Potential Role of Positron Emission Tomography/Magnetic Resonance Imaging in Gastrointestinal and Abdominal Malignancies: Preliminary Experience Sara Reis Teixera, MD,*,† Andres A. Kohan, MD,‡ Raj Mohan Paspulati, MD,*,‡ Rong Rong, MD,‡ and Karin Anna Herrmann, MD*,‡

Introduction

P

ositron emission tomography-magnetic resonance imaging (PET-MRI) is increasingly used in the clinical setting of oncologic malignancies. Comparing PET/computed tomography (CT) and PET-MR in oncologic diseases, an overall good to excellent correlation is reported by most published articles in this field.1-3 The individual value of PET-MR for distinct oncologic diseases in the abdomen, however, is still under investigation. This article (1) reviews the established role and value of PET and MRI as individual imaging modalities in the workup of certain oncologic diseases within the abdomen and (2) reports our initial experience in this field to provide a perspective of the potential future role and expected value of PET-MR in these clinical scenarios.

Secondary Malignant Disease to the Liver Secondary malignant liver disease is the most prevalent malignant condition in the liver, outnumbering primary hepatic tumors by up to 40-fold. The most common malignancies that metastasize to the liver originate from the gastrointestinal tract owing to its venous drainage via the hepatic portovenous system. For colorectal cancer (CRC), the liver is the sole site of secondary disease in approximately 40% of the *Department of Radiology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH. †Division of Radiology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil. ‡Case Western Reserve University, Cleveland, OH. Conflict of interest: Philips Healthcare Research Fellowship Coordinator. Address reprint requests to Karin Anna Herrmann, MD, Department of Radiology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH 44106. E-mail: Karin.Herrmann@ UHHospitals.org

http://dx.doi.org/10.1053/j.ro.2014.07.003 0037-198X/& 2014 Elsevier Inc. All rights reserved.

patients.4 Other common primary neoplasms that seed to the liver via hematogenous spread are breast cancer, lung cancer, and melanoma among others. The first imaging modality to be used to detect liver metastases in most clinical protocols is ultrasonography (US) followed by contrast-enhanced CT (CE-CT). However, in recent years MRI of the liver has proven its superiority5 particularly in detecting small lesions.6,7 The main advantages of MRI in the abdomen are the superior soft tissue contrast compared with CT and the options of characterization using contrast dynamics and functional information at a cellular level through diffusion-weighted imaging (DWI) sequences.8 Moreover, the use of liver-specific contrast agents has demonstrated to even further improve its sensitivity and specificity for detection of liver metastases.9 Another advantage of MRI is its lack of ionizing radiation. For detection of secondary liver lesions, 2-deoxy-2[18F]-fluoro-D-glucose ([18F]-FDG)-PET is considered highly sensitive and specific10; however, it lacks spatial resolution. In addition, the physiological glucose metabolism of the liver itself decreases the conspicuity of focal abnormal [18F]-FDG uptake in small lesions and, therefore, adds to the limits in detecting smaller lesions. The true strength of [18F]-FDG-PET/CT lies in the detection of extrahepatic metastatic disease. [18F]-FDG-PET/CT significantly improves the patient workup, including modifying the surgical approach in many conditions. Some studies comparing the accuracy of [18F]-FDG-PET and MRI showed similar results of both modalities individually; however, others are more controversial. In 1 meta-analysis, [18F]-FDG-PET was found to be more accurate than MRI.11 In a more recent study, MRI showed the highest accuracy.5 In both studies, the results were comparable, with PET being the best technique in the per-patient analysis to detect distant metastases and MRI more accurate in the per-lesion analysis. 321

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322 In the clinical setting of treatment monitoring, response assessment and restaging for recurrence, [18F]-FDG-PET/CT has shown good correlation to disease-free survival.12 This, again, makes it a very powerful tool in the comprehensive workup of a malignant disease in the abdomen. As the strength of MRI is to detect and characterize liver metastases, and the strength of [18F]-FDG-PET is to identify peripheral metastases, the combination of both in PET-MR appears ideal to evaluate patients with oncologic disease. Studies on retrospective fusion of MRI of the liver and PET/ CT have demonstrated in the past that there was significant value in combining the information of both the imaging modalities.7 The detection rate of liver lesions was shown to be significantly lower for PET/CT than for gadoliniumethoxibenzyl-diethylenetriamine pentaacetic acid-enhanced MRI and the fused PET-MR demonstrated significantly higher sensitivity and higher diagnostic confidence than PET/CT.7 Similar results were found by Yong et al13 who confirmed that retrospectively fused PET-MR images delivered higher sensitivity for liver metastases in CRC compared with PET/CT, with sensitivities of 84.2% for PET/CT and 98.3% for PET-MR.13 Initial reports on the preliminary experience with PETMR in comparison with PET/CT confirm these findings. PET-MR shows higher lesion conspicuity and diagnostic confidence,1,7 even without using a state-of-the-art MRI liver study.1 Both lesion conspicuity and diagnostic confidence in diagnosing liver lesions are improved with PETMR compared with PET/CT.1 A recent study reported on 55 patients with 120 liver lesions who underwent trimodality PET/CT/MR to investigate the minimal imaging protocol required for the detection of liver metastases. PET-MR imaging with T1weighted (T1w) or T2w sequences or both results in similar diagnostic accuracy for the detection of liver metastases compared with PET/CE-CT. To significantly improve the characterization of liver lesions, however, the use of dynamic CE imaging was still recommended.14 In our preliminary experience with PET-MR and liver lesions, we observe even further advantageous aspects of PET-MR compared with standard-of-care imaging. PET-MR has become a very helpful tool in comprehensively assessing CRC, more precisely rectal cancer, in which MRI plays an essential role for local staging. With PET-MR, both the local staging and the staging for synchronous liver metastases can be obtained in a single examination. This significantly enhances the specificity for small liver lesions, which are equivocal or less well characterized on standard CE-CT (Fig. 1). The fact that the staging of the local disease in the pelvis, secondary disease in the liver, and the peripheral metastases can be comprised in 1 examination has many advantages: it saves the patient's time, multiple appointments, and repeated contrast injections and is more time efficient from an administrative and managerial standpoint. In our opinion and from our current clinical practice, PET-MR may evolve into a comprehensive staging tool for CRC. Comprehensive disease staging with PET-MR in a single examination also applies successfully to other neoplasms of the gastrointestinal tract and gynecologic cancers both at initial diagnostic workup and in follow-up.

Another promising field for PET-MR is the assessment of disease following neoadjuvant treatment. In the setting of reevaluation of liver metastases after chemotherapy, tumors may become metabolically inactive, whereas morphologic residue of disease is still present. For potential surgical planning and secondary interventions with minimally invasive therapy such as radiofrequency ablation, cryoablation, or other locally ablative techniques, however, this morphologic information is still crucial. PET-MR (but not necessarily PET/CT) can provide information on how the tumor has responded to treatment in terms of size, morphology, and vascularity and if there is interval development of new disease with very small lesions in the liver that might escape the sensitivity of PET given its limited spatial resolution (Fig. 2). PET-MR of the liver can be performed in a convenient time frame when using the uptake phase of [18F]-FDG for the liver imaging with MRI. This is possible with a sequential design of the PET/MR device where MR and PET are obtained consecutively. A suggestion of an imaging protocol for PET-MR including whole-body imaging and focused dedicated MRI of the liver is provided in Figure 3. In this setting, MR and PET imaging can be performed in a little more than an hour.

Primary Hepatic Malignancies Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and ranks sixth in cancer incidence and third in mortality worldwide.15 The early diagnosis is important as curative treatment options are available. According to the different guidelines,16-19 the imaging tests are used for diagnosis and surveillance. US is the imaging modality for periodic surveillance in patients at risk for HCC, in conjunction with tumor markers (such as αfetoprotein or PIVKA II). Multiphase CE-CT and MRI are used for further evaluation when a nodule 41 cm is depicted by US. If a nodule Z2 cm demonstrates arterial enhancement and portal or delayed washout on CT or MRI, the diagnosis of HCC is established and histologic proof is not required.17,20 For nodules 41 cm, a single-image modality—CT or MRI— was proposed sufficient to confirm the diagnosis18; however, it requires a second study if atypical features are present. Biopsy may be required in select cases. The use of hepatocyte-specific contrast agents in MRI has shown to be useful, mainly to characterize small or atypical lesions.21 [18F]-FDG-PET is established for detecting extrahepatic metastases from HCC with a sensitivity of 83% for lesions 41 cm.22 For whole-body staging, [18F]-FDG-PET was superior to CT.23 Conversely, the sensitivity of [18F]-FDG-PET for detecting the primary tumor HCC was reported to be as low as 50%-55% compared with that of CT.24,25 Despite this fact, [18F]-FDG-PET is used to predict tumor differentiation, staging, and clinical outcomes in PET-positive cases. Seo et al26 demonstrated that low-grade and well-differentiated HCCs have low standardized uptake value (SUV). However, high SUV is found in poorly differentiated tumors.26 This is due to the activity of the glucose-6-phosphatase, an enzyme that

Potential role of PET/MRI in gastrointestinal and abdominal malignancies

Figure 1 [18F]-FDG-PET-MR in a 61-year-old female patient with recently diagnosed colon cancer in colonoscopy. Routine staging with contrast-enhanced CT (A) identified a hypodense lesion in the liver concerning for hepatic metastasis (arrows). Further evaluation with PET-MR was able to demonstrate that this lesion corresponded to a focal fatty infiltration as shown on in phase (B) and opposed phase (C) MRI derived from T1-weighted Dixon imaging. PET component of PET-MR ((D, F) axial view) confirmed the benign finding with a lack of [18F]-FDG avidity (circles). At the same time, comprehensive staging was completed with whole-body PET-MR (G-I). Dashed arrows (G-I) are pointing the primary colon tumor. (E and H) Axial and coronal reformatted water-Dixon imaging of the MR component of PET-MR at the same level as (A-C). (F and I) Axial and coronal reformatted fused PET-MR imaging. (Color version of figure is available online.)

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Figure 2 [18F]-FDG-PET-MR in a 61-year-old male patient with colon cancer: Pretreatment (A, C, and E) and posttreatment images are provided (B, D, and F). After chemotherapy, the liver lesion, previously [18F]-FDG avid (circle in (A)), was non– [18F]-FDG avid on PET images (circle in (B)). The MR image of the PET-MR showed the lesion was still present and decreased in size. The lesion demonstrates both less enhancement (arrow in (D)) and therefore less vascularity in postgadolinium imaging and increase in the ADC value (dashed arrow in (F)) on DWI. (A and B) Coronal PET imaging from PET/MR, (C and D) axial T1-weighted MRI with gadolinium, and (E and F) axial apparent diffusion coefficient map. ADC, apparent diffusion coefficient. (Color version of figure is available online.)

converts [18F]-FDG-6-P to [18F]-FDG and is high in normal liver and nearly zero in metastatic and undifferentiated tumors.27 In addition, hypermetabolic tumors were associated with shorter survival rates and higher recurrence after surgical resection.26,28 Patients with [18F]-FDG-avid primary HCCs had advanced stage disease, whereas patients with no accumulation in the tumor had a lower-stage disease.29 PET with delayed imaging or dual-time-point imaging has been reported helpful when evaluating liver lesions. [18F]-FDG uptake will decrease over time in normal liver parenchyma and benign lesions, tracer uptake in malignant lesions such as HCC or metastases tends to continuously increase.3

Other tracers have been proposed for the detection of HCC. [11C]-acetate is a tracer that serves as a substrate for the fatty acid and cholesterol synthesis. In a study, when performing dual-tracer PET/CT with [11C]-acetate in addition to [18F]-FDG, overall sensitivity for detecting HCC was improved although it still remained low for small lesions. In addition, it did not show significant improvement for extrahepatic staging compared with [18F]-FDGPET/CT.23 Radiolabeled [11C]-choline PET and PET/CT were shown to be more sensitive for detecting welldifferentiated HCC compared with [18F]-FDG-PET, with the latter being more sensitive in poorly differentiated

Figure 3 Workflow for a PET-MR imaging protocol including dedicated MRI of the liver and whole-body MRI. GRE, gradient echo; SSFSE, single-shot fast spin echo; WB, whole body; WB at MR, whole-body attenuation correction magnetic resonance imaging. (Color version of figure is available online.) The arrow indicates the turning of the table in the sequentially designed PET/MR.

Potential role of PET/MRI in gastrointestinal and abdominal malignancies tumors.30 Radiolabeled [11C]-choline tracers may also be used to assess extrahepatic disease, as it has an effect on staging and workup of these patients.31 As for other hepatic neoplasms, [18F]-fluoromethylcholinPET/CT can accurately differentiate focal nodular hyperplasia from hepatocellular adenoma when conventional imaging techniques fail to do so.32 [18F]-fluorothymidine (FLT), a tracer mainly used for imaging brain tumors, has been shown to have a sensitivity of approximately 70% for detecting HCC.33 Another tracer with promising results for this purpose is 2-[18F]-fluoro-2-deoxy-D-galactose.34 Given the fact that MRI is superior to CT for imaging the liver3 and in the perspective of this vast tracer spectrum and the potential of MRI as an anatomical and functional partner to these tracers, the combination of PET with MRI seems more than promising. To date, the potential has not been fully explored and no literature is available to demonstrate the value of PET-MR in this field.

Cholangiocellular Carcinoma Cholangiocellular carcinoma (CCC) is the second most common primary malignant hepatic tumor after HCC.35 It is a rare malignancy derived from the columnar epithelium of the bile ducts. It may be extrahepatic or intrahepatic or both, but the most common site is at or near the bifurcation of the common bile duct into the right and left hepatic ducts.36 Curative resection may increase the overall survival.37 Imaging plays an important role in the diagnosis, staging, assessment of resectability, and screening of high-risk patients. Multiphase CE-CT and CT cholangiography provide details of the biliary anatomy, tumor staging, and spread to the abdomen, and help surgical planning. MRI and MR cholangiopancreatography (MRCP) are established noninvasive tools to diagnose and stage CCC with high accuracy38 (92%-94.4% for MRI-MRCP compared with 88.9%-80.5% for PET/CT).39 The use of hepatobiliary target contrast agents,40 use of DWI, and development of specific coils41 and scanners have refined the performance of MRI in detecting these tumors, even for very small and intraluminal lesions.38 Endoscopic retrograde cholangiopancreatography helps in the diagnosis and, in addition, biopsies or cell brushing can deliver histopathologic proof of disease. It furthermore enables palliative treatment by placing stents to decompress the biliary system. The role of PET in CCC is reportedly rather limited. Overall sensitivity of [18F]-FDG-PET for detecting masslike intrahepatic CCC is higher (100%) than that for infiltrating type (76.8%),39 however, similar results have been reported by other groups.42,43 A potential explanation for this observation may be the histopathologic feature of the infiltrating type presenting with abundant fibrosis, associated with low [18F]FDG uptake.44 By contrast, [18F]-FDG-PET, however, may be positive in a number of other scenarios including benign conditions, such as sclerosing cholangitis, granulomatous diseases, abscesses, and patients with biliary stent, which makes a specific diagnosis difficult.43,45 A significant diagnostic problem in CCC remains the detection of nodal metastases using conventional imaging

325 techniques. [18F]-FDG-PET showed a lower sensitivity (38%) compared with CT (54%) for detecting regional lymph node (LN) metastases although specificity was higher (100% vs 59%).42,46 [18F]-FDG-PET changed the workup of patients by detecting “hidden” metastases of CCC in 30% of patients.43 Our experience with CCC and PET-MR is limited and refers to assessment of metastatic disease. Other than the primary tumor, metastases of CCC may exhibit [18F]-FDG avidity and therefore be detectable with PET. Of particular help is the improved anatomical reference in PET-MR of the abdomen for mesenteric structures and bowel compared with nonenhanced PET/CT. Serosal implants or lesions close to bowel may be misinterpreted as physiological bowel activity in PET. MRI with its high soft tissue contrast can provide better detailed information close to bowel structures and identify the morphologic correlate of serosal implants. Although serosal implants may not be the most typical site of metastatic disease from CCC, this feature is helpful in other neoplasms of the abdomen where peritoneal metastatic spread is more common such as in gastric cancer or pancreatic cancer and also in gynecologic tumors (Fig. 4).

Pancreatic Cancer Pancreatic ductal adenocarcinoma is the second most common gastrointestinal malignancy, after CRC. It is estimated as the fourth most common cause of cancer-related death in the United States, because of its aggressive disease biology and oftentimes unresectable stage at the time of diagnosis. The only cure is surgical resection; however, only approximately 15%20% of patients have potentially resectable disease at presentation.47 Even if the tumor is resectable, the 5-year survival rate is low, reportedly approximately 27%.48 Imaging evaluation plays a pivotal role in the initial decision making. Tumor staging is based on the lesion size, location in the pancreas, local extension in and beyond the pancreas as well as vascular involvement, and the presence of metastatic lesions. Multidetector CT angiography is the preferred method for initial evaluation of a patient with suspicious of pancreatic ductal adenocarcinoma.49 MRI-MRCP with dedicated pancreatic protocol is equally sensitive and specific and can be used interchangeably.47 Owing to its higher costs and less availability MRI seems less used than CT in this context. [18F]-FDG-PET or PET/CT has been reported to be more sensitive than morphologic imaging techniques to detect the primary tumor50; however, depicting the relationship of the pancreatic lesion with adjacent organs and vascular structures and detecting nodal involvement are poor with [18F]-FDGPET/CT. For local and nodal staging, PET/CT does not add any additional information to CT or MRI.51 Moreover, falsenegative results may occur with PET in hyperglycemic patients and for small lesions, whereas false-positive results may be found in case of inflammatory diseases such as pancreatitis, focal pancreatitis, infection of a pseudocyst, or presence of a biliary stent with adjacent inflammation.51 The main advantage of [18F]-FDG-PET/CT in pancreatic cancer is the ability to

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Figure 4 [18F]-FDG-PET-MR in a 64-year-old female patient with cholangiocellular carcinoma and mesenteric implants. Focally increased [18F]-FDG uptake is noted in the peritoneal cavity of the left lower abdomen (black arrow in (A)). MRI demonstrates clearly that this corresponds to a soft tissue nodule (B) (white arrows in (D)) next to small bowel (B) (asterisk in (D)). Note that there is even dilatation of the small bowel loop proximal to it, indicating some tethering and partial obstruction owing to the implant. (Color version of figure is available online.)

detect distant metastases, preventing unnecessary surgeries and changing management of patients in up to 16%.52,53 [18F]-FDG-PET/CT has also demonstrated value in the assessment of other neoplastic diseases of the pancreas, more specifically, intraductal papillary-mucinous neoplasms (IPMN). IPMNs express glucose transporter-1, which correlates with [18F]-FDG uptake.54 As glucose transporter-1 concentration is higher in malignant variants of IPMNs, [18F]-FDG-PET has a higher accuracy than CT and MRI in detecting malignant IPMNs (95% vs 72%), with a sensitivity of 92% and specificity of 97%.55 To differentiate various malignant neoplasms from benign cystic lesions of the pancreas, the accuracy of [18]-FDG-PET was reported as 94% compared with 80% of CT.56 However, there is controversial information when reviewing results of another study in which the sensitivity and specificity of PET to detect malignant lesions were 57% and 85%, respectively, not adding significant information compared with conventional imaging.57 They concluded that regardless of the PET findings, PET identified lesions primarily among those patients with cross-sectional imaging characteristics that would result in resection. The guidelines of the National Comprehensive Cancer Network state that PET should not be used routinely

for the assessment of pancreatic lesions and suspected cancer, but rather serves in diagnosis of indeterminate lesions.57 Our initial experience in pancreatic cancer indicates particular value of PET-MR in several distinct clinical scenarios. In unequivocal pancreatic masses or lesions, MRI and MRCP can provide excellent localization and guidance of surgical planning. PET will help in determining the likelihood of malignancy and the exact location. Of particularly incremental value in our experience is PETMR in the setting of postoperative changes after Whipple procedure to assess for recurrence. Major pancreatic surgery including gastrointestinal reconstruction and multiple bowel and organ anastomoses can be associated with significant postsurgical changes, scarring and modifications of normal anatomy. In the presence of these changes, detection of recurrence can be challenging. MRI compared with CT offers a better anatomical soft tissue detail and improved distinction of bowel from lymphadenopathy or recurrent neoplastic soft tissue especially when including DWI (Fig. 5). Other helpful indications of PET-MR could be to distinguish predominantly cystic mucinous neoplasms from complex cystic post inflammatory changes and ductal dilatation in chronic pancreatitis. Likewise, it may be helpful to identify

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Figure 5 [18F]-FDG-PET-MR in a 73-year-old female patient with recurrence from pancreatic cancer in a lymph node after Whipple procedure. MRI provides better anatomical resolution and soft tissue detail than CT in this area with postsurgical changes. MRI ((A) axial T2-weighted single-shot fast spin-echo imaging) with diffusion-weighted imaging (B) was able to show enlarged lymph nodes (arrows) with increased uptake on [18F]-FDG-PET (C) and PET-MR (D) suggestive of neoplastic involvement. (Color version of figure is available online.)

neoplasms developing in the presence of chronic pancreatitis. However, this indication needs to be further explored and determined whether there is an incremental value over existing standard imaging.

Neuroendocrine Tumors Gastroenteropancreatic neuroendocrine tumors (NETs) are rare endocrine lesions that derive from the diffuse neuroendocrine system, formed by the cells of the gut, bronchopulmonary tract, and scattered endocrine cells in other endodermal derivatives. The incidence is approximately 2.55 cases per 100,000 with a significant increase in the last decades.58 NETs can synthesize and secrete a variety of metabolic active hormones and amines leading to distinct syndromes of endocrine hyperfunction. However, most of these tumors are nonfunctioning and present in advanced disease stage with liver metastases or large masses with sitespecific symptoms. NETs may also be found incidentally following surgeries for unrelated reasons, such as appendiceal carcinoids. Treatment strategy planning of the patient with NETs is based on accurate diagnosis, assessment of location, and extent of the tumor. For this purpose, various imaging modalities may be used but none of them is 100% sensitive, and in many cases, multiple modalities might be needed. Regarding the sensitivity

and specificity of the various preoperative imaging modalities (US, CT, MRI, and endoscopic US), little data were obtained from the literature.59 For the detection of pancreatic NETs, MRI showed an overall sensitivity (mean of 93%) and specificity (mean of 88%), whereas endoscopic US was the most sensitive (sensitivity mean 93%) and specific (specificity mean 95%) for detection of pancreatic tumors.59 The detection rates of liver and extrahepatic abdominal soft tissue metastases were also higher using MRI, in up to 95%.59,60 MRI may also be used for therapy monitoring with no risk of radiation exposure.61 Radionuclide imaging has an important role in the management of patients with NETs. NET cells highly express somatostatin receptors subtypes S1 through S5. This feature allowed the development of specific target molecular imaging.62 Somatostatin receptor imaging, either by scintigraphy or more recently by PET, facilitates staging and detection of lesions.61 Gallium-68–labeled preparations of octreotide ([68Ga]-DOTATOC ((68) Gallium- 1,4,7,10-tetraazacyclododecane-N, N',N",N'"-tetraacetic acid (DOTA) -d-Phe(1)-Tyr (3)-Octreotide) and [68Ga]-DOTANOC ((68) Gallium- DOTA 1-NaI3-octreotide)) or octreate ([68Ga]-DOTATATE ((68)Gallium- DOTA - 1,Tyrosine-3-Octreotate)) have very high affinity to somatostatin receptors. Simultaneous PET/CT with 68 Ga-labeled preparations of somatostatin analogues ([68Ga]DOTA) were reported as superior to somatostatin imaging by scintigraphy63 and to conventional imaging.63,64 [68Ga]-DOTA

328 PET has better spatial resolution and high overall sensitivity.65 In addition, it offers logistical advantages in that [68Ga]-DOTA allows images in 30-60 minutes after injection.61 [18F]-FDG is a less effective tracer in the management of NETs. The sensitivity of [18F]-FDG-PET is related to the differentiation of the tumor and may have a prognostic value. It tends to be positive in more aggressive, dedifferentiated neuroendocrine carcinoma, grade 3 according to the WHO classification. Increased [18F]-FDG uptake in carcinoid tumors has been shown to be useful for identifying NETs with rapid growth and aggressive behavior.66 Thus, combined use of [18F]-FDG and [68Ga]-DOTA in PET studies provides complementary information regarding the tumor viability and expression of somatostatin receptors of NETs. In many countries, [68Ga]-DOTA PET/CT is currently considered the standard-of-care imaging modality in the staging and treatment monitoring of NETs.2 However, these receptor-specific radionuclides are not available in the United States, as they are not fully Food and Drug Administration approved. Therefore, the initial experience with PET-MR and somatostatin radionuclides has been gathered mostly in Europe and other parts of the world and has proven to be promising. An initial study on 8 patients reported the very first preliminary results in 2013.2 These stated an excellent correlation of SUV between PET/CT and PET-MR, a slightly lower detection rate of PET-MR for LNs but better performance for liver metastases. PET-MR identified all patients with disease whereas PET/CT missed 1 patient.2 Promising findings in favor of PET-MR were basically confirmed in another study based on 24 patients with neuroendocrine neoplasms and variable degree of metastatic disease that evaluated the feasibility of whole-body [68Ga]-DOTATOC PET-MR with good diagnostic image quality although slightly inferior to PET/CT. Lesion detection was similar on a per-patient basis.67 [68Ga]-DOTA PET-MR is feasible, with a higher rate of lesion detection compared with PET/CT2 but with the drawback of less accuracy of PET-MR for the depiction of small lung and sclerotic bone lesions.2 Overall, NETs appear to be an ideal tumor entity for PET-MR as the simultaneous information about morphologic disease extent and at the same time metabolically active tumor load is essential in these slow-growing tumors that oftentimes can be kept under control for a long time with biotherapy with somatostatin analogues. The combined information is essential in this specific tumor type and PET-MR may become the modality of choice for this particular indication.

Stomach Gastric cancer is a worldwide problem with more than 600,000 cases reported annually. The highest rates occur in Asia (mostly in Japan and China), Eastern Europe, and South America.68 The only proven curative treatment is complete resection of the gastric tumor and adjacent LNs. Addition of perioperative or postoperative chemoradiotherapy may improve the overall survival rates but most of patients will still die of recurrent metastatic disease.69 Therefore, accurate selection of patients who will benefit from surgical intervention

S.R. Teixera et al is vital to avoid the morbidity and mortality risk of unnecessary surgery. Preoperative staging is based on depth of mural invasion, adjacent organ invasion, nodal involvement, and distant metastases.70 Endoscopic biopsy and CE-CT of the chest, abdomen, and pelvis or MRI are currently used for staging. Staging laparoscopy is recommended for patients eligible for local regional therapy. [18F]-FDG-PET is preferred but not necessary in the absence of M1 category cancer.71 PET is not helpful for T staging in primary gastric tumors. [18F]-FDG-PET uptake in gastric adenocarcinomas is variable related to different histologic types of cancer.72 Furthermore, physiological increase in uptake within the gastric wall and in acute inflammatory conditions, such as gastritis, may obscure the primary tumor.73,74 Combined [18F]-FDG-PET/CT and stomach distension improved the diagnostic accuracy (91.2%) for detecting primary gastric cancer.75 [18F]-FLT-PET has been shown to be more sensitive than 18 [ F]-FDG-PET (100% vs 69%) for detecting advanced primary gastric tumors, independent of the histologic type.76 [18F]-FLT-PET reflects the proliferative activity of the tumor and may be useful as a diagnostic adjunct tool for gastric cancers.76 Also, it has been shown that the [18F]-FLT uptake was significantly lower in the gastric mucosa than that in the cancer tissue77 preventing false-negative studies. With respect to regional LN involvement, [18F]-FDG-PET has shown lower sensitivity (40%) but higher specificity (95%) compared with CE-CT.78 For identifying peritoneal metastases, [18F]-FDG-PET/CT did not add information to high-quality CECT.79 Conversely, occult metastatic disease was detected in bones, liver, and distant LNs changing the treatment planning in 10% of the patients with advanced gastric cancer and considerably reducing its costs.79 Thus, PET/CT has been proposed to initially stage patients in whom conventional imaging does not demonstrate metastatic disease, before laparoscopy. To assess recurrence of gastric cancer following curative resection, PET/CT showed 75% of accuracy80 and might have a role in staging and restaging of gastric cancer. However, De Potter et al81 reported low sensitivity, low specificity, and negative predictive values (70%, 69%, and 60%, respectively). [18F]-FDG-PET might not be suitable as a primary tool for screening purposes following gastric cancer treatment. Compared with abdominal CE-CT, [18F]-FDG-PET showed lower sensitivity, specificity, and accuracy (52.0%, 83.7%, 76.9% of PET vs 68.0%, 87.0%, 82.9% of CT, respectively), although with no significant difference (P 4 0.05).82 With regard to predicting prognosis, [18F]-FDG-PET may provide additional information. In patients with proven recurrence, the mean survival for the PET-negative group was higher compared with the PET-positive group (18.5 ⫾ 12.5 vs 6.9 ⫾ 6.5 months).81 Histopathologic response rate was correlated with metabolic response.83,84 Overall survival for patients with metabolic response after preoperative chemotherapy was higher compared with patients without metabolic response.85 In [18F]-FDG-avid tumors, following preoperative chemotherapy, [18F]-FDG-PET/CT has been shown to predict pathologic response and disease-free survival, enabling early changes in therapy in nonresponding patients.84

Potential role of PET/MRI in gastrointestinal and abdominal malignancies No studies or reports are currently available to address the feasibility or role of PET-MR in gastric cancer.

Colorectal Cancer CRC is the third most frequent cancer in the world and ranks as the second most frequent malignancy in developed countries. One-third of all newly diagnosed CRC per year occur in the rectum. When diagnosed early, the 5-year survival rate is more than 90%. Polyps are precancerous lesions that eventually develop into malignancies if not removed at an early stage. To prevent this deleterious sequence from happening, a colonoscopy is recommended after the age of 50 years. CRC may also be incidentally found on CT examinations performed for other reasons. When a rectal cancer is confirmed endoscopically, most often imaging is performed for local staging. Transrectal endoscopic ultrasound (TRUS) and MRI have been successfully used to stage the local extent of disease. Local staging of rectal cancer requires the assessment of the following criteria: mural and extramural tumor infiltration (T category); LN metastases; and involvement of the mesorectal fascia to determine the integrity of the circumferential resection margin (CRM), vascular invasion, and spread across the peritoneal lining. TRUS has shown an accuracy of 90% in T staging rectal tumors. It is limited in highly stenosing tumors and in tumors situated in the upper third of the rectum.86 The mesorectal fascia for the most part is not visualized with this technique. MRI as a noninvasive technique does not share the physical limitations of TRUS and provides excellent assessment of the local tumor spread. A particular strength of MRI is the visualization of the mesorectal fascia, a critical anatomical landmark for the surgeon. When compared with pathology, MR has demonstrated a surprising quantitative accuracy when assessing the tumor invasion close to 0.5 mm. MRI predicts with 92% specificity a clear CRM with a 1-mm cutoff being sufficient to predict CRM tumor involvement.87 MRI has been seen to predict extramural depth within a -0.046-mm difference (95% CI: 0.487 to 0.395) when compared with pathology without the reported limitations of TRUS.88 Extramural vascular invasion is another predictive factor linked to a higher rate of metastatic spread and a reduced 3year relapse-free survival, and MRI is an ideal tool to identify this risk factor. When assessing circumferential resection margin (CRM), extramural vascular invasion, and peritoneal involvement, TRUS is no longer useful, as these areas are outside its field of view. However, MRI has shown a specificity of 92%.89 CT, by contrast, is not useful for T staging rectal cancer; its accuracy is 52%-74% in smaller tumors and 79%94% in larger tumors.86 Correct N staging remains a challenge for all imaging modalities. With the introduction of the new surgical approach of a total mesorectal excision (TME), the determination of the nodal stage within the mesorectal fascia is less critical. After the introduction of TME neither histopathology nor MRI assessment of LN successfully predicted local recurrence, whereas pre-TME studies showed a strong correlation between the

329 variables.90 Furthermore, relapse in patients with positive LN that had an unsuccessful TME was shown to be 20%, whereas in similar patients with successful TME, it was only 6%.90 Correct staging is now focused on the LN outside the mesorectal fascia as well as on vascular invasion. MRI is reported to be among the most accurate diagnostic tools and yields 85% accuracy in staging nodal involvement.86 Besides the size, the intranodal MRI signal, the round shape and the irregularity of the nodal border are the most relevant imaging features to indicate metastatic involvement. TRUS has a reported accuracy of 73%-83% when evaluating LN 45 mm.86 In smaller LN o5 mm, the accuracy drops to 43%. It can be noted that approximately 50% of all metastatic LNs from rectal cancer are less than 5 mm.86 This is why PET/ CT is currently not recommended by the National Comprehensive Cancer Network as a standard diagnostic modality for initial (nodal) staging of rectal cancer.91 CT with a reported sensitivity of 22%-73% is the least helpful in this matter. By contrast, the assessment of distant metastatic spread is the domain of CE-CT and PET/CT. PET/ CT has been proven to be the best imaging method for detection of extrahepatic disease,92 whereas MRI is the strongest modality for detection of liver metastases.93 In the clinical scenario of disease follow-up, MRI and PET/ CT demonstrate their strength in detection of tumor recurrence or residue from scar formation and fibrosis. MRI is superior to TRUS to distinguish tumor from fibrosis or treatment changes.86 The grade of tumor regression after chemoradiotherapy as assessed by MRI can predict diseasefree and overall survival.90 DWI, including the measurement of apparent diffusion coefficients, are a valuable adjunct to identify responders from nonresponders to chemoradiation therapy.86 Based on our initial experience, the major potential future role of PET-MR in CRC is comprehensive staging integrating local, nodal, and whole-body staging in one and the same examination. With MRI being superior in local staging and PET/CT superior in distant metastatic disease staging, both the modalities are ideal to complement each other. One-stop-shop imaging with PET-MR is a suggestion, as local T and N categories, distant N category, and M category can be combined in a single examination. A resulting preeminent advantage of PET-MR could be the potential to guide the surgeon's operative strategy all with a single examination. Our preliminary results on 12 patients with 29 lesions reflect very good correlation between the findings in PET/CT and PET-MR with a 90% concordance rate. Overall, 71% true positive findings for PET/CT and 86% true positive findings in PETMR were obtained. T staging is superior with PET-MR, whereas distant metastasis staging was comparable.94 A critical limitation might be the assessment of metastatic disease to the lungs. There is certain controversy about whether MR and consequently PET-MR perform sufficiently well to detect lung cancer and nodules and therefore metastatic disease. In most cases of today's whole-body imaging in PET-MR, T1w Dixon and volume interpolating breath-hold examination sequences are used besides T2w single-shot fast spin echo sequences to assess for pulmonary metastases.

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330 Although the Dixon sequence has demonstrated considerable value in the detection of pulmonary nodules 410 mm,95 smaller lesions are still challenging for MRI technology both in sensitivity and specificity. In addition, the detection of calcification, which oftentimes is a guiding feature in characterization of pulmonary nodules, is clearly insufficient with MRI.96 A most recent study by Rauscher et al97 reports on 40 patients and 47 pulmonary lesions and concludes that Dixon sequence has clear limitations in detecting smaller lung nodules o5 mm. Volume interpolating breath-hold examination sequence performs better than Dixon but MRI remains significantly inferior to PET/CT in this matter.97 Although CE-CT represents the current standard of care for staging distant metastatic disease in rectal cancer, PET-MR deserves attention and may adopt a future role as a comprehensive tool for simultaneous T, N, and M staging of rectal cancer. One of the preeminent questions will be whether there is enough clinical evidence for PET-MR to demonstrate superior accuracy in comparison with the current standard of care so as to modify and adjust the current diagnostic algorithms.

Gastrointestinal Stromal Tumors Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs originate from the smooth muscle pacemaker cells of Cajal and are defined by its expression of KIT (CD117), a tyrosine kinase growth factor receptor. The expression of KIT (CD117) distinguishes GISTs from other mesenchymal lesions of the gastrointestinal tract, such as neural or true smooth muscle tumors.98 GISTs may occur from the esophagus to the anus, in the omentum, mesentery, and retroperitoneum. They are more prevalent in the stomach and the small intestine. According to a recent consensus,99 CT is the standard imaging method in tumor detection and staging. Abdominal MRI is used when contrast media is contraindicated or when there is a liverspecific question raised by CT. PET/CT is a potentially promising alternative to CT and is particularly indicated when results from CT or MRI or both are nonconclusive. Targeting treatment of GISTs using the tyrosine kinase inhibitor, imatinib mesylate, changed the management of patients in the last decade. However, many patients still show progressive disease, that not necessarily presents with an increase in lesion size. Patients may also show good response despite no change or increase in size of the lesions. Therefore, assessment of response to treatment or follow-up of patients with GIST with imaging must not be based only on measurements of the longest axial lesions diameter as addressed by the response evaluation criteria in solid tumors. It should be done including changes in density of the lesions on CT, in signal on MRI, and changes in the glucose metabolism assessed by [18F]FDG-PET.99 It has been shown that early response to treatment assessed by [18F]-FDG-PET is associated with a longer progression-free survival100 and is a better predictor of longterm outcomes.101 Moreover, [18F]-FDG-PET/CT can predict

malignant potential of GISTs102 and detect development of resistance to tyrosine kinase inhibitors.103 The conclusions of a recent systematic review confirm that [18F]-FDG-PET and PET/CT have a significant role in assessing treatment response to drugs including tyrosine kinase inhibitors.104 For MRI, promising results have shown that DWI is comparable to PET/CT in detecting the GIST lesions105,106 and correlates with the response of [18F]-FDG-PET to drug therapy.106,107 Therefore, MRI with DWI may be an alternative for tumor characterization and follow-up. Combined PET-MR may be of valuable importance in the management of patients; however, no data are available at current times on PET-MR in these tumors.

Conclusion PET-MR is a powerful tool that by now has already proven promising for many applications in oncologic clinical settings. According to our preliminary experience, PET-MR most of the time strengthens the diagnostic confidence, specifically for local tumor extent, smaller lesions, and lesions close to the bowel. Initial data demonstrate benefit in using PET-MR as a one-stop-shop modality for comprehensive staging of neoplastic disease including T, N, and M categories in a single examination. In addition, it has potential to reduce radiation exposure while providing performance comparable and similar to PET/CT, for example, for pediatric patients. Open questions to answer in the future are whether there are measurable incremental value and evidence-based superiority of PET-MR over current imaging standards. This is still work in progress. Future studies have to deliver information of the benefit of PET-MR in individual tumor types rather than in collective study populations on mixed disease entities. Also, the complementary value of morphologic, functional, and metabolic information has to be investigated with more diligence in the future, as no data are yet available on the complementary information of multiparametric MR imaging and metabolism. Finally, new tracers deserve to be explored with this new imaging device, adding the excellent soft tissue information of MRI to the equation. In our opinion PET-MR is a helpful diagnostic imaging modality and accepted in clinical practice already and will be more so in the future for dedicated applications.

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