkin’s lymphoma patients in the PET/CT era? Ann Oncol 17:117-122, 2006 38. Tateishi U, Yamaguchi U, Seki K, et al: Bone and soft-tissue sarcoma: Preoperative staging with fluorine 18 fluorodeoxyglucose PET/CT and conventional imaging. Radiology 245:839-847, 2007 39. Filippi L, Schillaci O: Usefulness of hybrid SPECT/CT in 99mTcHMPAO-labeled leukocyte scintigraphy for bone and joint infections. J Nucl Med 47:1908-1913, 2006 40. Ciernik IF, Dizendorf E, Ciernik IF, et al: Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): A feasibility study. Int J Radiation Biol Phys 57:853-863, 2003 41. Coleman RE, Delbeke D, Guiberteau MJ, et al: Intersociety dialogue on Concurrent PET-CT with an integrated imaging system: From the Joint ACR/SNM/SCBT-MR PET-CT Working Group. J Nucl Med 46: 1225-1239, 2005 42. Schreve P: PET/CT. Semin Ultrasound CT MRI 29:283-289, 2008 43. Delbeke D, Coleman RE, Guiberteau MJ, et al: Society of Nuclear Medicine procedure guidelines for tumor imaging using FDG PET/ CT. J Nucl Med 47:885-895, 2006

336 44. Delbeke D, Coleman RE, Guiberteau MJ, et al: Society of Nuclear Medicine procedure guidelines for SPECT/CT imaging. J Nucl Med 47:1227-1234, 2006 45. MacManus MP, Hicks RJ: Where do we draw the line? Contouring tumors on positron emission tomography/computed tomography Int J Radiat Oncol Biol Phys 71:2-4, 2008 46. Schillaci O, Filippi L, Manni C, et al: Single-photon emission computed tomography/computed tomography in brain tumors. Semin Nucl Med 37:34-47, 2007 47. Pirotte BJ, Lubansu A, Massager N, et al: Results of positron emission tomography guidance and reassessment of the utility of and indications for stereotactic biopsy in children with infiltrative brainstem tumors. J Neurosurg 107:392-399, 2007 48. Pirotte B, Goldman S, Massager N, et al: Comparison of 18F-FDG and 11C-methionine for PET-guided stereotactic brain biopsy of gliomas. J Nucl Med 45:1293-1298, 2004 49. Pirotte B, Goldman S, Van Bogaert P, et al: Integration of [11C]methionine-positron emission tomographic and magnetic resonance imaging for image-guided surgical resection of infiltrative low-grade brain tumors in children. Neurosurgery 57 (suppl):128-139, 2005 50. Pichler BJ, Wehrl HF, Kolb A, et al: Positron emission tomography/ magnetic resonance imaging: The next generation of multimodality imaging? Semin Nucl Med 38:199-208, 2008 51. McGuirt WF, Greven K, Williams D, et al: PET scanning in head and neck oncology: a review. Head Neck 20:208-215, 1998 52. Lowe VJ, Boyd JH, Dunphy FR, et al: Surveillance for recurrent head and neck cancer using PET. J Clin Oncol 18:651-658, 2000 53. Blodgett TM, Fukui MB, Snyderman CH, et al: Combined PET-CT in the head and neck: Part 1. Physiologic, altered physiologic, and artefactual FDG uptake. Radiographics 25:897-912, 2005 54. Uchida Y, Minoshima S, Kawata T, et al: Diagnostic value of FDG PET and salivary gland scintigraphy for parotid tumors. Clin Nucl Med 30:170-176, 2005 55. Branstetter BF IV, Blodgett TM, Zimmer LA, et al: Head and neck malignancy: Is PET/CT more accurate than PET or CT alone? Radiology 235:580-586, 2005 56. Shah J: Cervical lymph node metastases: Diagnostic, therapeutic and prognostic implications. Oncology 4:61-69, 1990 57. Schoder H, Carlson DL, Kraus DH, et al: FDG PET/CT for detecting nodal metastases in patients with oral cancer staged N0 by clinical examination and CT/MRI. J Nucl Med 47:755-762, 2006 58. Tenkos T, Rosenthal E, Lee D, et al: Positron emission tomography in evaluation of stage III and IV head and neck cancer. Head Neck 23:1056-1060, 2001 59. Delgado-Bolton RC, Fernandez-Perez C, Gonzalez-Mate A, et al: Metaanalysis of the performance of 18F-FDG PET in primary tumor detection in unknown primary tumors. J Nucl Med 44:1301-1314, 2003 60. Wartski M, Le Stanc E, Vilain D, et al: In search of unknown primary tumor presenting with cervical metastases: Performance of hybrid FDG-PET-CT. Nucl Med Commun 28:365-371, 2007 61. Zimmer LA, Branstetter BF, Nayak JV, et al: Current use of 18Ffluorodeoxyglucose positron emission tomography and computed tomography in squamous cell carcinoma of the head and neck. Laryngoscope 115:2029-2034, 2005 62. Lowe VJ, Dunphy FR, Varvares M, et al: Evaluation of chemotherapy response in patients with head and neck cancer using FDG PET. Head Neck 19:666-674, 1997 63. Kitagawa Y, Nishizawa S, Sano K, et al: Prospective comparison of 18F-FDG-PET with conventional imaging modalities (MRI, CT and 67Ga scintigraphy) in assessment of combined intraarterial chemotherapy and radiotherapy for head and neck carcinoma. J Nucl Med 44:198-206, 2003 64. Porceddu SV, Jarmolowski E, Hicks RJ, et al: Utility of positron emission tomography for the detection of disease in residual neck nodes after (chemo)radiotherapy in head and neck cancer. Head Neck 27: 175-181, 2005 65. Ong SC, Schöder H, Lee NY, et al: Clinical utility of 18F-FDG PET/CT in assessing the neck after concurrent chemoradiotherapy for locoregional advanced head and neck cancer. J Nucl Med 49:532-540, 2008

D. Delbeke et al 66. Yao M, Smith RB, Hoffman HT, et al: Clinical significance of postradiotherapy [18F]-fluorodeoxyglucose positron emission tomography imaging in management of head-and-neck cancer—A Long-term outcome report. Int J Radiat Oncol Biol Phys 74:9-14, 2009 67. Brouwer J, Bodar EJ, De Bree R, et al: Detecting recurrent laryngeal carcinoma after radiotherapy: Room for improvement. Eur Arch Otorhin 261:417-422, 2004 68. Gordin A, Daitzchman M, Doweck I, et al: FDG PET/CT imaging in patients with carcinoma of the larynx: Diagnostic accuracy and impact on clinical management. Laryngoscope 116:273-278, 2006 69. Wang D, Schultz CJ, Jursinic PA, et al: Initial experience of FDGPET/CT guided IMRT of head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 65:143-151, 2006 70. Zheng XK, Chen LH, Wang QS, et al: Influence of [18F] fluorodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 65:1020-1025, 2006 71. Koshy M, Paulino AC, Howell R, et al: F-18 FDG PET-CT fusion in radiotherapy treatment planning for head and neck cancer. Head Neck 27:494-502, 2005 72. Vernon MR, Maheshwari M, Schultz CJ, et al: Clinical outcomes of patients receiving integrated PET/CT-guided radiotherapy for head and neck carcinoma. Int J Radiat Oncol Biol Phys 70:678-684, 2008 73. Silvestri GA, Gould MK, Margolis ML, et al: Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd ed). Chest 132:178S-201S, 2007 74. van Tinteren H, Hoekstra OS, Smit EF, et al: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: The PLUS multicenter randomised trial. Lancet 359:1388-1393, 2002 75. Lardinois D, Weder W, Hany TF, et al: Staging of non–small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 348:2500-2507, 2003 76. Erdi YE, Rosenzweig K, Erdi AK, et al: Radiotherapy treatment planning for patients with non-small cell lung cancer using positron emission tomography (PET). Radiother Oncol 62:51-60, 2002 77. Deniaud-Alexandre E, Touboul E, Lerouge D, et al: Impact of computed tomography and 18F-deoxyglucose coincidence detection emission tomography image fusion for optimization of conformal radiotherapy in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 63:1432-1441, 2005 78. Mah K, Caldwell CB, Ung YC, et al: The impact of (18)FDG-PET on target and critical organs in CT-based treatment planning of patients with poorly defined non-small-cell lung carcinoma: a prospective study. Int J Radiat Oncol Biol Phys 52:339-350, 2002 79. Bradley J, Thorstad WL, Mutic S, et al: Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 59:78-86, 2004 80. Vanuytsel LJ, Vansteenkiste JF, Stroobants SG, et al: The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer. Radiother Oncol 55:317324, 2000 81. Kalff V, Hicks RJ, MacManus MP, et al: Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: A prospective study. J Clin Oncol 19:111118, 2001 82. Gondi V, Bradley K, Mehta M, et al: Impact of hybrid fluorodeoxyglucose positron-emission tomography/computed tomography on radiotherapy planning in esophageal and non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 67:187-195, 2007 83. Caldwell CB, Mah K, Ung YC, et al: Observer variation in contouring gross tumor volume in patients with poorly defined non-small-cell lung tumors on CT: The impact of 18FDG-hybrid PET fusion. Int J Radiat Oncol Biol Phys 51:923-931, 2001 84. Steenbakkers RJ, Duppen JC, Fitton I, et al: Reduction of observer variation using matched CT-PET for lung cancer delineation: A threedimensional analysis. Int J Radiat Oncol Biol Phys 64:435-448, 2006

Hybrid imaging to improve therapeutic decisions 85. Ashamalla H, Rafla S, Parikh K, et al: The contribution of integrated PET/CT to the evolving definition of treatment volumes in radiation treatment planning in lung cancer. Int J Radiat Oncol Biol Phys 63: 1016-1023, 2005 86. Fox JL, Rengan R, O’Meara W, et al: Does registration of PET and planning CT images decrease interobserver and intraobserver variation in delineating tumor volumes for non-small-cell lung cancer? Int J Radiat Oncol Biol Phys 62:70-75, 2005 87. van der Hoeven JJ, Hoekstra OS, Comans EF, et al: Determinants of diagnostic performance of [F-18]fluorodeoxyglucose positron emission tomography for axillary staging in breast cancer. Ann Surg 236:619-624, 2002 88. Wilking N, Rutqvist LE, Cartensen J, et al: Prognostic significance of axillary nodal status in primary breast cancer in relation to the number of resected nodes. Acta Oncol 31:29-35, 1992 89. Lim HS, Yoon W, Chung TW, et al: FDG PET/CT for the detection and evaluation of breast diseases: Usefulness and limitations. Radiographics 27:S197-S213, 2007 90. Rosen EL, Eubank WB, Mankoff DA: FDG PET, PET/CT, and breast cancer imaging. Radiographics 27:S215-S229, 2007 91. Avril N, Dose J, Janicke F, et al: Assessment of axillary lymph node involvement in breast cancer patients with positron emission tomography using radiolabeled 2-(fluorine-18)-fluoro-2-deoxy-D-glucose. J Natl Cancer Inst 88:1204-1209, 1996 92. Bellon JR, Livingston RB, Eubank WB, et al: Evaluation of the internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC). Am J Clin Oncol 27:407-410, 2004 93. Isasi CR, Moadel RM, Blaufox MD: A meta-analysis of FDG-PET for the evaluation of breast cancer recurrence and metastases. Breast Cancer Res Treat 90:105-112, 2005 94. Eubank WB, Mankoff D, Bhattacharya M, et al: Impact of FDG PET on defining the extent of disease and on the treatment of patients with recurrent or metastatic breast cancer. AJR Am J Roentgenol 183:479486, 2004 95. Yap CS, Seltzer MA, Schiepers C, et al: Impact of whole-body 18FFDG PET on staging and managing patients with breast cancer: The referring physician’s perspective. J Nucl Med 42:1334-1337, 2001 96. Pelosi E, Messa C, Sironi S, et al: Value of integrated PET/CT for lesion localisation in cancer patients: a comparative study. Eur J Nucl Med Mol Imaging 31:932-939, 2004 97. Fueger BJ, Weber WA, Quon A, et al: Performance of 2-deoxy-2-[F18]fluoro-D-glucose positron emission tomography and integrated PET/CT in restaged breast cancer patients. Mol Imag Biol 7:369-376, 2005 98. Tatsumi M, Cohade C, Mourtzikos KA, et al: Initial experience with FDG-PET/CT in the evaluation of breast cancer. Eur J Nucl Med Mol Imaging 33:254-262, 2006 99. Fogelman I, Cook G, Israel O, et al: Positron emission tomography and skeletal metastases. Semin Nucl Med 35:135-142, 2005 100. Du Y, Cullum I, Illidge TM, et al: Fusion of metabolic function and morphology: Sequential [18F]-fluorodeoxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of skeletal metastases in breast cancer. J Clin Oncol 25:3440-3447, 2007 101. Tateishi U, Gamez C, Dawood S, et al: Bone metastases in patients with metastatic breast cancer: Morphologic and metabolic monitoring of response to systemic therapy with integrated PET/CT. Radiology 247:189-196, 2008 102. Even-Sapir E, Metser U, Flusser G, et al: Assessment of malignant skeletal disease: initial experience with 18F-fluoride PET/CT and comparison between 18F-fluoride PET and 18F-fluoride PET/CT. J Nucl Med 45:272-278, 2004 103. Bruzzi JF, Munden RF, Truong MT, et al: PET/CT of esophageal cancer: its role in clinical management. Radiographics 27:1635-1652, 2007 104. Flamen P, Lerut A, Van Cutsem E, et al: Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 18:3202-3210, 2000

337 105. Wallace MB, Nietert PJ, Earle C, et al: An analysis of multiple staging management strategies for carcinoma of the esophagus: Computed tomography, endoscopic ultrasound, positron emission tomography, and thoracoscopy/laparoscopy. Ann Thorac Surg 74:1026-1032, 2002 106. Yuan S, Yu Y, Chao KS, et al: Additional value of PET/CT over PET in assessment of locoregional lymph nodes in thoracic esophageal squamous cell cancer. J Nucl Med 47:1255-1259, 2006 107. Bruzzi JF, Swisher SG, Truong MT, et al: Detection of interval distant metastases: Clinical utility of integrated CT-PET imaging in patients with esophageal carcinoma after neoadjuvant therapy. Cancer 109: 125-134, 2007 108. Das A, Chak A: Reassessment of patients with esophageal cancer after neoadjuvant therapy. Endoscopy 381:S13-S17, 2006 109. Leong T, Everitt C, Yuen K, et al: A prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer. Radiother Oncol 78:254-261, 2006 110. Zhong X, Yu J, Zhang B, et al: Using (18)F-fluorodeoxyglucose positron emission tomography to estimate the length of gross tumor in patients with squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 73:136-141, 2009 111. Drudi FM, Trippa F, Cascone F, et al: Esophagogram and CT vs endoscopic and surgical specimens in the diagnosis of esophageal carcinoma. Radiol Med (Torino) 103:344-352, 2002 112. Goerres GW, Stupp R, Barghouth G, et al: The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumors: Longterm outcome of treatment with imatinib mesylate. Eur J Nucl Med Mol Imaging 32:153-162, 2005 113. Basu S, Mohandas KM, Peshwe H, et al: FDG-PET and PET/CT in the clinical management of gastrointestinal stromal tumor. Nucl Med Commun 29:1026-1039, 2008 114. Huebner RH, Park KC, Shepherd JE, et al: A meta-analysis of the literature for whole-body FDG PET detection of colorectal cancer. J Nucl Med 41:1177-1189, 2000 115. Kinkel K, Lu Y, Both M, et al: Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): A meta-analysis. Radiology 224:748-756, 2002 116. Bipat S, van Leeuwen MS, Comans EF, et al: Colorectal liver metastases: CT, MR imaging, and PET for diagnosis—Meta-analysis. Radiology 237:123-1231, 2005 117. Valk PE, Abella-Columna E, Haseman MK, et al: Whole-body PET imaging with F-18-fluorodeoxyglucose in management of recurrent colorectal cancer. Arch Surg 134:503-511, 1999 118. Ruers TJ, Langenhoff BS, Neeleman N, et al: Value of positron emission tomography with [F-18]-fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. J Clin Oncol 20:388395, 2002 119. Fernandez FG, Drebin JA, Linehan DC, et al: Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18-fluorodeoxyglucose (FDG-PET). Ann Surg 240:438-447, 2004; discussion:447450 120. Cohade C, Osman M, Leal J, et al: Direct comparison of FDG PET and PET-CT imaging in colorectal carcinoma. J Nucl Med 44:1797-1803, 2003 121. Tateishi U, Maeda T, Morimoto T, et al: Non-enhanced CT vs. contrast-enhanced CT in integrated PET/CT studies for nodal staging of rectal cancer. Eur J Nucl Med Mol Imaging 34:1627-1634, 2007 122. Patel DA, Chang ST, Goodman KA, et al: Impact of integrated PET/CT on variability of target volume delineation in rectal cancer. Technol Cancer Res Treat 6:31-36, 2007 123. Ciernik IF, Huser M, Burger C, et al: Automated functional imageguided radiation treatment planning for rectal cancer. Int J Radiat Oncol Biol Phys 62:893-900,2005 124. Wudel LJ, Delbeke D, Morris D, et al: The role of FDG-PET imaging in the evaluation of hepatocellular carcinoma. Am Surg 69:117-126, 2003

338 125. Ho CL, Shen S, Young DWC, et al: Dual tracer PET/CT in the evaluation of hepatocellular carcinoma. J Nucl Med 48:902-909, 2007 126. Anderson CA, Rice MH, Pinson CW, et al: FDG PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg 8:90-97, 2004 127. Kim YJ, Yun M, Lee WJ, et al: Usefulness of 18F-FDG PET in intrahepatic cholangiocarcinomas. Eur J Nucl Med Mol Imaging 30:14671472, 2003 128. Moon CM, Bang S, Chung JB, et al: Usefulness of (18)F-fluorodeoxyglucose positron emission tomography in differential diagnosis and staging of cholangiocarcinomas. J Gastroenterol Hepatol 23:759-765, 2008 129. Corvera CU, Blumgart LH, Akhurst T, et al: 18F-fluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg 206:57-65, 2008 130. Delbeke D, Rose M, Chapman WC, et al: Optimal interpretation of F-18FDG imaging of FDG PET in the diagnosis, staging and management of pancreatic carcinoma. J Nucl Med 40:1784-1792, 1999 131. Buck AK, Nekolla S, Ziegler S, et al: SPECT/CT. J Nucl Med 49:13051319, 2008 132. Schillaci O, Filippi L, Danieli R, et al: Single-photon emission computed tomography/computed tomography in abdominal diseases. Semin Nucl Med 37:48-61, 2007 133. Hussain SM, Terkivatan T, Zondervan PE, et al: Focal nodular hyperplasia: Findings at state-of-the-art MR imaging, US, CT and pathologic analysis. Radiographics 24:3-17, 2004 134. Brancatell G, Vilgrain V, Zappa M, et al: Case 80: Splenosis. Radiology 234:1225-1229, 2005 135. Stehman FB, Bundy BN, DiSaia PJ, et al: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67:2776-2785, 1991 136. Grigsby PW, Siegel BA, Dehdashti F: Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19:3745-3749, 2001 137. Reinhardt MJ, Ehritt-Braun C, Vogelgesang D, et al: Metastatic lymph nodes in patients with cervical cancer: Detection with MR imaging and FDG PET. Radiology 218:776-782, 2001 138. Tran BN, Grigsby PW, Dehdashti F, et al: Occult supraclavicular lymph node metastasis identified by FDG-PET in patients with carcinoma of the uterine cervix. Gynecol Oncol 90:572-576, 2003 139. Havrilesky LJ, Kulasingam SL, Matchar DB, et al: FDG-PET for management of cervical and ovarian cancer. Gynecol Oncol 97:183-191, 2005 140. Lin LL, Mutic S, Low DA, et al: Adaptive brachytherapy treatment planning for cervical cancer using FDG-PET. Int J Radiat Oncol Biol Phys 67:91-96, 2007 141. Boughanim M, Leboulleux S, Rey A, et al: Histologic results of paraaortic lymphadenectomy in patients treated for stage IB2/II cervical cancer with negative [18F]fluorodeoxyglucose positron emission tomography scans in the para-aortic area. J Clin Oncol 26:2558-2561, 2008 142. Esthappan J, Chaudhari S, Santanam L, et al: Prospective clinical trial of positron emission tomography/computed tomography imageguided intensity-modulated radiation therapy for cervical carcinoma with positive Para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 72:1134-1139, 2008 143. Grab D, Flock F, Stohr I, et al: Classification of asymptomatic adnexal masses by ultrasound, magnetic resonance imaging, and positron emission tomography. Gynecol Oncol77:454-459, 2000 144. Zimny M, Siggelkow W, Schroder W, et al: 2-[Fluorine-18]-fluoro-2deoxy-D-glucose positron emission tomography in the diagnosis of recurrent ovarian cancer. Gynecol Oncol 83:310-315, 2001 145. Bristow RE, del CMG, Pannu HK, et al: Clinically occult recurrent ovarian cancer: Patient selection for secondary cytoreductive surgery using combined PET/CT. Gynecol Oncol 90:519-528, 2003 146. Bosniak MA: The current radiographic approaches to renal cysts. Radiology 158:1-10, 1986

D. Delbeke et al 147. Russo P: Renal cell carcinoma: Presentation, staging, and surgical treatment. Semin Oncol 27:160-176, 2000 148. Schoder H, Larson SM: Positron emission tomography for prostate, bladder, and renal cancer. Semin Nucl Med 34:274-292, 2004 149. Kang DE, White RL Jr, Zuger JH, et al: Clinical use of fluorodeoxyglucose F 18 positron emission tomography for detection of renal cell carcinoma. J Urol 171:1806-1809, 2004 150. Divgi CR, Pandit-Taskar N, Jungbluth AA, et al: Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: A phase I trial. Lancet Oncol: 304-310, 2007 151. Schöder H, Herrmann K, Gönen M, et al: 2-[18F]fluoro-2-deoxyglucose positron emission tomography for the detection of disease in patients with prostate-specific antigen relapse after radical prostatectomy. Clin Cancer Res 11:4761-4769, 2005 152. de Jong IJ, Pruim J, Elsinga PH, et al: 11C-choline positron emission tomography for the evaluation after treatment of localized prostate cancer. Eur Urol 44:32-38, 2003 153. Cimitan M, Bortolus R, Morassut S, et al: [(18)F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: Experience in 100 consecutive patients. Eur J Nucl Med Mol Imaging 33:1387-1398, 2006 154. Oyama N, Miller TR, Dehdashti F, et al: 11C-acetate PET imaging of prostate cancer: Detection of recurrent disease at PSA relapse. J Nucl Med 44:549-555, 2003 155. Nuñez R, Macapinlac HA, Yeung HW, et al: Combined 18F-FDG and 11C-methionine PET scans in patients with newly progressive metastatic prostate cancer. J Nucl Med 43:46-55, 2002 156. Wong TZ, Turkington TG, Polascik TJ, et al: ProstaScint (capromab pendetide) imaging using hybrid gamma camera-CT technology. AJR Am J Roentgenol 184:676-680, 2005 157. Sodee DB, Sodee AE, Bakale G: Synergistic value of single-photon emission computed tomography/computed tomography fusion to radioimmunoscintigraphic imaging of prostate cancer. Semin Nucl Med 37:17-28, 2007 158. Thomas CT, Bradshaw PT, Pollock BH, et al: Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol 21:1715-1721, 2003 159. Even-Sapir E, Metser U, Mishani E, et al: The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 47:287297, 2006 160. Hain SF, O’Doherty MJ, Timothy AR, et al: Fluorodeoxyglucose PET in the initial staging of germ cell tumours. Eur J Nucl Med 27:590594, 2000 161. De Santis M, Becherer A, Bokemeyer C, et al: 2-18fluoro-2-deoxy-Dglucose positron emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: An update of the prospective multicentric SEMPET trial. J Clin Oncol 22:1034-1039, 2004 162. Stephens AW, Gonin R, Hutchins GD, et al: Positron emission tomography of residual radiological abnormalities in postchemotherapy germ cell tumour patients. J Clin Oncol 14:1637-1641, 1996 163. Flechon A, Bompas E, Biron P, et al: Management of post-chemotherapy residual masses in advanced seminoma. J Urol 168:1975-1979, 2002 164. Even-Sapir E, Keidar Z, Sachs J, et al: The new technology of combined transmission and emission tomography in evaluation of endocrine neoplasms. J Nucl Med 42:998-1004, 2001 165. Song H, He B, Prideaux A, et al: Lung dosimetry for radioiodine treatment planning in the case of diffuse lung metastases. J Nucl Med 47:1985-1994, 2006 166. Pryma DA, Schöder H, Gönen M, et al: Diagnostic accuracy and prognostic value of 18F-FDG PET in Hürthle cell thyroid cancer patients. J Nucl Med 47:1260-1266, 2006 167. Ong SC, Schöder H, Patel SG, et al: Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels. J Nucl Med 48:501-507, 2007

Hybrid imaging to improve therapeutic decisions 168. Koopmans KP, de Groot JW, Plukker JT, et al: 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: Relation to tumor differentiation. J Nucl Med 49:524531, 2008 169. Grunwald F, Kalicke T, Feine U, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: Results of a multicenter study. Eur J Nucl Med 26:1547-1552, 1999 170. Wang W, Macapinlac H, Finn RD, et al: PET scanning with [18F] 2-fluoro2 deoxy-D-glucose (FDG) can localize residual differentiated thyroid cancer in patients with negative [131I]-iodine whole-body scans. J Clin Endocrinol Metab 84:2291-2302, 1999 171. Wang W, Larson SM, Fazzari M, et al: Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab 85:1107-1113, 2000 172. Leboulleux S, Schroeder PR, Busaidy NL, et al: Assessment of the incremental value of recombinant thyrotropin stimulation before 2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography/ computed tomography imaging to localize residual differentiated thyroid cancer. J Clin Endocrinol Metab 94:1310-1316, 2009 173. Palmedo H, Bucerius J, Joe A, et al: Integrated PET/CT in differentiated thyroid cancer: Diagnostic accuracy and impact on patient management. J Nucl Med 47:616-624, 2006 174. Chen YK, Ding HJ, Chen KT, et al: Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18F-fluorodeoxyglucose positron emission tomography for cancer screening in healthy subjects. Anticancer Res 25:1421-1426, 2005 175. Salvatori M, Melis L, Castaldi P, et al: Clinical significance of focal and diffuse thyroid diseases identified by (18)F-fluorodeoxyglucose positron emission tomography. Biomed Pharmacother 61:488-493, 2007 176. Leboulleux S, Schroeder PR, Schlumberger M, et al: The role of PET in follow-up of patients treated for differentiated epithelial thyroid cancers. Nat Clin Pract Endocrinol Metab 3:112-121, 2007 177. Krenning EP: Somatostatin receptor scintigraphy, in Sandler MP, Patton JA, Coleman RE, et al. (eds): Diagnostic Nuclear Medicine. (3rd ed). Philadelphia, Lippincott, 1996, pp 735-746 178. Gabriel M, Decristoforo C, Kendler D, et al: 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: Comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 48:508-518, 2007 179. Buchmann I, Henze M, Engelbrecht S, et al: Comparison of (68)GaDOTATOC PET and (111)In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 34:1617-1626, 2007 180. Baum R, Niesen A, Leonhardi J, et al: Receptor PET/CT imaging of neuroendocrine tumours using the Ga-68 labelled, high affinity somatostatin analogue DOTA-1-Nal3 octreotide (DOTA-NOC): Clinical results in 327 patients. Eur J Nucl Med Mol Imaging 32 (suppl 1): S54-S55, 2005 181. Prasad V, Fetscher S, Baum RP: Changing role of somatostatin receptor targeted drugs in NET: Nuclear medicine’s view. J Pharm Pharm Sci; 10:321s-337s, 2007 182. Scanga DR, Martin WH, Delbeke D: Value of FDG PET imaging in the management of patients with thyroid, neuroendocrine, and neural crest tumors. Clin Nucl Med 29:86-90, 2004 183. Belhocine T, Foidart J, Rigo P, et al: Fluorodeoxyglucose positron emission tomography and somatostatin receptor scintigraphy for diagnosing and staging carcinoid tumours: Correlations with the pathological indexes p53 and Ki-67. Nucl Med Commun 23:727-734, 2002 184. Rozovsky K, Koplewitz BZ, Krausz Y, et al: The added value of SPECT/CT for the correlation of MIBG scan and diagnostic CT in neuroblastoma and pheochromocytoma. AJR Am J Roentgenol 190: 1085-1090, 2008 185. Tang HR, Da Silva AJ, Matthay KK, et al: Neuroblastoma imaging using a combined CT scanner-scintillation camera and 131I-MIBG. J Nucl Med 42:237-247, 2001 186. Shulkin BL, Hutchinson RJ, Castle VP, et al: Neuroblastoma: Positron emission tomography with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose compared with metaiodobenzylguanidine scintigraphy. Radiology 199:743-750, 1996

339 187. Kushner BH, Yeung HW, Larson SM, et al: Extending positron emission tomography scan utility to high-risk neuroblastoma: Fluorine-18 fluorodeoxyglucose positron emission tomography as sole imaging modality in follow-up of patients. J Clin Oncol 19:3397-3405, 2001 188. Lavely WC, Goetze S, Friedman KP, et al: Comparison of SPECT/CT, SPECT, and planar imaging with single- and dual-phase (99m)Tcsestamibi parathyroid scintigraphy. J Nucl Med 48:1084-1089, 2007 189. Nichols KJ, Tomas MB, Tronco GG, et al: Preoperative parathyroid scintigraphic lesion localization: Accuracy of various types of readings. Radiology 248:221-232, 2008 190. Lu P: Staging and classification of lymphoma. Semin Nucl Med 35: 160-164, 2005 191. Schoder H, Noy A, Gonen M, et al: Intensity of 18fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin’s lymphoma. J Clin Oncol 23:46434651, 2005 192. Hicks RJ, Mac Manus MP, Seymour JF: Initial staging of lymphoma with positron emission tomography and computed tomography. Semin Nucl Med 35:165-175, 2005 193. Freudenberg LS, Antoch G, Schütt P, et al: FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging 31:325-329, 2004 194. Rodríguez-Vigil B, Gómez-León N, Pinilla I, et al: PET/CT in lymphoma: Prospective study of enhanced full-dose PET/CT vs. unenhanced low-dose PET/CT. J Nucl Med 47:1643-1648, 2006 195. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006 196. Alazraki N, Glass EC, Castronovo F, et al: Procedure guideline for lymphoscintigraphy and the use of intraoperative gamma probe for sentinel lymph node localization in melanoma of intermediate thickness, version 1.0. Available at: http://interactive.snm.org/docs/pg_ ch24_0403.pdf, 2002 197. Belhocine TZ, Scott AM, Evan-Sapir E, et al: Role of nuclear medicine in the management of cutaneous malignant melanoma. J Nucl Med 47:957-967, 2006 198. Garbe C, Paul A, Kohler-Späth H: Prospective evaluation of a follow-up schedule in cutaneous melanoma patients: Recommendations for an effective follow-up strategy. J Clin Oncol 21:520-529, 2003 199. Garbe C, Eigentler TK: Diagnosis and treatment of cutaneous melanoma: State of the art 2006. Melanoma Res 17:117-127, 2007 200. Schwimmer J, Essner R, Patel A, et al: A review of the literature for whole-body FDG PET in the management of patients with melanoma. Q J Nucl Med 44:153-167, 2000 201. Bastiaannet E, Oyen WJG, Meijer S, et al: Impact of [18F]fluorodeoxyglucose positron emission tomography on surgical management of melanoma patients. Br J Surg 93:243-249, 2006 202. Strobel K, Dummer R, Husarik D, et al: High-risk melanoma: Accuracy of FDG PET/CT with added CT morphologic information for detection of metastases. Radiology 244:566-674, 2007 203. Reinhardt MJ, Joe AY, Jaeger U, et al: Diagnostic performance of whole body dual modality 18F-FDG PET/CT imaging for N- and M-staging of malignant melanoma: Experience with 250 consecutive patients. J Clin Oncol 24:1178-1187, 2006 204. Even-Sapir E: Imaging of malignant bone involvement by morphologic, scintigraphic, and hybrid modalities. J Nucl Med 46:13561367, 2005 205. Römer W, Nömayr A, Uder M, et al: SPECT-guided CT for evaluating foci of increased bone metabolism classified as indeterminate on SPECT in cancer patients. J Nucl Med 47:1102-1106, 2006 206. Horger M, Eschmann SM, et al: Evaluation of combined transmission and emission tomography for classification of skeletal lesions. AJR 183:655-661, 2004 207. Utsunomiya D, Shiraishi S, Imuta M, et al: Added value of SPECT/CT fusion in assessing suspected bone metastasis: Comparison with scintigraphy alone and nonfused scintigraphy and CT. Radiology 238: 264-271, 2006 208. Strobel K, Burger C, Seifert B, et al: Characterization of focal bone lesions in the axial skeleton: Performance of planar bone scintigraphy

D. Delbeke et al

340

209.

210.

211.

212.

213.

214.

215.

216.

217.

compared with SPECT and SPECT fused with CT. AJR Am J Roentgenol 188:W467-W474, 2007 Kostakoglu L, Hardoff R, Mirtcheva R, et al: PET/CT fusion imaging in differentiating physiologic from pathologic FDG uptake. Radiographics 24: 1411-1431, 2004 Metser U, Lerman H, Blank A, et al: Malignant involvement of the spine: Assessment by 18F-FDG PET/CT. J Nucl Med 45:279-284, 2004 Nakai T, Okuyama C, Kubota T, et al: Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer. Eur J Nucl Med Mol Imag 32:1253-1258, 2005 Abe K, Sasaki M, Kuwabara Y, et al: Comparison of 18FDG-PET with 99mTc-HMDP scintigraphy for the detection of bone metastases in patients with breast cancer. Ann Nucl Med 19:573-579, 2005 Langsteger W, Heinisch M, Fogelman I: The role of fluorodeoxyglucose, 18F-dihydroxyphenylalanine, 18F-choline, and 18F-fluoride in bone imaging with emphasis on prostate and breast. Semin Nucl Med 36:73-92, 2006 Israel O, Goldberg A, Nachtigal A, et al: FDG-PET and CT patterns of bone metastases and their relationship to previously administered anti-cancer therapy. Eur J Nucl Med Mol Imaging 33:1280-1284, 2006 Horger M, Bares R: The role of single-photon emission computed tomography/computed tomography in benign and malignant bone disease. Semin Nucl Med 36:286-294, 2006 McDonald M, Cooper R, Wang MY: Use of computed tomographysingle-photon emission computed tomography fusion for diagnosing painful facet arthropathy. Technical note. Neurosurg Focus 22:E2, 2007 Even-Sapir E, Flusser G, Lerman H, et al: SPECT/multislice low-dose CT: A clinically relevant constituent in the imaging algorithm of nononcologic patients referred for BS. J Nucl Med 48:319-324, 2007

218. Ovadia D, Metser U, Lievshitz G, et al: Back pain in adolescents: Assessment with integrated 18F-fluoride positron-emission tomography-computed tomography. J Pediatr Orthop 27:90-93, 2007 219. Lim R, Fahey FH, Drubach LA, et al: Early experience with fluorine-18 sodium fluoride bone PET in young patients with back pain. J Pediatr Orthop 27:277-282, 2007 220. Even-Sapir E, Mishani E, Flusser G, et al: 18F-fluoride positron emission tomography and positron emission tomography/computed tomography. Semin Nucl Med 37:462-469, 2007 221. Metser U, Even-Sapir E: Increased (18)F-fluorodeoxyglucose uptake in benign, non-physiologic lesions found on whole-body positron emission tomography/computed tomography (PET/CT): Accumulated data from four years of experience with PET/CT. Semin Nucl Med 37:206-222, 2007 222. Horger M, Eschmann SM, Pfannenberg C, et al: Added value of SPECT/CT in patients suspected of having bone infection: Preliminary results. Arch Orthop Trauma Surg 127:211-221, 2007 223. Bar-Shalom R, Yefremov N, Guralnik L, et al: SPECT/CT using 67Ga and 111In-labeled leukocyte scintigraphy for diagnosis of infection. J Nucl Med 47:587-594, 2006 224. Love C, Tomas MB, Tronco GG, et al: FDG PET of infection and inflammation. Radiographics 25:1357-1368, 2005 225. Hartmann A, Eid K, Dora C, et al: Diagnostic value of 18F-FDG PET/CT in trauma patients with suspected chronic osteomyelitis. Eur J Nucl Med Mol Imaging 34:704-714, 2007 226. Keidar Z, Militianu D, Melamed E, et al: The diabetic foot: Initial experience with 18F-FDG PET/CT. J Nucl Med 46:444-449, 2005 227. Mahfouz T, Miceli MH, Saghafifar F, et al: 18F-fluorodeoxyglucose positron emission tomography contributes to the diagnosis and management of infections in patients with multiple myeloma: A study of 165 infectious episodes. J Clin Oncol 23:7857-7863, 2005 228. Keidar Z, Engel A, Hoffman A, et al: Prosthetic vascular graft infection: The role of 18F-FDG-PET/CT. J Nucl Med 48:1230-1236, 2007