G a s t r o i n t e s t i n a l I m a g i n g P i c t o r i a l E s s ay

Chung et al. RadiologicPathologic Correlation of HCC Variants Gastrointestinal Imaging Pictorial Essay

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Hepatocellular Carcinoma Variants: Radiologic Pathologic Correlation

OBJECTIVE. The purpose of this article is to show the imaging findings of variant types of hepatocellular carcinoma (HCC) with pathologic correlations. CONCLUSION. The variant types of HCC may not share its typical imaging characteristics. An understanding of the radiologic findings for variant types of HCC can be helpful in the differential diagnosis of hepatic tumors. epatocellular carcinoma (HCC) is the most common form of primary hepatic tumor and its incidence has increased in recent years. The risk factors for HCC are well established and include viral hepatitis, alcoholic liver cirrhosis, and exposure to hepatotoxins. The typical sonographic and unenhanced CT findings of HCC show a well-circumscribed hypoechoic or hypoattenuated mass with or without the hypoechoic rim of a tumor capsule. MRI typically shows that HCC is hyperintense relative to the liver on T2weighted images and hypointense on T1weighted images. On dynamic CT and MRI, HCC shows early enhancement in the arterial phase and contrast medium washout in the equilibrium phase. Equilibrium phase CT and MRI could show a thin rim-enhancing tumor capsule with variable incidence, ranging from 10% to 80.7% of the cases, depending on the series [1]. Although the prevalence is variable depending on the series, hemorrhage or calcification (~ 5%), central scar (~ 3%), or gross fat (~ 1.6%) may be seen within the HCC tumor [2]. HCC in noncirrhotic patients usually manifests as either a large solitary mass or a dominant mass with small satellite nodules that more frequently shows necrosis and central scar formation than HCC in cirrhotic patients [3]. Pathologically, there are several variant types of HCC: clear cell type HCC, fibrolamellar HCC, sarcomatoid HCC, combined HCCcholangiocarcinoma, and sclerosing HCC [4]. Clinically, sarcomatoid HCC and combined HCCcholangiocarcinoma show

Yong Eun Chung1 Mi-Suk Park1,2,3 Young Nyun Park 3,4 Hye-Jeong Lee1 Jae Yeon Seok 4 Jeong-Sik Yu1 Myeong-Jin Kim1,3
Chung YE, Park MS, Park YN, et al.

FOCUS ON:

Keywords: CT, hepatic tumors, hepatocellular carcinoma, liver, MRI, oncologic imaging DOI:10.2214/AJR.07.3947 Received March 5, 2008; accepted after revision December 7, 2008.
1 Department of Radiology, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea. 2 Department of Diagnostic Radiology, Yonsei University Health System, Severance Hospital, Seodaemun-ku, Shinchon-dong 134, Seoul 120-752, Korea. Address correspondence to M. S. Park (radpms@yuhs.ac). 3 Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. 4 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.

poorer prognosis than classic HCC, whereas fibrolamellar HCC shows better prognosis and sclerosing HCC shows prognosis similar to classic HCC [57]. Radiologically, these variants do not share imaging characteristics typical of HCC. The diagnosis of HCC larger than 2 cm can be made without biopsy if a mass in a cirrhotic liver shows the typical features of HCC on contrast-enhanced CT or MRI and the -fetoprotein level is greater than 200 ng/mL [8]. In the case of HCC with atypical imaging features, however, this guideline cannot be applied. Therefore, recognizing these variants and their imaging features has clinical consequences, even though a preoperative biopsy is still needed because these variants cannot be completely differentiated from other tumors by imaging only. In this article, we collectively review and illustrate the radiologic findings for variant types of HCC and correlate these findings with pathologic analyses. HCC, Predominantly Clear Cell Type Cytoplasmic fat is frequently present in well-differentiated HCC and is abundant in approximately 10% of cases. A large amount of cytoplasmic fat or glycogen can cause the cytoplasm to appear white in routine pathologic sections, producing a clear cell appearance. On microscopy, 19.6% of HCCs have been reported to have cytoplasmic fat. On imaging, however, only 1.6% of cases have been reported to show a cytoplasmic fat component [9]. HCCs with a clear cell appearance frequently show increased echogenicity on sonography and decreased attenuation on

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Chung et al. unenhanced CT without specificity [10]. A signal drop on opposed-phase T1-weighted MR images is diagnostic for the fat component within an HCC (Fig. 1). The differential diagnosis of a hepatic tumor with cytoplasmic fat includes hepatic adenoma, angiomyolipoma, and fat-containing metastasis. Hepatic adenoma occurs frequently in young women and is associated with oral contraceptive use and glycogen storage diseases. Imaging studies of hepatic adenoma usually reveal heterogeneous lesions because of the high frequency of hemorrhage. Angiomyolipoma is composed of smooth muscle, fat, and blood vessels in various combinations. When its fat content is low, angiomyolipoma can be difficult to differentiate from HCC. Although fat-containing metastases are extremely rare, they can originate in a desmoid tumor, liposarcoma, Wilms tumor, or clear celltype renal cell carcinoma. Clinical history correlation, evaluation of the extrahepatic primary tumor, and biopsy with immunohistochemical staining may all be helpful in narrowing the differential diagnosis [9]. Fibrolamellar HCC Fibrolamellar HCC is a distinctive HCC variant that is not associated with hepatitis or cirrhosis. This tumor occurs in young adults (second or third decade of life) without sex predominance [11, 12]. Pathologically, fibrolamellar HCC usually presents as a single, large, well-demarcated, but nonencapsulated tumor with a fibrous band infiltrating throughout. On microscopic examination, the tumor is composed of well-differentiated polygonal cells that grow in nests or cords and are separated by parallel lamellae of dense collagen bundles. The fibrotic tissue coalesces to form a central scar, which is reported in 2060% of cases [12]. Fibrolamellar HCC usually appears on ultrasound as a solitary, well-defined, lobulated mass with variable echotexture [12]. On unenhanced CT, the tumor is low-attenuating compared with the surrounding liver, whereas on dynamic contrast-enhanced CT it has predominant heterogeneous enhancement [11]. Intratumoral calcification (68%), a central scar (71%), and pseudocapsule (35%) are visible on CT [11, 12]. On MRI, fibrolamellar HCC appears hypointense on T1-weighted images and hyperintense on T2-weighted images relative to the surrounding liver. In addition, fibrolamellar HCC displays heterogeneous enhancement on gadolinium-enhanced MRI (Fig. 2). The fibrous central scar and radial septa usually show delay enhancement on dynamic CT and MRI and hypointense signal on all unenhanced MR images [11, 12]. The hypointensity on T2-weighted MRI of the central scar of fibrolamellar HCC has been used to differentiate HCC from focal nodular hyperplasia, which shows a hyperintense signal on T2-weighted MRI. If the fibrolamellar HCC scar has increased vascularity or necrosis, however, it could appear hyperintense on T2weighted images [12]. Sarcomatoid HCC Sarcomatous HCC is an aggressive variant of HCC with an incidence of 3.99.4%, with either a sarcomatous change in part of the HCC or coexistence of a sarcoma and HCC [13]. Histologically, sarcomatoid HCC consists of very poorly differentiated cells that grow rapidly, resulting in central necrosis or hemorrhage due to inadequate blood supply. No capsule, intratumoral fat, or central scar is present. On cross-sectional images, sarcomatoid HCC shows peripheral enhancement with an unenhanced central portion that correlates to viable cancerous tissue with fibrous stroma in the periphery and central necrosis of the tumor, respectively [13] (Fig. 3). The enhancement of the solid portion has been reported to be variable [14]. Combined HCCCholangiocarcinoma Combined HCCcholangiocarcinoma is composed of elements from both entities [15]. The characteristics of these tumors, as visualized by contrast-enhanced dynamic imaging, depend on the proportions of tumor components. On contrast-enhanced CT and MRI, the HCC-dominant tumor is well enhanced in the early phase and washed out in the late phase, and the cholangiocarcinoma-dominant tumor shows peripheral and delayed enhancement [15, 16]. Sometimes, these mixed tumors appear heterogeneously enhanced because the HCC component appears hyper enhanced, whereas the cholan giocarcinoma component appears hypoenhanced relative to the surrounding liver [16] (Fig. 4). On T1- and T2-weighted MR images, these tumors are hypointense and heterogeneously hyperintense, respectively. Sclerosing HCC Sclerosing or scirrhous HCC is a rare hepatic tumor characterized by intense fibrosis. Sclerosing HCC is frequently associated with hypercalcemia and hypophosphatemia, which may be related to the parathyroid hormonerelated protein produced by the tumor [17]. This tumor type appears as a heterogeneous echoic mass on ultrasound. On dynamic contrast-enhanced CT and MRI, sclerosing HCC shows hypervascularity and remarkable progressive and prolonged enhancement [7, 18] (Fig. 5). In large tumors, progressive central enhancement can be seen on delayed phase CT [7, 18]. These tumors appear hypointense on T1-weighted MR images and hyperintense on T2-weighted MR images [18]. The adjacent liver capsule may retract, especially in highly fibrotic tumors. Summary Variant types of HCC may not share the imaging characteristics typical of classic HCC. Familiarity with the disease entity and the radiologic findings of variant types of HCC can be helpful in the differential diagnosis of HCC. References
1. Grazioli L, Olivetti L, Fugazzola C, et al. The pseudocapsule in hepatocellular carcinoma: correlation between dynamic MR imaging and pathology. Eur Radiol 1999; 9:6267 2. Szklaruk J, Silverman PM, Charnsangavej C. Imaging in the diagnosis, staging, treatment, and surveillance of hepatocellular carcinoma. AJR 2003; 180:441454 3. Brancatelli G, Federle MP, Grazioli L, Carr BI. Hepatocellular carcinoma in noncirrhotic liver: CT, clinical, and pathologic findings in 39 U.S. residents. Radiology 2002; 222:8994 4. Hirohashi S, Ishak KG, Kojiro M, et al. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, eds. World Health Organization (WHO) classification tumours of the digestive system. Lyon, France: IARC Press, 2000:158172 5. Okuda K. Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants. J Gastroenterol Hepatol 2002; 17:401405 6. Lao XM, Chen DY, Zhang YQ, et al. Primary carcinosarcoma of the liver: clinicopathologic features of 5 cases and a review of the literature. Am J Surg Pathol 2007; 31:817826 7. Kim SH, Lim HK, Lee WJ, Choi D, Park CK. Scirrhous hepatocellular carcinoma: comparison with usual hepatocellular carcinoma based on CTpathologic features and long-term results after curative resection. Eur J Radiol 2009; 69:123 130 8. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of

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Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42:12081236 9. Valls C, Iannacconne R, Alba E, et al. Fat in the liver: diagnosis and characterization. Eur Radiol 2006; 16:22922308 10. Monzawa S, Omata K, Shimazu N, Yagawa A, Hosoda K, Araki T. Well-differentiated hepatocellular carcinoma: findings of US, CT, and MR imaging. Abdom Imaging 1999; 24:392397 11. Ichikawa T, Federle MP, Grazioli L, Madariaga J, Nalesnik M, Marsh W. Fibrolamellar hepatocellular carcinoma: imaging and pathologic findings in 31 recent cases. Radiology 1999; 213:352361 12. McLarney JK, Rucker PT, Bender GN, Goodman ZD, Kashitani N, Ros PR. Fibrolamellar carcinoma of the liver: radiologicpathologic correlation. RadioGraphics 1999; 19:453471 13. Honda H, Hayashi T, Yoshida K, et al. Hepatocellular carcinoma with sarcomatous change: characteristic findings of two-phased incremental CT. Abdom Imaging 1996; 21:3740 14. Koo HR, Park MS, Kim MJ, et al. Radiological and clinical features of sarcomatoid hepatocellular carcinoma in 11 cases. J Comput Assist Tomogr 2008; 32:745749 15. Fukukura Y, Taguchi J, Nakashima O, Wada Y, Kojiro M. Combined hepatocellular and cholan giocarcinoma: correlation between CT findings and clinicopathological features. J Comput Assist Tomogr 1997; 21:5258 16. Murakami T, Kim T, Tomoda K, et al. Combined hepatocellular and cholangiocellular carcinoma. Radiat Med 1997; 15:243246 17. Albar JP, De Miguel F, Esbrit P, Miranda R, Fernandez-Flores A, Sarasa JL. Immunohistochemical detection of parathyroid hormone-related protein in a rare variant of hepatic neoplasm (sclerosing hepatic carcinoma). Hum Pathol 1996; 27:728731 18. Yamashita Y, Fan ZM, Yamamoto H, et al. Sclerosing hepatocellular carcinoma: radiologic findings. Abdom Imaging 1993; 18:347351

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Fig. 1 59-year-old man with hepatocellular carcinoma (HCC) of predominantly clear cell type. A, Axial arterial phase CT scan shows heterogeneous enhancement of mass. B, On fat-suppressed T2-weighted image, mass shows heterogeneous high signal intensity relative to surrounding liver. C, T1-weighted in-phase MR image shows lobulated lesion (arrow ) with low signal intensity in right lobe of liver. D, T1-weighted opposed-phase MR image shows marked signal drop within mass (arrow ), suggesting high lipid content. Liver parenchyma also shows signal drop, suggesting diffuse steatosis. E, Photograph of gross section of resected specimen shows well-demarcated, lobulated, whitish-tan, firm mass possessing clear cell appearance. F, Photomicrograph of microscopic specimen shows HCC tumor cells with vacuolated appearance due to cytoplasmic accumulation of large amounts of glycogen and lipid. (H and E; original magnification, 200)

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Fig. 2 32-year-old man with fibrolamellar hepatocellular carcinoma (HCC). A, Longitudinal sonogram shows well-defined, heterogeneous, hypoechoic mass (arrow ) in right inferior tip of liver. B, On axial arterial phase CT scan, tumor (arrow ) shows subtle peripheral enhancement. C, On portal venous phase CT scan, peripheral portion of tumor shows isoattenuation (arrowhead ) relative to surrounding liver. Central portion of tumor shows low attenuation. D, On fat-suppressed T2-weighted MR image, central portion of tumor (arrowhead ) shows low signal intensity relative to adjacent liver. Innermost portion of central scar (arrow ) shows high signal intensity, which correlates to necrosis on microscopic specimen. E, On T1-weighted opposed-phase MR image, tumor shows low signal intensity. F and G, Gadolinium-enhanced arterial phase (F ) and portal venous phase (G) T1-weighted MR images show peripheral enhancement of mass. H, Equilibrium phase MR image shows delayed enhancement of central scar (arrow ). I, Photograph of gross specimen reveals well-defined yellow-to-greenish mass with central scar (long arrows ). Necrosis is noted within central scar (short arrow ). J, Photomicrograph of microscopic specimen shows well-differentiated polygonal cells that grow in nests or cords and are separated by parallel lamellae of dense collagen bundles. (H and E; original magnification, 100)

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Fig. 3 63-year-old man with sarcomatoid hepatocellular carcinoma (HCC). A, Axial arterial phase CT image shows well-defined lobulated mass with peripheral enhancement. B, Equilibrium phase CT image shows hypoattenuated peripheral portion of mass relative to surrounding liver; additionally, attenuation value (in Hounsfield units) is lower than that of arterial phase, suggesting contrast medium washout. Central portion of mass shows no enhancement during dynamic CT, which reflects necrosis. C, On T1-weighted in-phase MR image, mass (arrow ) shows low signal intensity. D, T2-weighted MR image shows hyperintense mass with multiple small intratumoral cystic lesions. At posterolateral aspect of tumor, there is crescent-shaped lesion that shows high signal intensity on T1-weighted image (C) and fluidfluid level on T2-weighted image (arrow ), which could be hemorrhage. E, Photograph shows gross specimen of sarcomatoid HCC. Section reveals well-defined pinkish-yellow solid mass. Tumor shows focal central necrosis (arrows ). F, Microscopic specimen shows HCC (arrowheads ) with marked atypia and malignant cartilage component (asterisk ) consistent with sarcomatoid HCC. (H and E; original magnification, 100)

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Fig. 4 52-year-old man with combined hepatocellular carcinoma (HCC) and cholangiocarcinoma. A, On axial arterial phase CT scan, tumor shows strong enhancement (arrowheads ), whereas portion of tumor shows low attenuation without enhancement (arrow ). Thin hyperenhancing capsule around mass is seen. B, On portal venous phase CT scan, mass shows low attenuation relative to surrounding liver due to washout of contrast medium. C, On T2-weighted MR image, mass shows high signal intensity (arrowheads ). Small portion of tumor shows isointense to slightly low signal intensity (arrow ). D, On T1-weighted MR image, mass (arrow ) shows low signal intensity relative to surrounding liver. E, On contrast-enhanced arterial phase T1-weighted MR image, portion of tumor that showed high signal intensity on T2-weighted image shows strong enhancement (arrowheads ), whereas portion that showed isointense or slightly low signal intensity on T2-weighted image shows no enhancement (arrow ). Strongly enhanced portion was confirmed to be HCC component, whereas unenhanced portion was correlated to cholangiocarcinoma component. F, On equilibrium phase MR image, mass shows low signal intensity compared with surrounding liver, suggesting contrast medium washout. Peripheral thin enhancing capsule is also well depicted around mass in this image. G, Photomicrograph of microscopic specimen shows cholangiocarcinoma component (asterisk ) and HCC component (arrowheads ) consistent with combined HCC and cholangiocarcinoma. (H and E; original magnification, 40)

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Fig. 5 52-year-old woman with sclerosing hepatocellular carcinoma (HCC). AC, Arterial ( A ), portal venous (B), and delayed phase (C) CT scans show heterogeneous, progressively enhancing mass in right lobe of liver. D, Photomicrograph of microscopic specimen shows hepatocellular differentiation with intense fibrosis (asterisk ) compatible with sclerosing HCC. (H and E; original magnification, 200)

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