Hepatocellular Carcinoma With Intra-atrial Extension Responding to Transarterial Chemoembolization via the Right Hepatic and Right Inferior Phrenic Arteries

CASE REPORT

A 72-year-old man presented with weight loss over 3 months in 2012. He had no history of alcoholism or hepatitis. The clinical examination was unremarkable. Results of a liver panel, including total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, and prothrombin time, and a basic metabolic profile were within normal limits.

Magnetic resonance imaging (MRI) with contrast, performed before referral, revealed a solitary, solid mass in segments 7/8, with heterogeneous T2 hyperintensity and postcontrast enhancement and associated loss of flow void in the right hepatic vein (Figure 1). Multiphasic, contrast-enhanced, multidetector computed tomography (MDCT) revealed a 9-cm lesion (Figure 2) with arterial-phase hyperenhancement and portal venous-phase hypoenhancement (LI-RADS category 5).¹ As suggested by the MRI, the presence of an enhancing tumor thrombus extending into the right atrium was confirmed. An image-guided core biopsy revealed hepatocellular carcinoma (HCC). The case was discussed by the multidisciplinary tumor board and, as the patient was outside the Milan criteria for liver transplantation, the consensus decision was to offer transhepatic arterial chemoembolization (TACE), given the unfavorable risk-to-benefit ratio associated with resection.

Figure 1.

MRI at initial presentation. (a) Axial T2 fat-saturated image demonstrated a solitary hyperintense mass in segments 7/8. (b, c) Superior images revealed a lack of normal flow void in the right hepatic vein extending to the right atrium (arrow). Postcontrast images confirmed hyperenhancement of the primary lesion and associated tumor thrombus in the hepatic vein.

Figure 2.

CT at initial presentation. Arterial-phase axial images showed (a) an enhancing, hyperdense lesion within the right atrium (arrow) consistent with tumor thrombus. (b) Early hyperenhancement within the primary lesion appeared in a nodular, nonuniform pattern (arrow).

At initial angiography (Figure 3), the tumor was found to be supplied by the right hepatic artery (RHA). TACE was performed with 200–400-μm Quadrasphere microspheres (Merit Medical Systems, South Jordan, UT) loaded with 50 mg doxorubicin and delivered through the RHA. Postembolization angiography of the RHA confirmed adequate embolization. One month after the initial TACE, a multiphase CT revealed considerably diminished arterial-phase hyperenhancement associated with the primary lesion; however, persistent enhancement was present within the associated tumor thrombus (Figure 4).

Figure 3.

First chemoembolization. (a) Selective right hepatic arteriogram before embolization revealed a large tumor blush associated with HCC in segments 7/8. (b) Post-TACE selective angiogram demonstrated optimal contrast stasis within the treated branches of the RHA.

Figure 4.

MDCT after the first TACE. (a) A favorable therapeutic response of the primary lesion was evidenced by the lack of arterial hyperenhancement, as well as diminished portal-phase enhancement, although (b) residual hyperenhancement was present within the associated tumor thrombus in the hepatic vein and right atrium.

Eleven weeks after the first TACE, the patient was re-evaluated, and a second round of TACE was recommended. A subsequent MDCT showed no residual arterial-phase hyperenhancement in the primary liver lesion, consistent with a favorable response to therapy. The hepatic vein and atrial tumor thrombus, however, were persistently enhancing, similar to the findings in the original scan. Additional 3-D reconstructions were obtained, and the source of the enhancement was identified as a hypertrophied extrahepatic vessel, the right inferior phrenic artery (RIPA) (Figure 5). Real-time manipulation of the 3-D CT volume clearly defined the origin of the RIPA, its subdiaphragmatic course, and close association with the tumor thrombus. After further discussions, a third TACE procedure was recommended with selective therapy directed at the RIPA, which not only confirmed that this vessel was supplying the hepatic and intracardiac tumor, but demonstrated no tumor vascularity from the (previously treated) RHA. Therefore, the right and middle branches of the RIPA were embolized with 100–300-μm LC bead microspheres (Biocompatibles, Oxford, CT), loaded with 50 mg of doxorubicin, sparing the left branch of the RIPA (Figure 6). The patient tolerated the procedures well, and no complications were observed. A follow-up MDCT 6 weeks later revealed no significant residual enhancement within either the primary liver mass or the newly treated tumor thrombus.

Figure 5.

MDCT angiogram. (a–c) Volume-rendering and (d, e) 3-D reconstructions identified a hypertrophied artery (arrow) superior to the celiac axis supplying the tumor thrombus after the second TACE.

Figure 6.

Third TACE. (a–c) Information gained during 3-D MDCT imaging was enhanced by a superselective angiogram, to demonstrate the hypertrophied RIPA originating from the aorta adjacent to the celiac axis and dividing into 3 branches. (a, b) The right and middle branches supplying the tumor thrombus were successfully embolized. (c) The left branch continues as a left intercostal artery and was spared during the procedure.

DISCUSSION

HCC is the fifth most common cancer and the third leading cause of cancer mortality worldwide.^2–4 Only 30–40% of patients with HCC present at a stage amenable to curative surgery.⁵ In such candidates, liver resection and transplantation provide a long-term response and improved survival. The remaining 60–70% present with advanced HCC and may be eligible for other therapies, such as TACE, radiation, ablation, and systemic chemotherapy.⁶

HCC is highly vascular, a property that is exploited during TACE. Now widely accepted as one of the procedures of choice in appropriate patients, TACE delivers chemotherapy to hypervascular HCC tumors via the feeding vessels, with subsequent embolization of the feeding arterial supply, which may occasionally include an extrahepatic arterial supply (EAS).

The incidence of portal vein tumor thrombus in HCC has been reported to range from 6.5% to 44%.^7–10 In comparison with the portal vein tumor thrombus, the invasion of a tumor thrombus into the inferior vena cava and right atrium is an infrequent occurrence, seen in about 3% to 4% of patients with HCC.^11–15 Cavoatrial tumor thrombus occurs as an extension of the tumor from one or more of the hepatic veins. Patients with HCC, who present with a cavoatrial tumor thrombus have a dismal prognosis, with the survival in this setting being less than 3 months without treatment.^16,17 Complications specific to the presence of the cavoatrial tumor thrombus include Budd-Chiari syndrome, pulmonary embolism, heart failure, and sudden cardiac arrest.

Because of the infrequency of HCC with cavoatrial tumor thrombus, there is no consensus regarding the best therapy for these patients. Options include systemic chemotherapy, surgical resection, and TACE. Response rates for systemic chemotherapy in the treatment of advanced HCC have been modest. A trial of sorafenib as a single-agent therapy resulted in stable disease for 4 months in only one-third of patients, and a partial response was seen in only 2.2%.¹⁸ However, Chang et al¹⁵ reported on the successful use of thalidomide in the treatment of HCC with atrial tumor thrombus in 3 patients who were not deemed to be candidates for surgery or TACE. Surgical resection in this setting involves resection of the involved liver and thrombectomy of the cavoatrial tumor under cardiopulmonary bypass and is limited to highly select patients.

There are few reports of treating HCC with right atrial tumor thrombus with TACE. Chern et al¹⁹ reported on the safety and efficacy of TACE in 26 patients with HCC with tumor thrombus, 5 of whom had tumor thrombus extending into the right atrium. Wang et al²⁰ reported on a cohort of 20 patients with cavoatrial tumor thrombus treated with TACE, with 1- and 3-year survival rates of 15% and 5%, respectively (median survival, 4.5 months). The remaining literature for TACE in this setting is limited to a small number of isolated case reports.^21–23 All these published cases describe a treatment protocol involving conventional TACE, which is an emulsion of chemotherapeutic agents and a vehicle such as Lipiodol delivered with embolic particles. However, over the past few years, conventional TACE has been modified with increasing frequency with embolic particles that sequester and then release the chemotherapeutic agent(s) in a sustained manner, referred to as drug-eluting bead TACE (DEB-TACE). DEB-TACE was recently shown in a randomized, controlled trial of 212 patients with HCC to have an improved safety and tolerability profile, when compared to conventional TACE.²⁴ Our search of the literature revealed no reports, however, of treating HCC with right atrial tumor thrombus with DEB-TACE, as described in the current report.

In our patient, the first two TACE procedures targeted the primary hepatic mass in the right hemiliver. The follow-up CT after the second procedure demonstrated a favorable response to treatment directed at the primary mass, and the only detectable residual neoplasm (arterial-phase hyperenhancement) was confined to the tumor thrombus. The hypertrophied branch of the RIPA was clearly visible by 3-D CT imaging and had become the dominant supplier to the residual neoplasm. The identification of this vessel on CT allowed for treatment planning of the third TACE procedure, in which the hepatic-vein and atrial tumor were selectively treated through a superiorly oriented branch of the RIPA, as well as additional treatment of the hepatic tumor through a right lateral branch of the RIPA.

Recruitment of the RIPA in HCC is a well-documented phenomenon. In a recent series of 85 patients undergoing 147 TACE procedures, 8 were found to have EAS, including only 1 via the RIPA (the others through the intercostal, internal mammary, omental, gastroduodenal arteries and a branch of the superior mesenteric artery).²⁵ In a larger Korean study by Chung et al²⁶ of 1629 sessions of TACE in 479 patients, the RIPA was the most common source of EAS to tumors—found in 50% of cases. The authors analyzed predictive factors and found that, although tumor size, patient age, a surface location, and a bare-area location were all significantly associated with the presence of EAS in univariate analysis, only tumor size retained significance in multivariate regression analysis. At the initial TACE in these 479 patients, only 3% of tumors 2–4 cm in diameter had an EAS, but this rose to 90% when the tumor diameter was >10 cm, with an intermediate proportion of tumors 6–8 cm having an EAS (38%).²⁶

The left and right inferior phrenic arteries are the major source of blood supply to the diaphragm and also send a few branches to the adrenal glands and, infrequently, to the liver and spleen. They arise from the following locations, in order of descending frequency: commonly from the aorta/celiac axis (either as a common trunk or independently) or the renal arteries, uncommonly from the left gastric and hepatic arteries, and rarely from the superior mesenteric and spermatic arteries or the contralateral inferior phrenic arteries.²⁷ In our case, the tumor was initially fed by the RHA, but extrahepatic collateral pathways from the RIPA eventually developed after TACE and supplied the HCC.

Although TACE is generally a safe and well-tolerated procedure, complications include fever, right upper quadrant pain, nausea, transaminitis (postembolization syndrome), biloma, cholecystitis, splenic infarction, gastrointestinal mucosal lesions, intrahepatic aneurysms, liver failure, pulmonary embolism, tumor rupture, hepatorenal syndrome, variceal bleeding, severe acute pancreatitis, and, paraparesis,^28–30 the last of which occurred in a patient with EAS via a RIPA.²⁸ Our patient tolerated all 3 procedures very well, the only complication being an asymptomatic and self-limiting rash after TACE via the RIPA, which is a known complication caused by nontargeted embolization of the cutaneous branches.³¹

In conclusion, we have reported a case of HCC without any identifiable risk factors, complicated by invasion of the right hepatic vein, inferior vena cava, and right atrium, with tumor thrombus treated by serial DEB-TACE, including the RIPA, which was the major blood supplier to the intra-atrial tumor. Subsequent to the third round of DEB-TACE, multiphasic CT showed no residual arterial-phase hyperenhancement within the primary lesion and within the tumor thrombus. Without the correct identification of the source of residual HCC from the extrahepatic arterial supply via the RIPA, through the use of volume-rendered 3-D CT and angiographic correlation, the patient would have been at significantly higher risk for rapid progression of the untreated portion of the HCC. The patient tolerated all three procedures very well and is alive with stable disease at 13 months. Identification of the presence of an EAS to large, inoperable HCCs is of immense importance in maximizing the therapeutic efficacy of TACE. Our case is consistent with the notion that transarterial therapy is safe and effective for limiting progression of advanced HCC with venous and atrial tumor thrombus.