I m a g i n g A p p ro a c h t o H epatoc e l l u l ar C arc i n o m a , C h o l a n g i o c a rc i n o m a , a n d M e t a s t a t i c C o l o re c t a l C a n c e r Kathryn J. Fowler,
MD
a,
*, Nael E. Saad,
MD
b
, David Linehan,
MD
c
KEYWORDS Liver imaging Metastatic liver disease Hepatocellular carcinoma Cholangiocarcinoma Colorectal liver metastases KEY POINTS Hepatocellular carcinoma (HCC) diagnostic criteria allow imaging diagnosis to supplant pathology. Determination of resectability is the main goal of imaging cholangiocarcinoma. MRI provides the best sensitivity for detecting colorectal metastases.
INTRODUCTION
Imaging has become an integral component of managing patients with suspected liver diseases and tumors. Options have evolved along with technology to provide important information and at times supplant pathology for diagnosis of liver lesions. This article provides an overview of the most common liver imaging modalities and their use in HCC, intrahepatic cholangiocarcinoma (ICC), and colorectal cancer (CRC) liver metastatic disease. LIVER IMAGING MODALITIES Ultrasound Ultrasound basics
Ultrasound (US) is one of the oldest modalities in radiology. Transducers (probes) create sound waves that transmit through tissues and are variably impeded and reflected back to the transducer. Structures appear of varying echogenicity (brightness) based on their acoustic impedance/density. When performing transcutaneous US, transducers of a Department of Radiology, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA; b Department of Interventional Radiology, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA; c Department of Surgery, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA * Corresponding author. E-mail address: [email protected]
Surg Oncol Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.soc.2014.09.002 surgonc.theclinics.com 1055-3207/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Fowler et al
different frequencies (lower frequencies of 3–5 MHz penetrate deeper than higher frequencies) are chosen based on the depth of the region of interest and tissues being penetrated. US gel is required to establish good acoustic contact because air acts as a reflector. Gray-scale and Doppler US have been used to evaluate focal liver lesions based on differences in echogenicity and vascularity; however, definitive diagnosis is often difficult. Transcutaneous US and in some instances endoscopic US can be used to guide percutaneous biopsies when imaging fails to provide definitive diagnosis. Contrast-enhanced ultrasound
Diagnostic accuracy of US is greatly improved with the addition of contrast; however, to date, the use of contrast-enhanced US (CEUS) has been limited in the United States due to lack of Food and Drug Administration (FDA) approval. There are 3 contrast agents currently used worldwide: SonoVue (Bracco, Milan, Italy), Definity (BristolMyers Squibb, New York, NY, USA), and Sonazoid (GE Healthcare, Oslo, Norway). The first 2 act as vascular agents only, providing information regarding the early dynamic appearance of lesions with no diffusivity outside of the vessels (which is slightly different from computerized tomography (CT) and magnetic resonance [MR] agents). Sonazoid is taken up by the Kupffer cells and exhibits a hepatobiliary phase for approximately 1 hour after injection, which has been likened to the hepatobiliary phase on MRI and may be useful for lesion detection, as in metastatic work-ups. The main role of CEUS has been in focal liver lesion characterization and monitoring local ablative treatments.1 The benefits of CEUS are the real-time visualization of contrast enhancement, lack of nephrotoxicity, lack of ionizing radiation, and decreased cost compared with CT or MRI. The main disadvantage of CEUS is the relative lack of availability in the United States. Additionally, CEUS was dropped from the most recent American Association for the Study of Liver Disease (AASLD) guidelines due to the potential risk of misdiagnosis of ICC as HCC.2 Computerized Tomography Computerized tomography basics
CT is rapidly available, demonstrates high diagnostic accuracy for many indications, and is well known to radiologists and clinicians alike. Image creation on CT is the result of an ionizing radiation (x-ray) source, which rotates around the patient with detectors opposite the source that measure the degree of attenuation of the x-ray beam. The end result is a cross-sectional image with different attenuation values (brightness) assigned to different structures based on their relative attenuation coefficient (degree to which they impede the x-ray beam). Most soft tissues have similar attenuation properties; hence, intravenous contrast is used to improve conspicuity of organs, lesions, and vasculature. CT contrast is composed of iodinated medium, which causes greater absorption and scatter of x-ray radiation, yielding increased attenuation (brighter appearance) of structures. The relative enhancement of organs is complex and related to an organ’s perfusion rate, tissue volume, composition, and permeability throughout the microvasculature. The initial enhancement is most influenced by the vascular supply and cardiac output, with later enhancement more dependent on intravascular dilution and redistribution of contrast within the extracellular space.3 Because iodinated contrast medium does not cross into the intracellular compartment, it can be assumed to distribute within the intravascular and extracellular compartments by way of diffusion or transcapillary exchange.4 A basic understanding of contrast pharmacokinetics allows greater appreciation for the different enhancement patterns (described later). In the liver, there are well-defined postcontrast phases, during which the parenchyma follows a predictable pattern of enhancement. These phases consist of the
Imaging Approach to Liver Neoplasms
late arterial, portal venous, equilibrium, and delayed phases.5 Most tumors within the liver (especially hypervascular lesions like HCC) receive preferential hepatic arterial blood supply compared with normal hepatic parenchyma, which is supplied predominately by portal venous blood.6–8 This differential blood supply allows for greatest lesion:background conspicuity of hypervascular tumors during the late arterial phase. Hypovascular tumors (many metastatic tumors) are generally seen most easily on the portal venous or equilibrium phases of contrast. A routine CT with contrast is usually timed for the portal venous phase; hence, arterially enhancing lesions may not be readily seen (Fig. 1). In addition to improved conspicuity of lesions, the pattern of enhancement on the different phases of contrast helps narrow the differential diagnosis and in some instances is pathognomonic, such as in hemangiomas (Fig. 2). Therefore, when assessing a liver tumor, multiple phases of contrast or a liver protocol CT should be obtained (Table 1).9 Nephrotoxicity of computerized tomography contrast
Although CT contrast is essential to liver tumor characterization, it should be avoided in patients with poor renal function because it is potentially nephrotoxic. The American College of Radiology defines contrast-induced nephrotoxicity (CIN) as sudden deterioration in renal function after recent administration of iodinated contrast in the absence of another nephrotoxic event.10 Controversy exists as to the diagnostic criteria for CIN with variable definitions in the literature leading to a lack of consensus as to the actual incidence, risk factors, and diagnosis. The Acute Kidney Injury Network in a consensus group suggested the diagnosis of acute kidney injury could be made if one of the following criteria is met within 48 hours of a nephrotoxic event: absolute serum creatinine increase of greater than or equal to 0.3 mg/dL; percentage
Fig. 1. Focal nodular hyperplasia. Note the clear demarcation of the lesion (arrow) on the arterial phase postcontrast MRI (A) and the near stealth appearance on the portal venous phase MRI (B). This demonstrates the importance of acquiring multiple phases for adequate lesion characterization. C-arterial, D-portal venous phase. Demonstrating the same phenomenon in a second patient with focal nodular hyperplasia on CT (arrow) during the arterial (C) and portal venous phases (D).
3
4
Fowler et al
Fig. 2. Pathognomic appearance of a hemangioma. A-arterial, B-portal venous, C-delayed phase. Dynamic postcontrast MRI (A–C) and fat-suppressed T2 image (D) show the pathognomic appearance of a hemangioma (arrows). Confident characterization requires multiple phases of contrast to show the classic centripetal filling pattern.
Table 1 Liver protocol CT Contrast Phases Comments Noncontrast
Late arterial phase
Portal venous phase Delayed phase
Technical Specifications
Provides information of lesion density Multidetector row scanner (minimum 8 detectors) (calcification, blood products, fat) Optional for lesion characterization Power injection for contrast (at least 3 mL/s) Mandatory in post-TACE setting to Minimum of 5 mm reconstructed evaluate enhancement relative to section thickness (slice thickness) dense Lipiodol/Ethiodol uptake Artery fully enhanced, some contrast in portal vein, no contrast in hepatic veins Optimal timing essential (bolus tracking) Peak liver parenchymal enhancement, beginning contrast enhancement of hepatic veins >120 s After injection, variable appearance
Abbreviation: TACE, transarterial chemoembolization.
Imaging Approach to Liver Neoplasms
increase in serum creatinine of greater than or equal to 50%; or urine output reduced to less than or equal to 0.5 mL/kg/hour for at least 6 hours.11 Given that these creatinine changes are small, it remains controversial and difficult to apply these strict cutoffs in practice. In a retrospective study, including 8826 contrast-enhanced CT studies, administration of iodinated contrast was identified as a nephrotoxic risk factor in patients with estimated glomerular filtration rate (eGFR) less than 30 mL/min/ 1.73 m2 and a trend toward significance in patients with eGFR 30 to 44 mL/min/ 1.73 m2.12 Clinical risk factors may also contribute to development of contrastinduced nephropathy, including diabetes, liver disease, chronic kidney disease, hypertension, low hematocrit, and heart failure.13 Policies for administration of contrast to patients with borderline function vary from institution to institution and screening patients who are potentially at risk is advised. See Table 2 for our institutional policy. Although there is abundant literature on the use of normal saline, bicarbonate drips, and other measures to reduce risk of nephrotoxicity, no clearly superior method exists and the best mitigation is avoidance of exposure in at-risk patients. In patients who cannot undergo a contrast-enhanced CT, MRI may be an option with a wider range of creatinine acceptance due to the lack of nephrotoxicity of gadolinium agents. In addition to CIN, allergy to iodinated contrast presents a challenge. Premedication for prior mild reactions (hives, itching, and so forth) can be performed with steroids and antihistamines; however, avoidance of contrast in patients with prior severe reactions (laryngeal edema, dyspnea, and shock) is recommended. Although a prior reaction indicates a degree of predisposition/atopia, there is insufficient evidence to support cross-reactivity between CT contrast and MR contrast. Therefore, depending on institutional policy, a contrast MRI examination may be an alternative in patients with prior severe reaction to CT contrast.
Table 2 Washington University CT contrast policy Renal Function
Guideline
Serum Cr 30, then contrast permitted
Acute elevation in serum Cr
Contrast should be avoided if possible
Patient on dialysis
Contrast may be permitted (allowing preservation of residual renal function is not a goal) Arrangement of dialysis after contrast administration is advised
When to check serum Cr During current admission for any acutely ill or hospitalized patient Adult patients 30
Contrast ok
GFR
MD
a,
*, Nael E. Saad,
MD
b
, David Linehan,
MD
c
KEYWORDS Liver imaging Metastatic liver disease Hepatocellular carcinoma Cholangiocarcinoma Colorectal liver metastases KEY POINTS Hepatocellular carcinoma (HCC) diagnostic criteria allow imaging diagnosis to supplant pathology. Determination of resectability is the main goal of imaging cholangiocarcinoma. MRI provides the best sensitivity for detecting colorectal metastases.
INTRODUCTION
Imaging has become an integral component of managing patients with suspected liver diseases and tumors. Options have evolved along with technology to provide important information and at times supplant pathology for diagnosis of liver lesions. This article provides an overview of the most common liver imaging modalities and their use in HCC, intrahepatic cholangiocarcinoma (ICC), and colorectal cancer (CRC) liver metastatic disease. LIVER IMAGING MODALITIES Ultrasound Ultrasound basics
Ultrasound (US) is one of the oldest modalities in radiology. Transducers (probes) create sound waves that transmit through tissues and are variably impeded and reflected back to the transducer. Structures appear of varying echogenicity (brightness) based on their acoustic impedance/density. When performing transcutaneous US, transducers of a Department of Radiology, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA; b Department of Interventional Radiology, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA; c Department of Surgery, Washington University, 510 S. Kingshighway Blvd, St. Louis, MO 63110, USA * Corresponding author. E-mail address: [email protected]
Surg Oncol Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.soc.2014.09.002 surgonc.theclinics.com 1055-3207/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Fowler et al
different frequencies (lower frequencies of 3–5 MHz penetrate deeper than higher frequencies) are chosen based on the depth of the region of interest and tissues being penetrated. US gel is required to establish good acoustic contact because air acts as a reflector. Gray-scale and Doppler US have been used to evaluate focal liver lesions based on differences in echogenicity and vascularity; however, definitive diagnosis is often difficult. Transcutaneous US and in some instances endoscopic US can be used to guide percutaneous biopsies when imaging fails to provide definitive diagnosis. Contrast-enhanced ultrasound
Diagnostic accuracy of US is greatly improved with the addition of contrast; however, to date, the use of contrast-enhanced US (CEUS) has been limited in the United States due to lack of Food and Drug Administration (FDA) approval. There are 3 contrast agents currently used worldwide: SonoVue (Bracco, Milan, Italy), Definity (BristolMyers Squibb, New York, NY, USA), and Sonazoid (GE Healthcare, Oslo, Norway). The first 2 act as vascular agents only, providing information regarding the early dynamic appearance of lesions with no diffusivity outside of the vessels (which is slightly different from computerized tomography (CT) and magnetic resonance [MR] agents). Sonazoid is taken up by the Kupffer cells and exhibits a hepatobiliary phase for approximately 1 hour after injection, which has been likened to the hepatobiliary phase on MRI and may be useful for lesion detection, as in metastatic work-ups. The main role of CEUS has been in focal liver lesion characterization and monitoring local ablative treatments.1 The benefits of CEUS are the real-time visualization of contrast enhancement, lack of nephrotoxicity, lack of ionizing radiation, and decreased cost compared with CT or MRI. The main disadvantage of CEUS is the relative lack of availability in the United States. Additionally, CEUS was dropped from the most recent American Association for the Study of Liver Disease (AASLD) guidelines due to the potential risk of misdiagnosis of ICC as HCC.2 Computerized Tomography Computerized tomography basics
CT is rapidly available, demonstrates high diagnostic accuracy for many indications, and is well known to radiologists and clinicians alike. Image creation on CT is the result of an ionizing radiation (x-ray) source, which rotates around the patient with detectors opposite the source that measure the degree of attenuation of the x-ray beam. The end result is a cross-sectional image with different attenuation values (brightness) assigned to different structures based on their relative attenuation coefficient (degree to which they impede the x-ray beam). Most soft tissues have similar attenuation properties; hence, intravenous contrast is used to improve conspicuity of organs, lesions, and vasculature. CT contrast is composed of iodinated medium, which causes greater absorption and scatter of x-ray radiation, yielding increased attenuation (brighter appearance) of structures. The relative enhancement of organs is complex and related to an organ’s perfusion rate, tissue volume, composition, and permeability throughout the microvasculature. The initial enhancement is most influenced by the vascular supply and cardiac output, with later enhancement more dependent on intravascular dilution and redistribution of contrast within the extracellular space.3 Because iodinated contrast medium does not cross into the intracellular compartment, it can be assumed to distribute within the intravascular and extracellular compartments by way of diffusion or transcapillary exchange.4 A basic understanding of contrast pharmacokinetics allows greater appreciation for the different enhancement patterns (described later). In the liver, there are well-defined postcontrast phases, during which the parenchyma follows a predictable pattern of enhancement. These phases consist of the
Imaging Approach to Liver Neoplasms
late arterial, portal venous, equilibrium, and delayed phases.5 Most tumors within the liver (especially hypervascular lesions like HCC) receive preferential hepatic arterial blood supply compared with normal hepatic parenchyma, which is supplied predominately by portal venous blood.6–8 This differential blood supply allows for greatest lesion:background conspicuity of hypervascular tumors during the late arterial phase. Hypovascular tumors (many metastatic tumors) are generally seen most easily on the portal venous or equilibrium phases of contrast. A routine CT with contrast is usually timed for the portal venous phase; hence, arterially enhancing lesions may not be readily seen (Fig. 1). In addition to improved conspicuity of lesions, the pattern of enhancement on the different phases of contrast helps narrow the differential diagnosis and in some instances is pathognomonic, such as in hemangiomas (Fig. 2). Therefore, when assessing a liver tumor, multiple phases of contrast or a liver protocol CT should be obtained (Table 1).9 Nephrotoxicity of computerized tomography contrast
Although CT contrast is essential to liver tumor characterization, it should be avoided in patients with poor renal function because it is potentially nephrotoxic. The American College of Radiology defines contrast-induced nephrotoxicity (CIN) as sudden deterioration in renal function after recent administration of iodinated contrast in the absence of another nephrotoxic event.10 Controversy exists as to the diagnostic criteria for CIN with variable definitions in the literature leading to a lack of consensus as to the actual incidence, risk factors, and diagnosis. The Acute Kidney Injury Network in a consensus group suggested the diagnosis of acute kidney injury could be made if one of the following criteria is met within 48 hours of a nephrotoxic event: absolute serum creatinine increase of greater than or equal to 0.3 mg/dL; percentage
Fig. 1. Focal nodular hyperplasia. Note the clear demarcation of the lesion (arrow) on the arterial phase postcontrast MRI (A) and the near stealth appearance on the portal venous phase MRI (B). This demonstrates the importance of acquiring multiple phases for adequate lesion characterization. C-arterial, D-portal venous phase. Demonstrating the same phenomenon in a second patient with focal nodular hyperplasia on CT (arrow) during the arterial (C) and portal venous phases (D).
3
4
Fowler et al
Fig. 2. Pathognomic appearance of a hemangioma. A-arterial, B-portal venous, C-delayed phase. Dynamic postcontrast MRI (A–C) and fat-suppressed T2 image (D) show the pathognomic appearance of a hemangioma (arrows). Confident characterization requires multiple phases of contrast to show the classic centripetal filling pattern.
Table 1 Liver protocol CT Contrast Phases Comments Noncontrast
Late arterial phase
Portal venous phase Delayed phase
Technical Specifications
Provides information of lesion density Multidetector row scanner (minimum 8 detectors) (calcification, blood products, fat) Optional for lesion characterization Power injection for contrast (at least 3 mL/s) Mandatory in post-TACE setting to Minimum of 5 mm reconstructed evaluate enhancement relative to section thickness (slice thickness) dense Lipiodol/Ethiodol uptake Artery fully enhanced, some contrast in portal vein, no contrast in hepatic veins Optimal timing essential (bolus tracking) Peak liver parenchymal enhancement, beginning contrast enhancement of hepatic veins >120 s After injection, variable appearance
Abbreviation: TACE, transarterial chemoembolization.
Imaging Approach to Liver Neoplasms
increase in serum creatinine of greater than or equal to 50%; or urine output reduced to less than or equal to 0.5 mL/kg/hour for at least 6 hours.11 Given that these creatinine changes are small, it remains controversial and difficult to apply these strict cutoffs in practice. In a retrospective study, including 8826 contrast-enhanced CT studies, administration of iodinated contrast was identified as a nephrotoxic risk factor in patients with estimated glomerular filtration rate (eGFR) less than 30 mL/min/ 1.73 m2 and a trend toward significance in patients with eGFR 30 to 44 mL/min/ 1.73 m2.12 Clinical risk factors may also contribute to development of contrastinduced nephropathy, including diabetes, liver disease, chronic kidney disease, hypertension, low hematocrit, and heart failure.13 Policies for administration of contrast to patients with borderline function vary from institution to institution and screening patients who are potentially at risk is advised. See Table 2 for our institutional policy. Although there is abundant literature on the use of normal saline, bicarbonate drips, and other measures to reduce risk of nephrotoxicity, no clearly superior method exists and the best mitigation is avoidance of exposure in at-risk patients. In patients who cannot undergo a contrast-enhanced CT, MRI may be an option with a wider range of creatinine acceptance due to the lack of nephrotoxicity of gadolinium agents. In addition to CIN, allergy to iodinated contrast presents a challenge. Premedication for prior mild reactions (hives, itching, and so forth) can be performed with steroids and antihistamines; however, avoidance of contrast in patients with prior severe reactions (laryngeal edema, dyspnea, and shock) is recommended. Although a prior reaction indicates a degree of predisposition/atopia, there is insufficient evidence to support cross-reactivity between CT contrast and MR contrast. Therefore, depending on institutional policy, a contrast MRI examination may be an alternative in patients with prior severe reaction to CT contrast.
Table 2 Washington University CT contrast policy Renal Function
Guideline
Serum Cr 30, then contrast permitted
Acute elevation in serum Cr
Contrast should be avoided if possible
Patient on dialysis
Contrast may be permitted (allowing preservation of residual renal function is not a goal) Arrangement of dialysis after contrast administration is advised
When to check serum Cr During current admission for any acutely ill or hospitalized patient Adult patients 30
Contrast ok
GFR
