Hepatocellular carcinoma (HCC) remains one of the commonest cancers worldwide especially in hepatitis B endemic regions. Its aggressive behavior is characterised by the natural history of increasing size, a tendency for vascular invasion into the hepatic veins and portal veins. Further growth into the inferior vena cava (IVC) and right atrium (RA) is an infrequent finding but signifies a pre-terminal event with a dismal prognosis. The reported incidence is 3%-4%.^[1] Patients are at high-risk of pulmonary embolism and systemic metastasis. Surgical resection with thrombectomy offers the only chance of tumor clearance and cure. The available evidence for surgery, however, is limited with only small case series and individual case reports published.^[1-4] We describe a case of HCC with IVC and RA tumor thrombus successfully treated with combined cavo-atrial thrombectomy under cardiopulmonary bypass (CPB) and hepatectomy.

 

A 47-year-old Asian man presented with severe right upper quadrant pain. He was a known HBV carrier but otherwise had no significant medical history. Physical examination revealed hepatomegaly with an irregular margin and hard consistency. Liver function tests, platelet count and coagulation screens showed nothing abnormal. Alpha-fetoprotein (AFP) was raised at 3401 ng/mL. Initial computed tomography (CT) scan identified a large right lobar tumor with invasion into the IVC extending to the RA. A rim of hyperdense fluid was seen around the right lobe suggestive of rupture. He was referred to our tertiary center for further assessment and treatment. Formal triphasic CT scan of the abdomen and thorax confirmed a large arterial enhancing tumor with delayed contrast washout occupying most of the right lobe involving segments V-VIII (Fig. 1). The tumor showed central necrosis and measured 11.3×15.5×19.6 cm. There was a satellite tumor (1.7×1.6 cm) in segment V. The right hepatic vein (RHV) was displaced by the tumor, which invaded into the IVC. The tumor mass extended superiorly into the RA and measured 5.8×4.4×4.3 cm (Figs. 2 and 3). Ascites and right pleural effusion were also seen but no pulmonary or other intra-abdominal metastasis could be identified. Dual tracer positron emission tomography (PET) CT scan confirmed this right liver tumor with moderately increased fluorodeoxyglucose (¹⁸FDG) uptake (SUV_max 4.2), highly suggestive of a moderately to poorly differentiated HCC. There was predominantly ¹¹C-acetate-avid foci (SUV_max 8.0) at the upper IVC and RA, consistent with active thrombi. The result of preoperative indocyanine green clearance (ICG) test was 13% at 15 minutes. Left lobe liver volume measured 972 mL. Echocardiogram demonstrated the RA tumor with structurally normal valves. The ejection fraction was 60% and the right ventricular systolic pressure was 30 mmHg.

 

An elective curative resection with thrombectomy was arranged for this patient. A bilateral subcostal incision with midline extension was used. On entry into the abdominal cavity, approximately 2 L of ascites was seen. The liver was congested due to IVC obstruction. A multifocal hard tumor of 15 cm was seen in the right lobe (Fig. 4). Intraoperative ultrasound confirmed extension of the tumor into the right portal vein, RHV, IVC and RA. The right hepatic artery was prominent. Following ligation of this, liver parenchymal transection by anterior approach was carried out using cavitron ultrasonic surgical aspirator (CUSA). Pringle maneuver (6 cycles at 10 minutes intervals, total 120 minutes) was applied as severe oozing was encountered from the engorged middle hepatic vein (MHV).

 

Continuing liver transection was hindered by the development of unstable hemodynamics as a result of right ventricular inflow obstruction secondary to ball-valve effect. A median sternotomy was made by the cardiac surgeons. Systemic heparin was then given. The patient was started on CPB via aorta and superior vena cava cannulation. A right atriotomy was made under beating heart. The atrial tumor was extending to the mid atrial septum abutting the tricuspid valve. After excision of the tumor, the atrial wall was closed with 4/0 prolene sutures. The total bypass time was 15 minutes. Heparinization was reversed with protamine following which liver transection resumed. Due to significant oozing, further 2 cycles of Pringle maneuver had to be applied before parenchymal transection was completed. Clamping of the supra and infrahepatic IVC was followed by an inverted T-shaped venotomy. The IVC tumor thrombus had a stalk, which was firmly adhered to the RHV and MHV junction. Caval thrombectomy and removal of tumor thrombus stalk was completed. Of particular importance to minimise tumor thrombus dislodgement, by using the anterior approach for right hepatectomy, mobilization of the right lobe was kept until the very end and to a minimum until after IVC thrombectomy and the tumor stalk was excised. Full mobilization of the right lobe for delivery of the specimen then followed. Gross tumor excision was achieved and confirmed by trans-oesophageal echocardiogram. Venotomy was closed with 5/0 prolene continuous sutures. The total blood loss was 30 L.

 

Postoperative recovery was uneventful and the patient was discharged on day 15. Pathological examination confirmed a moderately differentiated HCC with invasion into portal and hepatic veins. Atrial and IVC thrombi were also consistent with HCC. At 1 month postoperatively CT showed no recurrence of tumor and AFP had dropped to 94 ng/mL. He was started on adjuvant chemotherapy with cepacitabine and oxaloplatin. At 4 months post-surgery, the AFP level rebounded. Reassessment PET/CT identified bilateral pulmonary metastasis. The patient is alive and symptom-free at 7 months.

 

HCC with tumor thrombus in the IVC and RA poses a significant treatment challenge. Survival is extremely poor and has been quoted to be <4 months without any form of treatment.^[5] Patients not only die from a natural progression of the metastatic disease but are also at a high-risk of sudden demise due to pulmonary embolization and the ball-valve effect from tricuspid valve obstruction leading to heart failure. In the past, many patients were deemed inoperable and offered palliative care only due to the significantly high morbidity and mortality risks associated with surgery. We report a patient with successful tumor resection coupled with cavo-atrial thrombectomy. A review of previously reported cases in the English literature was also performed (Table).

 

There are currently no recommended management options for HCC with IVC and RA invasion. Several treatment strategies have been attempted but none has shown sufficient promise or received enough evidence to support their use. Thalidomide is an anti-angiogenic agent. It has been reported to cause tumor regression, prolong survival (12 months) and provide symptomatic relief.^[5] Transarterial chemoembolisation (TACE) has been reported to provide a survival of around 4 months, a survival time which is only comparable to symptomatic care.^[14] Theoretically, surgical resection of the primary HCC with thrombectomy provides the only chance of cure. Wakayama et al^[2] reported on a series of 13 patients with tumor thrombi in either the IVC or RA. Six of these patients had RA thrombus and underwent combined hepatectomy with sternotomy and CPB. One patient lived to 30.8 months and died from tumor recurrence and metastasis. Interestingly, this study included 8 patients who underwent non-curative surgery who either had residual intrahepatic tumor or distant metastasis. The authors suggested that since the survival of these patients would be extremely short with non-surgical treatment, distant metastasis should not be a contraindication for surgery and may be beneficial. Control of disease and prevention of sudden death could also provide these patients a chance of multidisciplinary treatments for improving survival. Indeed, the median survival of non-curative surgical patients in their study was 10.5 months which is already twice the quoted survival time of patients receiving no treatment at all. The median survival of the 5 patients (thrombus in 3 IVC, 2 RA patients) who underwent curative surgery was 30.8 months; however, all of them suffered from early postoperative recurrences. The median recurrence-free survival was only 3.8 months. Wang et al^[1] performed the only available comparative study on 56 patients who underwent hepatectomy and thrombectomy, TACE or symptomatic treatment only. In 25 patients who underwent surgical treatment, only 3 had RA thrombus. The median survival was 19 months in the surgical group, significantly higher than 4.5 months in the TACE group and 5 months in the symptomatic control group (P<0.001). The authors concluded that although technically challenging, hepatectomy with thrombectomy should be considered in those with a resectable primary tumor and sufficient hepatic reserve.

 

Combined hepatectomy and cavo-atrial thrombectomy is a highly specialized and challenging operation necessitating expertise from both liver and cardiothoracic surgeons. Consequently, surgical treatment is not common and mostly confined to specialist tertiary centers. A previous report has quoted a morbidity and mortality rate of 40% and 15%, respectively.^[2] With recent advances in surgical care and skills, these figures should be on the decrease. Nonetheless, there are several technical challenges to be considered in such a high-risk operation. Firstly, blood loss is always expected to be substantial. Bleeding has been shown to be a major predictor for operative outcome.^[15] This is an inevitable barrier to smooth operation as the majority of patients have cirrhotic livers with underlying coagulopathy. Budd-Chiari syndrome from IVC and RA obstruction leads to hepatic congestion, further increases the likelihood of torrential blood loss as exemplified in our patient (30 L blood loss). It is not our routine practice to apply the Pringle maneuver during hepatectomy. The Pringle maneuver was however required on several occasions in the present patient during liver transection highlighting the degree of bleeding encountered. Some authors have advocated the use of total hepatic vascular exclusion (THVE) for removing such high-risk tumors in an attempt to obtain a bloodless operative field and minimize blood loss.^{[8, 9]} In our experience, bleeding can be kept to a minimum and tolerable level for liver transection with meticulous hemostasis of parenchymal vessels through the use of metal clips, suture ligation and the use of CUSA. With THVE, there is also a risk of inducing liver failure from ischemic injury in a liver that is likely cirrhotic.^[10] A cardiac anesthetist should ideally be involved to provide an optimal central venous pressure for liver transection and to maintain hemodynamic stability through judicious administration of fluids, blood products and vasoactive agents.

 

Whether sternotomy and CPB is required depends on the extent of tumor thrombus in the RA. To minimize surgical trauma and to avoid a sternotomy and CPB, some authors have described division of the diaphragm, retracting the liver and IVC caudally after full mobilization to gain access to the supra-diaphragmatic IVC and RA thrombus for resection.^{[1, 9]} However, with a thrombus that fully enters the RA abutting the tricuspid valve, CPB is mandatory as in the case with our patient.

 

The general consensus from previous reports is to perform hepatectomy prior to cavo-atrial thrombectomy.^{[1, 11]} There is a concern of tumor thrombus dislodgment during liver transection. In our patient, hepatectomy was planned and carried out before thrombectomy. However, as a result of the ball-valve effect with worsening right ventricular in-flow obstruction and unstable hemodynamics, RA thrombectomy with CPB had to be instituted mid-way through hepatectomy to prevent further deterioration and cardiac arrest. Different strategies have been employed to decrease the risk of thrombus dislodgement into the circulation and pulmonary embolism during RA thrombectomy. Hypothermic cardioplegia (systemic temperature <28?��) has been advocated by some authors.^[12] This provides a stationary operating field and stops any risk of thrombus passing into the pulmonary circulation during thrombus extraction. Risks of neurological damage and coagulopathy make this technique challenging, especially in patients requiring prolonged cardiac arrest for tumor removal. Other methods described to minimize distal embolization include placing a Satinsky clamp at the atrial appendage when the atrial extension was slight or clamping of the pulmonary artery.^{[8, 13]} One disadvantage of performing thrombectomy with CPB first is the inherent risk of profuse bleeding after heparinization. As described above blood loss would already be high in such patients, liver transection would certainly be made more difficult by the effects of heparin. Complete reversal by protamine is absolutely necessary for hepatectomy to proceed.

 

Adding to the treatment challenges of these patients is the high recurrence rates observed. Despite complete excision of the primary HCC and tumor thrombus, intrahepatic and pulmonary metastases are common, and often at an early stage post-surgery.^{[1, 2]} This is exemplified in our patient. Postulated mechanisms for this include seedling of tumor cells upon handling of the tumor during surgery or through CPB.^[11] We performed right hepatectomy using the anterior approach. Tumor stalk excision at the IVC was completed before full mobilization of the liver. Through this approach, the chance of tumor dislodgement would be unlikely. Micrometastasis might already be present before surgery or early recurrence might simply be attributed to the aggressive nature of the primary tumor. Nevertheless, there should be a role for surgery as it not only relieves cardiorespiratory symptoms, but also prevents sudden death due to ventricular obstruction.

 

In conclusion, a patient with HCC and tumor thrombus extending to the IVC and RA successfully treated with cavo-atrial thrombectomy and hepatectomy is presented here. Prognosis of such patients is extremely poor without any form of treatment. Those who are otherwise physically fit with good hepatic reserve should be given a chance for surgery. Surgical resection in such patients is technically demanding. Patients should ideally be referred to high-volume tertiary centers under the care of expert hands. With advancing developments in surgical technique and perioperative care, such a high-risk procedure can be safely performed.

 

 

 

Contributors: CA proposed the study. TJ collected the data and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. LCM is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

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2 Wakayama K, Kamiyama T, Yokoo H, Kakisaka T, Kamachi H, Tsuruga Y, et al. Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium. World J Surg Oncol 2013;11:259. PMID: 24093164

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(doi: 10.1016/S1499-3872(16)60111-X)

Published online June 20, 2016.