Applied Radiology

Dr. Dunphy is a third-year radiology resident at the University of Florida in Gainesville. He received an MD from St. Louis University School of Medicine in 1997. He is planning a fellowship in magnetic resonance imaging/body imaging at Northwestern University in 2002.

Accurate detection and characterization of liver lesions is paramount for appropriate treatment in a wide variety of clinical settings. Correct identification of benign lesions (e.g., hemangioma) will prevent unnecessary invasive procedures. Detection, characterization, enumeration, and localization of primary or metastatic hepatic neoplasms is critical for planning appropriate therapy. During initial staging, after treatment, and during follow up, the status of the liver helps to predict patient outcome with many neoplasms, even those treated with only radiation or chemotherapy. Specific interventions rely on imaging for planning or guidance including cryoablation, laser photocoagulation, radiofrequency/microwave ablation, percutaneous ethanol injection, surgical resection, and transplantation. ¹ In general, magnetic resonance imaging (MRI) has become the modality of choice for the characterization of focal liver disease. The radiologist must have a solid understanding of current MRI techniques for appropriate management of focal liver lesions.

Researchers at the 86th Annual Meeting of the Radiologic Society of North America (RSNA 2000) presented data demonstrating the dynamic nature of liver MRI. Improved hardware, MR technique, and contrast agents allow MRI to evaluate the liver completely and noninvasively. MRI of the liver now encompasses parenchymal imaging, magnetic resonance angiography (MRA), magnetic resonance venography (MRV), and magnetic resonance cholangiopancreatography (MRCP). Biochemical imaging with MR spectroscopy is available, but largely experimental. The goal of a complete, noninvasive evaluation of the liver has been realized and is widely available with modern scanners and techniques.

The optimal imaging modality for the detection of focal liver lesions has been robustly debated over the past two decades. Imaging modalities currently available to specifically evaluate focal liver disease include transabdominal and intraoperative ul-trasound, triphasic computed tomography (CT), computed tomographic arterial portography (CTAP), and MRI enhanced with one or more types of contrast agent. These are often complementary and various combinations may be appropriate in different clinical settings.

At various times, delayed CT after high doses of iodinated contrast, intraoperative ultrasound, and CTAP have each held sway as the best method for the detection of focal liver lesions. Most would now agree that MRI with one or more types of contrast has surpassed all of these modalities in terms of characterization and is at least equal to each one for detection. This is due to the high intrinsic soft-tissue contrast, improved biochemical and anatomic information, sensitivity to perfusion differences, multiplanar capability, and lack of ionizing radiation. ¹ Though it is clearly superior for the detection and characterization of focal liver lesions, MRI has not yet replaced CT or ultrasound for general liver imaging because of cost and availability. ²

This review will present a practical guide for choosing sequences and contrast enhancement strategies for MR imaging of focal liver lesions, including data presented at RSNA 2000. The typical MRI findings for the most commonly encountered types of lesions will be described.

Examination technique

Quality MRI of the liver requires meticulous attention to technical detail. A carefully validated standard sequence set is critical for a successful examination. Clinical history should be sought to direct the study and appropriate optional sequences added if necessary. Moderate field strength magnets (1.5 T) are generally available and provide a good balance between spatial resolution and tissue differentiation. When possible, phased array multicoils should be used instead of the standard body coil. Phased array multicoils are surface coils that are placed around the abdomen allowing the receiver coils to be as close to the generated signal as possible, thus optimizing the signal-to-noise ratio. The increased signal-to-noise ratio af-forded by phased array coils allows one to obtain a smaller field of view (FOV), thinner slices, and higher resolution images compared to the body coil. One drawback to the phased array multicoil is that the subcutaneous fat immediately subjacent to the coils tends to have high signal. This can be suppressed with fat saturation techniques. The high signal intensity fat can also generate marked ghost artifact due to motion. ³

Significant improvements in convenience and efficacy of liver MRI over the last several years have occurred in large part due to improved gradients and fast imaging sequences. T1-weighted gradient echo (T1 GRE) images can now be performed during a single breath-hold. This rapid imaging capability is extremely important for dynamic post contrast T1-weighted imaging. Table 1 lists scanning parameters for a practical liver imaging protocol.

Scan orientation selection --There are several schools of thought concerning the choices of planes in which to scan. One paradigm suggests that a single orientation should be used for all sequence types (e.g., axial) both before and after contrast. This minimizes the number of necessary sequences, thus minimizing scanning time and simplifying image review. Lesions are compared across sequence types for characterization. Additional planes are then imaged only with one of the sequences (e.g., T1) for delineation of anatomic relationships.

Unenhanced T1-weighted im-ages --Precontrast axial T1-gradient echo (GRE) breath-hold sequences should be performed. Some institutions routinely acquire precontrast T1-weighted images (T1WI) using "in phase" (4.2 ms at 1.5 T) and "opposed phase" (2.1 ms at 1.5 T) sequences. ³ Just as in adrenal imaging, this chemical shift imaging (CSI) readily detects microscopic intracellular lipid. Such techniques can diagnose diffuse fatty infiltration of the liver, focal fatty infiltration, focal fatty sparing, and the intracellular lipid present within hepatocellular neoplasms. ^3-5 While unenhanced T1WI are the least sensitive imaging sequence for lesion detection, they can improve confidence in lesion detection, characterize blood and fat, and are important in the interpretation of post contrast images. ⁶

Unenhanced T2 weighted images --T2-weighted images (T2WI) should be performed using fast sequences termed fast spin echo (FSE) or turbo spin echo (TSE). These sequences are significantly faster than conventional spin echo (SE) T2WI. Studies have shown that FSE sequences are at least equivalent to conventional spin echo sequences for focal liver lesion detection and characterization. ^3,7-9 There are, however, differences in image contrast between FSE and conventional SE images. Fat has higher signal intensity on FSE images compared to conventional SE techniques. Also, magnetic susceptibility effects of iron and other metals are minimized on FSE images compared to conventional SE images. ^3,10 Thus using FSE techniques is advantageous when imaging patients with embolization coils, inferior vena cava filters, or spinal hardware ¹¹ and may be disadvantageous after injecting a superparamagnetic iron oxide agent. ^3,10

Optional special purpose sequence --Additional sequences and/ or imaging planes may be added to the protocol based on clinical history, prior imaging, or findings seen on initial images during the current examination. For suspected hemangioma, the second and third echoes of T2-weighted sequences are often helpful in confirming the diagnosis. Fat suppression added to either T1- or T2-weighted sequences can often help to distinguish focal fatty change or focal sparing with diffuse fatty infiltration from true hepatic masses.

Contrast agents

An extensive body of research has been published on liver-specific contrast agents. Three classes of MR contrast agents are now available for liver imaging: extracellular, hepatocyte-specific, and reticuloendothelial agents (RES). All are given by the intravenous (IV) route with manufacturer specified doses, dilutions, and injection durations. Only the four agents that are currently approved for clinical use in the United States will be discussed below (Table 2).

Extracellular agents --Three paramagnetic chelates of gadolinium have been approved for imaging in the United States: gadopentetate dimeglumine (Magnevist, Berlex Laboratories, Wayne, NJ), gadodiamide (Omniscan, Nycomed Amersham, Wayne, PA), and Gadoteridol (ProHance, Bracco Diagnostics, Princeton, NJ). ^13,14 Gadolinium chelates function in a manner similar to iodinated contrast media. They are nonspecific extracellular MR contrast agents that rapidly equilibrate between intravascular and extravascular spaces. ¹⁵ The nonspecific distribution of gadolinium chelates into the vascular and interstitial compartments of normal and pathologic tissues requires rapid dynamic MR to maximize differential enhancement of liver parenchyma and tumors. ^15-17 Gadolinium increases tissue signal intensity on T1WI. Optimal imaging parameters include a breath-hold, T1- weighted GRE during arterial (20 to 30 seconds postinjection), portal venous (60 to 80 seconds postinjection), and equilibrium (3 minutes postinjection) phases. ¹³ Specific lesions often demonstrate characteristic enhancement patterns.

Hepatocyte-specific agents --At present, only one product is available as a hepatocyte-specific contrast agent: mangafodipir trisodium (Teslascan, Nycomed Amersham, Wayne, PA). A chelate of paramagnetic manganese, Teslascan increases normal liver signal intensity on T1WI and is best seen on fat-saturated techniques. ¹³ Scans may be performed shortly after administration and up to 4 hours afterwards. The clinical utility of manganese chelates is unclear at this time and at this point it does not appear to offer more information than dynamic gadolinium imaging.

Reticuloendothelial specific agents --The only clinically approved RES specific agent in the United States is ferumoxides (Feridex-IV, Advanced Magnetics, Cambridge, MA). Ferumoxides are taken up by the RES, which includes hepatic Kupffer cells, the spleen, bone marrow, and lymph nodes. ¹⁸ Due to its magnetic susceptibility effects, the agent produces T2 shortening, thereby darkening the liver signal intensity on T2WI. ^13,18 Scanning may be done just after injection and can be delayed for up to 4 hours. Since most focal liver lesions and tumors have few Kupffer cells, they maintain their native bright signal intensity after ferumoxide injection. ^13,18 One notable pitfall in using ferumoxides is that well-differentiated hepatocellular carcinomas have been reported to take up iron oxides. ^19-21 The uptake of ferumoxides by well-differentiated hepatocellular carcinoma is usually not uniform throughout the lesion and, in general, should not provide a diagnostic dilemma, especially with comparison of precontrast images.

Choice of contrast agents --Over the last decade, there has been much interest in finding the optimal contrast agent and scanning technique for the detection and characterization of focal liver lesions. The debate has centered on clinical indications for gadolinium chelates, ferumoxides, manganese chelates, or some combination of these agents. A significant body of clinically relevant data was presented at RSNA 2000. The general consensus of evidence suggests that dynamic gadolinium-enhanced imaging alone is the best technique for detection and characterization of focal liver lesions. ^22-26 The perfusion information offered by dynamic gadolinium-enhanced imaging is useful not only to detect liver lesions, but also in characterizing them. Ferumoxide imaging is roughly equal to dynamic post-gadolinium imaging for detecting, but somewhat inferior for characterizing, focal liver lesions. ^22,26 Ferumoxides may have some utility in characterizing focal nodular hyperplasia by documenting Kupffer cells in the lesion. ²¹ However, ferumoxide uptake is also observed in well-differentiated hepatocellular carcinomas, adenomas, and hemangiomas. The role of manganese chelates at this time is unclear and may be of value when other contrast agents are equivocal. Many trials are actively being performed on new liver specific contrast agents. ^12,18

Clinically relevant hepatic anatomy

Classic anatomy --Standard nomenclature describes right and left lobes of the liver, each divided into two segments (right anterior, right posterior, left medial or quadrate, left lateral). The hepatic arteries, portal veins, and bile ducts each have similarly named branches. The caudate lobe is usually considered as a separate segment. There are typically three hepatic venous branches (right, middle, and left) and these define the borders of the lobes and segments superiorly. Inferiorly, the gallbladder fossa separates the right and left lobes and the fissure for the ligamentum teres separates the medial and lateral segments of the left lobe.

Surgical anatomy --Modern liver surgery has evolved into hemostatically controlled dissection along anatomic planes. Today, up to 75% of the liver can be resected, provided the postsurgical liver remnant is not functionally compromised. ^27,28 Accurate localization of liver lesions provides critical information for planning surgical and minimally invasive intervention. In order to accurately localize liver lesions, the radiologist must understand the refined functional anatomy of the liver as defined by Couinaud (figures 1 and 2). The advantage of this nomenclature is that it provides succinct information as to the potential resection planes through the liver. ^27,29,30 In this nomenclature, the liver is divided by vertical and oblique planes defined by the three main hepatic veins and a transverse plane following a line drawn through the right and left portal branches. The eight segments are numbered clockwise in a frontal view. Each segment is an independent functional unit supplied by an individual portal triad. ^27,29,30

Functional anatomy --In order to have a systematic and practical approach to the differential diagnosis of focal liver lesions, it is helpful to consider that the liver is composed of several cellular elements: hepatocytes, biliary tree (cholangiocellular epithelium), and mesenchymal tissue. Liver pathology can then be classified as hepatocellular, cholangiocellular, and mesenchymal. ³¹ Table 3 depicts this organizational scheme.

MRI characteristics of common benign lesions

Hemangioma --Hemangiomas (figure 3) are the most common benign lesion of the liver, with an incidence ranging from 0.4% to 20% by autopsy series. ³² Hemangiomas are more frequently seen in middle-aged females, and are unlikely to be seen in cirrhotic livers. ³³ Histologically, they are composed of large blood-filled spaces. Most lesions remain stable over time, but may enlarge during pregnancy due to an estrogen effect. ^34,35 The major hazard of hemangiomas is the potential for misclassification as a malignant lesion. ³⁶

Hemangiomas have characteristic MR features that allow confident diagnosis in most cases. They are well-defined masses with high signal on T2WI that become progressively brighter on second and third echoes of T2WI. Dynamic gadolinium imaging demonstrates progressive nodular, centripetal enhancement to eventual uniform enhancement. ^37,38 Most hemangiomas fill in completely with contrast within 5 to 30 minutes as observed on delayed post-contrast T1WI. ³⁶

Focal nodular hyperplasia --Focal nodular hyperplasia (FNH) is the second most common benign liver lesion comprising 8% of all primary hepatic neoplasms. ³⁹ FNH is not a tumor but a tumor-like condition which results from hyperplasia of normal hepatocytes due to a vascular malformation. ⁴⁰ Eighty percent of these lesions are seen in middle-aged woman, and like hepatic adenomas, are associated with oral contraceptive use. Malignant transformation has never been reported. ⁴¹

FNH is classically a solitary lesion with a central radiating scar that is felt to be the arteriovascular malformation. MR diagnosis of FNH requires certain classic imaging features. The T1WI appearance is variable while the central scar is hyperintense on T2WI. On dynamic gadolinium imaging, the lesion becomes hyperintense on the arterial phase except the central scar, which remains hypointense. During the equilibrium phase, the lesion becomes isointense to hypointense and the central scar becomes hyperintense. FNH lesions contain Kupffer cells and normal hepatocytes, and therefore will take up ferumoxides and manganese chelates. ^15,41

FNH can be confused with fibrolamellar hepatocellular carcinoma (HCC). Fibrolamellar HCC is a rare form of HCC seen in young patients without underlying liver disease. Fibrolamellar HCC, which has a better prognosis than conventional HCC, is typically a large mass with a central scar that is low signal intensity on T2WI. After gadolinium administration, there is intense heterogeneous enhancement on the arterial phase and the central scar may enhance on the delayed images. ¹⁵ If there is any question that a lesion may be fibrolamellar HCC, biopsy is mandatory. ^31,41

Hepatic cyst --Hepatic cysts occur in 2.5% of patients referred for ultrasound. ⁴² The prevalence of cysts increases with age and in women, and unlike hemangiomas, is seen in cirrhotic livers. Ultrasound is typically diagnostic, but MR may be of value when complicated cysts are present, in the setting of multiple cysts (polycystic kidney disease), or when multiple liver lesions are present and all lesions need to be characterized. ^15,41 Liver cysts should be very high signal on T2WI with a thin, well-circumscribed wall. No contrast enhancement should occur. MR is particularly helpful in demonstrating intracystic hemorrhage. ⁴¹

Hepatocellular adenoma --Hepatocellular adenoma (HCA) is a benign tumor of hepatocytes. Oral contraceptive pills (OCP) and androgenic steroids are causative agents in HCA. The incidence is 3 per year per 100,000 long-term OCP users, but only 1 per million in nonusers or women using OCPs for less than 2 years. ⁴³ HCAs are often found incidentally in young women on OCPs. They have a propensity to cause life-threatening hemorrhage and there is a controversial risk of malignant transformation. ^44,45 Therefore, surgical resection is the treatment of choice in most cases.

HCAs have variable signal characteristic on T1WI and T2WI due to the presence of fat, blood, and hepatocytes within the lesion. Dynamic gadolinium demonstrates most lesions to be hypervascular in the arterial phase. ⁴⁶ As with hepatic cysts, MRI is particularly useful in demonstrating hemorrhage within the lesion. If clinical history and MRI features are still nondiagnostic, biopsy or surgical resection is recommended. ⁴¹

MRI characteristics of common malignant lesions

Metastases --The most common cause of malignant liver lesions in the United States (Table 4) is metastatic disease; they outnumber primary hepatic neoplasms by anywhere from 18:1 to 40:1. ^31,39,47 The most common primary sites that metastasize to the liver are colon, stomach, pancreas, breast, and lung. The MRI characteristics vary with each tumor, but are generally classified as hypervascular or hypovascular. ^1,15,31

Hypervascular metastases (figure 4) are usually from renal cell carcinoma, pancreatic islet cell tumors, breast carcinoma, melanoma, thyroid carcinoma, sarcomas, choriocarcinoma, and carcinoid tumors. These lesions draw their blood supply from the hepatic artery, which is reflected in the enhancement pattern seen on dynamic gadolinium imaging. These lesions will show marked peripheral rim enhancement during the arterial phase with delayed peripheral or central washout in the portal venous and equilibrium phases. ^15,48

Hypovascular hepatic metastases (figure 5) usually arise from colon carcinoma, pancreatic carcinoma, transitional cell carcinoma, and lung carcinoma. These lesions derive little blood supply from the hepatic artery or portal vein and are best imaged in the portal venous phase of gadolinium enhanced imaging. These lesions will have low signal compared to liver parenchyma. ¹⁵

Hepatocellular carcinoma --Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm (figure 6). HCC usually occurs in the settings of chronic liver disease and cirrhosis, ³⁹ which include hepatitis B and C, aflatoxins, alcoholism, and hemochromatosis. The incidence of HCC is greatest in the Far East and Africa due to the high prevalence of hepatitis B and C and aflatoxins. Alpha fetoprotein is elevated in 80% of cases. ⁴⁹

The liver responds to chronic insults and inflammation by forming regenerative nodules. Some of these regenerative nodules become dysplastic and evolve into HCC. ^50,51 This sequence of dedifferation of regenerative nodules to dysplastic nodules to HCC has important imaging implications.

HCCs present as a solitary liver mass in 50% of cases, multifocal liver masses in 40% of cases, and diffuse infiltration in 10% of cases. They have a propensity for vascular invasion, which is seen in 30% to 50% of cases. ^15,52 The most important factors affecting long-term survival are the presence of vascular invasion, the number of tumors, and size greater than 5 cm. ⁵³ MRI has become the modality of choice to characterize the number and size of lesions and to assess vascular invasion.

The T1 and T2 signal intensity of HCC is highly variable. The pattern and degree of enhancement with gadolinium is directly related to tumor differentiation, histologic subtype, and degree of vascularity. ⁵² Well-differentiated HCC has minimal arterial enhancement that washes out on portal venous images. As stated earlier, well-differentiated HCC contains Kupffer cells and will take up ferumoxides. Moderate and poorly differentiated HCCs show marked hypervascularity and therefore enhance on the arterial phase. In a cirrhotic liver, any abnormal enhancement should be considered suspicious for HCC. ¹⁵

Cholangiocarcinoma --Cholangiocarcinoma (CAC) is a malignant tumor arising from bile duct epithelium. ³⁹ Risk factors include Clonorchis sinensis infection, prior exposure to Thorotrast, primary sclerosing cholangitis, and Carolis disease. ²⁷ The prognosis is poor and patients typically die within months of diagnosis.

Although not technically considered an intraheptic neoplasm, the most common type of CAC is hilar cholangiocarcinoma or Klatskin tumor. These tumors may be small and obstruct the biliary tree. As the tumor grows, the hilum of the liver may be involved, resulting in biliary obstruction. Dynamic gadolinium enhanced imaging demonstrates a characteristic pattern of slow, gradual enhancement best seen on the equilibrium phase. ^15,54,55

Intrahepatic cholangiocarcinoma is a rare primary malignant liver neoplasm. ^15,49 These lesions usually present as a large solitary mass without biliary obstruction. Dynamic gadolinium imaging demonstrates peripheral enhancement on the arterial phase, and incomplete central enhancement on the delayed images. ^15,51,54

Conclusion

Modern MRI scanners with improved gradients and fast imaging techniques have become the modality of choice for accurate detection and characterization of focal liver lesions. The accurate detection, characterization, and localization of liver lesions is imperative for appropriate patient care and surgical planning.

Currently dynamic gadolinium imaging combined with T1WI and T2WI provides the best technique to evaluate focal liver lesions. The role of liver-specific contrast agents is still unclear and future research will better define their appropriate clinical utility.

Future directions in liver MRI include the development of improved pulse sequences to better characterize lesions in a time- and cost-efficient manner. In addition, the clinical utility of the current and future liver-specific contrast agents needs to be defined.

Acknowledgements

The author wishes to thank Drs. Chris Sistrom, Pat Mergo, Patricia Abbitt, Walter Drane, and Scott Klioze of the University of Florida for their assistance with this manuscript.