Canadian Association of Radiologists Journal 65 (2014) 60e66www.carjonline.org

Abdominal Imaging / Imagerie abdominale

Extrahepatic Metastases of Hepatocellular Carcinoma: A Spectrumof Imaging Findings

Annalisa K. Becker, MD, FRCPC*, David K. Tso, MD, Alison C. Harris, MD, FRCPC,David Malfair, MD, FRCPC, Silvia D. Chang, MD, FRCPC

Department of Radiology, Vancouver General Hospital, University of British Columbia, Vancouver British Columbia, Canada

Abstract

Hepatocellular carcinoma (HCC) is the most common primary tumour of the liver, responsible for significant morbidity and mortality

worldwide. In the Western world, it primarily affects patients with cirrhosis, secondary to hepatitis C virus and alcoholism. In the rest of theworld, HCC is closely associated with hepatitis B virus infections. Radiologists play a key role in accurately staging HCC, which hasimportant implications for treatment planning. This pictorial review aims to describe the routes of HCC spread and the most frequent sites ofmetastases, to recognize extrahepatic HCC findings on computed tomography and magnetic resonance imaging, and to understand theimplications of HCC staging on treatment planning.

R�esum�e

Tumeur primitive du foie la plus courante, le carcinome h�epatocellulaire (CHC) est une cause importante de morbidit�e et de

mortalit�e �a l’�echelle mondiale. En Occident, il touche principalement les patients atteints d’une cirrhose cons�ecutive �a uneinfection par le virus de l’h�epatite C et �a l’alcoolisme. Ailleurs dans le monde, il est �etroitement associ�e aux infections par le virus del’h�epatite B. Les radiologistes jouent un role de premier plan dans la stadification exacte du carcinome h�epatocellulaire,laquelle entraıne des r�epercussions notables sur la planification du traitement. Cette revue illustr�ee vise �a d�ecrire les voies depropagation du CHC et les si�eges de m�etastases les plus fr�equents, �a reconnaıtre les images de CHC observ�ees par tomodensitom�etrieet imagerie par r�esonance magn�etique, ainsi qu’�a comprendre la mani�ere dont la stadification du CHC influe sur la planification dutraitement.� 2014 Canadian Association of Radiologists. All rights reserved.

Key Words: Hepatocellular carcinoma; Extrahepatic metastasis

Hepatocellular carcinoma (HCC) is the most commonprimary tumour of the liver [1]. Worldwide, an estimated250,000 people die from the disease each year [2].HCC develops in the setting of chronic liver disease. In theWestern world, cirrhosis is present in 85%-90% ofHCC cases, mostly associated with hepatitis C virus andalcoholism. The global distribution is closely linked toprevalence of hepatitis B virus [1].

* Address for correspondence: Annalisa K. Becker, MD, FRCPC,

Department of Radiology, Vancouver General Hospital, 3350-950 W 10th

Avenue, Vancouver, British Columbia V5Z 4E3, Canada.

E-mail address: becker.annalisa@gmail.com (A. K. Becker).

0846-5371/$ - see front matter � 2014 Canadian Association of Radiologists. A

http://dx.doi.org/10.1016/j.carj.2013.05.004

Pathophysiology of HCC Metastases

Extrahepatic HCC can occur in 1 of 3ways: direct extension,hematogenous spread, or lymphatic invasion. Rupture of aHCCfocus may result in intraperitoneal implantation of tumour cellsonto peritoneal or omental surfaces [3]. Reported frequencies ofHCCmetastatic sites include lungs (55%), lymph nodes (53%),bone (28%), adrenal glands (11%), peritoneumand/or omentum(11%), and brain (2%). Rare sites of metastasis include therectum, spleen, diaphragm, duodenum, esophagus, pancreas,seminal vesicle, and bladder [4].

HCC Diagnosis and Treatment Options

Despite improvements in detection and treatment of HCC,the 5-year survival rate remains below 12% [5]. Many

ll rights reserved.

Figure 1. (A) A 54-year-old man with hepatocellular carcinoma. Axial contrast-enhanced computed tomography images in portal venous phase, demonstrating

a portion of the primary lesion (white arrow) that is causing thrombosis of the posterior branch of the right portal vein (black arrow); complicated perihepatic

and perisplenic fluid (24 HU) raises the possibility of capsular rupture; the nodular contour of the liver is consistent with a background of cirrhosis. (B) A 66-

year-old man with hepatocellular carcinoma; an axial contrast-enhanced computed tomography in portal venous phase, demonstrating left portal vein tumour

thrombosis with extension into the right portal vein confluence (white arrow).

Figure 2. A 58-year-old man with hepatocellular carcinoma and direct invasion of hepatic veins. Axial contrast-enhanced computed tomography in the (A)

arterial phase and (B) portal venous phase, demonstrating a large hepatic mass with central low attenuation that involves segments VII and VIII, and obliterates

the right hepatic vein (white arrows). The mass demonstrates enhancement in the arterial phase and portal venous washout, characteristic of hepatocellular

carcinoma, which was confirmed at biopsy.

Figure 3. A 58-year old man with hepatocellular carcinoma. (A, B) Axial contrast-enhanced computed tomography in the portal venous phase, demonstrating

invasion of the intrahepatic inferior vena cava (A and B, white arrow). Portions of the primary tumour are visualized within the right lobe (black arrows). (C)

Axial contrast-enhanced computed tomography images in the portal venous phase, demonstrating invasion of the right hepatic vein (white arrow) with the

primary lesion seen again in the right lobe (black arrows).

61Extrahepatic metastases of HCC / Canadian Association of Radiologists Journal 65 (2014) 60e66

Figure 4. A 42-year-old man with hepatocellular carcinoma and metastatic lung nodules. (A) Posteroanterior radiograph, demonstrating metastatic lung nodules

with a lower lobe predominance. (B) Axial contrast-enhanced computed tomography image, demonstrating multiple, nonspecific pulmonary nodules at the lung

bases (arrows).

Figure 5. A 68-year-old woman with hepatocellular carcinoma and meta-

static lung nodules. Axial T1-weighted gadolinium-enhanced image,

demonstrating a metastatic nodule at the right lung base (white arrow).

Figure 6. A 55-year-old man with hepatocellular carcinoma treated with hepatic e

computed tomography in the (A) arterial phase and (B) portal venous phase, demo

enhancement (white arrows); the inferior margin of the hepatocellular carcinoma p

are expected after treatment, up to 7-10 days.

62 A. K. Becker et al. / Canadian Association of Radiologists Journal 65 (2014) 60e66

patients are diagnosed late in the disease, owing to thelack of unique symptoms and the liver’s large functionalreserve [6]. Guidelines from the American Association forthe Study of Liver Diseases recommend screening withultrasound in patients with known hepatitis B or cirrhosis dueto other pathologies [6]. Hepatic lesions larger than 1 cmshould be further evaluated with multidetector computedtomography (CT) or dynamic magnetic resonance imaging(MRI). Typical findings of HCC on CT or MRI are hyper-vascularity on the arterial phase with subsequent washout[6]. Atypical findings may require follow-up imaging orbiopsy.

Several HCC staging systems are recognized. For patientswith resectable disease, the American Joint Committee onCancer classification system is considered most useful,based on tumour, node, and metastasis. In addition, hepaticfunction plays an integral role in treatment planning,

mbolization with invasion of regional lymph nodes. Axial contrast-enhanced

nstrating portal and peripancreatic necrotic lymphadenopathy with peripheral

rimary tumour is visualized after embolization (black arrows). Locules of gas

Figure 7. A 42-year-old man with hepatocellular carcinoma and metastases to distant lymph nodes. (A) Axial and (B) coronal contrast-enhanced computed

tomography images, demonstrating a conglomerate mass of necrotic nodes below the level of the renal vessels (A and B, black arrow). It is causing

compression and possible invasion of the cava (A and B, white arrow). (C) Subcarinal and (D) paraesophageal lymph node metastases are also identified

(C and D, white arrow).

Figure 8. A 48-year-old man with hepatocellular carcinoma and multiple bony metastases secondary to hepatitis-related hepatoma. (A) Axial contrast-enhanced

computed tomography image on soft-tissue windows, demonstrating a lytic, expansile lesion in the right rib, vertebral body, and posterior elements (white

arrows). (B) Axial T2-weighted image, demonstrating the magnetic resonance appearance of the same lesions seen in (A) (white arrows). (C) Computed

tomography bone window image, demonstrating further involvement of the right sacrum (white arrows).

63Extrahepatic metastases of HCC / Canadian Association of Radiologists Journal 65 (2014) 60e66

Figure 9. A 48-year-old man with hepatocellular carcinoma and metastases

to the thoracic spine. Coronal T2-weighted image, demonstrating near-

complete collapse of T7 and T8 vertebral bodies (grey arrow). Extension

into the spinal canal is causing severe cord compression, with high signal

change, which extends from T6 to T9 (white arrow).

64 A. K. Becker et al. / Canadian Association of Radiologists Journal 65 (2014) 60e66

generally classified according to the Child-Pugh system(A, well compensated; B, significant functional compromise;C, decompensated) [2].

The best long-term survival is achieved through surgicalmanagement. However, only approximately 20% of patientsare surgical candidates at initial diagnosis [2]. Spread toregional lymph nodes and distant metastases are definitecontraindications for resection [6]. Nonsurgical patientsare offered palliative locoregional therapies, includingradiofrequency ablation, percutaneous ethanol injection,transarterial chemoembolization, and selective internalradiation therapy [6]. Radiofrequency ablation may havea role in the complete ablation of lesions smaller than 2 cm,

Figure 10. A 46-year-old man with hepatitis B and hepatocellular carcinoma. (A)

the right posterior superior iliac spine and the left sacral ala and body (thin arrows)

T1-weighted image in the same patient, demonstrating invasion of the left aceta

but further studies are required before recommending it asa first-line approach for early HCC [6].

Extrahepatic Findings of HCC

HCC has a predilection to directly invade veins, mostcommonly the portal, followed by the hepatic, and, lastly,the inferior vena cava (Figures 1-3) [7]. MRI can help tofurther characterize HCC lesions, which typically are lowsignal, precontrast, enhance on arterial phase, and washouton portal venous phase. The lungs are the most commonsite of HCC metastases, which occurs via hemato-genous dissemination to the pulmonary capillary network[8]. This typically results in noncalcified soft-tissue noduleswith lower lobe predominance and the same appearanceas lung metastases from other primary tumours (Figures 4and 5) [8].

The second most common sites of spread are regional anddistant lymph nodes with regional involvement significantlymore common [4]. In a study of 403 patients with HCC, 41%had regional lymph node involvement, with 33% havingaffected the periceliac node, followed by portohepatic nodesat 23% (Figure 6) [4]. Distant nodal metastases are mostcommonly reported in the mediastinum (Figure 7) [4]. Whenassessing lymphadenopathy, it is important to consider thatpatients with HCC often have hepatitis and/or cirrhosis,which is frequently associated with reactive lymphadeno-pathy. Vascularity, heterogeneity, and central necrosis shouldraise concern for malignancy.

Occasionally, bone metastasis is the initial presentationof HCC, which typically presents as skeletal pain or path-ologic fractures [9]. In a study of 300 patients with HCC,7.3% were found to have skeletal metastasis, with almost allhaving multiple bony lesions [10]. Bone metastases aretypically lytic, hypervascular, and often expansile. Thelumbosacral and thoracic spine are the most common sites[9]. Metastases to the ribs and ilium commonly have asso-ciated soft-tissue masses (Figure 8). Thoracic spine metas-tases may cause collapse of vertebral bodies, with extensioninto the spinal canal, which results in severe cord

Axial T1-weighted image, demonstrating low signal metastases that involves

, with extension into the S1 and S2 neural foramina (curved arrow). (B) Axial

bular roof (white arrow).

Figure 11. A 66-year-old man with hepatocellular carcinoma and peritoneal

deposits. Axial contrast-enhanced computed tomography image in portal

venous phase, demonstrating peritoneal deposits deep to the abdominal wall

(white arrows).

65Extrahepatic metastases of HCC / Canadian Association of Radiologists Journal 65 (2014) 60e66

compression (Figure 9). Bone metastases are best demon-strated as low signal lesions on T1-weighted sequences(Figure 10).

HCC may disseminate to the peritoneum (Figure 11) andthe omentum (Figure 12) through tumour cells in ascites,hematogenously through variceal collaterals, or by means ofdirect invasion from an exophytic tumour. HCC mayalso involve the falciform ligament [11]. The falciformligament establishes a continuous pathway between thepancreatoduodenal area in the retroperitoneum and anteriorabdominal wall. Adrenal involvement may be unilateral orbilateral (Figure 13). The presence of an enlarged adrenalmass may not necessarily represent malignancy [4]. Evenwith known primary HCC, adrenal enlargement is statisti-cally more likely to represent an adrenal adenoma [4].

Figure 12. A 65-year-old man with hepatocellular carcinoma and mesenteric depo

phase, demonstrating a large, lobulated metastatic soft-tissue nodule in the right he

arrow). (B) Axial contrast-enhanced computed tomography in the portal venous ph

arrow).

Enhancement of the adrenal metastasis can range fromhypoattenuation, typical of adrenal metastases from primarytumours other than HCC, to marked enhancement. Centralnervous system metastases are extremely rare, typicallyconsisting of multiple, small enhancing masses at the grey-white matter junction (Figure 14) [4]. Although thefrequency of cardiac tumours is quite low, metastaticinvolvement is 40 times more prevalent than primarytumours [12]. HCC may spread via direct transvenousextension through the great veins.

Conclusion

HCC is an aggressive malignancy, and accurate staging isrequired for optimal treatment planning. Metastatic spreadis by direct invasion, through ascites or via hematogenous orlymphatic routes. The most common sites of metastasesinclude lung, followed by lymph nodes, bone, mesenteryand/or omentum, adrenal glands, and brain. Because HCCcan present initially as bulky extrahepatic disease, it isimportant to consider HCC as a primary source in theworkup of malignancy [13]. Surgical resection is thetreatment of choice for small unifocal tumours. Tumoursthat are confined to the liver but are not eligible for resec-tion are treated with palliative locoregional therapies.Extrahepatic HCC carries a dismal prognosis in which onlysystemic treatment or supportive care is available. Theradiologist plays a crucial role in the assessment of HCCstaging, which will determine the best treatment for thepatient.

Acknowledgements

This paper was originally presented at the 2009 AnnualMeeting of the Radiological Society of North America.

sits. (A) Axial contrast-enhanced computed tomography in the portal venous

mi-abdomen, immediately posterior and inferior to the hepatic flexure (white

ase demonstrates a satellite nodule inferior to segment IVb of the liver (white

Figure 13. A 60-year-old man with hepatocellular carcinoma treated with radiofrequency ablation. (A) Axial contrast-enhanced computed tomography image in

the portal venous phase, demonstrating a left retroperitoneal mass, biopsy proven to represent well-differentiated hepatocellular carcinoma (white arrow).

(B) Arterial phase enhancement, demonstrating the claw sign, confirms that the mass is arising from the lateral limb of the left adrenal gland (white arrow).

Figure 14. A 71-year-old man with multifocal hepatocellular carcinoma who

presented with a history of falls and dizziness. Axial contrast-enhanced

computed tomography, demonstrating a large, rim-enhancing lesion in the

left frontal lobe (grey arrow), with a significant amount of associated

ogenic oedema (white arrows).

66 A. K. Becker et al. / Canadian Association of Radiologists Journal 65 (2014) 60e66

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