With the widespread use of hepatic imaging, liver masses

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1 2B: Liver Assessment of the Liver Mass: What Do You Need to Know? With the widespread use of hepatic imaging, liver masses are detected either unexpectedly or in the course of screening for liver cancer on a regular basis. Such masses are often benign lesions of no clinical significance but can also be malignant or have malignant potential. Missing the diagnosis can, therefore, be greatly detrimental for the patient. The assessment of these masses and their subsequent management are, therefore, of great clinical importance. Core Principles of Assessment of a Liver Mass There are three core principles that guide the assessment of a liver mass: What could it be: benign vs malignant Which diagnosis would be particularly bad if missed What will we do if we make the diagnosis Differential Diagnosis of a Liver Mass It is important to know if a liver mass develops in the context of cirrhosis or not. When a patient is known to have chronic liver disease especially cirrhosis, one should aggressively look for a primary hepatocellular cancer (HCC). The a priori likelihood of developing HCC in the absence of cirrhosis is much lower in the United States. In countries where hepatitis B is highly prevalent, HCC can occur in the absence of cirrhosis or advanced fibrosis. Recent reports indicate that HCC can occur in subjects with NAFLD without significant fibrosis in the liver. The true incidence of such lesions is not known but this is a worrisome emerging trend. Common lesions seen in a subject with cirrhosis: HCC Hemangiomas Regenerative nodules Nodules with dysplasia Common lesions seen in a subject without cirrhosis: Hemangiomas Hepatic adenomas Extrahepatic malignancy with metastases Focal nodular hyperplasia Focal fat sparing HCC Cholangiocarcinomas Hepatoblastoma Rare tumors: angiosarcoma Biliary cystadenoma It is important to remember that in many cases, the presence of cirrhosis is not known. Also, the conditions listed in the differential diagnosis of a mass in cirrhosis can theoretically be seen in subjects with cirrhosis as well. Of these, it is very important to be able to diagnose HCC because left untreated it is usually fatal within a year and if diagnosed early, can be cured in many subjects. Results with liver transplantation for HCC are exceptionally good and can provide disease free survival of up to 80% or more at five years. Vascular Physiology of HCC and its Relevance for Diagnosis of HCC Changes in vascular supply and draining with evolution to HCC Hepatocellular cancer (HCC) typically arises in a cirrhotic liver. In certain diseases, e.g., hepatitis B virus infection, it may occur in the absence of cirrhosis. Hepatocarcinogenesis may occur de novo or as a multi-step process in which a focus of dysplasia develops in a nodule which progresses to frank carcinoma. This progression involves transition from a dysplastic nodule to a nodule with a small focus of HCC, a small but entirely cancerous nodule and then to a larger nodule with or without invasion of surrounding blood vessels. Morphologically, cirrhotic nodules are considered to be micronodular (< 3 mm diameter) or macronodular (> 3 mm diameter). These nodules retain their blood supply from the portal vein but have minimal hepatic arterial supply. With progression to high grade dysplasia and cancer, the portal venous supply diminishes and the nodules are fed mainly by arterial branches that develop as a result of neoangiogenesis. This is reflected histologically in the form of unpaired arteries and capillarization of the tumor. The venous drainage of these malignant tumors typically occur in to the portal venous branches which is reflected in a high propensity for HCC to invade the portal vein and cause portal vein thrombosis which has been reported in up to 44% of cases of HCC. Hepatic venous invasion is seen less commonly. HCC can also take several morphologic patterns noted below: Massive: a single large lesion (> 3 cm) with or without a few satellite lesions Nodular: multiple lesions (usually < 3 cm) in one or more lobes of the liver Diffuse: multiple small lesions (usually < 1 cm) throughout the liver 172 2B: Liver

2 HCC > 2 cm in diameter usually have the changes in vascular supply noted above. In contrast, these changes are more variably present in smaller lesions. Such lesions (< 2 cm in diameter) are referred to as small HCC. How changes in vascular supply are used to detect HCC Arterial phase When contrast is injected intravenously in to the systemic circulation, it moves via the heart and pulmonary bed to the arterial circulation for delivery to the intestine and liver. This normally takes seconds. During this arterial phase, regenerative nodules which retain most portal venous inflow do not show the presence of the contrast, i.e., enhance. On the other hand, malignant nodules, which are mainly supplied by an arterial branch, will show enhancement. This arterial enhancement is a hallmark of HCC and is accepted by the United Network for Organ Sharing (UNOS) as a non-invasive finding diagnostic of HCC in contrast enhanced CT scans or MR imaging. Venous phase In this phase, blood from the splanchnic circulation (the intestine and spleen) carrying the contrast has found its way to the portal vein and then in to the liver. During this phase, regenerative nodules enhance reflecting their supply from the portal vein. In contrast, HCC have already drained their arterially supplied contrast and no longer have contrast in them and become non-enhancing. This creates a contrast in the brightness of the lesion with respect to the surrounding liver. This wash-out phenomenon is another important feature of HCC and when present in the absence of marked arterial enhancement, can be a clue to the presence of HCC. Delayed phase During this phase, the liver is being drained of contrast from portal venous origin. The washout phenomenon often persists during this phase and can become even more exaggerated in this phase particularly in smaller lesions. The time-dependence of detection of the these findings makes it imperative that centers performing imaging studies for the detection of HCC must have established and rigorously implemented protocols for imaging with cuts obtained at appropriate and pre-specified intervals to detect these changes and thus improve their diagnostic capability. How to Diagnose HCC Using Imaging Techniques A biopsy or histologic examination of a resected specimen provides definitive proof of HCC. However, it is not feasible to obtain such tissue simply for diagnostic purposes in most cases. There are several parameters that allow the diagnosis of HCC to be made using non-invasive methods. These include: Surrounding liver: (if it is normal, i.e., non-cirrhotic, it is less likely to be HCC except in HBV and a few other selected conditions) Size: Larger masses (> 3 cm) are more likely to be malignant although large regenerative nodules up to 5 cm diameter have been described on occasion. Arterial enhancement: This is a very important feature. It may be less commonly present in very small lesions because the neo-arterialization has not fully developed. Washout phenomenon: This is again a very important feature and may be the only clue in small lesions that do not show enough arterial enhancement to make a confident diagnosis. It is important to obtain images in both the venous and delayed phases to evaluate washout. While the presence of the washout phase helps diagnose HCC, the absence of the washout phase does not exclude the presence of HCC. Corona enhancement: It has been reported that large HCC show a halo of enhancement during the portal venous phase during CT hepatic arteriography. This finding however has only limited utility given its invasive and expensive nature. Transient hepatic arterial enhancement: This is an area of peri-tumoral enhancement seen in the arterial phase and reflects increased arterial supply to the area due to portal venous occlusion or compression locally. It is usually wedge shaped and conforms to a segmental distribution. The biology is similar to corona enhancement. Thrombosis of the portal vein: Portal vein thrombosis can occur in subjects with cirrhosis without HCC in up to 10-15%. HCC is more often associated with portal vein invasion and malignant thrombosis can be diagnosed when the thrombus is adjacent to the tumor, shows arterial enhancement or if the portal vein is expanded with thrombus. Rate of growth: HCC generally show progressive growth over months. Circulating Biomarkers of HCC and Their Use in Clinical Practice Alpha-fetoprotein (AFP) The AFP gene is expressed in hepatocytes and endodermal cells of the yolk sac in fetal life. Its expression decreases after birth. It is increased in HCC, hepatic regeneration and embryonal carcinomas. Circulating AFP levels correlate with tumor size especially with levels > 500 ng/ml. The sensitivity of such levels drops to 25% from 52% with a decrease in size of HCC from > 3 cm to < 3 cm. Lens Culinaris Agglutinin reactive AFP (AFP-L3) There are several AFP glyco-isoforms; AFP-L1 is mainly seen in cirrhosis while AFP-L3 is increased in HCC. It is used mainly as an ancillary test to AFP with non-specifically 2B: Liver 173

3 elevated total AFP. AFP-L3 levels greater than 10% of total AFP has a sensitivity of about 50% and specificity of > 95% for detection of HCC. The modest sensitivity of AFP-L3 and high specificity means that, if positive, it helps make the diagnosis of HCC but a low level does not exclude HCC with confidence. Des-carboxyl prothrombin (DCP) This is an abnormal prothrombin that is formed in HCC. DCP is more specific than total AFP for the diagnosis of HCC. Its overall sensitivity and specificity is comparable to AFP-L3. The diagnostic utility of elevated DCP is limited in severe intrahepatic cholestasis, biliary obstruction and use of warfarin. DCP is involved in angiogenesis and is associated with a greater risk of portal vein invasion and thrombosis, intrahepatic metastases, and capsular infiltration. Newer agents Several additional biomarkers are currently being evaluated. These include glypican-3, E-cadherin, α1-fucosidase, vascular endothelial growth factor and cytokeratin-18 fragments. Their clinical utility remains to be determined. Approach to the Imaging Assessment of a Liver Mass Several practice guidelines have provided criteria for the initial diagnosis of HCC. The principal imaging techniques to be used include contrast-enhanced ultrasound (CEUS), multidetector CT imaging or dynamic MRI with 4 phase imaging (precontrast, arterial phase, venous phase and delayed phase). A CT scan or MRI is the preferred initial approach. MRI is somewhat superior to CT scan for the diagnostic evaluation of a mass in the liver. Usually in large masses (> 2-3 cm in diameter), there is little difficulty in making the diagnosis. The diagnostic hallmarks of HCC on MR imaging include: Precontrast imaging: T1 weighted images are variable with occasional high intensity due to fat, copper or glycogen in the tumor or to zinc in the surrounding tissue. T2-weighted images are usually moderately hyperintense. Contrast imaging: This demonstrates the typical arterial enhancement with washout. With these findings, a mass > 2 cm with an AFP > 200 ng/ml in a person at risk of HCC is diagnostic. There are several clinical scenarios where there are diagnostic difficulties The approach to such a situation requires consideration of the degree of AFP elevation, the rate of increase of AFP and the nature of the imaging used initially. If the imaging conditions were not appropriate, it is worth repeating the imaging with Gadolinum-MRI (gad-mri) or contrast-enhanced CT scan. If an adequate initial diagnostic evaluation does not show a lesion, the choices then involve: Repeat studies over time This approach leverages the growth pattern of HCC. Imaging studies and AFP levels repeated over time may show evidence of tumor as the tumor enlarges. This approach may be suitable when the AFP elevation is mild and highly non-specific, e.g., up to ng/ml. In such cases, it is worth repeating the AFP and imaging in three months to determine if it is rising. If it is rising, additional testing is warranted. This is because it is imperative to make the diagnosis at an early stage so that potentially curative treatments can be provided. Additional testing This is appropriate if the AFP levels are high (e.g., > several hundred ng/ml) or if there is a trend showing rising AFP and/ or if the patient is particularly at risk for HCC. If a CT scan was used initially, a correctly performed dynamic MRI may be used. If a gad-enhanced MRI was used initially, the addition of superparamagentic iron-mri (SPIO-MRI) may provide additional diagnostic clarity. Using this technique, HCC appears hyperintense in T2-weighted images because HCC does not contain Kupffer cells that take up the contrast. Also, AFP-L3 and DCP can be used to augment the diagnostic capabilities. If no lesions are seen after two serial imaging tests performed over a 6-12 month time frame and with at least two imaging modalities, and if the AFL levels have decreased or remained stable in a modest range, one may return to routine screening intervals but with the addition of AFP-L3 and use of MRI or 4 phase CT scan as the imaging method of choice. Ideally it is best to use the same method (usually MRI) so that the data can be compared. It is also important to exclude an alternate source of AFP, e.g., a testicular tumor if imaging does not reveal a hepatic mass. Imaging Characteristics of Other Liver Masses Regenerative nodules These can grow to a size of up to several cm. They mainly cause a dilemma when the nodules are < 2 cm in diameter. They are isointense on T1- and T2-weighted imaging usually because they are made up of non-malignant hepatocytes surrounded by a fibrous stroma. Regenerative nodules with iron are hypointense on both T1 and T2-weighted images. This has not been established to be a pre-malignant lesion yet. Dysplastic nodules These are nodules of at least 1 mm diameter with dysplastic hepatocytes. They usually have the same signal intensity and characteristics as regenerative nodules. If variable arterial enhancement is seen, it may reflect retention of Cu in the cells or the beginning of neo-arterialization. If these nodules 174 2B: Liver

4 infarct, they appear hyperintense of T2-weighted images and can be confused with HCC. The decision to proceed to further testing or empiric treatment depends on the AFP and AFP- L3 levels, size of the lesion and the potential for curative therapy. Another option is to repeat imaging in 3-6 months to see if the characteristics of the lesion have become more typical for HCC. Dysplastic nodules have been reported to disappear on follow up. Arterio-portal shunts These can be spontaneous or follow a liver biopsy and show arterial enhancement and may be confused for HCC. They are distinguished from HCC by their shape, distribution and the fat that they are usually isointense on T2 weighted imaging (HCC is hyperintense). They also do not displace internal vasculature. Focal confluent hepatic fibrosis This is typically seen in one lobe with massive fibrosis e.g., in sclerosing cholangitis. It can be diffuse. It is wedge shaped with a wide base towards the capsule along with capsular retraction. It is usually present in the anterior and medial segments and associated with atrophy of the surrounding liver. It has a low intensity on T1-weighted imaging and a high intensity on T2-weighted images. However, in contrast to HCC, fibrosis related mass effects enhance in the delayed phase. Hemangiomas While these are commonly seen in normal livers, they are relatively uncommon in cirrhotic livers. They have a typical appearance on MRI. Focal nodular hyperplasia (FNH) and hepatic adenomas These are rare in a cirrhotic liver. It can be difficult to distinguish them from HCC. The presence of a central scar is a helpful clue for the diagnosis of FNH. The lack of Kupffer cells in these lesions can be exploited by using SPIO-MRI. Using gad-mri or manganofodipir, enhancement in the delayed phase can be seen with these lesions. Gadexetic acid has also been used as a contrast agent in such cases. Intrahepatic cholangiocarcinoma These usually show a thick rim of enhancement in the arterial and venous phases with progressive and concentric filling of contrast material in the later phases. There may be postobstructive biliary dilation, capsular retraction and compression of the portal vein. Hepatic metastases from extrahepatic malignancies Approach It is worth considering these in the context of the presence or absence of cirrhosis and the presence of a clinical condition known to be a risk factor for HCC. In the absence of cirrhosis and a risk factor for HCC and a mass > 2-3 cm, the a priori likelihood of a diagnosis other than HCC such as hepatic adenoma or FNH become more likely. Nodules should be evaluated by a properly performed complementary imaging method when the features on the initial imaging method do not provide a clear diagnosis. For example, those who were initially evaluated by a 4 phase helical CT scan could be evaluated by gad-mri and vice versa. The presence of a characteristic finding for such a lesion, e.g., a central scar for FNH and absence of features of HCC such as arterial enhancement with washout and peri-tumoral enhancement in the arterial phase along with a normal AFP and AFP-L3 allow one to diagnose these conditions with greater certainty. In cases where the mass is < 2 cm in size, there is greater diagnostic difficulty. This is often because the vascular supply has not matured to the pattern seen in well established HCC. If all the features of HCC especially arterial enhancement and washout are present, the diagnosis is relatively easy. The usual problem that is encountered is that the arterial phase enhancement is either atypical or absent. In such cases, the importance of the washout phenomenon can not be overemphasized and needs to be looked for in the portal venous and delayed phases of contrast imaging. Also, peritumoral enhancement and involvement of vessels along with elevation of AFP provide clues that one is dealing with a HCC. Recently, the use of SPIO-MRI has been found to be useful in this setting and enhances the diagnostic ability of gad-mri. The value of SPECT imaging especially in the setting of a confusing MRI picture has not been fully established. CEUS has recently been shown to have a diagnostic sensitivity of 87%, specificity of 100% and diagnostic accuracy of 93% for HCC lesions between 1-2 cms. These data need to be validated in larger cohorts of subjects. The role of a liver biopsy If a diagnosis cannot be made with these methods, a biopsy should be considered. It is recommended that lesions between 1-2 cms may be biopsied under CT or US guidance. The tissue, especially if it is not obviously malignant, should be staining with available markers such as CD34, CK7, glypican, etc. If the biopsy is negative, the lesion should be followed at 3-6 month intervals until the nodule disappears, enlarges or displays features of HCC. If the lesion remains unchanged for over 1-2 years, resumption of routine surveillance can be done. If the lesion enlarges but does not have typical features of HCC, a repeat biopsy is recommended. The role of biopsy was decreased considerably over the last five years as imaging modalities have become progressively better. 2B: Liver 175

5 What to do with nodules < 1 cm in diameter Nodules less than 1 cm in size with a normal AFP can be followed with US at 3-6 month intervals and if no growth has occurred in 1-2 years, the normal screening interval of six months can be resumed. Selected references 1. Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR imaging of hepatocellular carcinoma in the cirrhotic liver: Challenges and controversies. Radiology 2008;247: Bruix J, Sherman M. Diagnosis of small HCC. Gastroenterology 2005;129: Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42: Leoni S, Piscaglia F, Golfieri R, et al. The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol 2010;105: Malaguarnera G, Giordano M, Paladina I, et al. Serum markers of hepatocellular carcinoma. Dig Dis Sci 2010;55: Zech CJ, Grazioli L, Breuer J, et al. Diagnostic performance and description of morphological features of focal nodular hyperplasia in Gd-EOB-DTPA-enhanced liver magnetic resonance imaging: Results of a multicenter trial. Invest Radiol 2008;43: Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47: Sturgeon CM, Duffy MJ, Hofmann BR, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Liver, Bladder, Cervical, and Gastric Cancers. Clin Chem 2010;56:e Jang HJ, Kim TK, Wilson SR. Small nodules (1-2 cm) in liver cirrhosis: Characterization with contrast-enhanced ultrasound. Eur J Radiol 2009;72: Boutros,C, Katz SC, Espat NJ. Management of an incidental liver mass. Surg Clin North Am 2010;90: B: Liver