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Functional imaging in liver tumours

  • Maxime Ronot
    Affiliations
    Department of Radiology, APHP, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France

    University Paris Diderot, Sorbonne Paris Cité, Paris, France

    INSERM U1149, Centre de recherche biomédicale Bichat-Beaujon, CRB3, Paris, France
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  • Ashley Kieran Clift
    Affiliations
    Department of Surgery and Cancer, Imperial College London, London, UK
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  • Valérie Vilgrain
    Correspondence
    Corresponding author. Address: Radiology Department, Beaujon Hospital 100, Bd du Général Leclerc, 92110 Clichy, France. Tel.: +33 1 4087 55 66.
    Affiliations
    Department of Radiology, APHP, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France

    University Paris Diderot, Sorbonne Paris Cité, Paris, France

    INSERM U1149, Centre de recherche biomédicale Bichat-Beaujon, CRB3, Paris, France
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  • Andrea Frilling
    Affiliations
    Department of Surgery and Cancer, Imperial College London, London, UK
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      Summary

      Functional imaging encompasses techniques capable of assessing physiological parameters of tissues, and offers useful clinical information in addition to that obtained from morphological imaging. Such techniques may include magnetic resonance imaging with diffusion-weighted sequences or hepatobiliary contrast agents, perfusion imaging, or molecular imaging with radiolabelled tracers. The liver is of major importance in oncological practice; not only is hepatocellular carcinoma one of the malignancies with steadily rising incidence worldwide, but hepatic metastases are regularly observed with a range of solid neoplasms. Within the realm of hepatic oncology, different functional imaging modalities may occupy pivotal roles in lesion characterisation, treatment selection and follow-up, depending on tumour size and type. In this review, we characterise the major forms of functional imaging, discuss their current application to the management of patients with common primary and secondary liver tumours, and anticipate future developments within this field.

      Abbreviations:

      DW (diffusion-weighted), MRI (magnetic resonance imaging), CE (contrast-enhanced), US (ultrasound), CT (computed tomography), PET (positron emission tomography), HCC (hepatocellular carcinoma), MFC (mass-forming cholangiocarcinoma), OATP (organic anionic transporting polypeptides), MRPs (multidrug resistance proteins), Gd-BOPTA (Gadobendate dimeglumine), Gd-EOD-OTPA (Gadoxetic acid), ADC (apparent diffusion coefficient), 18F-FDG (18F-fluorodeoxyglucose), 18F-FLT (18F-fluorothymidine), LM (liver metastases), CRC (colorectal carcinoma), NET (neuroendocrine tumours), CR (colorectal), NE (neuroendocrine), NEC (neuroendocrine carcinoma), SIRT (selective internal radiotherapy), PRRT (peptide receptor radionuclide therapy), G (grade), SSTR (somatostatin receptor), GLP-1R (glucagon-like peptide-1 receptor), 18F-DOPA (6-18F-L-3,4-dihydroxyphenylalanine), 11C-5-HTP (β-[11C]-5-hydroxy-L-tryptophan), SPECT (single positron emission computed tomography), SRS (somatostatin receptor scintigraphy), SSAs (somatostatin analogues), 68Ga-SSAs (68Ga-radiolabelled somatostatin analogues), 68Ga-DOTATOC ([68Ga-DOTA0,Tyr3]octreotide), 68Ga-DOTANOC ([68Ga-DOTA,1-Nal3]octreotide), 68Ga-DOTATATE ([68Ga-DOTA0,Tyr3]octreotate))

      Keywords

      Introduction

      Functional imaging assesses in vivo physiological parameters of tissues, and may be used in tumour detection, characterisation, treatment selection and follow-up.
      The term ‘functional imaging’ refers to a collection of techniques providing information regarding the physiological properties of tissues. In the field of liver oncology, functional imaging may be used for tumour detection and characterisation, selection of treatment, monitoring of treatment response and patient follow-up. These techniques do not compete with morphological imaging work-up but may yield additional information.
      Four main functional modalities are utilised in liver tumour imaging: diffusion-weighted (DW) magnetic resonance imaging (MRI) is sensitive to the Brownian motion of water molecules, and is considered as a marker of tissue cellularity and microarchitecture [
      • Taouli B.
      • Koh D.-M.
      Diffusion-weighted MR imaging of the liver.
      ]; perfusion imaging using contrast-enhanced (CE) ultrasound (US), computed tomography (CT) or MRI provides information about tissue microcirculation or the movement of water and solutes [
      • Ronot M.
      • Lambert S.
      • Daire J.-L.
      • Lagadec M.
      • Doblas S.
      • Garteiser P.
      • et al.
      Can we justify not doing liver perfusion imaging in 2013?.
      ,
      • Van Beers B.E.
      • Doblas S.
      • Sinkus R.
      New acquisition techniques: fields of application.
      ]; imaging of the hepatocellular function using hepatospecific MR contrast agents [
      • Van Beers B.E.
      • Pastor C.M.
      • Hussain H.K.
      Primovist, Eovist: what to expect?.
      ,
      • Vilgrain V.
      • Van Beers B.E.
      • Pastor C.M.
      Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI.
      ]; and nuclear metabolic imaging using positron emission tomography (PET)/CT with targeted radiotracers to assess specific metabolic pathways. Some are currently included in routine practice, such as DW MRI and hepatospecific MR contrast agents, some may be used in specific settings (nuclear metabolic imaging), and finally others are still restricted to research settings (perfusion imaging).
      Here, we provide an overview of functional imaging methods. Thereafter, we review the role of functional imaging techniques in the commonest primary liver tumours, i.e., hepatocellular carcinoma (HCC) and mass-forming cholangiocarcinoma (MFC), as well as in the most clinically relevant types of liver metastases (LM), including those of colorectal and neuroendocrine origins.

      Functional imaging methods

      Imaging hepatocellular function: hepatobiliary MR contrast agents

      Hepatobiliary MR contrast agents are gadolinium chelates that are taken-up by functioning hepatocytes. Their internalisation is mediated by organic anionic transporting polypeptides (OATP) expressed on the sinusoidal membrane of functional hepatocytes [
      • Kitao A.
      • Matsui O.
      • Yoneda N.
      • Kozaka K.
      • Shinmura R.
      • Koda W.
      • et al.
      The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging.
      ]. Subsequently, 50% of the contrast agent is excreted into the biliary canals through multidrug resistance-associated proteins (MRPs) [
      • Vilgrain V.
      • Van Beers B.E.
      • Pastor C.M.
      Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI.
      ,
      • Kitao A.
      • Zen Y.
      • Matsui O.
      • Gabata T.
      • Kobayashi S.
      • Koda W.
      • et al.
      Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging–correlation with molecular transporters and histopathologic features.
      ]. The level of expression of these proteins is significantly decreased in impaired hepatocytes. As a consequence, these contrast agents are accurate markers of hepatocellular function.
      Hepatospecific CE MR sequences are T1-weighted, and are obtained when the liver and the bile ducts are markedly enhanced. On these images, non-hepatocellular tumours, tumours containing impaired hepatocytes, and also vessels or cysts appear black. Currently, two hepatobiliary MR contrast agents are commercially available: gadobenate dimeglumine or Gd-BOPTA (Multihance, Bracco Imaging) and gadoxetate disodium also called gadoxetic acid or Gd-EOB-DTPA (Primovist/Eovist, Bayer). The latter is the most frequently used worldwide because 50% of the injected dose is rapidly taken-up by hepatocytes, allowing for acquisition of the “hepatobiliary phase” 20 min after injection. With gadobenate dimeglumine, around 5% is taken-up, and the hepatobiliary phase is obtained 1–3 h after injection. Due to the rapid entry of Gd-EOB-DTPA into hepatocytes, classical features of liver tumours are modified on sequences classically referred to as delayed phase sequences (3–5 min after injection). Indeed, these images combine the extracellular and intrahepatocellular components of the contrast agent and are best defined as transitional phase images [
      • Nakamura Y.
      • Toyota N.
      • Date S.
      • Oda S.
      • Namimoto T.
      • Yamashita Y.
      • et al.
      Clinical significance of the transitional phase at gadoxetate disodium-enhanced hepatic MRI for the diagnosis of hepatocellular carcinoma: preliminary results.
      ]. This is not observed with Gd-BOPTA.

      Imaging tissue cellularity and architecture: diffusion-weighted MRI

      DW MRI is a technique based on the random mobility of protons in tissues. In highly cellular tissues such as tumours, the diffusion of water protons is restricted. Thus, both qualitative (signal intensity) and quantitative (apparent diffusion coefficient [ADC]) variables reflect tissue cellularity and cellular membrane integrity [
      • Taouli B.
      • Koh D.-M.
      Diffusion-weighted MR imaging of the liver.
      ]. ‘Diffusion restriction’ refers to a tumour signal intensity that is higher than that of the surrounding liver on high b value DW MR images, corresponding to low ADC values on quantitative maps. DW MRI with a mono-exponential model is now part of the routine MR protocol for liver diseases. A more refined approach, referred to as the intravoxel incoherent motion (IVIM) theory allows the separation of pure molecular diffusion parameters from perfusion-related diffusion parameters within a tissue [
      • Le Bihan D.
      • Breton E.
      • Lallemand D.
      • Aubin M.L.
      • Vignaud J.
      • Laval-Jeantet M.
      Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging.
      ].

      Imaging tumour microvasculature: perfusion imaging

      Perfusion imaging provides information about tissue microcirculation or the movement of water and solutes at levels far below the spatial resolution of conventional imaging techniques. Thus, perfusion imaging is not the dynamic, qualitative analysis commonly obtained with tissue enhancement, but a quantitative extraction of physiological perfusion parameters of the liver. It requires the injection of a tracer and the acquisition by rapid temporal sampling of signal intensity/time curves that provide information on variations in tracer concentrations over time. The physiological parameters are extracted from these curves by adjusting them to mathematical perfusion models. Various imaging techniques can be used: CEUS, CT (perfusion CT), or MRI (commonly named dynamic CE MRI).

      Imaging tumour metabolism: PET

      In routine oncologic imaging, metabolic imaging is mostly based on gluconeogenesis. Indeed, gluconeogenesis is increased in most malignant tissues, and can be visualized using 18F-fluorodeoxyglucose (18F-FDG). Recently, several other tracers have been developed for imaging different malignancies: 18F-fluorothymidine (18F-FLT) has been validated as a specific biomarker of proliferation, 11C- or 18F-acetate and 11C- or 18F-choline as indicators of tumour growth or invasiveness.

      Primary liver tumours

      Primary liver tumours are a group of malignancies derived from various liver cells. The most frequent is HCC, accounting for 85–90% of all primary liver tumours. It is the sixth most common malignancy worldwide and the second most common cause of cancer-related mortality []. Cholangiocarcinoma is the second most common primary liver tumour and derives from the bile ducts. It is classically classified into extrahepatic (80–90%) and intrahepatic (5–10%) types. Intrahepatic cholangiocarcinoma can present as mass-forming (so called ‘peripheral type’), or more rarely as periductal-infiltrating, or intraductal growing tumours [
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.-W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      ].
      HCC and MFC present with variable imaging features depending on their extension and biological behaviour. In daily practice however, the detection, characterisation and follow-up of these lesions rely on morphological features assessed on CE imaging techniques, mostly CT and MRI. The hallmarks of HCC are the association of hypervascularity on the arterial phase and washout on the portal venous and/or delayed phases [
      • Ronot M.
      • Vilgrain V.
      Hepatocellular carcinoma: diagnostic criteria by imaging techniques.
      ]. MFCs appear as focal lesions with various degrees of peripheral hypervascularity, and progressive contrast uptake due to their fibrous stroma [
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • Llovet J.M.
      • Park J.-W.
      • Patel T.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      ].
      Based on morphological criteria, the sensitivity of MRI for the diagnosis of HCC is 77–100% using extracellular contrast agents, whilst that of CT is 68–91% [
      EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ,
      • Rimola J.
      • Forner A.
      • Tremosini S.
      • Reig M.
      • Vilana R.
      • Bianchi L.
      • et al.
      Non-invasive diagnosis of hepatocellular carcinoma ⩽ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI.
      ,
      • Sersté T.
      • Barrau V.
      • Ozenne V.
      • Vullierme M.-P.
      • Bedossa P.
      • Farges O.
      • et al.
      Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy.
      ]. Indeed, the diagnostic performance is strongly related to tumour size. The sensitivity for large HCC (>2 cm), is close to 100% for both imaging techniques, but drops to around 45–80% (MRI) and 40–75% (CT) for 1–2 cm lesions and is lower in HCCs <1 cm [
      • Rode A.
      • Bancel B.
      • Douek P.
      • Chevallier M.
      • Vilgrain V.
      • Picaud G.
      • et al.
      Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver.
      ,
      • Kim Y.K.
      • Kim C.S.
      • Chung G.H.
      • Han Y.-M.
      • Lee S.Y.
      • Bin Chon S.
      • et al.
      Comparison of gadobenate dimeglumine-enhanced dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma.
      ].

      Added value of hepatobiliary MR contrast agents in primary liver tumours

      Loss of hepatocellular function occurs early during the carcinogenesis of liver tumours, often prior to the tumour neoangiogenesis which predicates lesion hypervascularity. Consequently, most HCCs appear hypointense during the hepatobiliary phase [
      • Sano K.
      • Ichikawa T.
      • Motosugi U.
      • Sou H.
      • Muhi A.M.
      • Matsuda M.
      • et al.
      Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging.
      ] whilst most non-HCC, cirrhosis–associated regenerative or dysplastic nodules appear iso- or hyperintense (Fig. 1). A recent meta-analysis focusing on the diagnostic performance of MRI for diagnosing HCC up to 2 cm has shown that Gd-EOB-DTPA MRI had significantly increased sensitivity compared to extracellular contrast agent MRI (92% and 67%, respectively) [
      • Kierans A.S.
      • Kang S.K.
      • Rosenkrantz A.B.
      The diagnostic performance of dynamic contrast-enhanced MR imaging for detection of small hepatocellular carcinoma measuring up to 2 cm: a meta-analysis.
      ]. The high contrast between the background liver and hypointense lesions in the hepatobiliary phase explains why some early HCCs are only visible on this sequence [
      • Kim M.-J.
      • Lee M.
      • Choi J.-Y.
      • Park Y.N.
      Imaging features of small hepatocellular carcinomas with microvascular invasion on gadoxetic acid-enhanced MR imaging.
      ]. Kim et al. showed that the use of Gd-EOB-DTPA MRI may also result in increased overall survival of patients with early-stage lesions showing additional HCC nodules in 16% of patients diagnosed with a single-nodular HCC by multiphasic CT [
      • Kim H.-D.
      • Lim Y.-S.
      • Han S.
      • An J.
      • Kim G.-A.
      • Kim S.Y.
      • et al.
      Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival.
      ]. This explains why Korean and Japanese guidelines recommend the use of Gd-EOB-DTPA MRI as first line imaging for the diagnosis of HCC [
      KLCSG-NCC Korea practice guideline for the management of hepatocellular carcinoma.
      ,
      • Kudo M.
      • Matsui O.
      • Izumi N.
      • Iijima H.
      • Kadoya M.
      • Imai Y.
      • et al.
      JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the liver cancer study group of Japan.
      ]. Nevertheless, the specificity of diagnosing HCC using Gd-EOB-DTPA MRI with transitional or hepatobiliary phases seems to be lower than with extracellular MR contrast agents. To keep the specificity high when using Gd-EOB-DTPA MRI, washout should be determined on the portal venous phase alone [
      • Joo I.
      • Lee J.M.
      • Lee D.H.
      • Jeon J.H.
      • Han J.K.
      • Choi B.I.
      Noninvasive diagnosis of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: can hypointensity on the hepatobiliary phase be used as an alternative to washout?.
      ]. This may explain why extracellular contrast MR agents are still recommended in Western guidelines [
      EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      • Bruix J.
      • Sherman M.
      Management of hepatocellular carcinoma: an update.
      ].
      Figure thumbnail gr1
      Fig. 1Hepatobiliary contrast MRI in typical unifocal hepatocellular carcinoma in a 55 year-old female with hepatitis B virus (HBV) and HIV infection. Gd-EOB-DTPA enhanced MR imaging showed a supracentimetric hypervascular lesion located in the left liver lobe (A) with washout on portal venous phase images (B), allowing for the non-invasive diagnosis of HCC. On the hepatobiliary phase images acquired 20 min after the injection (C) the lesion showed marked signal hypointensity, consistent with the presence of impaired hepatocytes.
      The optimum circumstances for utilising the additional information yielded by hepatobiliary MR contrast agents should be considered. When HCC harbour the typical enhancement pattern, hypointensity during the hepatobiliary phase is almost always observed, limiting its added value [
      • Choi J.W.
      • Lee J.M.
      • Kim S.J.
      • Yoon J.-H.
      • Baek J.H.
      • Han J.K.
      • et al.
      Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR Images and their value as an imaging biomarker.
      ]. Therefore, Gd-EOB-DTPA MRI appears to be most useful in atypical HCC (i.e., lacking hypervascularity or washout during the portal venous or delayed phases). Interestingly, hypovascular HCCs are hypointense on hepatobiliary phase in 96% of cases [
      • Choi J.W.
      • Lee J.M.
      • Kim S.J.
      • Yoon J.-H.
      • Baek J.H.
      • Han J.K.
      • et al.
      Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR Images and their value as an imaging biomarker.
      ]. Such hypovascular, hypointense lesions are challenging because not all of them correspond to HCC at the time of imaging, and around one third may eventually progress to hypervascular HCC over a period of 12–18 months [
      • Hyodo T.
      • Murakami T.
      • Imai Y.
      • Okada M.
      • Hori M.
      • Kagawa Y.
      • et al.
      Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma.
      ,
      • Motosugi U.
      • Ichikawa T.
      • Sano K.
      • Sou H.
      • Onohara K.
      • Muhi A.
      • et al.
      Outcome of hypovascular hepatic nodules revealing no gadoxetic acid uptake in patients with chronic liver disease.
      ,
      • Akai H.
      • Matsuda I.
      • Kiryu S.
      • Tajima T.
      • Takao H.
      • Watanabe Y.
      • et al.
      Fate of hypointense lesions on Gd-EOB-DTPA-enhanced magnetic resonance imaging.
      ]. In this setting, ancillary findings such as hyperintensity on DW- or on T2-weighted MR sequences have been shown to be associated with early HCC [
      • Lee M.H.
      • Kim S.H.
      • Park M.J.
      • Park C.K.
      • Rhim H.
      Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease.
      ,
      • Hwang J.
      • Kim Y.K.
      • Jeong W.K.
      • Choi D.
      • Rhim H.
      • Lee W.J.
      Nonhypervascular hypointense nodules at gadoxetic acid-enhanced MR imaging in chronic liver disease: diffusion-weighted imaging for characterization.
      ].
      Data are scarcer regarding the added value of hepatospecific MR contrast agents in MFC. Typically using Gd-EOB-DTPA MRI, most MFCs show a thin peripheral rim with internal heterogeneous enhancement during the dynamic phase and hypointensity on the hepatobiliary phase [
      • Kang Y.
      • Lee J.M.
      • Kim S.H.
      • Han J.K.
      • Choi B.I.
      Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images.
      ]. This peculiar enhancement on dynamic sequences may help differentiating small HCCs from MFCs [
      • Kim R.
      • Lee J.M.
      • Shin C.-I.
      • Lee E.S.
      • Yoon J.H.
      • Joo I.
      • et al.
      Differentiation of intrahepatic mass-forming cholangiocarcinoma from hepatocellular carcinoma on gadoxetic acid-enhanced liver MR imaging.
      ]. It has also been shown that the hepatobiliary phase demonstrates increased lesion conspicuity and better delineation of daughter nodules and intrahepatic metastasis [
      • Kang Y.
      • Lee J.M.
      • Kim S.H.
      • Han J.K.
      • Choi B.I.
      Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images.
      ].

      Added value of diffusion-weighted MRI in primary liver tumours

      The combination of MRI with diffusion-weighted sequences and hepatobiliary contrast agents play a central role in the detection and characterisation of cirrhosis-related focal liver lesions.
      Most HCC (80%) are hyperintense on high b value DW MR sequences [
      • Wu L.-M.
      • Xu J.-R.
      • Lu Q.
      • Hua J.
      • Chen J.
      • Hu J.
      A pooled analysis of diffusion-weighted imaging in the diagnosis of hepatocellular carcinoma in chronic liver diseases.
      ]. The addition of DW sequences to MRI examinations increases the detection rate of HCC and helps characterise small lesions [
      • Vandecaveye V.
      • De Keyzer F.
      • Verslype C.
      • Op de Beeck K.
      • Komuta M.
      • Topal B.
      • et al.
      Diffusion-weighted MRI provides additional value to conventional dynamic contrast-enhanced MRI for detection of hepatocellular carcinoma.
      ,
      • Piana G.
      • Trinquart L.
      • Meskine N.
      • Barrau V.
      • Van Beers B.
      • Vilgrain V.
      New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases.
      ]. DW MR sequences are most useful in HCCs smaller than 2 cm when classical morphological criteria are not met; CE and DW images may increase the sensitivity for diagnosing HCC up to 85% [
      • Piana G.
      • Trinquart L.
      • Meskine N.
      • Barrau V.
      • Van Beers B.
      • Vilgrain V.
      New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases.
      ,
      • Park M.-S.
      • Kim S.
      • Patel J.
      • Hajdu C.H.
      • Do R.K.G.
      • Mannelli L.
      • et al.
      Hepatocellular carcinoma: detection with diffusion-weighted versus contrast-enhanced magnetic resonance imaging in pretransplant patients.
      ]. Hyperintensity on DW MRI has been recently endorsed by the liver imaging reporting and data system (Li-Rads) recently introduced by the American College of Radiology [

      Liver Imaging Reporting and Data System (LI-RADS) – American College of Radiology [Internet]. [cited 2016 Jan 7]. Available from: http://www.acr.org/Quality-Safety/Resources/LIRADS.

      ] as an ancillary feature for the non-invasive diagnosis of HCC. DW MRI has also been demonstrated to increase the detection of small MFCs, with better conspicuity when compared to other MR sequences (Fig. 2) [
      • El Fattach H.
      • Dohan A.
      • Guerrache Y.
      • Dautry R.
      • Boudiaf M.
      • Hoeffel C.
      • et al.
      Intrahepatic and hilar mass-forming cholangiocarcinoma: Qualitative and quantitative evaluation with diffusion-weighted MR imaging.
      ]. DW MRI has also been evaluated in assessing tumour differentiation – ADC values are decreased in moderately- or poorly differentiated HCCs compared to well-differentiated HCC, and also correlate with microvascular invasion, presence of progenitor cell markers, and early recurrence after resection [
      • Nakanishi M.
      • Chuma M.
      • Hige S.
      • Omatsu T.
      • Yokoo H.
      • Nakanishi K.
      • et al.
      Relationship between diffusion-weighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma.
      ]. However, these data have not been applied to routine practice because individual values are still a matter of ongoing investigation. DW MRI may also help differentiate tumoural venous invasion from bland thrombus [
      • Catalano O.A.
      • Choy G.
      • Zhu A.
      • Hahn P.F.
      • Sahani D.V.
      Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging.
      ].
      Figure thumbnail gr2
      Fig. 2Diffusion-weighted MRI in intrahepatic cholangiocarcinoma in a 57-year-old male. The lesion was located in the posterior part of the right liver lobe. The patient was initially referred for a right hepatectomy. On CE MR imaging after injection of extracellular contrast agent, the portal venous phase images showed a heterogeneous lesion, with a central necrotic area, and peripheral enhancement, consistent with the fibrous stroma of the tumour (B). The left liver lobe was unremarkable (B). On diffusion-weighted images, the conspicuity of the main lesion is better (C), and several infracentimetric nodules are visible in the left lobe (D). These lesions were proven to be intrahepatic distant metastasis, and led to a change in the management of the patient.
      If the qualitative evaluation of DW images is mostly used for tumour detection and characterisation, the quantitative approach has mostly been studied to assess tumour response to various treatments. Pre-clinical and clinical studies have shown that ADC measurements could indicate the degree of tumour necrosis in HCCs treated with loco-regional therapy as necrotic tissue shows higher ADC values than viable tissue [
      • Mannelli L.
      • Kim S.
      • Hajdu C.H.
      • Babb J.S.
      • Clark T.W.I.
      • Taouli B.
      Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver.
      ,
      • Namimoto T.
      • Yamashita Y.
      • Sumi S.
      • Tang Y.
      • Takahashi M.
      Focal liver masses: characterization with diffusion-weighted echo-planar MR imaging.
      ,
      • Bonekamp S.
      • Li Z.
      • Geschwind J.-F.H.
      • Halappa V.G.
      • Corona-Villalobos C.P.
      • Reyes D.
      • et al.
      Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part I. Identification and validation of volumetric functional response criteria.
      ,
      • Bonekamp S.
      • Jolepalem P.
      • Lazo M.
      • Gulsun M.A.
      • Kiraly A.P.
      • Kamel I.R.
      Hepatocellular carcinoma: response to TACE assessed with semiautomated volumetric and functional analysis of diffusion-weighted and contrast-enhanced MR imaging data.
      ,
      • Bonekamp S.
      • Halappa V.G.
      • Geschwind J.-F.H.
      • Li Z.
      • Corona-Villalobos C.P.
      • Reyes D.
      • et al.
      Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.
      ,
      • Yuan Z.
      • Zhang J.
      • Yang H.
      • Ye X.-D.
      • Xu L.-C.
      • Li W.-T.
      Diffusion-weighted MR imaging of hepatocellular carcinoma: current value in clinical evaluation of tumor response to locoregional treatment.
      ]. Interestingly, these alterations can be observed as early as one week after the treatment, thus helping predict further response [
      • Kamel I.R.
      • Liapi E.
      • Reyes D.K.
      • Zahurak M.
      • Bluemke D.A.
      • Geschwind J.-F.H.
      Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.
      ,
      • Chen C.-Y.
      • Li C.-W.
      • Kuo Y.-T.
      • Jaw T.-S.
      • Wu D.-K.
      • Jao J.-C.
      • et al.
      Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constants–initial experience.
      ,
      • Chung J.C.
      • Naik N.K.
      • Lewandowski R.J.
      • Deng J.
      • Mulcahy M.F.
      • Kulik L.M.
      • et al.
      Diffusion-weighted magnetic resonance imaging to predict response of hepatocellular carcinoma to chemoembolization.
      ]. Several teams have also investigated the role of the pre-treatment ADC value in predicting tumour response. Although these series are preliminary, tumour ADC obtained before transarterial chemoembolisation or radioembolisation can be used to predict tumour response and patient survival [
      • Mannelli L.
      • Kim S.
      • Hajdu C.H.
      • Babb J.S.
      • Taouli B.
      Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: Prediction and assessment of response to transarterial chemoembolization. Preliminary experience.
      ,
      • Dong S.
      • Ye X.-D.
      • Yuan Z.
      • Xu L.-C.
      • Xiao X.-S.
      Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization.
      ,
      • Kokabi N.
      • Camacho J.C.
      • Xing M.
      • Qiu D.
      • Kitajima H.
      • Mittal P.K.
      • et al.
      Apparent diffusion coefficient quantification as an early imaging biomarker of response and predictor of survival following yttrium-90 radioembolization for unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis.
      ]. Similar results have been reported with MFC treated with intra-arterial therapy [
      • Halappa V.G.
      • Bonekamp S.
      • Corona-Villalobos C.P.
      • Li Z.
      • Mensa M.
      • Reyes D.
      • et al.
      Intrahepatic cholangiocarcinoma treated with local-regional therapy: quantitative volumetric apparent diffusion coefficient maps for assessment of tumor response.
      ].

      Added value of perfusion imaging in primary liver tumours

      Several studies have investigated the ability of perfusion imaging to characterise HCC in patients with cirrhosis. Arterial hepatic blood flow and hepatic perfusion index have been found to be higher, whilst the portal venous hepatic blood flow was significantly lower in HCC compared to liver parenchyma [
      • Taouli B.
      • Johnson R.S.
      • Hajdu C.H.
      • Oei M.T.H.
      • Merad M.
      • Yee H.
      • et al.
      Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI.
      ,
      • Ippolito D.
      • Sironi S.
      • Pozzi M.
      • Antolini L.
      • Ratti L.
      • Meloni F.
      • et al.
      Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease: initial observations.
      ,
      • Ippolito D.
      • Sironi S.
      • Pozzi M.
      • Antolini L.
      • Ratti L.
      • Alberzoni C.
      • et al.
      Hepatocellular carcinoma in cirrhotic liver disease: functional computed tomography with perfusion imaging in the assessment of tumor vascularization.
      ], suggesting that perfusion techniques can provide quantitative information about tumour-related angiogenesis. Thus, analysis of perfusion maps might increase the sensitivity for detection of HCC (Fig. 3) [
      • Fischer M.A.
      • Kartalis N.
      • Grigoriadis A.
      • Loizou L.
      • Stål P.
      • Leidner B.
      • et al.
      Perfusion computed tomography for detection of hepatocellular carcinoma in patients with liver cirrhosis.
      ]. Perfusion parameters (evaluated by perfusion CT) were also shown to correlate with tumour differentiation, with well-differentiated HCC having significantly higher perfusion values than other grades [
      • Sahani D.V.
      • Holalkere N.-S.
      • Mueller P.R.
      • Zhu A.X.
      Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue–initial experience.
      ].
      The role of perfusion imaging is limited, but data are encouraging regarding future clinical utility in assessing the effects of loco-regional and systemic therapies.
      Figure thumbnail gr3
      Fig. 3Perfusion imaging in hepatocellular carcinoma. (A) Example of perfusion parametric maps (total perfusion, hepatic perfusion index, mean transit time and regional blood volume) obtained from a patient with hepatocellular carcinoma 7 days after the initiation of sorafenib treatment. Perfusion parameters were extracted using a non-linear least square fit on a dual-input one-compartment model including two delays (arterial and portal). (B) The lesion was located in the dome of the liver. Comparison between the lesion (upper part) and the surrounding liver (lower part). The lesion showed a significant total perfusion decrease, with significant hepatic perfusion index and mean transit time increase consistent with a tumoural response to the treatment.
      Perfusion studies of loco-regional treatment of liver tumours, especially HCC provide limited additional information during and after percutaneous microwave or radiofrequency ablation because morphological imaging criteria are sufficiently reliable for assessing tumour response and recurrence [
      • Chopra S.
      • Dodd G.D.
      • Chintapalli K.N.
      • Leyendecker J.R.
      • Karahan O.I.
      • Rhim H.
      Tumor recurrence after radiofrequency thermal ablation of hepatic tumors: spectrum of findings on dual-phase contrast-enhanced CT.
      ,
      • Forner A.
      • Ayuso C.
      • Varela M.
      • Rimola J.
      • Hessheimer A.J.
      • de Lope C.R.
      • et al.
      Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?.
      ]. One perfusion CT study suggested that analysis of blood volume was useful for detecting recurrence in contact with ablation zones [
      • Meijerink M.R.
      • van Waesberghe J.H.T.M.
      • van der Weide L.
      • van den Tol P.
      • Meijer S.
      • Comans E.F.
      • et al.
      Early detection of local RFA site recurrence using total liver volume perfusion CT initial experience.
      ], but these results have not been validated.
      More studies have been published regarding the role of perfusion imaging (using either perfusion CT or dynamic CE MRI) to assess the efficacy of intra-arterial therapy. Animal studies have shown that early changes in perfusion parameters (at 1 week) are observed after transarterial chemoembolisation in treated compared to untreated areas [
      • Choi S.H.
      • Chung J.W.
      • Kim H.-C.
      • Kim H.-C.
      • Baek J.H.
      • Park C.M.
      • et al.
      The role of perfusion CT as a follow-up modality after transcatheter arterial chemoembolization: an experimental study in a rabbit model.
      ,
      • Wang D.
      • Bangash A.K.
      • Rhee T.K.
      • Woloschak G.E.
      • Paunesku T.
      • Salem R.
      • et al.
      Liver tumors: monitoring embolization in rabbits with VX2 tumors–transcatheter intraarterial first-pass perfusion MR imaging.
      ,
      • Braren R.
      • Altomonte J.
      • Settles M.
      • Neff F.
      • Esposito I.
      • Ebert O.
      • et al.
      Validation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization.
      ]. Similar results have been observed in humans, i.e., the ability to detect tumour residues following transarterial chemoembolisation [
      • Taouli B.
      • Johnson R.S.
      • Hajdu C.H.
      • Oei M.T.H.
      • Merad M.
      • Yee H.
      • et al.
      Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI.
      ,
      • Ippolito D.
      • Bonaffini P.-A.
      • Ratti L.
      • Antolini L.
      • Corso R.
      • Fazio F.
      • et al.
      Hepatocellular carcinoma treated with transarterial chemoembolization: dynamic perfusion-CT in the assessment of residual tumor.
      ,
      • Larson A.C.
      • Wang D.
      • Atassi B.
      • Sato K.T.
      • Ryu R.K.
      • Lewandowski R.J.
      • et al.
      Transcatheter intraarterial perfusion: MR monitoring of chemoembolization for hepatocellular carcinoma–feasibility of initial clinical translation.
      ,
      • Gaba R.C.
      • Wang D.
      • Lewandowski R.J.
      • Ryu R.K.
      • Sato K.T.
      • Kulik L.M.
      • et al.
      Four-dimensional transcatheter intraarterial perfusion MR imaging for monitoring chemoembolization of hepatocellular carcinoma: preliminary results.
      ,
      • Wang D.
      • Jin B.
      • Lewandowski R.J.
      • Ryu R.K.
      • Sato K.T.
      • Mulcahy M.F.
      • et al.
      Quantitative 4D transcatheter intraarterial perfusion MRI for monitoring chemoembolization of hepatocellular carcinoma.
      ]. Pre-treatment perfusion parameters before transarterial chemoembolisation have been shown to predict progression-free-survival, independently of tumour size and number of lesions [
      • Michielsen K.
      • De Keyzer F.
      • Verslype C.
      • Dymarkowski S.
      • van Malenstein H.
      • Oyen R.
      • et al.
      Pretreatment DCE-MRI for prediction of PFS in patients with inoperable HCC treated with TACE.
      ].
      In patients treated with targeted therapies, perfusion parameters (using either CT or MR) decrease early and significantly in responders when compared to non-responders. Higher baseline perfusion values are also observed in patients in whom the disease was controlled [
      • Hsu C.-Y.
      • Shen Y.-C.
      • Yu C.-W.
      • Hsu C.
      • Hu F.-C.
      • Hsu C.-H.
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil.
      ,
      • Zhu A.X.
      • Sahani D.V.
      • Duda D.G.
      • di Tomaso E.
      • Ancukiewicz M.
      • Catalano O.A.
      • et al.
      Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
      ,
      • Sahani D.V.
      • Jiang T.
      • Hayano K.
      • Duda D.G.
      • Catalano O.A.
      • Ancukiewicz M.
      • et al.
      Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.
      ]. French teams also reported that standardized quantitative CEUS could predict tumour progression [
      • Lassau N.
      • Chapotot L.
      • Benatsou B.
      • Vilgrain V.
      • Kind M.
      • Lacroix J.
      • et al.
      Standardization of dynamic contrast-enhanced ultrasound for the evaluation of antiangiogenic therapies: the French multicenter Support for Innovative and Expensive Techniques Study.
      ,
      • Frampas E.
      • Lassau N.
      • Zappa M.
      • Vullierme M.-P.
      • Koscielny S.
      • Vilgrain V.
      Advanced Hepatocellular Carcinoma: early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results.
      ,
      • Lassau N.
      • Bonastre J.
      • Kind M.
      • Vilgrain V.
      • Lacroix J.
      • Cuinet M.
      • et al.
      Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study.
      ]. This technique is not based on pharmacokinetic models allowing for the extraction of quantitative perfusion parameters. It is based on the descriptive but quantitative analysis of intensity-time enhancement curves.

      Added value of metabolic imaging in primary liver tumours

      Most published studies have used 18F-FDG. The sensitivity of PET using 18F-FDG is low (approximately 50%), especially for small and/or well-differentiated HCCs [
      • Ho C.
      • Chen S.
      • Yeung D.W.C.
      • Cheng T.K.C.
      Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma.
      ]. Overall, around 30–50% of all HCC are missed [
      • Hennedige T.
      • Venkatesh S.K.
      Imaging of hepatocellular carcinoma: diagnosis, staging and treatment monitoring.
      ], explaining why 18F-FDG PET is not routinely used in the management of HCC. Nevertheless, 18F-FDG uptake is mostly observed in high-grade HCCs, thus providing potentially interesting information regarding tumour biology [
      • Torizuka T.
      • Tamaki N.
      • Inokuma T.
      • Magata Y.
      • Sasayama S.
      • Yonekura Y.
      • et al.
      In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET.
      ,
      • Seo S.
      • Hatano E.
      • Higashi T.
      • Hara T.
      • Tada M.
      • Tamaki N.
      • et al.
      Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma.
      ]. Indeed, some teams use 18F-FDG PET for patient selection before liver transplantation, with promising results [
      • Hong G.
      • Suh K.-S.
      • Suh S.
      • Yoo T.
      • Kim H.
      • Park M.-S.
      • et al.
      Preoperative Alpha-fetoprotein and (18)F-FDG PET predict tumor recurrence better than milan criteria in living donor liver transplantation.
      ]. Other indications include detection of extrahepatic disease with a reported 83% sensitivity for supra-centimetre extrahepatic metastases [
      • Sugiyama M.
      • Sakahara H.
      • Torizuka T.
      • Kanno T.
      • Nakamura F.
      • Futatsubashi M.
      • et al.
      18F-FDG PET in the detection of extrahepatic metastases from hepatocellular carcinoma.
      ], or diagnosis of recurrent HCC especially in patients with poorly differentiated HCC [
      • Lin C.-Y.
      • Chen J.-H.
      • Liang J.-A.
      • Lin C.-C.
      • Jeng L.-B.
      • Kao C.-H.
      18F-FDG PET or PET/CT for detecting extrahepatic metastases or recurrent hepatocellular carcinoma: a systematic review and meta-analysis.
      ]. MFCs has been reported to be highly FDG avid [
      • Jiang L.
      • Tan H.
      • Panje C.M.
      • Yu H.
      • Xiu Y.
      • Shi H.
      Role of 18F-FDG PET/CT Imaging in Intrahepatic Cholangiocarcinoma.
      ], with 84–94% sensitivity and 79–100% specificity [
      • Jadvar H.
      • Henderson R.W.
      • Conti P.S.
      [F-18]fluorodeoxyglucose positron emission tomography and positron emission tomography: computed tomography in recurrent and metastatic cholangiocarcinoma.
      ,
      • Kim J.Y.
      • Kim M.-H.
      • Lee T.Y.
      • Hwang C.Y.
      • Kim J.S.
      • Yun S.-C.
      • et al.
      Clinical role of 18F-FDG PET-CT in suspected and potentially operable cholangiocarcinoma: a prospective study compared with conventional imaging.
      ]. Nevertheless, there are limited data available on the influence of PET/CT imaging for the management of MFC [
      • Jiang L.
      • Tan H.
      • Panje C.M.
      • Yu H.
      • Xiu Y.
      • Shi H.
      Role of 18F-FDG PET/CT Imaging in Intrahepatic Cholangiocarcinoma.
      ], and this examination is not routinely performed by most teams.
      Published data with other radiotracers is limited, and most studies have compared alternative tracers to 18F-FDG PET only. In all cases, tracers are metabolised in normal hepatocytes, resulting in high background uptake, limiting their utility. Choline has been the most studied tracer. Various studies have shown that 11C-choline and 18F-choline have increased uptake in moderately differentiated HCC, but lower uptake in poorly differentiated lesions. A recent meta-analysis reported a detection rate of 84% [
      • Bertagna F.
      • Bertoli M.
      • Bosio G.
      • Biasiotto G.
      • Sadeghi R.
      • Giubbini R.
      • et al.
      Diagnostic role of radiolabelled choline PET or PET/CT in hepatocellular carcinoma: a systematic review and meta-analysis.
      ], significantly higher than that of 18F-FDG [
      • Talbot J.-N.
      • Fartoux L.
      • Balogova S.
      • Nataf V.
      • Kerrou K.
      • Gutman F.
      • et al.
      Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease.
      ]. Finally, 11C-acetate showed an encouraging sensitivity of 75% for detecting HCC, but decreased to 32% in HCC smaller than 2 cm [
      • Park J.-W.
      • Kim J.H.
      • Kim S.K.
      • Kang K.W.
      • Park K.W.
      • Choi J.-I.
      • et al.
      A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma.
      ].

      Secondary liver tumours

      The dual blood supply of the liver from the portal venous system and hepatic artery, and the sinusoidal cytoarchitecture of the liver parenchyma with its vessel fenestrations both favour the invasion of circulating tumour cells for establishing metastatic foci. Liver metastases (LM) occur in approximately 50% of patients with colorectal carcinoma (CRC) [
      • Taylor A.
      • Langeberg W.
      • Mowat F.
      • Alexander D.
      • Choti M.
      • Poston G.
      Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors.
      ], and in approximately 10% of all cases of breast cancer [
      • Page A.J.
      • Weiss M.J.
      • Pawlik T.M.
      Surgical management of noncolorectal cancer liver metastases.
      ]. Depending on primary tumour site and grade, LM may occur in up to 95% of patients with neuroendocrine tumours (NET) [
      • Frilling A.
      • Modlin I.M.
      • Kidd M.
      • Russell C.
      • Breitenstein S.
      • Salem R.
      • et al.
      Recommendations for management of patients with neuroendocrine liver metastases.
      ]. If liver biopsy is performed for tumour characterisation, the apparition of focal liver lesions showing typical imaging features in patients with a pathologically proven primary cancer, with or without elevated tumour markers, do not require a pathological proof of LM. Advances in the management of LM with surgical and non-surgical modalities underscore the importance of their morphologic and functional characterisation as they play crucial roles in staging and thus treatment selection. Furthermore, assessment of extrahepatic disease triggers treatment decisions for LM.
      MRI with diffusion-weighted sequences and hepatobiliary MR contrast agents are the most accurate modality for characterising and detecting colorectal and neuroendocrine liver metastases.
      Meticulous characterisation of colorectal (CR) LM is essential for optimal treatment selection. Whilst chemotherapy is the mainstay of colorectal liver metastasis (CRLM) treatment, modern onco-surgical techniques for controlling CRLM have been associated with 5-year survival rates of up to 58% with two-stage hepatectomy [
      • Brouquet A.
      • Abdalla E.K.
      • Kopetz S.
      • Garrett C.R.
      • Overman M.J.
      • Eng C.
      • et al.
      High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome.
      ], compared to as low as 5% for those with disease not amenable for resection [
      • Tzeng C.-W.D.
      • Aloia T.A.
      Colorectal liver metastases.
      ]. Accurate imaging information on extent of tumour burden, intrahepatic anatomy and topography including calculation of future liver remnant is pre-requisite for advanced surgical planning [
      • Radtke A.
      • Sotiropoulos G.C.
      • Molmenti E.P.
      • Schroeder T.
      • Peitgen H.O.
      • Frilling A.
      • et al.
      Computer-assisted surgery planning for complex liver resections: when is it helpful? A single-center experience over an 8-year period.
      ].
      Hepatic metastases from NET are often small (<10 mm) with a bilobar distribution, with morphological imaging underestimating true hepatic disease burden by at least 50% as compared to meticulous pathological examination [
      • Elias D.
      • Lefevre J.H.
      • Duvillard P.
      • Goéré D.
      • Dromain C.
      • Dumont F.
      • et al.
      Hepatic metastases from neuroendocrine tumors with a ‘thin slice’ pathological examination: they are many more than you think.
      ]. Various therapeutic strategies may be employed in the management of neuroendocrine LM, including resection, transplantation, transarterial or percutaneous liver-directed modalities including SIRT, peptide receptor radionuclide therapy (PRRT) [
      • Frilling A.
      • Modlin I.M.
      • Kidd M.
      • Russell C.
      • Breitenstein S.
      • Salem R.
      • et al.
      Recommendations for management of patients with neuroendocrine liver metastases.
      ], and medical treatment with targeted drugs or chemotherapy. Treatment of neuroendocrine (NE) LM is often multimodal, with therapy planning underpinned by accurate radiological interrogation of hepatic disease. Neuroendocrine LM are classically described as hypervascular lesions. This is partly true as they indeed tend to be more vascularised than LM from other, commoner primary tumours, yet hypovascular NE LM are relatively common. The technique for MRI of NE LM should incorporate T1, T2 and CE sequences.

      Added value of hepatobiliary contrast and diffusion-weighted MRI in secondary liver tumours

      Magnetic resonance imaging with DW sequences and hepatobiliary contrast agents are extremely useful modalities for lesion characterisation. A recent meta-analysis [
      • Vilgrain V.
      • Esvan M.
      • Ronot M.
      • Caumont-Prim A.
      • Aube C.
      • Chatellier G.
      A meta-analysis of diffusion-weighted and gadoxetic acid-enhanced MR imaging for the detection of colorectal liver metastases.
      ] of 39 studies (1989 patients, 3854 metastases) compared hepatobiliary CE MRI with DW MRI in detecting CRLM. This demonstrated per-lesion sensitivity estimates for DW-, gadoxetic acid-enhanced MRI, and the combined sequence for detecting CRLM of 87.1%, 90.6% and 95.5%, respectively. Gadoxetic acid-enhanced MRI and the combined sequence were significantly more sensitive than DW MRI (p = 0.0001 and p <0.0001, respectively), with combined sequence imaging in turn significantly more sensitive than gadoxetic acid-enhanced MRI (p <0.0001). Similar results were observed in studies comparing these 3 techniques simultaneously. The combination of DW and CE MR sequences provides the optimal sensitivity for CRLM. Experience with DW MRI in NE LM is relatively restricted, although existing data are promising: DW MRI possesses a higher sensitivity than T2 MRI and dynamic MRI [
      • d’Assignies G.
      • Fina P.
      • Bruno O.
      • Vullierme M.-P.
      • Tubach F.
      • Paradis V.
      • et al.
      High sensitivity of diffusion-weighted MR imaging for the detection of liver metastases from neuroendocrine tumors: comparison with T2-weighted and dynamic gadolinium-enhanced MR imaging.
      ] in NE LM characterisation, and has been used to evaluate response to treatment with transarterial chemoembolisation [
      • Liapi E.
      • Geschwind J.-F.
      • Vossen J.A.
      • Buijs M.
      • Georgiades C.S.
      • Bluemke D.A.
      • et al.
      Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization.
      ] and SIRT [
      • Kukuk G.M.
      • Mürtz P.
      • Träber F.
      • Meyer C.
      • Ullrich J.
      • Gieseke J.
      • et al.
      Diffusion-weighted imaging with acquisition of three b-values for response evaluation of neuroendocrine liver metastases undergoing selective internal radiotherapy.
      ] although these roles are not yet routine.

      Added value of perfusion imaging in secondary liver tumours

      Perfusion imaging has been analysed in the context of assessing the response of CRLM to treatment with combined targeted and cytotoxic therapies. A significantly higher baseline vascular permeability was reported in responders to such treatment, as was a significant decrease after 6 weeks of treatment [
      • Coenegrachts K.
      • Bols A.
      • Haspeslagh M.
      • Rigauts H.
      Prediction and monitoring of treatment effect using T1-weighted dynamic contrast-enhanced magnetic resonance imaging in colorectal liver metastases: potential of whole tumour ROI and selective ROI analysis.
      ]. Furthermore, improved progression-free survival has been demonstrated in those with reductions of >40% in the transfer constant on dynamic CE MRI [
      • De Bruyne S.
      • Van Damme N.
      • Smeets P.
      • Ferdinande L.
      • Ceelen W.
      • Mertens J.
      • et al.
      Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases.
      ]. Regarding SIRT, significant differences in arterial perfusion have been identified between responders and non-responders on pre-treatment CT perfusion imaging [
      • Morsbach F.
      • Pfammatter T.
      • Reiner C.S.
      • Fischer M.A.
      • Sah B.-R.
      • Winklhofer S.
      • et al.
      Computed tomographic perfusion imaging for the prediction of response and survival to transarterial radioembolization of liver metastases.
      ], with higher perfusion associated with a significantly improved 1-year survival. Experience with perfusion imaging in NE LM is limited, although the existing data are consistent with those obtained in CRLM [
      • Miyazaki K.
      • Orton M.R.
      • Davidson R.L.
      • d’Arcy J.A.
      • Lewington V.
      • Koh T.S.
      • et al.
      Neuroendocrine tumor liver metastases: use of dynamic contrast-enhanced MR imaging to monitor and predict radiolabeled octreotide therapy response.
      ].

      Added value of molecular imaging in colorectal liver metastases

      Three recent systematic reviews/meta-analyses have compared imaging CRLM with PET and morphological modalities [
      • Niekel M.C.
      • Bipat S.
      • Stoker J.
      Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment.
      ,
      • Patel S.
      • McCall M.
      • Ohinmaa A.
      • Bigam D.
      • Dryden D.M.
      Positron emission tomography/computed tomographic scans compared to computed tomographic scans for detecting colorectal liver metastases: a systematic review.
      ,
      • Maffione A.M.
      • Lopci E.
      • Bluemel C.
      • Giammarile F.
      • Herrmann K.
      • Rubello D.
      Diagnostic accuracy and impact on management of (18)F-FDG PET and PET/CT in colorectal liver metastasis: a meta-analysis and systematic review.
      ]. Although the number of studies directly comparing these modalities is low, it appears that CT and MRI possess higher sensitivity than PET in per-lesion and per-patient bases. Nevertheless, PET may be more specific and is capable of altering initial management plans in 24% of patients on average [
      • Maffione A.M.
      • Lopci E.
      • Bluemel C.
      • Giammarile F.
      • Herrmann K.
      • Rubello D.
      Diagnostic accuracy and impact on management of (18)F-FDG PET and PET/CT in colorectal liver metastasis: a meta-analysis and systematic review.
      ], with noted power in detecting extrahepatic deposits and thus impact on selection for hepatectomy. However, prospective studies have not demonstrated survival benefit of including PET in the radiological work-up for CRLM [
      • Ruers T.J.M.
      • Wiering B.
      • van der Sijp J.R.M.
      • Roumen R.M.
      • de Jong K.P.
      • Comans E.F.I.
      • et al.
      Improved selection of patients for hepatic surgery of colorectal liver metastases with (18)F-FDG PET: a randomized study.
      ,
      • Moulton C.-A.
      • Gu C.-S.
      • Law C.H.
      • Tandan V.R.
      • Hart R.
      • Quan D.
      • et al.
      Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial.
      ].
      The use of 18F-FDG PET for monitoring of chemotherapy is not recommended [
      • van Kessel C.S.
      • Buckens C.F.M.
      • van den Bosch M.A.A.J.
      • van Leeuwen M.S.
      • van Hillegersberg R.
      • Verkooijen H.M.
      Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis.
      ,
      • Glazer E.S.
      • Beaty K.
      • Abdalla E.K.
      • Vauthey J.N.
      • Curley S.A.
      Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases.
      ], a notable consideration given that the mainstay of metastatic CRC treatment is cytotoxic chemotherapy. Indeed, the optimal modalities for assessing CRLM patients treated with neoadjuvant chemotherapeutics are CE or DW MRI [
      • van Kessel C.S.
      • Buckens C.F.M.
      • van den Bosch M.A.A.J.
      • van Leeuwen M.S.
      • van Hillegersberg R.
      • Verkooijen H.M.
      Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis.
      ]. For non-surgical patients the albeit limited data suggests that 18F-FDG PET and 18F-FDG PET/CT are useful for evaluating response of CRLM after treatment with SIRT [
      • Annunziata S.
      • Treglia G.
      • Caldarella C.
      • Galiandro F.
      The role of 18F-FDG-PET and PET/CT in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review.
      ]. Early metabolic response, defined as >50% reduction of liver-to-tumour ratio on 18F-FDG PET may correlate with survival post-SIRT and aid adaptation of management to tumour response [
      • Sabet A.
      • Meyer C.
      • Aouf A.
      • Sabet A.
      • Ghamari S.
      • Pieper C.C.
      • et al.
      Early post-treatment FDG PET predicts survival after 90Y microsphere radioembolization in liver-dominant metastatic colorectal cancer.
      ]. Furthermore, 18F-FDG PET/CT-derived factors such as functional tumour volume and total lesion glycolysis have been demonstrated to be significant prognosticators for patient survival following SIRT in small cohorts [
      • Annunziata S.
      • Treglia G.
      • Caldarella C.
      • Galiandro F.
      The role of 18F-FDG-PET and PET/CT in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review.
      ]. Hybrid 18F-FDG PET/MRI has been shown to possess higher accuracy in the diagnosis of LM in a number of reports either in mixed cohorts [
      • Beiderwellen K.
      • Geraldo L.
      • Ruhlmann V.
      • Heusch P.
      • Gomez B.
      • Nensa F.
      • et al.
      Accuracy of [18F]FDG PET/MRI for the detection of liver metastases.
      ,
      • Reiner C.S.
      • Stolzmann P.
      • Husmann L.
      • Burger I.A.
      • Hüllner M.W.
      • Schaefer N.G.
      • et al.
      Protocol requirements and diagnostic value of PET/MR imaging for liver metastasis detection.
      ] or in exclusively CRC cohorts [
      • Brendle C.
      • Schwenzer N.F.
      • Rempp H.
      • Schmidt H.
      • Pfannenberg C.
      • la Fougère C.
      • et al.
      Assessment of metastatic colorectal cancer with hybrid imaging: comparison of reading performance using different combinations of anatomical and functional imaging techniques in PET/MRI and PET/CT in a short case series.
      ] however further studies specific to CRLM are required.

      Added value of molecular imaging in neuroendocrine liver metastases

      The molecular imaging repertoire for NET encompasses an array of radiotracers (Table 1). Selection is dependent on tumour grade (G) and availability. Based on Ki67 index, NET may be classified as G1 (Ki67 ⩽2%), G2 (Ki67 3–20%) and G3 (Ki67 >20%, neuroendocrine carcinoma [NEC]) [
      • Rindi G.
      • Klöppel G.
      • Couvelard A.
      • Komminoth P.
      • Körner M.
      • Lopes J.M.
      • et al.
      TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.
      ]. Radiotracers may exploit the observation that G1/2 NET commonly express somatostatin receptors (SSTRs) on their cell membranes, most commonly SSTR2. Such SSTR-targeted imaging includes SSTR scintigraphy (SRS) with the radioligand [111In-DTPA0]octreotide (OctreoScan), or SSTR PET using somatostatin analogues (SSAs) radiolabelled with the positron emitters Gallium-68 (68Ga), or Copper-64 (64Cu). Functional SSTR-targeted imaging is the ideal modality capable of ascertaining the suitability of PRRT as a treatment strategy. Recently developed tracers include radioligands with high affinity for glucagon-like peptide-1 receptors (GLP-1R), mostly utilised in single photon emission computed tomography (SPECT)/CT for the localisation of occult insulinoma, which typically have lower expression of SSTRs [
      • Christ E.
      • Wild D.
      • Ederer S.
      • Béhé M.
      • Nicolas G.
      • Caplin M.E.
      • et al.
      Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study.
      ] and are often challenging to localise. GLP-1R based imaging has been shown to guide surgical decision and enable parenchyma-sparring pancreatic resections [
      • Wenning A.S.
      • Kirchner P.
      • Antwi K.
      • Fani M.
      • Wild D.
      • Christ E.
      • et al.
      Preoperative Glucagon-like peptide-1 receptor imaging reduces surgical trauma and pancreatic tissue loss in insulinoma patients: a report of three cases.
      ].
      Molecular imaging with radiolabelled somatostatin analogues represents the gold-standard imaging approach for the majority of neuroendocrine tumours.
      Table 1Technical and clinical considerations of molecular imaging with the most widely used radiotracers for neuroendocrine tumours.
      FDA, Food and Drug Administration; EMA, European Medicines Agency; CT, computed tomography; MRI, magnetic resonance imaging; SPECT, single photon emission CT; LM, liver metastases; NET, neuroendocrine tumours; NEC, neuroendocrine carcinomas. Adapted from
      • Bodei L.
      • Sundin A.
      • Kidd M.
      • Prasad V.
      • Modlin I.M.
      The status of neuroendocrine tumor imaging: from darkness to light?.
      .
      Alternatively, tumour cell metabolism may be targeted; 18F-FDG is useful in imaging NEC or poorly differentiated NET. Other tracers that target neuroendocrine cell amine precursor uptake and metabolism are available for NET, including 6-18F-L-3,4-dihydroxyphenylalanine (18F-DOPA) and β-[11C]-5-hydroxy-L-tryptophan (11C-5-HTP).
      Globally, OctreoScan is the most widely utilised imaging modality for NET, and is typically combined with SPECT or SPECT/CT to optimise lesion localisation and characterisation [
      • van Essen M.
      • Sundin A.
      • Krenning E.P.
      • Kwekkeboom D.J.
      Neuroendocrine tumours: the role of imaging for diagnosis and therapy.
      ]. Imaging may be done at 24 h and 48 h post-injection, due to a half-life of 2.8 days. To avert potential competition at SSTRs between radiolabelled analogues and therapeutic SSAs and thus image degradation, it has been posited that short-acting SSAs and long-acting SSAs be temporarily discontinued for at 24 h and 3–6 weeks before SRS, respectively, although this is debated [
      • Balon H.R.
      • Brown T.L.Y.
      • Goldsmith S.J.
      • Silberstein E.B.
      • Krenning E.P.
      • Lang O.
      • et al.
      The SNM practice guideline for somatostatin receptor scintigraphy 2.0.
      ,
      • Bombardieri E.
      • Ambrosini V.
      • Aktolun C.
      • Baum R.P.
      • Bishof-Delaloye A.
      • Del Vecchio S.
      • et al.
      111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging.
      ]. Primary tumour localisation rates with OctreoScan have been reported to be as low as 37% [
      • Maxwell J.E.
      • Sherman S.K.
      • Menda Y.
      • Wang D.
      • O’Dorisio T.M.
      • Howe J.R.
      Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors.
      ] in recent studies, although its performance in detecting LM appears better, with sensitivities from 49.3% [
      • Dromain C.
      • de Baere T.
      • Lumbroso J.
      • Caillet H.
      • Laplanche A.
      • Boige V.
      • et al.
      Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging.
      ] to 91% being reported [
      • Shi W.
      • Johnston C.F.
      • Buchanan K.D.
      • Ferguson W.R.
      • Laird J.D.
      • Crothers J.G.
      • et al.
      Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging.
      ]. However, one study by Dromain and colleagues [
      • Dromain C.
      • de Baere T.
      • Lumbroso J.
      • Caillet H.
      • Laplanche A.
      • Boige V.
      • et al.
      Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging.
      ] demonstrated MRI as superior to CT and SRS in detecting NE LM. The predominant limiting factors for SRS in detecting neuroendocrine LM appear to be tumour size [
      • Maxwell J.E.
      • Sherman S.K.
      • Menda Y.
      • Wang D.
      • O’Dorisio T.M.
      • Howe J.R.
      Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors.
      ], relatively high tracer uptake in the liver due to hepatocyte SSTR expression, and hepatic and renal tracer excretion [
      • Kwekkeboom D.J.
      • Kam B.L.
      • van Essen M.
      • Teunissen J.J.M.
      • van Eijck C.H.J.
      • Valkema R.
      • et al.
      Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors.
      ]. Technetium-99 (99mTc) labelled SSAs, such as 99mTc-EDDA/HYNIC-Tyr3-octreotide (99mTc-EDDA/HYNIC-TOC), which is alternatively known as 99mTc-Tecktroyd are mostly used in Eastern Europe.
      Functional imaging with 68Ga-radiolabelled SSAs (68Ga-SSAs) is restricted mostly to specialist European centres at present. Currently available 68Ga-SSAs include: [68Ga-DOTA0,Tyr3]octreotide (68Ga-DOTATOC), [68Ga-DOTA,1-Nal3]octreotide (68Ga-DOTANOC) and [68Ga-DOTA0,Tyr3]octreotate (68Ga-DOTATATE), which possess comparable sensitivities and specificities [
      • Johnbeck C.B.
      • Knigge U.
      • Kjær A.
      PET tracers for somatostatin receptor imaging of neuroendocrine tumors: current status and review of the literature.
      ]. However, 68Ga-SSA PET is increasingly expected to become the global gold standard by virtue of its improved lesion detection capabilities as compared to SRS [
      • Geijer H.
      • Breimer L.H.
      Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis.
      ,
      • Gabriel M.
      • Decristoforo C.
      • Kendler D.
      • Dobrozemsky G.
      • Heute D.
      • Uprimny C.
      • et al.
      68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT.
      ] and CT/MRI (Fig. 4, Fig. 5) [
      • Ambrosini V.
      • Campana D.
      • Bodei L.
      • Nanni C.
      • Castellucci P.
      • Allegri V.
      • et al.
      68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors.
      ,
      • Frilling A.
      • Sotiropoulos G.C.
      • Radtke A.
      • Malago M.
      • Bockisch A.
      • Kuehl H.
      • et al.
      The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors.
      ] with obvious ramifications on informing treatment strategies [
      • Frilling A.
      • Sotiropoulos G.C.
      • Radtke A.
      • Malago M.
      • Bockisch A.
      • Kuehl H.
      • et al.
      The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors.
      ,
      • Ruf J.
      • Heuck F.
      • Schiefer J.
      • Denecke T.
      • Elgeti F.
      • Pascher A.
      • et al.
      Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors.
      ], as well as reported cost-effectiveness [
      • Schreiter N.F.
      • Brenner W.
      • Nogami M.
      • Buchert R.
      • Huppertz A.
      • Pape U.-F.
      • et al.
      Cost comparison of 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATOC PET/CT for staging enteropancreatic neuroendocrine tumours.
      ]. Molecular imaging with 68Ga-SSA PET plays a major role in the selection of patients for PRRT and their personalised management [
      • Baum R.P.
      • Kulkarni H.R.
      THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy – The Bad Berka Experience.
      ]. Recent studies have suggested that the combination of 68Ga-DOTA PET and MRI with [
      • Hope T.A.
      • Pampaloni M.H.
      • Nakakura E.
      • VanBrocklin H.
      • Slater J.
      • Jivan S.
      • et al.
      Simultaneous (68)Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor.
      ,
      • Armbruster M.
      • Sourbron S.
      • Haug A.
      • Zech C.J.
      • Ingrisch M.
      • Auernhammer C.J.
      • et al.
      Evaluation of neuroendocrine liver metastases: a comparison of dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography/computed tomography.
      ,
      • Armbruster M.
      • Zech C.J.
      • Sourbron S.
      • Ceelen F.
      • Auernhammer C.J.
      • Rist C.
      • et al.
      Diagnostic accuracy of dynamic gadoxetic-acid-enhanced MRI and PET/CT compared in patients with liver metastases from neuroendocrine neoplasms.
      ] or without [
      • Flechsig P.
      • Zechmann C.M.
      • Schreiweis J.
      • Kratochwil C.
      • Rath D.
      • Schwartz L.H.
      • et al.
      Qualitative and quantitative image analysis of CT and MR imaging in patients with neuroendocrine liver metastases in comparison to (68)Ga-DOTATOC PET.
      ] contrast is an optimal imaging strategy for gastroenteropancreatic NE LM, with the two modalities providing complementary information regarding the state of disease intrinsic to the liver.
      Figure thumbnail gr4
      Fig. 4Comparison of CT and 68Ga-DOTATATE PET/CT in a patient with pulmonary NET. (A) Axial CT of liver. (B) Axial PET image of liver. (C) Fused PET/CT demonstrates involvement of liver, pancreatic tail and several abdominal lymph nodes not otherwise evident on morphological imaging. (D) Maximum intensity projection of 68Ga-DOTATATE uptake, also demonstrating radiotracer uptake in left-sided metastatic supra-clavicular lymph nodes.
      Figure thumbnail gr5
      Fig. 5Identification of primary NET, hepatic and extrahepatic metastases on 68Ga-DOTATATE PET/CT. (A) Uptake corresponding to primary pancreatic NET. (B) Bilobar neuroendocrine liver metastases. (C) Identification of a small, solitary bone metastasis not evident on morphological imaging.
      Despite the overall improved capabilities of 68Ga-SSA PET over morphological imaging in assessing disease stage, even SSTR-targeted imaging has been shown to underestimate true disease burden, particularly sub-centimetre lesions such as miliary LM. A group from Copenhagen recently developed the novel tracer 64Cu-DOTATATE which can identify LM that 111In-DTPA SRS cannot [
      • Pfeifer A.
      • Bardram Johnbeck C.
      • Knigge U.
      • Mortensen J.
      • Oturai P.
      • Loft A.
      • et al.
      Clinical PET imaging of neuroendocrine tumors using 64Cu-DOTA-Tyr3-octreotate.
      ], although there have been no studies comparing 64Cu-DOTATATE PET with 68Ga-DOTATATE PET.
      The glucose analogue 18F-FDG is limited to the imaging of NEC and poorly differentiated NET. On a per-patient basis, 18F-FDG PET has inferior sensitivity compared to both SRS [
      • Binderup T.
      • Knigge U.
      • Loft A.
      • Mortensen J.
      • Pfeifer A.
      • Federspiel B.
      • et al.
      Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET.
      ] and 68Ga-SSA PET [
      • Naswa N.
      • Sharma P.
      • Gupta S.K.
      • Karunanithi S.
      • Reddy R.M.
      • Patnecha M.
      • et al.
      Dual tracer functional imaging of gastroenteropancreatic neuroendocrine tumors using 68Ga-DOTA-NOC PET-CT and 18F-FDG PET-CT: competitive or complimentary?.
      ]. However, a correlation between higher tumour grade and 18F-FDG uptake has been demonstrated in NET [
      • Binderup T.
      • Knigge U.
      • Loft A.
      • Federspiel B.
      • Kjaer A.
      18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors.
      ]. Clinical experience with 11C-5-HTP PET in NET is mostly confined to Dutch and Swedish centres, arguably due to the complexities of tracer synthesis. Contrastingly, 18F-DOPA is more widely available due to implementation in functional neurological imaging, and targets NET amine metabolism. Both 18F-DOPA and 11C-5-HTP may be alternative or problem-solving modalities in tumours negative on SSTR imaging. The study of Koopmans et al. [
      • Koopmans K.P.
      • Neels O.C.
      • Kema I.P.
      • Elsinga P.H.
      • Sluiter W.J.
      • Vanghillewe K.
      • et al.
      Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography.
      ] compared these against CT and SRS in both enteric and pancreatic islet cell tumours. For LM from enteric tumours, 18F-DOPA PET/CT significantly out-performed 11C-5-HTP PET/CT (sensitivities 100% and 91%, respectively); whereas for metastases from pancreatic NET, 11C-5-HTP PET/CT significantly out-performed 18F-DOPA PET/CT (sensitivities 96% and 86%, respectively). Whilst the data directly comparing 68Ga-SSA PET and 18F-DOPA PET are limited, it appears that the former detects more liver lesions than the latter [
      • Ambrosini V.
      • Tomassetti P.
      • Castellucci P.
      • Campana D.
      • Montini G.
      • Rubello D.
      • et al.
      Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours.
      ,
      • Haug A.
      • Auernhammer C.J.
      • Wängler B.
      • Tiling R.
      • Schmidt G.
      • Göke B.
      • et al.
      Intraindividual comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in patients with well-differentiated metastatic neuroendocrine tumours.
      ].
      Interestingly, SSTR-antagonists such as 111In-DOTA-BASS have emerged as a promising novel approach. These have displayed higher, prolonged retention in tumours and predicated improved imaging quality compared to 111In-pentreotide scans in small patient series [
      • Wild D.
      • Fani M.
      • Behe M.
      • Brink I.
      • Rivier J.E.F.
      • Reubi J.C.
      • et al.
      First clinical evidence that imaging with somatostatin receptor antagonists is feasible.
      ]. Early evidence also suggests a potential role for 89Zr-labelled bevacizumab in assessing NET treatment response to everolimus [
      • van Asselt S.J.
      • Oosting S.F.
      • Brouwers A.H.
      • Bongaerts A.H.H.
      • de Jong J.R.
      • Lub-de Hooge M.N.
      • et al.
      Everolimus reduces (89)Zr-bevacizumab tumor uptake in patients with neuroendocrine tumors.
      ].

      Added role of molecular imaging in non-colorectal, non-neuroendocrine liver metastases

      Although functional imaging does not exert much influence on the assessment of loco-regional disease in pancreatic cancer, studies have demonstrated appreciable effects of PET/CT in detecting metastatic deposits. A recent meta-analysis of the use of 18F-FDG PET in pancreatic cancer [
      • Wang Z.
      • Chen J.-Q.
      • Liu J.-L.
      • Qin X.-G.
      • Huang Y.
      FDG-PET in diagnosis, staging and prognosis of pancreatic carcinoma: a meta-analysis.
      ] demonstrated pooled sensitivity and specificity values of 67% and 96%, respectively, for LM. Unsurprisingly, combined PET/CT was significantly more sensitive than PET alone in pancreatic LM evaluation (82% vs. 67%). Not to be used as a stand-alone modality, studies have demonstrated the effect of PET as an add-on to morphological imaging in altering initial management plans for up to 26% of patients based on its power in detecting distant disease [
      • Kauhanen S.P.
      • Komar G.
      • Seppänen M.P.
      • Dean K.I.
      • Minn H.R.
      • Kajander S.A.
      • et al.
      A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer.
      ,
      • Burge M.E.
      • O’Rourke N.
      • Cavallucci D.
      • Bryant R.
      • Francesconi A.
      • Houston K.
      • et al.
      A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers.
      ].
      Whilst occupying limited roles in radiologically assessing oesophageal carcinomas due to low sensitivity (18–100%) and resolution limits [
      • Dai T.
      • Popa E.
      • Shah M.A.
      The role of 18F-FDG PET imaging in upper gastrointestinal malignancies.
      ], PET has clinically useful accuracy in pre-operatively detecting distant metastases. The meta-analysis of van Vliet et al. [
      • van Vliet E.P.M.
      • Heijenbrok-Kal M.H.
      • Hunink M.G.M.
      • Kuipers E.J.
      • Siersema P.D.
      Staging investigations for oesophageal cancer: a meta-analysis.
      ] demonstrated a sensitivity and specificity of PET of 71% and 93%, respectively, vs. 52% and 91% for CT, respectively. Furthermore, PET has been shown to alter strategies in approximately one third of patients [
      • Chatterton B.E.
      • Ho Shon I.
      • Baldey A.
      • Lenzo N.
      • Patrikeos A.
      • Kelley B.
      • et al.
      Positron emission tomography changes management and prognostic stratification in patients with oesophageal cancer: results of a multicentre prospective study.
      ,
      • Barber T.W.
      • Duong C.P.
      • Leong T.
      • Bressel M.
      • Drummond E.G.
      • Hicks R.J.
      18F-FDG PET/CT has a high impact on patient management and provides powerful prognostic stratification in the primary staging of esophageal cancer: a prospective study with mature survival data.
      ]. Nevertheless, data specifically pertaining to PET for oesophageal LM is scarce, likely due to the limited impact that LM specifically exert on management strategies, as distant metastases of any site preclude a curative surgical approach in oesophageal carcinoma, and the repertoire of therapies for such disease is limited to cytotoxic and molecularly-targeted therapies and not inclusive of liver-targeted modalities.

      Limitations and realistic clinical use of functional imaging techniques

      Functional imaging techniques are widely performed for various purposes, yet some are routinely used, whilst others remain restricted to the field of clinical of pre-clinical research. This is mostly due to the strength and limitations that each technique individually bears.
      Most techniques are used as qualitative rather than quantitative tools because they provide valuable information about tumour tissue. DW imaging is now well established and validated as a cellularity/architecture biomarker, hepatospecific MR contrast agents are accurate biomarkers of the hepatocellular functions, and molecular imaging of tumour biology. This illustrates the difference between functional imaging and quantitative imaging. They all suffer from limitations (technical, clinical, biological, etc.). Regarding DW imaging, reproducibility and sequence standardization need to be further improved. The use of hepatospecific contrast agents requires clinical validation in specific clinical context. Molecular imaging is limited either by a lack of tracer uptake (for instance in HCC), or the lack of validation or evidence that its use positively impact patients’ outcome (for instance in cholangiocarcinoma and colorectal LM). Nevertheless, and interestingly, these limitations do not prevent us from using these functional imaging techniques either routinely and worldwide (DW imaging and hepatospecific MR contrast agents), or in more selected cases (molecular imaging).
      Perfusion imaging is different because it is not used in clinical practice due to major technical limitations: lack of standardization of acquisition protocols, mathematical models, and post-processing. This leads to a high variability and to the difficulty to replicate and compare results issues from different vendors and teams.

      Concluding perspectives

      Functional imaging offers useful clinical information as alterations in parameters such as tumour perfusion and cellular metabolic activity often precede – and are thus observed earlier than – morphological changes evident on conventional imaging.
      For the commonest primary liver tumours, HCC and MFC, functional imaging plays central roles in radiological work-up. Particular examples include the delineation between HCC and non-HCC cirrhotic nodules on MRI with hepatobiliary contrast agents based on lesion signal intensity, and also the increased detection of HCC with the addition of DW sequences. Whilst experience with perfusion imaging is relatively limited, the data are encouraging regarding future clinical utility in assessing the effects of loco-regional and systemic therapies. Whilst molecular imaging with 18F-FDG PET has been used by some centres in patient selection for liver transplantation for HCC, and also for imaging of MFC, these indications are not widely acknowledged.
      Whilst CE CT is typically employed as the first-step staging modality in primary colorectal cancer, CE and DW MRI are typically regarded as the gold standard in the diagnostic work-up of patients with CRLM due to their high accuracy of lesion detection. The data regarding 18F-FDG PET as an add-on modality for CRLM is conflicting across studies. Whilst some studies suggest a favourable effect on patient selection for hepatectomy by virtue of its capabilities in detecting extrahepatic disease, the clinical role for this functional modality is yet to be established.
      Molecular SSTR-targeted imaging represents the gold standard imaging approach in the majority of cases of metastatic NET. Whilst 68Ga-SSA PET/CT is seemingly the most accurate (established) molecular tracer with a sensitivity of 82–100% and a specificity of 67–100% [
      • Breeman W.A.P.
      • de Blois E.
      • Sze Chan H.
      • Konijnenberg M.
      • Kwekkeboom D.J.
      • Krenning E.P.
      (68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives.
      ], its availability is limited. The archetypal oncological imaging radiotracer 18F-FDG is limited to imaging high-grade NET. Novel tracers including those targeting GLP-1 receptors represent useful advances in tumour type-specific imaging in this heterogeneous family of neoplasms.
      Data regarding functional imaging of LM from other primary tumour types is limited, arguably mostly attributable to the lack of specific, LM-targeted therapies for such tumours and thus futility of extensive functional characterisation of hepatic disease.
      With expansions in the armamentarium for the management of liver tumours, functional imaging may play key roles in treatment selection and assessing disease response during the treatment journey, for example, as is evident in the preliminary reports discussed above. The recent realisation of PET/MRI hybrid scanners [
      • Beiderwellen K.
      • Geraldo L.
      • Ruhlmann V.
      • Heusch P.
      • Gomez B.
      • Nensa F.
      • et al.
      Accuracy of [18F]FDG PET/MRI for the detection of liver metastases.
      ] and the introduction of radiomics – comprehensive quantification of tumour phenotypes by applying a large number of quantitative features from imaging, [
      • Aerts H.J.W.L.
      • Velazquez E.R.
      • Leijenaar R.T.H.
      • Parmar C.
      • Grossmann P.
      • Cavalho S.
      • et al.
      Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach.
      ] represent exciting prospects in liver tumour imaging.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Authors’ contributions

      Review of the literature and data extraction: MR, AKC. Drafting of the manuscript: MR, AKC. Review of the manuscript and amendments: VV, AF. Final approval: MR, AKC, VV, AF.

      References

        • Taouli B.
        • Koh D.-M.
        Diffusion-weighted MR imaging of the liver.
        Radiology. 2010; 254: 47-66
        • Ronot M.
        • Lambert S.
        • Daire J.-L.
        • Lagadec M.
        • Doblas S.
        • Garteiser P.
        • et al.
        Can we justify not doing liver perfusion imaging in 2013?.
        Diagn Interv Imaging. 2013; 94: 1323-1336
        • Van Beers B.E.
        • Doblas S.
        • Sinkus R.
        New acquisition techniques: fields of application.
        Abdom Imaging. 2012; 37: 155-163
        • Van Beers B.E.
        • Pastor C.M.
        • Hussain H.K.
        Primovist, Eovist: what to expect?.
        J Hepatol. 2012; 57: 421-429
        • Vilgrain V.
        • Van Beers B.E.
        • Pastor C.M.
        Insights into the diagnosis of hepatocellular carcinomas with hepatobiliary MRI.
        J Hepatol. 2016; 64: 708-716
        • Kitao A.
        • Matsui O.
        • Yoneda N.
        • Kozaka K.
        • Shinmura R.
        • Koda W.
        • et al.
        The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging.
        Eur Radiol. 2011; 21: 2056-2066
        • Kitao A.
        • Zen Y.
        • Matsui O.
        • Gabata T.
        • Kobayashi S.
        • Koda W.
        • et al.
        Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR Imaging–correlation with molecular transporters and histopathologic features.
        Radiology. 2010; 256: 817-826
        • Nakamura Y.
        • Toyota N.
        • Date S.
        • Oda S.
        • Namimoto T.
        • Yamashita Y.
        • et al.
        Clinical significance of the transitional phase at gadoxetate disodium-enhanced hepatic MRI for the diagnosis of hepatocellular carcinoma: preliminary results.
        J Comput Assist Tomogr. 2011; 35: 723-727
        • Le Bihan D.
        • Breton E.
        • Lallemand D.
        • Aubin M.L.
        • Vignaud J.
        • Laval-Jeantet M.
        Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging.
        Radiology. 1988; 168: 497-505
      1. http://globocan.iarc.fr/Default.aspx Last accessed June 20, 2016.

        • Bridgewater J.
        • Galle P.R.
        • Khan S.A.
        • Llovet J.M.
        • Park J.-W.
        • Patel T.
        • et al.
        Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
        J Hepatol. 2014; 60: 1268-1289
        • Ronot M.
        • Vilgrain V.
        Hepatocellular carcinoma: diagnostic criteria by imaging techniques.
        Best Pract Res Clin Gastroenterol. 2014; 28: 795-812
      2. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.
        J Hepatol. 2012; 56: 908-943
        • Bruix J.
        • Sherman M.
        Management of hepatocellular carcinoma: an update.
        Hepatology. 2011; 53: 1020-1022
        • Rimola J.
        • Forner A.
        • Tremosini S.
        • Reig M.
        • Vilana R.
        • Bianchi L.
        • et al.
        Non-invasive diagnosis of hepatocellular carcinoma ⩽ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI.
        J Hepatol. 2012; 56: 1317-1323
        • Sersté T.
        • Barrau V.
        • Ozenne V.
        • Vullierme M.-P.
        • Bedossa P.
        • Farges O.
        • et al.
        Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy.
        Hepatology. 2012; 55: 800-806
        • Rode A.
        • Bancel B.
        • Douek P.
        • Chevallier M.
        • Vilgrain V.
        • Picaud G.
        • et al.
        Small nodule detection in cirrhotic livers: evaluation with US, spiral CT, and MRI and correlation with pathologic examination of explanted liver.
        J Comput Assist Tomogr. 2011; 25: 327-336
        • Kim Y.K.
        • Kim C.S.
        • Chung G.H.
        • Han Y.-M.
        • Lee S.Y.
        • Bin Chon S.
        • et al.
        Comparison of gadobenate dimeglumine-enhanced dynamic MRI and 16-MDCT for the detection of hepatocellular carcinoma.
        AJR Am J Roentgenol. 2006; 186: 149-157
        • Sano K.
        • Ichikawa T.
        • Motosugi U.
        • Sou H.
        • Muhi A.M.
        • Matsuda M.
        • et al.
        Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging.
        Radiology. 2011; 261: 834-844
        • Kierans A.S.
        • Kang S.K.
        • Rosenkrantz A.B.
        The diagnostic performance of dynamic contrast-enhanced MR imaging for detection of small hepatocellular carcinoma measuring up to 2 cm: a meta-analysis.
        Radiology. 2016; 278: 82-94
        • Kim M.-J.
        • Lee M.
        • Choi J.-Y.
        • Park Y.N.
        Imaging features of small hepatocellular carcinomas with microvascular invasion on gadoxetic acid-enhanced MR imaging.
        Eur J Radiol. 2012; 81: 2507-2512
        • Kim H.-D.
        • Lim Y.-S.
        • Han S.
        • An J.
        • Kim G.-A.
        • Kim S.Y.
        • et al.
        Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival.
        Gastroenterology. 2015; 148: 1371-1382
      3. KLCSG-NCC Korea practice guideline for the management of hepatocellular carcinoma.
        Gut Liver. 2015; 9: 267-317
        • Kudo M.
        • Matsui O.
        • Izumi N.
        • Iijima H.
        • Kadoya M.
        • Imai Y.
        • et al.
        JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the liver cancer study group of Japan.
        Liver Cancer. 2014; 3: 458-468
        • Joo I.
        • Lee J.M.
        • Lee D.H.
        • Jeon J.H.
        • Han J.K.
        • Choi B.I.
        Noninvasive diagnosis of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: can hypointensity on the hepatobiliary phase be used as an alternative to washout?.
        Eur Radiol. 2015; 25: 2859-2868
        • Choi J.W.
        • Lee J.M.
        • Kim S.J.
        • Yoon J.-H.
        • Baek J.H.
        • Han J.K.
        • et al.
        Hepatocellular carcinoma: imaging patterns on gadoxetic acid-enhanced MR Images and their value as an imaging biomarker.
        Radiology. 2013; 267: 776-786
        • Hyodo T.
        • Murakami T.
        • Imai Y.
        • Okada M.
        • Hori M.
        • Kagawa Y.
        • et al.
        Hypovascular nodules in patients with chronic liver disease: risk factors for development of hypervascular hepatocellular carcinoma.
        Radiology. 2013; 266: 480-490
        • Motosugi U.
        • Ichikawa T.
        • Sano K.
        • Sou H.
        • Onohara K.
        • Muhi A.
        • et al.
        Outcome of hypovascular hepatic nodules revealing no gadoxetic acid uptake in patients with chronic liver disease.
        J Magn Reson Imaging. 2011; 34: 88-94
        • Akai H.
        • Matsuda I.
        • Kiryu S.
        • Tajima T.
        • Takao H.
        • Watanabe Y.
        • et al.
        Fate of hypointense lesions on Gd-EOB-DTPA-enhanced magnetic resonance imaging.
        Eur J Radiol. 2012; 81: 2973-2977
        • Lee M.H.
        • Kim S.H.
        • Park M.J.
        • Park C.K.
        • Rhim H.
        Gadoxetic acid-enhanced hepatobiliary phase MRI and high-b-value diffusion-weighted imaging to distinguish well-differentiated hepatocellular carcinomas from benign nodules in patients with chronic liver disease.
        AJR Am J Roentgenol. 2011; 197: W868-W875
        • Hwang J.
        • Kim Y.K.
        • Jeong W.K.
        • Choi D.
        • Rhim H.
        • Lee W.J.
        Nonhypervascular hypointense nodules at gadoxetic acid-enhanced MR imaging in chronic liver disease: diffusion-weighted imaging for characterization.
        Radiology. 2015; 277: 309
        • Kang Y.
        • Lee J.M.
        • Kim S.H.
        • Han J.K.
        • Choi B.I.
        Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images.
        Radiology. 2012; 264: 751-760
        • Kim R.
        • Lee J.M.
        • Shin C.-I.
        • Lee E.S.
        • Yoon J.H.
        • Joo I.
        • et al.
        Differentiation of intrahepatic mass-forming cholangiocarcinoma from hepatocellular carcinoma on gadoxetic acid-enhanced liver MR imaging.
        Eur Radiol. 2015;
        • Wu L.-M.
        • Xu J.-R.
        • Lu Q.
        • Hua J.
        • Chen J.
        • Hu J.
        A pooled analysis of diffusion-weighted imaging in the diagnosis of hepatocellular carcinoma in chronic liver diseases.
        J Gastroenterol Hepatol. 2013; 28: 227-234
        • Vandecaveye V.
        • De Keyzer F.
        • Verslype C.
        • Op de Beeck K.
        • Komuta M.
        • Topal B.
        • et al.
        Diffusion-weighted MRI provides additional value to conventional dynamic contrast-enhanced MRI for detection of hepatocellular carcinoma.
        Eur Radiol. 2009; 19: 2456-2466
        • Piana G.
        • Trinquart L.
        • Meskine N.
        • Barrau V.
        • Van Beers B.
        • Vilgrain V.
        New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases.
        J Hepatol. 2011; 55: 126-132
        • Park M.-S.
        • Kim S.
        • Patel J.
        • Hajdu C.H.
        • Do R.K.G.
        • Mannelli L.
        • et al.
        Hepatocellular carcinoma: detection with diffusion-weighted versus contrast-enhanced magnetic resonance imaging in pretransplant patients.
        Hepatology. 2012; 56: 140-148
      4. Liver Imaging Reporting and Data System (LI-RADS) – American College of Radiology [Internet]. [cited 2016 Jan 7]. Available from: http://www.acr.org/Quality-Safety/Resources/LIRADS.

        • El Fattach H.
        • Dohan A.
        • Guerrache Y.
        • Dautry R.
        • Boudiaf M.
        • Hoeffel C.
        • et al.
        Intrahepatic and hilar mass-forming cholangiocarcinoma: Qualitative and quantitative evaluation with diffusion-weighted MR imaging.
        Eur J Radiol. 2015; 84: 1444-1451
        • Nakanishi M.
        • Chuma M.
        • Hige S.
        • Omatsu T.
        • Yokoo H.
        • Nakanishi K.
        • et al.
        Relationship between diffusion-weighted magnetic resonance imaging and histological tumor grading of hepatocellular carcinoma.
        Ann Surg Oncol. 2012; 19: 1302-1309
        • Catalano O.A.
        • Choy G.
        • Zhu A.
        • Hahn P.F.
        • Sahani D.V.
        Differentiation of malignant thrombus from bland thrombus of the portal vein in patients with hepatocellular carcinoma: application of diffusion-weighted MR imaging.
        Radiology. 2010; 254: 154-162
        • Mannelli L.
        • Kim S.
        • Hajdu C.H.
        • Babb J.S.
        • Clark T.W.I.
        • Taouli B.
        Assessment of tumor necrosis of hepatocellular carcinoma after chemoembolization: diffusion-weighted and contrast-enhanced MRI with histopathologic correlation of the explanted liver.
        AJR Am J Roentgenol. 2009; 193: 1044-1052
        • Namimoto T.
        • Yamashita Y.
        • Sumi S.
        • Tang Y.
        • Takahashi M.
        Focal liver masses: characterization with diffusion-weighted echo-planar MR imaging.
        Radiology. 1997; 204: 739-744
        • Bonekamp S.
        • Li Z.
        • Geschwind J.-F.H.
        • Halappa V.G.
        • Corona-Villalobos C.P.
        • Reyes D.
        • et al.
        Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part I. Identification and validation of volumetric functional response criteria.
        Radiology. 2013; 268: 420-430
        • Bonekamp S.
        • Jolepalem P.
        • Lazo M.
        • Gulsun M.A.
        • Kiraly A.P.
        • Kamel I.R.
        Hepatocellular carcinoma: response to TACE assessed with semiautomated volumetric and functional analysis of diffusion-weighted and contrast-enhanced MR imaging data.
        Radiology. 2011; 260: 752-761
        • Bonekamp S.
        • Halappa V.G.
        • Geschwind J.-F.H.
        • Li Z.
        • Corona-Villalobos C.P.
        • Reyes D.
        • et al.
        Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.
        Radiology. 2013; 268: 431-439
        • Yuan Z.
        • Zhang J.
        • Yang H.
        • Ye X.-D.
        • Xu L.-C.
        • Li W.-T.
        Diffusion-weighted MR imaging of hepatocellular carcinoma: current value in clinical evaluation of tumor response to locoregional treatment.
        J Vasc Interv Radiol. 2016; 27: 20-30
        • Kamel I.R.
        • Liapi E.
        • Reyes D.K.
        • Zahurak M.
        • Bluemke D.A.
        • Geschwind J.-F.H.
        Unresectable hepatocellular carcinoma: serial early vascular and cellular changes after transarterial chemoembolization as detected with MR imaging.
        Radiology. 2009; 250: 466-473
        • Chen C.-Y.
        • Li C.-W.
        • Kuo Y.-T.
        • Jaw T.-S.
        • Wu D.-K.
        • Jao J.-C.
        • et al.
        Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constants–initial experience.
        Radiology. 2006; 239: 448-456
        • Chung J.C.
        • Naik N.K.
        • Lewandowski R.J.
        • Deng J.
        • Mulcahy M.F.
        • Kulik L.M.
        • et al.
        Diffusion-weighted magnetic resonance imaging to predict response of hepatocellular carcinoma to chemoembolization.
        World J Gastroenterol. 2010; 16: 3161-3167
        • Mannelli L.
        • Kim S.
        • Hajdu C.H.
        • Babb J.S.
        • Taouli B.
        Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: Prediction and assessment of response to transarterial chemoembolization. Preliminary experience.
        Eur J Radiol. 2013; 82: 577-582
        • Dong S.
        • Ye X.-D.
        • Yuan Z.
        • Xu L.-C.
        • Xiao X.-S.
        Relationship of apparent diffusion coefficient to survival for patients with unresectable primary hepatocellular carcinoma after chemoembolization.
        Eur J Radiol. 2012; 81: 472-477
        • Kokabi N.
        • Camacho J.C.
        • Xing M.
        • Qiu D.
        • Kitajima H.
        • Mittal P.K.
        • et al.
        Apparent diffusion coefficient quantification as an early imaging biomarker of response and predictor of survival following yttrium-90 radioembolization for unresectable infiltrative hepatocellular carcinoma with portal vein thrombosis.
        Abdom Imaging. 2014; 39: 969-978
        • Halappa V.G.
        • Bonekamp S.
        • Corona-Villalobos C.P.
        • Li Z.
        • Mensa M.
        • Reyes D.
        • et al.
        Intrahepatic cholangiocarcinoma treated with local-regional therapy: quantitative volumetric apparent diffusion coefficient maps for assessment of tumor response.
        Radiology. 2012; 264: 285-294
        • Taouli B.
        • Johnson R.S.
        • Hajdu C.H.
        • Oei M.T.H.
        • Merad M.
        • Yee H.
        • et al.
        Hepatocellular carcinoma: perfusion quantification with dynamic contrast-enhanced MRI.
        AJR Am J Roentgenol. 2013; 201: 795-800
        • Ippolito D.
        • Sironi S.
        • Pozzi M.
        • Antolini L.
        • Ratti L.
        • Meloni F.
        • et al.
        Perfusion computed tomographic assessment of early hepatocellular carcinoma in cirrhotic liver disease: initial observations.
        J Comput Assist Tomogr. 2008; 32: 855-858
        • Ippolito D.
        • Sironi S.
        • Pozzi M.
        • Antolini L.
        • Ratti L.
        • Alberzoni C.
        • et al.
        Hepatocellular carcinoma in cirrhotic liver disease: functional computed tomography with perfusion imaging in the assessment of tumor vascularization.
        Acad Radiol. 2008; 15: 919-927
        • Fischer M.A.
        • Kartalis N.
        • Grigoriadis A.
        • Loizou L.
        • Stål P.
        • Leidner B.
        • et al.
        Perfusion computed tomography for detection of hepatocellular carcinoma in patients with liver cirrhosis.
        Eur Radiol. 2015; 25: 3123-3132
        • Sahani D.V.
        • Holalkere N.-S.
        • Mueller P.R.
        • Zhu A.X.
        Advanced hepatocellular carcinoma: CT perfusion of liver and tumor tissue–initial experience.
        Radiology. 2007; 243: 736-743
        • Chopra S.
        • Dodd G.D.
        • Chintapalli K.N.
        • Leyendecker J.R.
        • Karahan O.I.
        • Rhim H.
        Tumor recurrence after radiofrequency thermal ablation of hepatic tumors: spectrum of findings on dual-phase contrast-enhanced CT.
        AJR Am J Roentgenol. 2001; 177: 381-387
        • Forner A.
        • Ayuso C.
        • Varela M.
        • Rimola J.
        • Hessheimer A.J.
        • de Lope C.R.
        • et al.
        Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?.
        Cancer. 2009; 115: 616-623
        • Meijerink M.R.
        • van Waesberghe J.H.T.M.
        • van der Weide L.
        • van den Tol P.
        • Meijer S.
        • Comans E.F.
        • et al.
        Early detection of local RFA site recurrence using total liver volume perfusion CT initial experience.
        Acad Radiol. 2009; 16: 1215-1222
        • Choi S.H.
        • Chung J.W.
        • Kim H.-C.
        • Kim H.-C.
        • Baek J.H.
        • Park C.M.
        • et al.
        The role of perfusion CT as a follow-up modality after transcatheter arterial chemoembolization: an experimental study in a rabbit model.
        Invest Radiol. 2010; 45: 427-436
        • Wang D.
        • Bangash A.K.
        • Rhee T.K.
        • Woloschak G.E.
        • Paunesku T.
        • Salem R.
        • et al.
        Liver tumors: monitoring embolization in rabbits with VX2 tumors–transcatheter intraarterial first-pass perfusion MR imaging.
        Radiology. 2007; 245: 130-139
        • Braren R.
        • Altomonte J.
        • Settles M.
        • Neff F.
        • Esposito I.
        • Ebert O.
        • et al.
        Validation of preclinical multiparametric imaging for prediction of necrosis in hepatocellular carcinoma after embolization.
        J Hepatol. 2011; 55: 1034-1040
        • Ippolito D.
        • Bonaffini P.-A.
        • Ratti L.
        • Antolini L.
        • Corso R.
        • Fazio F.
        • et al.
        Hepatocellular carcinoma treated with transarterial chemoembolization: dynamic perfusion-CT in the assessment of residual tumor.
        World J Gastroenterol. 2010; 16: 5993-6000
        • Larson A.C.
        • Wang D.
        • Atassi B.
        • Sato K.T.
        • Ryu R.K.
        • Lewandowski R.J.
        • et al.
        Transcatheter intraarterial perfusion: MR monitoring of chemoembolization for hepatocellular carcinoma–feasibility of initial clinical translation.
        Radiology. 2008; 246: 964-971
        • Gaba R.C.
        • Wang D.
        • Lewandowski R.J.
        • Ryu R.K.
        • Sato K.T.
        • Kulik L.M.
        • et al.
        Four-dimensional transcatheter intraarterial perfusion MR imaging for monitoring chemoembolization of hepatocellular carcinoma: preliminary results.
        J Vasc Interv Radiol. 2008; 19: 1589-1595
        • Wang D.
        • Jin B.
        • Lewandowski R.J.
        • Ryu R.K.
        • Sato K.T.
        • Mulcahy M.F.
        • et al.
        Quantitative 4D transcatheter intraarterial perfusion MRI for monitoring chemoembolization of hepatocellular carcinoma.
        J Magn Reson Imaging. 2010; 31: 1106-1116
        • Michielsen K.
        • De Keyzer F.
        • Verslype C.
        • Dymarkowski S.
        • van Malenstein H.
        • Oyen R.
        • et al.
        Pretreatment DCE-MRI for prediction of PFS in patients with inoperable HCC treated with TACE.
        Cancer Imaging. 2011; 11 (S114–S114)
        • Hsu C.-Y.
        • Shen Y.-C.
        • Yu C.-W.
        • Hsu C.
        • Hu F.-C.
        • Hsu C.-H.
        • et al.
        Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil.
        J Hepatol. 2011; 55: 858-865
        • Zhu A.X.
        • Sahani D.V.
        • Duda D.G.
        • di Tomaso E.
        • Ancukiewicz M.
        • Catalano O.A.
        • et al.
        Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study.
        J Clin Oncol. 2009; 27: 3027-3035
        • Sahani D.V.
        • Jiang T.
        • Hayano K.
        • Duda D.G.
        • Catalano O.A.
        • Ancukiewicz M.
        • et al.
        Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.
        J Hematol Oncol. 2013; 6: 51
        • Lassau N.
        • Chapotot L.
        • Benatsou B.
        • Vilgrain V.
        • Kind M.
        • Lacroix J.
        • et al.
        Standardization of dynamic contrast-enhanced ultrasound for the evaluation of antiangiogenic therapies: the French multicenter Support for Innovative and Expensive Techniques Study.
        Invest Radiol. 2012; 47: 711-716
        • Frampas E.
        • Lassau N.
        • Zappa M.
        • Vullierme M.-P.
        • Koscielny S.
        • Vilgrain V.
        Advanced Hepatocellular Carcinoma: early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results.
        Eur J Radiol. 2013; 82: e205-e211
        • Lassau N.
        • Bonastre J.
        • Kind M.
        • Vilgrain V.
        • Lacroix J.
        • Cuinet M.
        • et al.
        Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study.
        Invest Radiol. 2014; 49: 794-800
        • Ho C.
        • Chen S.
        • Yeung D.W.C.
        • Cheng T.K.C.
        Dual-tracer PET/CT imaging in evaluation of metastatic hepatocellular carcinoma.
        J Nucl Med. 2007; 48: 902-909
        • Hennedige T.
        • Venkatesh S.K.
        Imaging of hepatocellular carcinoma: diagnosis, staging and treatment monitoring.
        Cancer Imaging. 2013; 12: 530-547
        • Torizuka T.
        • Tamaki N.
        • Inokuma T.
        • Magata Y.
        • Sasayama S.
        • Yonekura Y.
        • et al.
        In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG-PET.
        J Nucl Med. 1995; 36: 1811-1817
        • Seo S.
        • Hatano E.
        • Higashi T.
        • Hara T.
        • Tada M.
        • Tamaki N.
        • et al.
        Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma.
        Clin Cancer Res. 2007; 13: 427-433
        • Hong G.
        • Suh K.-S.
        • Suh S.
        • Yoo T.
        • Kim H.
        • Park M.-S.
        • et al.
        Preoperative Alpha-fetoprotein and (18)F-FDG PET predict tumor recurrence better than milan criteria in living donor liver transplantation.
        J Hepatol. 2016; 64: 852-859
        • Sugiyama M.
        • Sakahara H.
        • Torizuka T.
        • Kanno T.
        • Nakamura F.
        • Futatsubashi M.
        • et al.
        18F-FDG PET in the detection of extrahepatic metastases from hepatocellular carcinoma.
        J Gastroenterol. 2004; 39: 961-968
        • Lin C.-Y.
        • Chen J.-H.
        • Liang J.-A.
        • Lin C.-C.
        • Jeng L.-B.
        • Kao C.-H.
        18F-FDG PET or PET/CT for detecting extrahepatic metastases or recurrent hepatocellular carcinoma: a systematic review and meta-analysis.
        Eur J Radiol. 2012; 81: 2417-2422
        • Jiang L.
        • Tan H.
        • Panje C.M.
        • Yu H.
        • Xiu Y.
        • Shi H.
        Role of 18F-FDG PET/CT Imaging in Intrahepatic Cholangiocarcinoma.
        Clin Nucl Med. 2016; 41: 1-7
        • Jadvar H.
        • Henderson R.W.
        • Conti P.S.
        [F-18]fluorodeoxyglucose positron emission tomography and positron emission tomography: computed tomography in recurrent and metastatic cholangiocarcinoma.
        J Comput Assist Tomogr. 2007; 31: 223-228
        • Kim J.Y.
        • Kim M.-H.
        • Lee T.Y.
        • Hwang C.Y.
        • Kim J.S.
        • Yun S.-C.
        • 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. 2008; 103: 1145-1151
        • Bertagna F.
        • Bertoli M.
        • Bosio G.
        • Biasiotto G.
        • Sadeghi R.
        • Giubbini R.
        • et al.
        Diagnostic role of radiolabelled choline PET or PET/CT in hepatocellular carcinoma: a systematic review and meta-analysis.
        Hepatol Int. 2014; 8: 493-500
        • Talbot J.-N.
        • Fartoux L.
        • Balogova S.
        • Nataf V.
        • Kerrou K.
        • Gutman F.
        • et al.
        Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease.
        J Nucl Med. 2010; 51: 1699-1706
        • Park J.-W.
        • Kim J.H.
        • Kim S.K.
        • Kang K.W.
        • Park K.W.
        • Choi J.-I.
        • et al.
        A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma.
        J Nucl Med. 2008; 49: 1912-1921
        • Taylor A.
        • Langeberg W.
        • Mowat F.
        • Alexander D.
        • Choti M.
        • Poston G.
        Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors.
        Clin Epidemiol. 2012; 4: 283
        • Page A.J.
        • Weiss M.J.
        • Pawlik T.M.
        Surgical management of noncolorectal cancer liver metastases.
        Cancer. 2014; 120: 3111-3121
        • Frilling A.
        • Modlin I.M.
        • Kidd M.
        • Russell C.
        • Breitenstein S.
        • Salem R.
        • et al.
        Recommendations for management of patients with neuroendocrine liver metastases.
        Lancet Oncol. 2014; 15: e8-e21
        • Brouquet A.
        • Abdalla E.K.
        • Kopetz S.
        • Garrett C.R.
        • Overman M.J.
        • Eng C.
        • et al.
        High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome.
        J Clin Oncol. 2011; 29: 1083-1090
        • Tzeng C.-W.D.
        • Aloia T.A.
        Colorectal liver metastases.
        J Gastrointest Surg. 2013; 17 ([Quiz p.201–202]): 195-201
        • Radtke A.
        • Sotiropoulos G.C.
        • Molmenti E.P.
        • Schroeder T.
        • Peitgen H.O.
        • Frilling A.
        • et al.
        Computer-assisted surgery planning for complex liver resections: when is it helpful? A single-center experience over an 8-year period.
        Ann Surg. 2010; 252: 876-883
        • Elias D.
        • Lefevre J.H.
        • Duvillard P.
        • Goéré D.
        • Dromain C.
        • Dumont F.
        • et al.
        Hepatic metastases from neuroendocrine tumors with a ‘thin slice’ pathological examination: they are many more than you think.
        Ann Surg. 2010; 251: 307-310
        • Vilgrain V.
        • Esvan M.
        • Ronot M.
        • Caumont-Prim A.
        • Aube C.
        • Chatellier G.
        A meta-analysis of diffusion-weighted and gadoxetic acid-enhanced MR imaging for the detection of colorectal liver metastases.
        Eur Radiol. 2016; ([Epub ahead of print])
        • d’Assignies G.
        • Fina P.
        • Bruno O.
        • Vullierme M.-P.
        • Tubach F.
        • Paradis V.
        • et al.
        High sensitivity of diffusion-weighted MR imaging for the detection of liver metastases from neuroendocrine tumors: comparison with T2-weighted and dynamic gadolinium-enhanced MR imaging.
        Radiology. 2013; 268: 390-399
        • Liapi E.
        • Geschwind J.-F.
        • Vossen J.A.
        • Buijs M.
        • Georgiades C.S.
        • Bluemke D.A.
        • et al.
        Functional MRI evaluation of tumor response in patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization.
        AJR Am J Roentgenol. 2008; 190: 67-73
        • Kukuk G.M.
        • Mürtz P.
        • Träber F.
        • Meyer C.
        • Ullrich J.
        • Gieseke J.
        • et al.
        Diffusion-weighted imaging with acquisition of three b-values for response evaluation of neuroendocrine liver metastases undergoing selective internal radiotherapy.
        Eur Radiol. 2014; 24: 267-276
        • Coenegrachts K.
        • Bols A.
        • Haspeslagh M.
        • Rigauts H.
        Prediction and monitoring of treatment effect using T1-weighted dynamic contrast-enhanced magnetic resonance imaging in colorectal liver metastases: potential of whole tumour ROI and selective ROI analysis.
        Eur J Radiol. 2012; 81: 3870-3876
        • De Bruyne S.
        • Van Damme N.
        • Smeets P.
        • Ferdinande L.
        • Ceelen W.
        • Mertens J.
        • et al.
        Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases.
        Br J Cancer. 2012; 106: 1926-1933
        • Morsbach F.
        • Pfammatter T.
        • Reiner C.S.
        • Fischer M.A.
        • Sah B.-R.
        • Winklhofer S.
        • et al.
        Computed tomographic perfusion imaging for the prediction of response and survival to transarterial radioembolization of liver metastases.
        Invest Radiol. 2013; 48: 787-794
        • Miyazaki K.
        • Orton M.R.
        • Davidson R.L.
        • d’Arcy J.A.
        • Lewington V.
        • Koh T.S.
        • et al.
        Neuroendocrine tumor liver metastases: use of dynamic contrast-enhanced MR imaging to monitor and predict radiolabeled octreotide therapy response.
        Radiology. 2012; 263: 139-148
        • Niekel M.C.
        • Bipat S.
        • Stoker J.
        Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment.
        Radiology. 2010; 257: 674-684
        • Patel S.
        • McCall M.
        • Ohinmaa A.
        • Bigam D.
        • Dryden D.M.
        Positron emission tomography/computed tomographic scans compared to computed tomographic scans for detecting colorectal liver metastases: a systematic review.
        Ann Surg. 2011; 253: 666-671
        • Maffione A.M.
        • Lopci E.
        • Bluemel C.
        • Giammarile F.
        • Herrmann K.
        • Rubello D.
        Diagnostic accuracy and impact on management of (18)F-FDG PET and PET/CT in colorectal liver metastasis: a meta-analysis and systematic review.
        Eur J Nucl Med Mol Imaging. 2015; 42: 152-163
        • Ruers T.J.M.
        • Wiering B.
        • van der Sijp J.R.M.
        • Roumen R.M.
        • de Jong K.P.
        • Comans E.F.I.
        • et al.
        Improved selection of patients for hepatic surgery of colorectal liver metastases with (18)F-FDG PET: a randomized study.
        J Nucl Med. 2009; 50: 1036-1041
        • Moulton C.-A.
        • Gu C.-S.
        • Law C.H.
        • Tandan V.R.
        • Hart R.
        • Quan D.
        • et al.
        Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial.
        JAMA. 2014; 311: 1863-1869
        • van Kessel C.S.
        • Buckens C.F.M.
        • van den Bosch M.A.A.J.
        • van Leeuwen M.S.
        • van Hillegersberg R.
        • Verkooijen H.M.
        Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis.
        Ann Surg Oncol. 2012; 19: 2805-2813
        • Glazer E.S.
        • Beaty K.
        • Abdalla E.K.
        • Vauthey J.N.
        • Curley S.A.
        Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases.
        Arch Surg. 2010; 145 ([Discussion 345]): 340-345
        • Annunziata S.
        • Treglia G.
        • Caldarella C.
        • Galiandro F.
        The role of 18F-FDG-PET and PET/CT in patients with colorectal liver metastases undergoing selective internal radiation therapy with yttrium-90: a first evidence-based review.
        Sci World J. 2014; 2014: 879469
        • Sabet A.
        • Meyer C.
        • Aouf A.
        • Sabet A.
        • Ghamari S.
        • Pieper C.C.
        • et al.
        Early post-treatment FDG PET predicts survival after 90Y microsphere radioembolization in liver-dominant metastatic colorectal cancer.
        Eur J Nucl Med Mol Imaging. 2015; 42: 370-376
        • Beiderwellen K.
        • Geraldo L.
        • Ruhlmann V.
        • Heusch P.
        • Gomez B.
        • Nensa F.
        • et al.
        Accuracy of [18F]FDG PET/MRI for the detection of liver metastases.
        PLoS One. 2015; 10 (e0137285)
        • Reiner C.S.
        • Stolzmann P.
        • Husmann L.
        • Burger I.A.
        • Hüllner M.W.
        • Schaefer N.G.
        • et al.
        Protocol requirements and diagnostic value of PET/MR imaging for liver metastasis detection.
        Eur J Nucl Med Mol Imaging. 2014; 41: 649-658
        • Brendle C.
        • Schwenzer N.F.
        • Rempp H.
        • Schmidt H.
        • Pfannenberg C.
        • la Fougère C.
        • et al.
        Assessment of metastatic colorectal cancer with hybrid imaging: comparison of reading performance using different combinations of anatomical and functional imaging techniques in PET/MRI and PET/CT in a short case series.
        Eur J Nucl Med Mol Imaging. 2016; 43: 123-132
        • Rindi G.
        • Klöppel G.
        • Couvelard A.
        • Komminoth P.
        • Körner M.
        • Lopes J.M.
        • et al.
        TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.
        Virchows Arch. 2007; 451: 757-762
        • Christ E.
        • Wild D.
        • Ederer S.
        • Béhé M.
        • Nicolas G.
        • Caplin M.E.
        • et al.
        Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study.
        Lancet Diabetes Endocrinol. 2013; 1: 115-122
        • Wenning A.S.
        • Kirchner P.
        • Antwi K.
        • Fani M.
        • Wild D.
        • Christ E.
        • et al.
        Preoperative Glucagon-like peptide-1 receptor imaging reduces surgical trauma and pancreatic tissue loss in insulinoma patients: a report of three cases.
        Patient Saf Surg. 2015; 9: 23
        • van Essen M.
        • Sundin A.
        • Krenning E.P.
        • Kwekkeboom D.J.
        Neuroendocrine tumours: the role of imaging for diagnosis and therapy.
        Nat Rev Endocrinol. 2014; 10: 102-114
        • Balon H.R.
        • Brown T.L.Y.
        • Goldsmith S.J.
        • Silberstein E.B.
        • Krenning E.P.
        • Lang O.
        • et al.
        The SNM practice guideline for somatostatin receptor scintigraphy 2.0.
        J Nucl Med Technol. 2011; 39: 317-324
        • Bombardieri E.
        • Ambrosini V.
        • Aktolun C.
        • Baum R.P.
        • Bishof-Delaloye A.
        • Del Vecchio S.
        • et al.
        111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging.
        Eur J Nucl Med Mol Imaging. 2010; 37: 1441-1448
        • Maxwell J.E.
        • Sherman S.K.
        • Menda Y.
        • Wang D.
        • O’Dorisio T.M.
        • Howe J.R.
        Limitations of somatostatin scintigraphy in primary small bowel neuroendocrine tumors.
        J Surg Res. 2014; 190: 548-553
        • Dromain C.
        • de Baere T.
        • Lumbroso J.
        • Caillet H.
        • Laplanche A.
        • Boige V.
        • et al.
        Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging.
        J Clin Oncol. 2005; 23: 70-78
        • Shi W.
        • Johnston C.F.
        • Buchanan K.D.
        • Ferguson W.R.
        • Laird J.D.
        • Crothers J.G.
        • et al.
        Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging.
        QJM. 1998; 91: 295-301
        • Kwekkeboom D.J.
        • Kam B.L.
        • van Essen M.
        • Teunissen J.J.M.
        • van Eijck C.H.J.
        • Valkema R.
        • et al.
        Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors.
        Endocr Relat Cancer. 2010; 17: R53-R73
        • Johnbeck C.B.
        • Knigge U.
        • Kjær A.
        PET tracers for somatostatin receptor imaging of neuroendocrine tumors: current status and review of the literature.
        Future Oncol. 2014; 10: 2259-2277
        • Geijer H.
        • Breimer L.H.
        Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis.
        Eur J Nucl Med Mol Imaging. 2013; 40: 1770-1780
        • Gabriel M.
        • Decristoforo C.
        • Kendler D.
        • Dobrozemsky G.
        • Heute D.
        • Uprimny C.
        • et al.
        68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT.
        J Nucl Med. 2007; 48: 508-518
        • Ambrosini V.
        • Campana D.
        • Bodei L.
        • Nanni C.
        • Castellucci P.
        • Allegri V.
        • et al.
        68Ga-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors.
        J Nucl Med. 2010; 51: 669-673
        • Frilling A.
        • Sotiropoulos G.C.
        • Radtke A.
        • Malago M.
        • Bockisch A.
        • Kuehl H.
        • et al.
        The impact of 68Ga-DOTATOC positron emission tomography/computed tomography on the multimodal management of patients with neuroendocrine tumors.
        Ann Surg. 2010; 252: 850-856
        • Ruf J.
        • Heuck F.
        • Schiefer J.
        • Denecke T.
        • Elgeti F.
        • Pascher A.
        • et al.
        Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors.
        Neuroendocrinology. 2010; 91: 101-109
        • Schreiter N.F.
        • Brenner W.
        • Nogami M.
        • Buchert R.
        • Huppertz A.
        • Pape U.-F.
        • et al.
        Cost comparison of 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATOC PET/CT for staging enteropancreatic neuroendocrine tumours.
        Eur J Nucl Med Mol Imaging. 2012; 39: 72-82
        • Baum R.P.
        • Kulkarni H.R.
        THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy – The Bad Berka Experience.
        Theranostics. 2012; 2: 437-447
        • Hope T.A.
        • Pampaloni M.H.
        • Nakakura E.
        • VanBrocklin H.
        • Slater J.
        • Jivan S.
        • et al.
        Simultaneous (68)Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor.
        Abdom Imaging. 2015; 40: 1432-1440
        • Armbruster M.
        • Sourbron S.
        • Haug A.
        • Zech C.J.
        • Ingrisch M.
        • Auernhammer C.J.
        • et al.
        Evaluation of neuroendocrine liver metastases: a comparison of dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography/computed tomography.
        Invest Radiol. 2014; 49: 7-14
        • Armbruster M.
        • Zech C.J.
        • Sourbron S.
        • Ceelen F.
        • Auernhammer C.J.
        • Rist C.
        • et al.
        Diagnostic accuracy of dynamic gadoxetic-acid-enhanced MRI and PET/CT compared in patients with liver metastases from neuroendocrine neoplasms.
        J Magn Reson Imaging. 2014; 40: 457-466
        • Flechsig P.
        • Zechmann C.M.
        • Schreiweis J.
        • Kratochwil C.
        • Rath D.
        • Schwartz L.H.
        • et al.
        Qualitative and quantitative image analysis of CT and MR imaging in patients with neuroendocrine liver metastases in comparison to (68)Ga-DOTATOC PET.
        Eur J Radiol. 2015; 84: 1593-1600
        • Pfeifer A.
        • Bardram Johnbeck C.
        • Knigge U.
        • Mortensen J.
        • Oturai P.
        • Loft A.
        • et al.
        Clinical PET imaging of neuroendocrine tumors using 64Cu-DOTA-Tyr3-octreotate.
        J Nucl Med. 2013; 54: 1854
        • Binderup T.
        • Knigge U.
        • Loft A.
        • Mortensen J.
        • Pfeifer A.
        • Federspiel B.
        • et al.
        Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET.
        J Nucl Med. 2010; 51: 704-712
        • Naswa N.
        • Sharma P.
        • Gupta S.K.
        • Karunanithi S.
        • Reddy R.M.
        • Patnecha M.
        • et al.
        Dual tracer functional imaging of gastroenteropancreatic neuroendocrine tumors using 68Ga-DOTA-NOC PET-CT and 18F-FDG PET-CT: competitive or complimentary?.
        Clin Nucl Med. 2014; 39: e27-e34
        • Binderup T.
        • Knigge U.
        • Loft A.
        • Federspiel B.
        • Kjaer A.
        18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors.
        Clin Cancer Res. 2010; 16: 978-985
        • Koopmans K.P.
        • Neels O.C.
        • Kema I.P.
        • Elsinga P.H.
        • Sluiter W.J.
        • Vanghillewe K.
        • et al.
        Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography.
        J Clin Oncol. 2008; 26: 1489-1495
        • Ambrosini V.
        • Tomassetti P.
        • Castellucci P.
        • Campana D.
        • Montini G.
        • Rubello D.
        • et al.
        Comparison between 68Ga-DOTA-NOC and 18F-DOPA PET for the detection of gastro-entero-pancreatic and lung neuro-endocrine tumours.
        Eur J Nucl Med Mol Imaging. 2008; 35: 1431-1438
        • Haug A.
        • Auernhammer C.J.
        • Wängler B.
        • Tiling R.
        • Schmidt G.
        • Göke B.
        • et al.
        Intraindividual comparison of 68Ga-DOTA-TATE and 18F-DOPA PET in patients with well-differentiated metastatic neuroendocrine tumours.
        Eur J Nucl Med Mol Imaging. 2009; 36: 765-770
        • Wild D.
        • Fani M.
        • Behe M.
        • Brink I.
        • Rivier J.E.F.
        • Reubi J.C.
        • et al.
        First clinical evidence that imaging with somatostatin receptor antagonists is feasible.
        J Nucl Med. 2011; 52: 1412-1417
        • van Asselt S.J.
        • Oosting S.F.
        • Brouwers A.H.
        • Bongaerts A.H.H.
        • de Jong J.R.
        • Lub-de Hooge M.N.
        • et al.
        Everolimus reduces (89)Zr-bevacizumab tumor uptake in patients with neuroendocrine tumors.
        J Nucl Med. 2014; 55: 1087-1092
        • Wang Z.
        • Chen J.-Q.
        • Liu J.-L.
        • Qin X.-G.
        • Huang Y.
        FDG-PET in diagnosis, staging and prognosis of pancreatic carcinoma: a meta-analysis.
        World J Gastroenterol. 2013; 19: 4808-4817
        • Kauhanen S.P.
        • Komar G.
        • Seppänen M.P.
        • Dean K.I.
        • Minn H.R.
        • Kajander S.A.
        • et al.
        A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer.
        Ann Surg. 2009; 250: 957-963
        • Burge M.E.
        • O’Rourke N.
        • Cavallucci D.
        • Bryant R.
        • Francesconi A.
        • Houston K.
        • et al.
        A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers.
        HPB (Oxford). 2015; 17: 624-631
        • Dai T.
        • Popa E.
        • Shah M.A.
        The role of 18F-FDG PET imaging in upper gastrointestinal malignancies.
        Curr Treat Options Oncol. 2014; 15: 351-364
        • van Vliet E.P.M.
        • Heijenbrok-Kal M.H.
        • Hunink M.G.M.
        • Kuipers E.J.
        • Siersema P.D.
        Staging investigations for oesophageal cancer: a meta-analysis.
        Br J Cancer. 2008; 98: 547-557
        • Chatterton B.E.
        • Ho Shon I.
        • Baldey A.
        • Lenzo N.
        • Patrikeos A.
        • Kelley B.
        • et al.
        Positron emission tomography changes management and prognostic stratification in patients with oesophageal cancer: results of a multicentre prospective study.
        Eur J Nucl Med Mol Imaging. 2008; 36: 354-361
        • Barber T.W.
        • Duong C.P.
        • Leong T.
        • Bressel M.
        • Drummond E.G.
        • Hicks R.J.
        18F-FDG PET/CT has a high impact on patient management and provides powerful prognostic stratification in the primary staging of esophageal cancer: a prospective study with mature survival data.
        J Nucl Med. 2012; 53: 864-871
        • Breeman W.A.P.
        • de Blois E.
        • Sze Chan H.
        • Konijnenberg M.
        • Kwekkeboom D.J.
        • Krenning E.P.
        (68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives.
        Semin Nucl Med. 2011; 41: 314-321
        • Aerts H.J.W.L.
        • Velazquez E.R.
        • Leijenaar R.T.H.
        • Parmar C.
        • Grossmann P.
        • Cavalho S.
        • et al.
        Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach.
        Nat Commun. 2014; 5: 4006
        • Bodei L.
        • Sundin A.
        • Kidd M.
        • Prasad V.
        • Modlin I.M.
        The status of neuroendocrine tumor imaging: from darkness to light?.
        Neuroendocrinology. 2015; 101: 1-17