Radiological Reasoning: Incidentally Discovered Liver Mass

AJR Integrative Imaging LIFELONG LEARNING FOR RADIOLOGY This Radiological Reasoning article is available for SAM credit and CME credits when completed with the additional educational material provided in Imaging of Hepatocellular Carcinoma: Self-Assessment Module. See page S431 for details. Michelle M. Bittle 1 Felix S. Chew Keywords: cancer, CT, liver disease, sonography DOI:10.2214/AJR.05.1767 Received October 7, 2005; accepted after revision December 19, 2005. 1 Both authors: Department of Radiology, University of Washington, Harborview Medical Center, 325 Ninth Ave., Box 359728, Seattle, WA 98104-2499. Address correspondence to M. M. Bittle (mbittle@u.washington.edu). AJR 2006; 186:S434 S441 0361 803X/06/1866 S434 American Roentgen Ray Society Radiological Reasoning: Incidentally Discovered Liver Mass Objective A 49-year-old woman presented to the emergency department after a fall in which she sustained a right subcapital hip fracture. During her hospital stay she developed abdominal pain, and a hypoechoic liver mass was found on sonography. Multiphase CT showed a hepatic mass with brisk arterial phase, rapid washout on the portal venous phase, and delayed phase hypodensity. The final pathology diagnosis was hepatocellular carcinoma. Conclusion Incidental lesions are frequently discovered during routine radiographic evaluations. Correlation with clinical history and additional confirmatory imaging is essential for appropriate diagnosis and management. Case History A 49-year-old woman presented to the emergency department complaining of right hip pain after a fall. An impacted right subcapital femoral neck fracture was suspected on conventional radiography and confirmed with MRI. The patient underwent operative compression screw fixation of the fracture. On postoperative day 5, the patient complained of abdominal pain, and splenomegaly was found on physical examination. Abdominal sonography was subsequently performed. Sonography Sonography shows a 5.7 6.7 5.4 cm rounded hypoechoic mass in segments V and VI of the right lobe of the liver (Fig. 1A). The mass is expansile and partially exophytic with internal vascular flow (Fig. 1B). The patient is also found to have splenomegaly and cholelithiasis with no sonographic evidence of acute cholecystitis (not shown). Expert Discussion (Dr. Bittle) Acute abdominal pain in a postoperative patient is not unexpected, and it is doubtful that the patient s pain in this case is related to the hepatic mass or cholelithiasis. The hepatic mass is a solitary solid lesion with several possible benign and malignant causes. The finding of splenomegaly suggests portal hypertension and cirrhosis, putting hepatocellular carcinoma (HCC) on the top of my differential diagnosis list. Numerous benign and malignant possibilities exist, however. The most common benign causes include hemangioma, focal nodular hyperplasia, and hepatic adenoma. Hemangiomas are typically hyperechoic, which this lesion is not. Adenomas can have a variable appearance and nearly all occur in women. Additional clinical history regarding the use of oral contraception or hormone therapy in S434 AJR:186, June 2006

Incidentally Discovered Liver Mass A C Fig. 1. 49-year-old woman hospitalized after fall in whom incidental liver mass was found. A and B, Gray-scale (A) and color Doppler (B) sonograms of right lobe of liver. Arrows in A indicate hypoechoic mass. C, Unenhanced CT scan through liver. Note mixed isodense hypodense mass (arrows) in segments V and VI of right lobe with attenuation of 37 H. (Fig. 1 continues on next page) this 49-year-old woman would be useful. Focal nodular hyperplasia is also a possibility because these lesions are usually seen in young women as well. The sonographic appearance may be isoechoic to surrounding normal liver, given the presence of hepatocytes that are normal to hypoechoic in appearance. The most common malignant causes include metastasis, HCC, and cholangiocarcinoma. Metastatic disease is the most common malignant lesion; HCC is usually multiple but may be solitary. The sonographic appearance is variable but often shows a hypoechoic mass. Occasionally, a hypoechoic halo is seen surrounding the mass, the so-called target or bull s-eye pattern. The hypoechoic rim represents compressed liver parenchyma and tumor fibrosis. HCC also has a variable sonographic appearance. Small HCCs are usually hypoechoic, larger lesions (> 3 cm) are typically of heterogeneous echogenicity, and the subset of fibrolamellar HCCs are typically hyperechoic. Cholangiocarcinomas may be central (Klatskin s tumor), usually with bile duct dilation, or peripheral, similar to the mass in this patient. Peripheral cholangio- B AJR:186, June 2006 S435

Bittle and Chew Fig. 1 (continued) 49-year-old woman hospitalized after fall in whom incidental liver mass was found. D F, Contrast-enhanced CT scans through liver in arterial (D), portal venous (E), and 10-min delayed (F) phases. In D, note mixed of mass that replaces caudal aspect of segments V and VI. Rapid washout is seen in E, and mass remains hypodense in F. (Fig. 1 continues on next page) carcinomas are typically hypoechoic and surround a bile duct. The sonographic appearance of the mass presented in this patient is nonspecific, and the differential diagnosis remains quite broad. Multiphase CT should be performed. D Clinical Management Pertinent laboratory values obtained included decreased platelets (85 10 3 /µl), decreased albumin (3 g/dl), and elevated α-fetoprotein (46.7 ng/ml) levels. The patient also revealed a history of alcohol abuse. Multiphase CT was performed after sonography. CT CT of the liver was performed before the administration of IV contrast material, and in arterial, portal venous, and 10-min delayed phases after IV contrast administration. Unenhanced images (Fig. 1C) show a rounded mixed isodense hypodense mass E F S436 AJR:186, June 2006

Incidentally Discovered Liver Mass Fig. 1 (continued) 49-year-old woman hospitalized after fall in whom incidental liver mass was found. G and H, Contrast-enhanced sagittal (G) and coronal (H) reformatted images show prominent hepatic artery extending to margin of mass (arrow). in segments V and VI of the right lobe of the liver having an attenuation of 37 H. The mass is partially exophytic and expands the normal liver contour. Arterial phase images (Fig. 1D) show mixed of the mass, which replaces the caudal aspect of segments V and VI. The is less than that of the common iliac arteries. Rapid washout is seen on portal venous phase images (Fig. 1E), and the mass remains hypodense on the 10-min delayed images (Fig. 1F). Sagittal (Fig. 1G) and coronal (Fig. 1H) reformatted images show a prominent hepatic artery extending to the margin of the mass. No other liver lesions are identified. Expert Discussion (Dr. Bittle) Once the history of alcohol abuse and an elevated α-fetoprotein level were provided, the hepatic mass found on sonography should be considered HCC until proven otherwise. Multiphase CT confirms this top differential diagnosis. Unenhanced images show the mass to be hypodense to the remaining liver, but the attenuation is greater than expected for a simple cyst. The arterial phase images show rapid and a heterogeneous mosaic pattern. The mass enhances greater than the surrounding liver but not as great as blood pool. Portal venous phase images show globular with rapid washout relative to the surrounding liver. A subtle fibrous capsule is also seen on portal venous phase images, which can be seen with HCC. On 10-min delayed phase images, the lesion remains hypodense. G Although the clinical history and imaging findings in this patient are typical of HCC, it is pertinent to review the imaging characteristics of other malignant and benign hepatic masses (Table 1). Malignant lesions to consider include metastases, fibrolamellar HCC, and intrahepatic cholangiocarcinoma. Common benign lesions include hemangioma, focal nodular hyperplasia, and adenoma. In addition, benign lesions seen in cirrhotic livers include regenerative nodules, transient hepatic attenuation differences, and focal confluent fibrosis. Metastases, particularly hypervascular metastases such as those from melanoma, renal cell carcinoma, sarcoma, carcinoid, islet cell tumors, and some breast cancers, are best seen on arterial phase images, similar to HCC. However, most metastases are hypovascular and best detected on portal venous phase images. Multiple enhancing hepatic lesions in a patient with known carcinoma obviously favors metastases, but solitary metastases also occur; therefore, a solitary metastasis should be considered in the differential diagnosis for this patient. Calcifications seen with metastases from mucinous primary tumors and ovarian, thyroid, renal, lung, and breast primary cancers are best detected on unenhanced images, but calcifications are not seen in this patient. Fibrolamellar HCC is uncommon and occurs in younger patients with no preexisting liver disease. Αlpha-fetoprotein levels are usually normal, and the prognosis is much better than for conventional HCC. These tumors are usually large, with a large central scar that often calcifies. In contrast to focal nodular H AJR:186, June 2006 S437

Bittle and Chew TABLE 1: Imaging Characteristics of Common Malignant and Benign Hepatic Masses Imaging Technique Hemangioma Focal Nodular Hyperplasia Sonography Hyperechoic Homogeneously isoechoic or slightly hypo-/hyperechoic; central scar shows spoke-wheel arterial pattern radiating to periphery MDCT Unenhanced Hypodense Isodense to hypodense; central scar is hypodense Arterial phase Portal venous phase Delayed phase MRI Globular discontinuous peripheral Gradual centripetal fill after blood pooling Continued filling after blood pooling Homogeneous hypervascular; ; central scar is hypodense Homogenous ; central scar is hypodense Isodense; central scar shows delayed T1-weighted Low signal Isointense to nearly isointense; central scar is low signal T2-weighted High signal Isointense to nearly isointense; central scar is high signal Adenoma Solitary welldefined hyperechoic mass, but variable; large masses show heterogeneous echogenicity Hypodense; variable depending on hemorrhage and necrosis Cirrhotic Nodules Regenerative Dysplastic Isoechoic Variable echogenicity depending on fat content Isodense; siderotic nodules are hyperdense Isodense to occasionally hyperdense HCC Fibrolamellar HCC Metastasis Variable; < 3-cm masses have hypoechoic rim with slightly hyperechoic center; > 3-cm masses have heterogeneous echogenicity Variable; hyperechoic to heterogeneous echogenicity; central scar may calcify Hypodense to isodense Heterogeneous, variable; central scar is hypodense, may calcify Hypervascular Isodense Isodense Homogeneously hypervascular in smaller lesions; heterogeneous (mosaic) in larger lesions Isodense to nearly isodense Isodense Isodense Hypodense (washout) to isodense Heterogeneous, variable; central scar is hypodense Isodense to hypodense Isodense Isodense Isodense Isodense Isodense; central scar is nonenhancing; occasional High signal; variable heterogeneity depending on hemorrhage and necrosis High signal; variable heterogeneity depending on hemorrhage and necrosis Isointense; rarely nearly isointense; siderotic nodules are low signal Isointense to rarely low signal; siderotic nodules are low signal High signal 50% High signal; 50% variably isointense to low signal; capsule is low signal Low signal High signal; capsule is low signal Variable depending on primary; tumor may show hypoechoic halo Cholangiocarcinoma Peripheral, hypoechoic surrounding bile ducts Hypodense to isodense Hypodense to isodense Isodense to hypervascular depending on primary tumor Homogeneous Isodense Mild peripheral Isodense Increasing Low signal Low signal Low signal High signal; central scar is low signal High signal High signal Table 1 continues on next page S438 AJR:186, June 2006

Incidentally Discovered Liver Mass TABLE 1: Imaging Characterisitics of Common Malignant and Benign Hepatic Masses (continued) Cholangiocarcinoma Cirrhotic Nodules HCC Fibrolamellar HCC Metastasis Adenoma Imaging Technique Hemangioma Regenerative Dysplastic Focal Nodular Hyperplasia MRI (continued) Gadoliniumenhanced Mild to moderate peripheral Hypovascular lesions show rim ; hypervascular lesions show homogeneous Heterogeneous Homogeneously hypervascular in smaller lesions; heterogeneous (mosaic) in larger lesions Hypervascular Isointense Isointense to occasional mild Hypervascular; central scar is unenhanced Arterial phase Globular discontinuous peripheral Progressive centripetal from portal venous to delayed phase Hypovascular lesions show homogeneous ; hypervascular lesions are isointense; delayed images show peripheral washout Heterogeneous to homogeneous Isointense Isointense Low signal (washout) to isointense; capsule shows delayed Isointense to nearly isointense Isointense; central scar shows delayed Gradual centripetal fill after blood pooling Portal venous phase Note HCC = hepatocellular carcinoma. hyperplasia, the central scar typically does not enhance. None of these features are present in this patient. Intrahepatic cholangiocarcinoma is typically a hypovascular lesion with prolonged contrast on delayed images because of slow diffusion into the fibrous stroma interstitium, which is not present in this patient. Portal venous phase images often show mild peripheral. Hemangiomas are common benign lesions with typical characteristics of discontinuous peripheral puddling of contrast material after blood pool, a finding that is not present in this patient. Fibrotic or necrotic areas may be present and will not enhance. The peripheral rim of hypoattenuation often seen with malignant lesions is also absent. Focal nodular hyperplasia typically shows homogeneous arterial and of the central scar on delayed images. The mass is usually peripheral and may be pedunculated. Although the mass in this patient is peripheral and expansile, no central scar is seen and the is heterogeneous. Hepatic adenomas occur predominantly in women of childbearing age and are associated with oral contraceptive use or, in men, with steroid use. Adenomas are usually solitary, may be encapsulated, and have a tendency to hemorrhage. Their CT appearance is variable, but uncomplicated adenomas often show arterial and portal venous. Unfortunately, hepatic adenomas usually are not reliably differentiated from HCC on the basis of imaging alone; they are considered in this patient. Nonmalignant lesions are also seen in cirrhotic livers. Regenerative nodules are typically isodense to liver and essentially indistinguishable unless they contain iron. Regenerative nodules containing iron are called siderotic nodules and are best seen as hyperdense nodules on unenhanced images. Transient hepatic attenuation differences are typically arterioportal shunts that may or may not be associated with tumors. Wedge-shaped hyper during arterial phase imaging that is isodense to normal liver in the portal venous phase is typically seen. Focal confluent fibrosis is usually a wedge-shaped lesion radiating from the porta hepatis with capsular retraction and associated parenchymal atrophy. None of the features described for nonmalignant cirrhotic liver lesions are present in this patient. Clinical Management A sonographically guided biopsy of the lesion was performed, and moderately differentiated HCC with a pseudoglandular pattern was confirmed. The patient chose palliative care treatment. Commentary Worldwide, HCC is the most common abdominal malignancy, and 80% of cases result from the hepatitis B virus [1, 2]. The incidence of HCC has nearly doubled in the United States in the past 20 years, primarily because of hepatitis C virus leading to cirrhosis [3]. The risk of HCC is also increased with alcoholic hepatitis, α 1 -antitrypsin deficiency, excessive androgen and oral contraceptive use, hemochromatosis, and exposure to aflatoxin or vinyl chloride [2]. AJR:186, June 2006 S439

Bittle and Chew Cirrhosis results from the development of diffuse fibrosis and nodules from cellular necrosis. Microscopically, the nodules encountered progress sequentially from regenerative nodules to low- and high-grade dysplastic nodules to the nodule within a nodule appearance of a dysplastic nodule with a focus of HCC to frank HCC (small, < 2 cm; large, > 2 cm) [4]. Siderotic regenerative and dysplastic nodules accumulating iron are also seen. Tumor angiogenesis also occurs during this process, developing nontriadal arterial neovascularity in dysplastic nodules pathologically [1], which later aids the detection of HCC when multiphase imaging techniques are used. Macroscopically, Eggel has classified HCC as nodular, massive, and diffuse [5]. HCC may be solitary, multifocal, or diffuse. Most high-risk patients are screened with hepatic sonography and serum α-fetoprotein tests, but no convincing evidence suggests that screening improves survival [6]; however, early detection does improve the long-term outcome. A recent study found sonography to have a 4.3% false-negative rate in patients with known hepatitis B and elevated α-fetoprotein levels [7]. Lesions smaller than 2 cm are particularly difficult to detect with sonography [8]. Contrast-enhanced Doppler sonography has shown promise distinguishing cirrhotic nodules from early HCC by detecting the intratumoral arterial blood flow that is present in HCC but not seen in nonmalignant cirrhotic nodules [2]. MDCT and MRI improve detection of the changes of cirrhosis and the development of HCC; however, a wide range of sensitivities of these techniques exists, and all have a low sensitivity for detection of lesions smaller than 2 cm [8]. Dynamic phase contrast-enhanced imaging is essential for both CT and MRI evaluation of HCC. MDCT of the liver includes three or four phases, including unenhanced, arterial, and portal venous phases and an optional delayed equilibrium phase. Sensitivities reported for detecting HCC are 59 68% for multiphase contrast-enhanced CT [1] and 33 77% for multiphase contrast-enhanced MRI [9]. Even with adequate multiphase MDCT and MRI techniques, many small HCCs are not visualized because their characteristics follow those of the liver parenchyma. The CT appearance of regenerative and dysplastic nodules can be confusing. Both have predominantly a portal venous blood supply and thus often resemble the adjacent liver parenchyma. Regenerative nodules without iron deposition are isodense to liver on unenhanced CT but typically distort the liver contour. They remain isodense to liver in the arterial phase and enhance homogeneously in the portal venous phase, also after the liver parenchyma; therefore they are not directly detected. Also, siderotic regenerative nodules with iron deposition are hyperdense on unenhanced CT. The portal venous of the regenerative and dysplastic nodules parallels the of the fibrotic changes in the liver, making them often indistinguishable. Transient hepatic attenuation differences with wedgeshaped arterial that becomes isodense in the portal venous phase may be associated with regenerative and dysplastic nodules, HCC, and benign hepatic tumors such as hemangioma and focal nodular hyperplasia. Transient hepatic attenuation differences also occur without masses in cirrhotic livers because of hemodynamic alterations, arterioportal shunts, and aberrant blood supply [10]. The CT appearance of HCC is reflective of the size of the lesion. Smaller HCCs (< 2 cm) are typically hypodense on unenhanced images, show diffuse in the arterial phase, and are hypodense relative to the remaining liver on portal venous phase images. Larger HCCs often show heterogeneous arterial, necrosis, and occasionally a tumor capsule. In addition, peripheral exophytic HCCs have an increased risk of spontaneous rupture resulting in hemoperitoneum and are seen in approximately 10% of HCCs [11]. Faster acquisition times and an increased rate of contrast injection with MDCT allow more consistent arterial phase imaging when compared with single-detector CT [12]. Using MDCT, Lee et al. [12] found the most common pattern of HCC to be hypervascularity in the arterial phase and a heterogeneous mosaic pattern in both the arterial and portal venous phases. Abnormal internal vessels were also frequently seen during arterial phase imaging, also likely because of the rapid MDCT acquisition and injection rate. Additional findings of HCC include satellite nodules, vascular invasion, extrahepatic spread to lymph nodes, and metastatic dissemination. Venous invasion is most often seen with HCC and is rare in other hepatic neoplasms. Continued advances in MRI techniques, such as faster imaging to decrease respiratory and motion artifacts, have improved the MRI detection of regenerative and dysplastic nodules in the cirrhotic liver and HCC. Regenerative nodules have a variable T1 appearance related to the presence of siderotic nodules and iron deposition. Siderotic nodules typically show low T1 signal because of the increased susceptibility effects of iron. Nonsiderotic nodules are typically best seen on T2-weighted and gradient-echo imaging as low-signal nodules. Regenerative nodules do not enhance after the administration of gadolinium and remain isointense relative to the liver parenchyma. Dysplastic nodules also have a variable imaging appearance as they progress from low- to high-grade. They are typically hyperintense on T1-weighted and hypointense on T2-weighted images [5]. As the dysplastic nodule becomes highergrade, the hepatic arterial supply increases and arterial after gadolinium administration may be seen, but the T2 signal on unenhanced images will help differentiate the dysplastic nodule from HCC. The nodule-within-a-nodule sign of HCC developing within a dysplastic nodule is seen as a focus of increased T2 signal in the low-t2-signal dysplastic nodule. The focus of HCC will also show arterial. The MRI appearance of HCC can be quite variable and is often related to the degree of differentiation. The T1 appearance is variable, with 40% showing low signal and 35% having high signal [5]; 90% show increased T2 signal [5]. The increased T1 signal may be related to a variable amount of fat, copper, or S440 AJR:186, June 2006

Incidentally Discovered Liver Mass glycoproteins [1]. Dynamic phase gadolinium is an essential sequence to detect HCC. As on CT, small HCCs show homogeneous arterial. Large HCCs typically show heterogeneous with necrosis and fatty metamorphosis. A tumor capsule may also be seen. A mosaic pattern is often seen, reflecting a confluence of multiple small tumor nodules with thin septa and areas of necrosis [4]. Vascular invasion of the portal vein is seen as a flow void on T1 gradient-refocused echo images [4]. The tumor thrombus may also enhance during the arterial phase after gadolinium administration. In summary, despite the rising incidence of HCC worldwide, early detection, particularly of small lesions, which have a better prognosis, remains difficult. Screening with serial sonography and serum α-fetoprotein levels is common, but sonography may be falsely negative. Progressive advancements in MDCT and MRI continue to improve the detection of small resectable lesions, but the survival rates remain low, with 23% 1-year and 5% 5-year survival rates [2]. References 1. Baron RL, Peterson MS. Screening the cirrhotic liver for hepatocellular carcinoma with CT and MR imaging: opportunities and pitfalls. RadioGraphics 2001; 21[spec no]:s117 S132 2. Szklaruk J, Silverman PM, Charnsangavej C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma. AJR 2003; 180:441 454 3. Kamel IR, Liapi E, Fishman EK. Multidetector CT of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19:63 89 4. Hussain SM, Zondervan PE, Ijzermans JMN, Schalm SW, de Man RA, Krestin GP. Benign versus malignant hepatic nodules: MR imaging findings with pathologic correlation. RadioGraphics 2002; 22:1023 1039 5. Murakami T, Hori M, Kim T, Kawata S, Abe H, Nakamura H. Multidetector row CT and MR imaging in diagnosing hepatocellular carcinoma. Intervirology 2004; 47:209 226 6. Daniele B, Bencivenga A, Megna AS, Tinessa V. Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 2004; 127[5 suppl 1]:S108 S112 7. Mok TSK, Yu SCH, Lee C, et al. False-negative rate of abdominal sonography for detecting hepatocellular carcinoma in patients with hepatitis B and elevated serum alpha-fetoprotein levels. AJR 2004; 183:453 458 8. Bhartia B, Ward J, Guthrie JA, Robinson PJ. Hepatocellular carcinoma in cirrhotic livers: double-contrast thin-section MR imaging with pathologic correlation of explanted tissue. AJR 2003; 180:577 584 9. Taouli B, Losada M, Holland A, Krinsky G. Magnetic resonance imaging of hepatocellular carcinoma. Gastroenterology 2004; 127[5 suppl 1]:S144 S152 10. Kim HJ, Kim AY, Kim TK, et al. Transient hepatic attenuation differences in focal hepatic lesions: dynamic CT features. AJR 2005; 184:83 90 11. Choi BC, Park SH, Byun JY, Jung SE, Choi KH, Han J-Y. The findings of ruptured hepatocellular carcinoma on helical CT. Br J Radiol 2001; 74:142 146 12. Lee KHY, O Malley ME, Haider MA, Hanbridge A. Triple-phase MDCT of hepatocellular carcinoma. AJR 2004; 182:643 649 AJR:186, June 2006 S441