Mobile Right Atrial Thrombus with Pulmonary Thromboembolism in a Patient with Advanced Hepatocellular Carcinoma and Disseminated Tumor Thrombosis

Abstract

We report a 61-year-old male patient who presented with one month history of exertional dyspnea, persistent dry cough, abdominal pain with distension, poor appetite, and weight loss. This case illustrates a rare presentation of hepatocellular carcinoma with mobile right atrial thrombus and pulmonary embolism along with disseminated tumor thrombosis at multiple sites. Furthermore, this case reiterates that an early detection and diagnosis may have increasing importance in the advent of new therapies for treating advanced hepatocellular carcinoma

INTRODUCTION

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality and has highest incidence in Asia (including Far East / Middle East) and sub-Saharan Africa.[1,2] The prognosis is very poor without any specific treatment, and the median survival time in patients with early and advanced tumor is 6–9 months and 1–2 months, respectively.[2] We report a rare presentation of HCC with mobile right atrial (RA) thrombus and pulmonary embolism (PE) along with disseminated tumor thrombosis at multiple sites.

CASE REPORT

A 61 year-old-man with no significant past medical history was admitted in acute medical unit with one month history of exertional dyspnea, persistent dry cough, abdominal pain with distension, poor appetite, and weight loss. He was admitted in a regional hospital and was treated for chest infection. There was no history of fever, alcohol intake, or smoking.

On the physical examination, the patient was icteric, not in distress with room air saturation of 93%, blood pressure of 132/76 mmHg, and heart rate of 94/bpm. Abdominal examination revealed tender hepatomegaly with the liver palpable 4 cm below the lower edge of the ribs with multiple ‘wasam’ marks on skin (hot iron branding marks). There was moderate ascites and mild pedal edema, but no signs of hepatic failure or cirrhosis stigmata. Chest examination elicited few scattered crepitations bilaterally. Laboratory results on admission were as follows: hemoglobin 12.4 g/dl (n = 14–18.1), hematocrit 40.9% (n = 35–53), leukocyte 14 × 10pwr9/L (n = 3.6–11.5), platelets 195 × 10pwr9/L (n = 150–450), erythrocyte sedimentation rate 35 mm/h, prothrombin time 12.2 sec (control 9.1–11.6), activated partial thromboplastin time 30.8 sec (n = 27.2–39.1), alkaline phosphatase 353 IU/L (n = 30–110), aspartate aminotransferase 281 IU/L (n = 10–45), alanine aminotransferase 91 IU/L (n = 10–40), gamma glutamyltranspeptidase 200 IU/L (n = 5–85), total bilirubin 47 μmol/L (n = 3–17), albumin 29 g/L (n = 35–50), and alpha-feto protein (AFP) 8.0 and 11 μg/L done twice (n = 0–15). Hepatitis B surface antigen was positive. Hepatitis C virus antibody and human immunodeficiency virus antibody were negative. Thrombophilia profile revealed normal antiphospholipid antibodies, lupus anticoagulant, factor V Leiden and prothrombin mutation, but low levels of protein C activity 39% (n = 65–130), protein S activity 51% (n = 60–130), antithrombin III assay 50% (n = 75–125).

Abdominal ultrasound examination showed ascites, enlarged liver measuring 18 cm cranio-caudally with heterogenousechogenecity, and multiple hyper echoic nodules all over liver with the largest lesion measuring 6.6 × 2.9 cm [Figure 1a] along with thrombosis of the inferior vena cava (IVC) [Figure 1b, arrow heads] extending to RA.

Figure 1.

Abdominal ultrasound examination showing a heterogenous liver mass measuring 6.6 × 2.9 cm along with multiple hyper echoic nodules all over the liver (a) and thrombosis of the inferior vena cava (b, arrow heads)

Chest radiograph and lower limb venous doppler were normal. Transthoracic echocardiogram was done to assess right atrial extension of the thrombus. Echocardiogram confirmed a large IVC thrombus entering RA [Figure 2a, arrow heads]. There was a large mobile lobulated, serpentine-like right atrial thrombus measuring 8 × 4 cm prolapsing from right atrium to right ventricle [Figure 2b and c, arrow heads, Video 1]. There was no significant gradient across the tricuspid valve and the right ventricular systolic pressure was 30 mmHg with good left and right ventricular systolic function.

Figure 2.

Transthoracic echocardiogram showing a large lobulated inferior vena cava thrombus entering RA (a, arrow heads). There was a large mobile lobulated right atrial thrombus (b, arrow heads) measuring 8 × 4 cm prolapsing from right atrium to right ventricle (c) in a patient with hepatocellular carcinoma and disseminated tumor thrombosis. Abbreviations: RA = Right atrium; RV = Right ventricle; LA = Left atrium; LV = Left ventricle; IVC = Inferior vena cava

Computed tomography (CT) pulmonary angiogram revealed bilateral lobar and segmental/sub segmental pulmonary artery embolism [Figure 3a, arrow heads] with no lung metastasis. Triple phase abdominal CT demonstrated enlarged liver with multiple lesions, hepatic vein and IVC enhancing tumor thrombosis [Figure 3b, arrow heads] along with portal vein [Figure 4a, arrow heads] and bilateral femoral vein thrombosis [Figure 4b, arrowheads]. The lesions demonstrated typical arterial phase enhancement and venous/delayed phase washout diagnostic of HCC [The American Association for Study of Liver Diseases (AASLD) guidelines 2010].[1] In addition, there were multiple large paraaortic, aortocaval, and portocaval lymphadenopathy (1.2 cm). Kidney, gall bladder, pancreas, and spleen were normal.

Figure 3.

Computed tomography imaging showing pulmonary artery segmental emboli (a, arrow heads) and extensive thrombosis of hepatic veins and inferior vena cava (b, arrow heads) in a patient with multifocal hepatocellular carcinoma and disseminated tumor thrombosis

Figure 4.

Triple phase contrast-enhanced axial computed tomography scan of abdomen shows a large tumor thrombus in portal vein (a, right arrow heads) and bilateral femoral veins (b, arrow heads) in a patient with hepatocellular carcinoma and disseminated tumor thrombosis

Since the disease was at a very advanced stage, a multidisciplinary team involving physicians, gastroenterologists, oncologists, cardiovascular surgeons advised conservative treatment. Patient was heparinised and was started on chronic warfarin therapy.

A follow-up echocardiogram done 4-weeks later showed persistence of tumor thrombus in the IVC and RA [Figure 5a–b, arrow heads]. Patient expired after 12 weeks.

Figure 5.

Transthoracic echocardiogram showing persistence of tumor thrombus in inferior vena cava (a) and right atrium (b) on oral anticoagulation for 4 weeks in a patient with hepatocellular carcinoma and disseminated tumor thrombosis. Abbreviations: RA = Right atrium; IVC = Inferior vena cava; RV = Right ventricle

DISCUSSION

The diagnosis of HCC is typically made by radiological liver imaging without need for biopsy, especially in patients with cirrhosis or chronic hepatitis B infection.[1,2] Revised AASLD guidelines for diagnosing HCC do not require elevation of alpha-feto protein > 200 ng/mL, as it is observed that there are significant false-positives (in cirrhotic patients) and false negatives.[1] Underlying cirrhosis is the major etiology in more than 80%-90% of patients with HCC.[2,3] In those patients without underlying cirrhosis, hepatitis C infection, hepatitis B infection and heavy alcohol intake are involved in 3–54%, 4–29%, and 0–28%, respectively.[3] This patient had underlying hepatitis B infection as the cause for HCC and he had all the typical radiological features of HCC, even though alpha-feto protein done twice did not show any elevation.

HCC commonly metastasize to lung, bone, brain, and adrenal glands. In addition, HCC (like renal cell carcinoma) is associated with haemostatic activation with a tendency to invade vascular structures and cause tumor thrombosis.[4,5] Portal vein thrombosis (PVT) is common (20%-65%) followed by systemic venous thromboembolism (VTE) (6%); with majority being lower extremity deep vein thrombosis.[5] Hepatic vein/inferior vena cava thrombosis (Budd-Chiari syndrome) occurs in < 1% of the patients with HCC.[6] In patients with HCC, the incidence of cardiac metastasis is 0.67–3%.[4,7]

Intra atrial thrombosis of HCC, if large and obstructive can present as right heart failure and is a potentially life threatening condition with high risk of death either due to acute PE or acute obstruction of the tricuspid valve or both.[8] RA thrombi are commonly described in patients with atrial fibrillation/flutter, indwelling transvenous pacing leads or patients on prolonged central venous catheters. Primary thrombi develop within the RA (in situ thrombi) and are usually immobile attached to atrial wall. Secondary thrombi result from venous embolization, are mobile and temporarily lodged in the RA or right ventricle (emboli-in-transit). In the case presented, there was hepatic vein and PVT along with IVC and RA thrombosis but no tricuspid valve obstruction, and lobar and segmental/sub segmental pulmonary artery embolism indicating progressive showering of emboli from the RA thrombus.

His clinical manifestations started with “respiratory” symptoms possibly due to peripheral pulmonary embolism, which was misinterpreted. The abdominal pain requiring multiple branding was ignored. This could have led to delay in the diagnosis in this patient.

In a study, nearly one third of patients with HCC had PVT, with the majority identified at the time of presentation, as seen in this patient.[5] It was also observed that patients with PVT also suffered from a higher incidence of systemic VTE (as in this patient) suggesting an underlying common haemostatic activation that predisposes to both local and systemic thrombotic events in patients with HCC. Expression of tissue factor by HCC has been implicated for both the local and systemic hypercoagulable state of HCC.[5] In addition, it has been observed that a deficiency in the natural anticoagulant system in HCC, even in the absence of pre-existing liver failure may actually contribute to a prothrombotic state as observed in this patient with low levels of protein C, protein S and antithrombin III levels.[5]

Vascular invasion in patients with HCC is a major predictor of mortality as well as tumor recurrence following surgical intervention.[5,9] In a study, tumor size and serum AFP level, alone or in combination, were found useful in predicting the presence or absence of vascular invasion.[9] The incidence of vascular invasion increased as the tumor size increased,: < 2 cm, 3%; 2.1–3 cm, 20%; 3.1–5 cm, 38%; and >5 cm, 65%. Patients with both tumors >5 cm and serum AFP levels >1000 ng/mL had an 82% incidence of vascular invasion.[9] In this patient, AFP was normal, but he had a 6.6 cm tumor detected in the right lobe which could be the cause for disseminated tumor thrombosis.

Surgical resection is the first choice of treatment for HCC, but approximately 80% of cases are unresectable due to late presentation, major vascular invasion, poor general and/or hepatic functional reserve or multifocality of its presentation.[2,10] However, recently newer combination therapies have been found to be useful in increasing survival in HCC.[2,10,11] Hence, early detection and staging of HCC is very important for planning management strategies like resection, transplantation, percutaneous local ablative therapy (radiofrequency ablation, microwave coagulation therapy or percutaneous ethanol injection), transarterial regional techniques (transarterial embolization or chemotherapy, transarterialradioembolization, transarterial chemoembolization-TACE), and extracorporeal energy therapy.[2,10]

In a natural history study, investigating advanced HCC patients with an IVC invasion or RA tumor thrombus, the overall survival was 3 months with a 6-month survival rate of 24% in untreated group compared to 29% in the treated group (systemic chemotherapy, TACE, chemo-radiation). The 12 months survival rate was 0% and 25%, respectively.[11] There are few reports of en bloc hepatectomy and resection of the RA thrombus under cardiopulmonary bypass, with a median survival of 11 months.[12]

CONCLUSION

In conclusion, this case illustrates a rare presentation of advanced HCC with mobile right atrial thrombosis along with disseminated tumor thrombosis at multiple sites. Furthermore, this case reiterates that an early detection and diagnosis may have increasing importance in the advent of new therapies for treating advanced HCC.