CT of Atypical and Uncommon Presentations of

G a s t r o i n t e s t i n a l I m a g i n g • R ev i ew Shriki et al. CT of Atypical Presentations of Hepatocellular Carcinoma

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Gastrointestinal Imaging Review

CT of Atypical and Uncommon Presentations of Hepatocellular Carcinoma Jabi E. Shriki1,2 Adeel R. Seyal 3 Manjiri K. Dighe1 Matthew M. Yeh 4 Florencia G. Jalikis 4 Nicole K. Andeen 4 Chandana Lall 5 Puneet Bhargava1,2 Shriki JE, Seyal AR, Dighe MK, et al.

Keywords: CT, hepatocellular carcinoma, imaging DOI:10.2214/AJR.14.14000 Received October 20, 2014; accepted after revision February 7, 2015. P. Bhargava is editor in chief of Current Problems in Diagnostic Radiology, Elsevier Inc. 1 Department of Radiology, University of Washington School of Medicine, Seattle, WA. 2 Department of Radiology, VA Puget Sound Health Care System, Mail Box 358280, S-114, 1660 S Columbian Way, Seattle, WA 98108. Address correspondence to P. Bhargava ([email protected]). 3 Department of Radiology, Northwestern University, Chicago, IL. 4 Department of Pathology, University of Washington School of Medicine, Seattle, WA. 5 Department of Radiology, University of California, Irvine, Orange, CA.

This article is available for credit. WEB This is a web exclusive article. AJR 2015; 205:W411–W423 0361–803X/15/2054–W411 © American Roentgen Ray Society

OBJECTIVE. The purpose of this article is to familiarize radiologists with uncommon presentations of hepatocellular carcinoma (HCC) with an emphasis on the CT spectrum of atypical appearances. CONCLUSION. HCC is the fifth most common neoplasm worldwide and the second most common cause of cancer-related death. In many cases, HCC can be confidently diagnosed with noninvasive imaging. However, there are numerous unusual appearances of HCC with which the radiologist must be familiar.

H

epatocellular carcinoma (HCC) poses a burden on global health. It has become the fifth most common malignant neoplasm worldwide. Because of its poor prognosis, HCC is the second leading cause of cancerrelated mortality, recently surpassing gastric cancer. In 2012, HCC was responsible for more than 700,000 cancer-related deaths worldwide [1]. Moreover, the impact of HCC on global health is expected to increase in coming years. In Asian nations, the prevalence of HCC remains high owing to persistently high rates of viral hepatitis [2, 3]. In the United States, the aging patient population with hepatitis C virus infection has contributed to the growing prevalence of HCC since the incidence of new infections with hepatitis C virus peaked in the 1970s [4, 5]. The prevalence of chronic hepatitis C infection peaked in the United States in 1994 with 3.3 million cases [6]. It is also increasingly recognized in the United States, Canada, western Europe, and other developed nations with high rates of obesity. Concomitantly high rates of nonalcoholic steatohepatitis are also an important contributing factor to the increasing prevalence of HCC [7–9]. The clinical diagnosis of HCC is difficult. The clinical signs and symptoms frequently overlap with other, nonspecific signs of underlying liver disease [10]. Alpha-fetoprotein often plays a role in the initial diagnosis and monitoring of patients at risk of HCC [11], but as many as one third of patients with HCC have no detectable elevation of

α-fetoprotein level, even in advanced disease [12]. Early diagnosis of HCC is critical to optimizing the survival advantages offered by various therapies, and clinical outcomes worsen when treatment is delayed [13, 14]. Imaging can frequently provide enough information for a definitive diagnosis of HCC [10, 15, 16]. Although biopsy and tissue diagnosis are usually necessary in the management of most solid tumors, imaging findings alone are frequently sufficient for a confident and specific diagnosis of HCC without biopsy. The typical pattern of enhancement after IV contrast administration on both CT and MR images is arterial phase hyperenhancement with washout in the portal venous and delayed phases. Imaging in the late arterial phase of contrast administration is important for visualizing hyperenhancement. At our institution, we generally image patients 35 seconds after the start of contrast administration to obtain a satisfactory late arterial phase study. The characteristic pattern of arterial phase hyperenhancement and subsequent portal venous or delayed phase hypoenhancement is seen in approximately 60% of HCC lesions [17]. When these imaging features are present in patients with cirrhosis, tissue diagnosis of HCC is unnecessary. It is important to evaluate studies for signs of cirrhosis and chronic liver disease to determine which patients are at risk of HCC [18, 19]. Although HCC can occur in normal, noncirrhotic livers, this is an extremely rare occurrence [20]. Large cross-sectional studies of patient populations have shown a growing role of the

AJR:205, October 2015 W411

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Shriki et al. diagnostic radiologist in the detection and diagnosis of HCC. Analysis of the Surveillance, Epidemiology, and End Results registry showed that between 1992 and 2008, the incidence of HCC diagnosed with noninvasive means increased 2.5 times faster than the incidence of HCC diagnosed with biopsy [21]. The American College of Radiology has developed a set of criteria for reporting and stratifying imaging findings designed to standardize reporting and increase radiologists’ confidence in discriminating HCC from other lesions. The Liver Imaging Reporting and Data System (LI-RADS) grew out of this effort [22]. Focal observations in the liver are assigned a LI-RADS category from 1 to 5 on a scale of increasing likelihood of HCC. This classification and reporting system encompasses several findings, including masslike features, arterial phase enhancement, portal venous or delayed phase washout, growth over time, and definite tumor within the lumen of a vein [23]. Although most HCCs can be confidently diagnosed on the basis of the typical imaging findings described, a small number of cases present a diagnostic challenge. The imaging patterns of HCC have been addressed by other authors [24, 25]. The goal of this article is to review the constellation of atypical and uncommon CT features of HCC that may also be encountered. Small Well-Differentiated Hepatocellular Carcinoma The presence or absence of typical enhancement patterns in small HCCs depends on the size and degree of cellular differentiation of the tumor. In a study of pathologically proven HCC nodules smaller than 30 mm, Yoon et al. [26] reported that nodules smaller than 20 mm had arterial phase enhancement in 66% of cases, whereas lesions with diameters between 20 and 30 mm had arterial phase enhancement in 75% of cases. The visibility of arterial enhancement at preoperative imaging was also noted to be related to the degree of tumor dedifferentiation. Well-differentiated HCCs had arterial phase enhancement in 52% of cases, whereas moderately or poorly differentiated HCCs had arterial phase enhancement in 79% of cases in the same study. Visualization of washout was also noted to be related to size and degree of dedifferentiation. Lesions smaller than 20 mm had portal venous phase washout in 27% of cases, compared with 47% of lesions between 20 and 30 mm. Well-differentiated lesions had portal

W412

venous phase washout in 13% of cases compared with moderately and poorly differentiated HCCs, which had portal venous phase washout in 48% of cases. Lee et al. [17] had similar results. They found that portal venous phase washout was present in 75.6% of poorly differentiated HCCs and 74.8% of moderately differentiated HCCs. Well-differentiated HCC exhibited portal venous phase washout in only 50% of cases. A higher index of suspicion should be used in evaluating smaller lesions, which may have typical enhancement patterns less commonly. More well-differentiated tumors may also exhibit characteristic enhancement less frequently. An example of a small welldifferentiated HCC without typical enhancement is shown in Figure 1. Fat Within Hepatocellular Carcinoma The presence of fat within HCC lesions is often underrecognized and underdiagnosed. On images, HCC may exhibit either macrovesicular or microvesicular steatosis, microvesicular steatosis being more common [27]. Fatty metamorphosis may be seen in as many as 20% of HCCs [27–29]. Microvesicular steatosis accounts for most of these cases and has been found in 14% of HCC lesions on MRI [30]. Fat within lesions may be focal (Fig. 2), diffuse, or patchy on images [31]. In pathologic series, smaller HCC lesions tend to have intralesional fat more commonly than larger lesions do. In a histologic series of 260 lesions [28], fat was more common (incidence, 35%) in lesions measuring 1.0–1.5 cm. Steatosis or microscopic fat within a lesion can be visualized on MRI as areas of low signal intensity on opposed-phase chemical-shift images [30]. This finding has been incorporated into the most recent version of LI-RADS, in which the presence of intralesion steatosis out of proportion to steatosis elsewhere in the liver is an ancillary sign of HCC [23]. CT is useful for visualization of macroscopic, or grossly observable, fat within a lesion. On CT, fatty metamorphosis results in an area of hypoattenuation (–10 to –100 HU) compared with the surrounding liver parenchyma. Rarely, HCC lesions with large amounts of macroscopic fat mimic benign lesions, such as hemangiomas and lipomas, which also have increased echogenicity [27]. Care should be taken when a hyperechoic lesion is encountered in ultrasound examinations, and further characterization with multiphasic CT or MRI is usually helpful in differentiating benign from malignant lesions.

Both microscopic and macroscopic fat can contribute to a mosaic appearance of a lesion, where areas of fat are geographically interspersed with areas of nonfatty tumor. The presence of a mosaic pattern within a lesion is also an ancillary sign of HCC in LI-RADS [23]. The presence of fatty metamorphosis may also mask areas of arterial phase enhancement because the attenuation effects of fat may overwhelm the effects of arterial phase contrast enhancement [30]. In addition, lesions with fat tend to have less well-developed internal angioarchitecture in pathologic series, suggesting a possible role of ischemia in fatty degeneration of HCC [28]. Cystic Degeneration Although several neoplastic processes in the liver may present with cystic degeneration, the observation of cystic areas within HCC is extremely rare, there being few cases in literature [31–33]. Much more commonly, cystic tumors in the liver can be caused by biliary cystadenocarcinoma, metastatic disease, and in rare instances, cholangiocarcinoma [34]. When present, cystic degeneration of HCC is usually the result of internal necrosis within large lesions that have outgrown their blood supply. Cystic degeneration of HCC is also rarely seen after treatment [35] (Fig. 3). Cystic degeneration and subsequent involution of HCC have been reported in patients with gastrointestinal hemorrhage who have an abrupt decrease in serum hematocrit level [36]. Necrosis of treated HCC is a subject of ongoing research. After locoregional treatment with chemoembolization, visualization of necrosis within a tumor is associated with lower rates of recurrence [37, 38]. Conversely, tumors that exhibit incomplete necrosis have a higher possibility of recurrence [39]. DWI is playing an increasing role in showing necrosis as a parameter for predicting tumor response [40–42]. Notably, a predominantly cystic form of HCC has been reported in several patients without underlying cirrhosis [31, 32, 43, 44]. The initial presentation of HCC with cystic areas may pose a substantial diagnostic challenge, especially when other findings of HCC are absent [43]. Rupture Rupture of HCC is considered a rare presentation, although reports of prevalence vary. In one large review [35], rupture was found in 1.1% of 495 patients with HCC. Another study [36] showed rupture in 0.8% of 385 patients

AJR:205, October 2015

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

CT of Atypical Presentations of Hepatocellular Carcinoma with HCC. When rupture of HCC occurs, patients commonly present in an emergency situation with acute abdominal pain due to hemoperitoneum (Fig. 4). The CT findings may include hemoperitoneum, perihepatic or pericapsular hematoma, extravasation of contrast material, discontinuity of the liver surface, and an enucleation sign (focal discontinuity of the capsule around the tumor). CT findings of large tumor size, especially with prominent intratumoral neovascularity, contour protrusion, and portal vein thrombosis, are considered risk factors for subsequent rupture [45]. Some case reports have described rupture of HCC after trauma [46] and after transarterial chemoembolization (TACE) [47]. However, rupture is thought to be a rare complication of TACE. TACE has been used in the emergency treatment of patients who present with rupture [48]. Fibrolamellar Hepatocellular Carcinoma The fibrolamellar variant is an uncommon form of HCC with distinct histopathologic findings, including large neoplastic cells with abundant granular cytoplasm; eosinophilic cytoplasmic inclusion bodies termed “pale bodies,” prominent nucleoli; and a background of thick collagen bundles arranged in parallel [49]. This variant is much less common than conventional HCC and accounts for less than 1% of primary liver tumors [50]. Fibrolamellar HCC also notably presents in a younger patient population (usually in the third decade of life) and without cirrhosis or other risk factors commonly associated with conventional HCC. Serum α-fetoprotein levels are generally normal, in contradistinction to the levels in conventional HCC. Fibrolamellar HCC masses also tend to be much larger at presentation [51]. Masses are usually heterogeneous in CT attenuation and on MR images. The characteristic pattern of arterial phase enhancement and portal venous phase washout is generally absent in the fibrolamellar variant, although patchy areas of arterial phase enhancement are commonly seen. Central scars are frequently seen and may be associated with calcifications. Borders are frequently lobulated but sharply defined. The tumors have heterogeneous internal characteristics, including areas of necrosis and, rarely, cystic degeneration [49, 52] (Fig. 5). Venous Invasion Patients with cirrhosis often have thrombosis within portal venous structures. It is

important, however, to differentiate bland thrombus from neoplastic involvement of venous structures. In general, tumor invasion by HCC portends a poor outcome [53]. Involvement of portal veins is commonly encountered (as many as 29–56% of cases). Hepatic veins are less commonly invaded by HCC, although this may occur in as many as 12–54% of cases [54]. In rare instances, thrombus in the hepatic veins can also propagate into the lumen of the inferior vena cava and can at times extend further into the right atrium [55] (Fig. 6). LI-RADS recognizes tumor within a vessel as a major criterion for the diagnosis of HCC [10, 23]. Along with other findings, in LI-RADS [23] findings are categorized that indicate definite or probable tumor within a vessel, including unequivocal arterial phase hyperenhancement and venous phase hypoenhancement within a vessel (definite), occlusion and expansion of a vein (probable), and the presence of arterial structures within a vein (probable). Bile Duct Tumor Thrombus Direct tumor invasion into the biliary tree or bile duct tumor thrombus is a rare complication of HCC and is mostly described in case reports [56]. CT may show a soft-tissue mass in the bile ducts with ductal dilatation proximal to the obstruction (Fig. 7). Although bile duct tumor thrombus is rarely observed in HCC, the pattern of invasion is usually reported as an intraluminal mass within the duct, rather than invasion of tumor along the wall of the biliary tree. The typical pattern of arterial phase hyperenhancement with washout in the later phases may be seen within the duct in areas of tumor invasion [57]. Giant Hepatocellular Carcinoma Several algorithms for the treatment of HCC stratify patients on the basis of tumor size. For example, the Milan criteria state that transplantion should be performed on patients with a single lesion smaller than 5 cm or with several lesions smaller than 3 cm [58]. Masses larger than 5 cm are generally considered large. Masses larger than 10 cm have been called giant [59–61]. Masses larger than 20 cm are uncommon [58] (Fig. 8). Large lesions may more commonly have a mosaic pattern of attenuation with areas of hemorrhage, necrosis, fat, and fibrous tissue. Larger HCCs are more likely to have a well-defined fibrous capsule (33–50% of

large HCCs on CT images) than are smaller tumors [59]. Successful surgical resection has been reported as effective management of single large HCC masses. The long-term survival is comparable to that of single small HCC, provided that liver functional reserve is acceptable for resection and there are no other contraindications to surgical management, such as distant dissemination [62, 63]. Hepatocellular Carcinoma Mimicking a Liver Abscess In rare instances, HCC can mimic an abscess on imaging (Fig. 9). This is a rare presentation, however, and may be seen when cystic degeneration is present within a tumor [64, 65]. The usual appearance of an abscess is described as a double target sign, which consists of an area of low attenuation similar to that of fluid surrounded by a thin but hyperattenuating wall and adjacent ill-defined edema in the liver parenchyma [66]. Some patients may also present with symptoms of infection, suggesting that there is coexistence of areas of abscess formation within tumors [65]. The converse, in which hepatic abscesses mimic HCC, has also been reported in rare instances [67]. Cooccurrence of Hepatocellular Carcinoma and Other Malignancies In a small percentage of cases of HCC, histologic findings of other neoplastic tissues coexist with HCC, the most common being cholangiocarcinoma. Tissues may have heterogeneous features of both neoplasms (Fig. 10), or there may be geographic, interspersed areas similar to cholangiocarcinoma in some regions and more characteristic of HCC in other areas (Fig. 11). Combined HCC and cholangiocarcinoma is found in 1.0–4.7% of cases, according to results of histopathologic studies [68, 69]. The pathogenesis of this carcinoma with dual differentiation is not clear. Some sources have proposed a hepatic progenitor cell origin, and cytogenetic studies have shown similar chromosomal changes (loss of heterozygosity at 3p and 14p) in cholangiocarcinoma and combined HCC and cholangiocarcinoma but not in HCC alone, suggesting a closer relation to cholangiocarcinoma [70]. Enhancement patterns within combined HCC and cholangiocarcinoma may be geographic, with areas of enhancement that are characteristic of HCC and other areas that exhibit enhancement beginning in the portal venous phase and persisting or increasing slightly in later phases [71].

AJR:205, October 2015 W413

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Shriki et al. Simultaneous occurrence of HCC and lymphoma (Fig. 12) has also been rarely reported [72]. It has been proposed that patients with viral hepatitis may be at greater risk of lymphoma because of the lymphotrophic nature of viral causes of hepatitis, including hepatitis C virus infection [73]. Extrahepatic manifestations are usually reported, including lymphadenopathy, splenomegaly, and involvement of other organs. Hypoattenuating nonenhancing areas of lymphomatous tumor may be present and can usually be differentiated from the typically enhancing areas of HCC [73, 74]. Extrahepatic Metastatic Disease Kanda et al. [75] reported that extrahepatic metastatic disease develops in 13% of patients with treated HCC during the first 5 years of follow-up. HCC may spread via the lymphatic or hematogenous routes. Lymphatic spread is reported in 27–42% of cases. Regional lymph nodes, including peripancreatic, perihepatic, and retroperitoneal groups, are most commonly involved [53]. Among remote sites of involvement, thoracic metastases are reported most commonly, affecting approximately 18–60% of patients with extrahepatic metastatic disease. After thoracic metastases, skeletal structures (6– 39% of cases) and adrenal glands (8–17%) are the most common sites of hematogenous spread. Lymphatic spread is reported in 27– 42% of cases. Regional lymph nodes (peripancreatic, perihepatic, and retroperitoneal) are most commonly involved [75]. Diffuse Cirrhosislike Hepatocellular Carcinoma and Infiltrative Hepatocellular Carcinoma Cirrhosislike HCC is a rare variant of HCC that mimics cirrhosis and presents as a diffusely nodular liver without a dominant mass. This entity is radiographically occult, but histologic examination reveals diffusely infiltrating HCC throughout the liver parenchyma (Fig. 13). This entity is usually discovered at liver explantation or at autopsy. On images, the liver is noted to be nodular, but the appearance is indistinguishable from the nodular regeneration seen in cirrhosis. Jakate et al. [76] identified 10 cases of cirrhosislike HCC over 9 years. Grossly the livers contained multiple (20 to > 1000) small (< 0.6 cm) cirrhosislike HCC nodules scattered among cirrhotic nodules. Microscopic examination in these cases revealed well to moderately differentiated HCCs and small-vessel invasion. Jakate et al. also found that this variant was

W414

associated with favorable features, including better histologic differentiation, low proliferative tumor activity, and lack of metastasis at orthotopic liver transplantation. Cirrhosislike HCC should be differentiated from infiltrative HCC, in which a neoplastic HCC mass is seen with ill-defined and irregular borders and is nonencapsulated [76]. As many as 8–18% of HCCs may have an infiltrative appearance [73, 74, 77]. Infiltrative HCC can mimic confluent fibrosis and be less conspicuous than the background liver disease and difficult to differentiate from it [78, 79]. One study showed that a discrete lesion could not be identified in 42.7% of cases of infiltrative HCC [80]. Infiltrative HCC also has a greater propensity to present with vascular invasion [78, 79, 81–83] (Fig. 14). Conclusion HCC usually presents with typical imaging characteristics but at times can present with a wide spectrum of atypical appearances. Although these atypical appearances are uncommon, familiarity with unusual presentations and their imaging findings is critical to ensuring prompt, accurate diagnosis and treatment. When imaging findings are not diagnostic of HCC, biopsy is needed if the patient’s condition allows. References 1. International Agency for Research on Cancer website. The Globocan project. globocan.iarc.fr. Accessed February 12, 2014 2. Asian Pacific Association for the Study of the Liver (APASL) Hepatitis C Working Party, McCaughan GW, Omata M, Amarapurkar D, et al. Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management, and treatment of hepatitis C virus infection. J ­Gastroenterol Hepatol 2007; 22:615–633 3. [No authors listed]. Global surveillance and control of hepatitis C: report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6:35–47 4. Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997; 26(3 suppl 1):34S–38S 5. Davis GL, Alter MJ, El-Serag H, Poynard T, ­Jennings LW. Aging of hepatitis C virus (HCV)infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138:513–521 6. Razavi H, Elkhoury AC, Elbasha E, et al. Chronic hepatitis C virus (HCV) disease burden and cost in the United States. Hepatology 2013; 57:2164–2170 7. Center MM, Jemal A. International trends in liver can-

cer incidence rates. Cancer Epidemiol ­Biomarkers Prev 2011; 20:2362–2368 8. Bedogni G, Miglioli L, Masutti F, Tiribelli C, ­Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. ­Hepatology 2005; 42:44–52 9. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. ­Hepatology 2002; 36:1349–1354 10. Bruix J, Sherman M; Practice Guidelines Committee American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42:1208–1236 11. Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 2001; 5:145–159 12. Schwarz RE, Smith DD. Trends in local therapy for hepatocellular carcinoma and survival outcomes in the US population. Am J Surg 2008; 195:829–836 13. Bolondi L, Sofia S, Siringo S, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001; 48:251–259 14. Sherman M. The radiological diagnosis of hepatocellular carcinoma. Am J Gastroenterol 2010; 105:610–612 15. Mitchell DG, Bruix J, Sherman M, Sirlin CB. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology 2015; 61:1056–1065 16. Bruix J, Sherman M, Llovet JM, et al.; European Association for the Study of the Liver. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. J Hepatol 2001; 35:421–430 17. Lee JH, Lee JM, Kim SJ, et al. Enhancement patterns of hepatocellular carcinomas on multiphasic multidetector row CT: comparison with pathological differentiation. Br J Radiol 2012; 85:e573–e583 18. Becker-Weidman DJ, Kaib B, Sharma P, et al. Hepatocellular carcinoma lesion characterization: single-institution clinical performance review of multi-phase gadolinium-enhanced MR imaging—comparison to prior same-center results after MR systems improvements. Radiology 2011; 261:824–833 19. Lee KH, Omalley ME, Haider MA, Hanbidge A. Triple-phase MDCT of hepatocellular carcinoma. AJR 2004; 182:643–649 20. Gaddikeri S, McNeeley MF, Wang CL, et al. Hepatocellular carcinoma in the noncirrhotic liver. AJR 2014; 203:[web]W34–W47 21. Altekruse SF, McGlynn KA, Dickie LA, Kleiner DE. Hepatocellular carcinoma confirmation, treat-

AJR:205, October 2015

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

CT of Atypical Presentations of Hepatocellular Carcinoma ment, and survival in surveillance, epidemiology and end results registries, 1992-2008. H ­ epatology 2012; 55:476–482 22. Radiological Society of North America. LI-RADS enables standardized interpretation, reporting, of HCC. RSNA News 2012; 22:13–14 23. American College of Radiology website. Quality and safety resources: liver imaging-reporting and data system. www.acr.org/Quality-Safety/Resources/ LIRADS. Accessed February 20, 2014 24. Choi JY, Lee JM, Sirlin CB. CT and MR imaging diagnosis and staging of hepatocellular carcinoma. Part 1. Development, growth, and spread: key pathologic and imaging aspects. Radiology 2014; 272:635–654 25. Choi JY, Lee JM, Sirlin CB. CT, Imaging MR. diagnosis and staging of hepatocellular carcinoma. Part 2. Extracellular agents, hepatobiliary agents, and ancillary imaging features. Radiology 2014; 273:30–50 26. Yoon SH, Lee JM, So YH, et al. Multiphasic MDCT enhancement pattern of hepatocellular carcinoma smaller than 3 cm in diameter: tumor size and cellular differentiation. AJR 2009; 193:[web]W482–W489 27. Fasih N, Shanbhogue AK, Thipphavong S, et al. Gamut of focal fatty lesions in the liver: imaging manifestations with emphasis on magnetic resonance imaging. Curr Probl Diagn Radiol 2010; 39:137–151 28. Kutami R, Nakashima Y, Nakashima O, et al. Pathomorphologic study on the mechanism of fat change in small hepatocellular carcinoma in humans. J Hepatol 2000; 33:282–289 29. Martín J, Sentís M, Zidan A, et al. Fatty metamorphosis of hepatocellular carcinoma: detection with chemical shift gradient-echo MR imaging. Radiology 1995; 195:125–130 30. Pupulim LF, Hakime A, Barrau V, et al. Fatty hepatocellular carcinoma: radiofrequency ablationimaging findings. Radiology 2009; 250:940–948 31. Nagano K, Fukuda Y, Nakano I, et al. An autopsy case of multilocular cystic hepatocellular carcinoma without liver cirrhosis. ­Hepatogastroenterology 2000; 47:1419–1421 32. Gonwa ME, Casillas J, Livingstone AS, Robinson PG. Cystic hepatocellular carcinoma: CT findings. J Comput Assist Tomogr 1991; 15:1045–1047 33. Pombo F, Rodriguez E, Arnal-Monreal F. Multicystic fibrolamellar hepatocellular carcinoma CT appearance. Clin Imaging 1993; 17:67–69 34. Mortelé KJ, Ros PR.. Cystic focal liver lesions in the adult: differential CT and MR imaging features. RadioGraphics 2001; 21:895–910 35. Alobaidi M, Shirkhoda A. Malignant cystic and necrotic liver lesions: a pattern approach to discrimination. Curr Probl Diagn Radiol 2004; 33:254–268 36. Bastawrous S, Kogut M, Bhargava P. Spontaneous

regression of hepatocellular carcinoma in a cirrhotic patient: possible vascular hypothesis. S­ ingapore Med J 2012; 53:e218 37. Sotiropoulos GC, Malago M, Molmenti EP, et al. Disease course after liver transplantation for hepatocellular carcinoma in patients with complete tumor necrosis in liver explants after performance of bridging treatments. Eur J Med Res 2005; 10:539–542 38. Majno PE, Adam R, Bismuth H, et al. Influence of preoperative transarterial Lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 1997; 226:688–701 39. Ravaioli M, Grazi GL, Ercolani G, et al. Partial necrosis on hepatocellular carcinoma nodules facilitates tumor recurrence after liver transplantation. Transplantation 2004; 78:1780–1786 40. Mannelli L, Kim S, Hajdu CH, et al. Serial diffusion-weighted MRI in patients with hepatocellular carcinoma: prediction and assessment of response to transarterial chemoembolization—preliminary experience. Eur J Radiol 2013; 82:577–582 41. Vandecaveye V, Michielsen K, De Keyzer F, et al. Chemoembolization for hepatocellular carcinoma: 1-month response determined with apparent diffusion coefficient is an independent predictor of outcome. Radiology 2014; 270:747–757 42. Sahin H, Harman M, Cinar C, et al. Evaluation of treatment response of chemoembolization in hepatocellular carcinoma with diffusion-weighted imaging on 3.0 T MR imaging. J Vasc Interv ­Radiol 2012; 23:241–247 43. Battula N, Madanur M, Priest O, et al. Spontaneous rupture of hepatocellular carcinoma: a Western experience. Am J Surg 2009; 197:164–167 44. Chung JW, Park JH, Han JK, et al. Hepatic tumors: predisposing factors for complications of transcatheter oily chemoembolization. Radiology 1996; 198:33–40 45. Kim HC, Yang DM, Jin W, Park SJ. The various manifestations of ruptured hepatocellular carcinoma: CT imaging findings. Abdom Imaging 2008; 33:633–642 46. Kew MC, Hodkinson J. Rupture of hepatocellular carcinoma as a result of blunt abdominal trauma. Am J Gastroenterol 1991; 86:1083–1085 47. Jia Z, Tian F, Jiang G. Ruptured hepatic carcinoma after transcatheter arterial chemoembolization. Curr Ther Res Clin Exp 2013; 74:41–43 48. Sun JH, Wang LG, Bao HW, et al. Emergency embolization in the treatment of ruptured hepatocellular carcinoma following transcatheter arterial chemoembolization. Hepatogastroenterology 2010; 57:616–619 49. 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; 213:352–361

50. El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004; 39:798–803 51. Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular carcinoma. Am J Gastroenterol 2009; 104:2617–2624 52. Ganeshan D, Szklaruk J, Kindra V, et al. Imaging features of fibrolamellar hepatocellular carcinoma. AJR 2014; 202:544–552 53. Sakata J, Shirai Y, Wakai T, et al. Preoperative predictors of vascular invasion in hepatocellular carcinoma. Eur J Surg Oncol 2008; 34:900–905 54. Sneag DB, Krajewski K, Giardino A, et al. Extrahepatic spread of hepatocellular carcinoma: spectrum of imaging findings. AJR 2011; 197:[web] W658–W664 55. Agelopoulou P, Kapatais A, Varounis C, et al. Hepatocellular carcinoma with invasion into the right atrium: report of two cases and review of the literature. Hepatogastroenterology 2007; 54:2106–2108 56. Wang JH, Wang LY, Lin ZY, et al. Doppler sonography of common hepatic duct tumor invasion in hepatocellular carcinoma: report of two cases. J Ultrasound Med 1995; 14:471–474 57. Liu QY, Zhang WD, Chen JY, et al. Hepatocellular carcinoma with bile duct tumor thrombus: dynamic computed tomography findings and histopathologic correlation. J Comput Assist Tomogr 2011; 35:187–194 58. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693–699 59. Cho YB, Lee KU, Lee HW, et al. Outcomes of hepatic resection for a single large hepatocellular carcinoma. World J Surg 2007; 31:795–801 60. Ba MC, Cui SZ, Lin SQ, et al. Resection of a giant hepatocellular carcinoma weighing over 10 kg. World J Gastroenterol 2010; 16:1422–1424 61. Hironori K, Masaru T, Yuichiro O, et al. Laparoscopy-assisted hepatectomy for giant hepatocellular carcinoma. Surg Laparosc Endosc Percutan Tech 2008; 18 (5 suppl 1):127–131 62. Baron RL, Brancatelli G. Computed tomographic imaging of hepatocellular carcinoma. G­astroenterology 2004; 127:S133–S143 63. Shin DS, Ingraham CR, Dighe MK, et al. Surgical resection of a malignant liver lesion: what the surgeon wants the radiologist to know. AJR 2014; 203:[web]W21–W33 64. Chung YF, Thng CH, Lui HF, et al. Clinical mimicry of hepatocellular carcinoma: imaging-pathological correlation. Singapore Med J 2005; 46:31–36 65. Yeh TS, Jan YY, Jeng L, et al. Hepatocellular carcinoma presenting as pyogenic liver abscess: characteristics, diagnosis, and management. Clin Infect Dis 1998; 26:1224–1226

AJR:205, October 2015 W415

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Shriki et al. 66. Mathieu D, Vasile N, Fagniez PL, et al. Dynamic CT features of hepatic abscesses. Radiology 1985; 154:749–752 67. Chou YP, Changchien CS, Chiu K, et al. Salmonellosis with liver abscess mimicking hepatocellular carcinoma in a diabetic and cirrhotic patient: a case report and review of the literature. Liver Int 2006; 26:498–501 68. Allen RA, Lissa JR. Combined liver cell and bile duct carcinoma. Am J Pathol 1949; 25:647–655 69. Jarnagin WR, Weber S, Tickoo SK, et al. Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors. Cancer 2002; 94:2040–2046 70. Goodman Z, Terracciano L, Wee A. Tumours and tumour-like lesions of the liver. In: Burt A, ­Portmann B, Ferrell L, eds. MacSween’s ­pathology of the liver, 6th ed. London, UK: Churchill Livingstone, 2012:761–851 71. Aoki K, Takayasu K, Kawano T, et al. Combined hepatocellular and cholangiocarcinoma: clinical features and computed tomographic findings. Hepatology 1993; 18:1090–1095 72. Heidecke S, Stippel DL, Hoelscher AH, ­Wedemeyer I, Dienes HP, Drebber U. Simultaneous occurrence of a

hepatocellular carcinoma and a hepatic non-Hodgkin’s lymphoma infiltration. World J Hepatol 2010; 2:246–250 73. Shapira MY, Muszkat M, Braunstein I, Gotsman I. Co-occurrence of hepatocellular carcinoma and lymphoma in patients with hepatitis C virus cirrhosis. J Clin Gastroenterol 2001; 32:368–369 74. Lin A, Kadam JS, Bodenheimer HC, et al. Concomitant diffuse large B-cell lymphoma and hepatocellular carcinoma in chronic hepatitis C virus liver disease: a study of two cases. J Med Virol 2008; 80:1350–1353 75. Kanda M, Tateishi R, Yoshida H, et al. Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors. Liver Int 2008; 28:1256–1263 76. Jakate S, Yabes A, Giusto D, et al. Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis. Am J Surg Pathol 2010; 34:935–941 77. Trevisani F, Caraceni P, Bernardi M, et al. Gross pathologic types of hepatocellular carcinoma in Italian patients: relationship with demographic, environmental, and clinical factors. Cancer 1993; 72:1557–1563 78. Park YS, Lee CH, Kim BH, et al. Using Gd-EOB-

DTPA-enhanced 3-T MRI for the differentiation of infiltrative hepatocellular carcinoma and focal confluent fibrosis in liver cirrhosis. Magn Reson Imaging 2013; 31:1137–1142 79. Rosenkrantz AB, Lee L, Matza BW, Kim S. Infiltrative hepatocellular carcinoma: comparison of MRI sequences for lesion conspicuity. Clin ­Radiol 2012; 67:e105–e111 80. Kneuertz PJ, Demirjian A, Firoozmand A, et al. Diffuse infiltrative hepatocellular carcinoma: assessment of presentation, treatment, and outcomes. Ann Surg Oncol 2012; 19:2897–2907 81. Kanematsu M, Semelka RC, Loenardou P, et al. Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations. J Magn Reson Imaging 2003; 18:189–195 82. Benvegnù L, Noventa F, Bernardinello E, ­Pontisso P, Gatta A, Alberti A. Evidence for an association between the aetiology of cirrhosis and pattern of hepatocellular carcinoma development. Gut 2001; 48:110–115 83. Okuda K, Noguchi T, Kubo Y, Shimokawa Y, ­Kojiro M, Nakashima T. A clinical and pathological study of diffuse type hepatocellular carcinoma. Liver 1981; 1:280–289

A

B

Fig. 1—66-year-old man with small hepatocellular carcinoma. A, Axial contrast-enhanced hepatic arterial phase CT image shows lack of characteristic arterial phase enhancement. Lesion is not clearly evident. B, Axial contrast-enhanced portal venous phase CT image shows 19-mm area of washout (arrow) consistent with small hepatocellular carcinoma.

W416

AJR:205, October 2015

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

CT of Atypical Presentations of Hepatocellular Carcinoma

A

B

C

D

E

Fig. 2—52-year-old man with focal fat within hepatocellular carcinoma. A, Axial contrast-enhanced late arterial phase CT image shows hyperattenuating mass (arrowheads). Focal area of hypoattenuation (–60 HU) (arrow) within lesion suggests fat deposition, which makes arterial phase enhancement difficult to detect in this area of tumor. B, Portal venous phase CT image shows hypoattenuation throughout lesion (arrowheads). Focal area of more pronounced hypoattenuation consistent with fat (arrow) remains unchanged. C, Axial in-phase MR image shows lesion (arrowheads) with area of subtly increased T1 signal intensity (arrow). D, Axial opposed-phase MR image shows lesion (arrowheads) with area of notable signal-intensity dropout (arrow), indicating presence of steatosis. E, High-magnification photomicrograph (H and E, ×200) shows ballooning degeneration associated with fatty change.

A

B

Fig. 3—57-year-old man with cystic degeneration of hepatocellular carcinoma. A, Axial late arterial phase contrast-enhanced CT image from screening examination shows lesion (arrow) with typical late arterial phase enhancement on initial scan. B, Arterial phase CT obtained after episode of massive gastrointestinal hemorrhage shows lesion (arrow) has low attenuation (< 10 HU) with isoattenuation to ascites. Findings are consistent with cystic degeneration.

AJR:205, October 2015 W417

Shriki et al.

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Fig. 4—61-year-old man who presented to emergency department with decreasing hematocrit level. CT showed ruptured hepatocellular carcinoma. Axial portal venous phase CT image shows hypoenhancement within tumor (arrowheads), capsular hematoma (arrow), and probable blood within ascites as evidenced by hyperattenuation (asterisk). Capsular hematoma and hemoperitoneum were confirmed at surgery.

A

B

Fig. 5—15-year-old boy with fibrolamellar hepatocellular carcinoma who presented with abdominal pain. A, Axial contrast-enhanced portal venous phase CT image shows large, heterogeneous hypoattenuating central tumor (arrowheads) with well-defined margins and large central scar. Tumor occupies entire right lobe of liver. Arterial phase images (not shown) showed enhancement. B, Photomicrograph shows oncocytic neoplastic cells with prominent nucleoli in dense fibrotic background (H and E, ×200).

A

W418

B

Fig. 6—73-year-old man who presented with shortness of breath. Right atrial mass with thrombus in inferior vena cava (IVC) was identified at echocardiography. Subsequent CT images show hepatocellular carcinoma with tumor thrombus extending into middle hepatic vein, IVC, and right atrium. A, Axial late arterial phase CT image shows large right atrial mass (arrows). B, Coronal portal venous phase CT image shows enhancing tumor thrombus in IVC in superior aspect and nonenhancing bland thrombus in inferior aspect (arrowheads). (Fig. 6 continues on next page)

AJR:205, October 2015

CT of Atypical Presentations of Hepatocellular Carcinoma

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Fig. 6 (continued)—73-year-old man who presented with shortness of breath. Right atrial mass with thrombus in inferior vena cava (IVC) was identified at echocardiography. Subsequent CT images show hepatocellular carcinoma with tumor thrombus extending into middle hepatic vein, IVC, and right atrium. C, Photomicrograph (H and E, ×10) shows portal vein branch distended by tumor thrombus.

C Fig. 7—52-year-old woman with abdominal pain and jaundice. CT shows hepatocellular carcinoma (HCC) and bile duct tumor thrombus. A, Axial portal venous phase CT image shows large hypoattenuating HCC (arrowheads) with extension of tumor into common bile duct (arrow). B, Coronal CT image shows tumor extension into common bile duct (arrow) and mild dilatation of intrahepatic biliary ducts (arrowheads). Gallbladder (asterisk) is moderately distended.

A

A

B

B

Fig. 8—59-year-old man with abdominal pain and fullness. CT image shows giant hepatocellular carcinoma (HCC). A, Coronal CT image shows craniocaudal extent of HCC (arrowheads), which measures 25 cm. B, Photomicrograph (immunohistochemical stain for Hep Par 1 hepatocyte-specific antigen, ×40) shows uniform positive cytoplasmic staining, supporting diagnosis of HCC.

AJR:205, October 2015 W419

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Shriki et al.

A

B Fig. 9—58-year-old man with fever and leukocytosis. A, Sagittal ultrasound image shows hypoechoic mass (arrow) in left lobe of liver with thick hyperechoic wall thought to be consistent with abscess in given clinical context. B, Axial CT image shows hypodense mass (arrow) and small peripheral areas of enhancement. C, Photomicrograph (H and E, x200) shows closely packed neoplastic cells. Immunohistochemical stain for Hep Par 1 hepatocyte-specific antigen was positive (not shown).

C

A

B

Fig. 10—59-year-old man with chronic hepatitis B with mass found at screening CT. CT shows combined hepatocellular carcinoma (HCC) and cholangiocarcinoma. A, Axial late arterial phase CT image shows mass (arrow) in segment VII with less arterial phase enhancement than expected for HCC. B, Axial portal venous phase CT image shows persistent hypoattenuation (arrow) in tumor. (Fig. 10 continues on next page)

W420

AJR:205, October 2015

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

CT of Atypical Presentations of Hepatocellular Carcinoma

C

D

Fig. 10 (continued)—59-year-old man with chronic hepatitis B with mass found at screening CT. CT shows combined hepatocellular carcinoma (HCC) and cholangiocarcinoma. C, Axial delayed phase CT image shows mild delayed hyperattenuation (arrow) as may be seen in cholangiocarcinoma. D, Photomicrograph (H and E, ×200) shows intermixed cells of chromatic cholangiocarcinoma with disordered gland and tube formation in background of HCC with typical features.

A

B

Fig. 11—56-year-old man with jaundice. CT shows double-cancer hepatocellular carcinoma (HCC) and central cholangiocarcinoma. A, Axial arterial phase CT image shows early hyperattenuation of HCC (white arrow) but hypoattenuation within cholangiocarcinoma (black arrow). Arrowheads indicate biliary ductal dilatation. B, Axial delayed phase CT image shows hypoattenuation of HCC (white arrow) and some delayed hyperattenuation within cholangiocarcinoma (black arrow). Biliary ductal dilatation (arrowheads) is evident. Both lesions were biopsied (percutaneous technique for HCC and endoscopic brushing of cholangiocarcinoma) for diagnostic confirmation (not shown).

AJR:205, October 2015 W421

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

Shriki et al.

A

B Fig. 12—57-year-old man with incidental finding of liver mass at annual surveillance CT performed for lymphoma. CT shows typical hepatocellular carcinoma (HCC). A, Axial contrast-enhanced portal venous phase CT image shows soft tissue with homogeneously low attenuation surrounding kidney, inferior vena cava, and renal vessels. Findings are consistent with lymphoma (arrowheads). B, Axial contrast-enhanced portal venous phase CT image obtained 1 year after A shows regression of lymphoma but interval development of new liver lesion with washout and pseudocapsule typical of HCC (arrow). C, Photomicrograph (H and E, ×200) shows pseudoglandular features consistent with HCC.

C

A

B

Fig. 13—65-year-old man with diffuse cirrhosislike hepatocellular carcinoma (HCC). A, CT image shows no focal mass. B, Photograph of resected specimen shows nodular liver contour consistent with cirrhosis and without dominant lesion. No lesions were detected on preoperative imaging (not shown). (Fig. 13 continues on next page)

W422

AJR:205, October 2015

Fig. 13 (continued)—65-year-old man with diffuse cirrhosislike hepatocellular

CT of Atypical Presentations ofcarcinoma Hepatocellular Carcinoma (HCC).

Downloaded from www.ajronline.org by 73.83.217.29 on 04/06/17 from IP address 73.83.217.29. Copyright ARRS. For personal use only; all rights reserved

C, Photomicrograph (H and E, ×100) shows extensive, diffuse, infiltrating HCC with moderate differentiation.

C

A

C

B

Fig. 14—58-year-old man with extensive venous invasion by hepatocellular carcinoma (HCC). A, Transverse contrast-enhanced late arterial phase CT image shows invasion into left portal vein (arrow). B, CT image shows invasion by HCC extending into pars umbilicus of left portal vein (arrow) and extensive central abdominal and celiac lymphadenopathy (arrowheads). C, CT image caudal to B shows invasion extending into recanalized left paraumbilical vein (arrow) and invasion into splenic vein (arrowheads).

F O R YO U R I N F O R M AT I O N

This article is available for CME and Self-Assessment (SA-CME) credit that satisfies Part II requirements for maintenance of certification (MOC). To access the examination for this article, follow the prompts.

AJR:205, October 2015 W423