Histologically confirmed case of complete atrioventricular block due to hepatocellular carcinoma

Abstract

A 72-year-old man, who had been diagnosed as having hepatocellular carcinoma (HCC) with multiple extrahepatic metastasis, complained a general fatigue which appeared 2 weeks before admission. Because bradycardia was detected on physical examination, ECG was performed which revealed the complete atrioventricular (AV) block. We stopped Ca-blocker and β-blocker, but the bradycardia persisted. He was admitted to our hospital for an emergent pacemaker implantation. On admission, he complained dyspnoea. After the surgery, he died due to deterioration of heart failure. The autopsy revealed cardiac metastasis of HCC on AV node, so it was suspected that cardiac metastasis caused the AV block. We thought that the cause of his death was the exacerbation of heart failure associated with bradycardia. It was likely that complete AV block as a very rare complication caused by cardiac metastasis of HCC influenced the prognosis of this patient.

Background

Neoplastic diseases occasionally complicate cardiac metastases. However, cardiac metastasis of hepatocellular carcinoma (HCC) is comparatively rare. Metastatic cancer in the heart is difficult to diagnose before death because of the lack of typical symptoms and signs.¹ In this case, the patient complained of fatigue and showed complete atrioventricular (AV) block on the ECG. Two weeks later, a permanent pacemaker implantation was performed, but he expired soon after the operation. We could confirm metastasis on the AV node histologically.

The current case suggests that when we find patients who have neoplasms and show signs of heart failure, such as malaise or dyspnoea, we have to list arrhythmia caused by cardiac metastasis as a differential diagnosis. Early treatment might affect his survival time.

Case presentation

In August 2013, a 72-year-old man with hypertension complained of epigastric pain and weight loss of 6 kg over the last 2 months. Contrast CT and MRI were performed, and he was diagnosed as having HCC of Barcelona clinic liver cancer stage A (PS 0, Child-Pugh A) (figure 1). He did not have hepatitis B and C. He underwent left hepatectomy with resection of middle hepatic vein and cholecystectomy. On the result of histological examination, two lesions were detected, one lesion is larger than 10 cm (well-differentiated HCC, im(−), fc(+), fc-inf(+), s0, vp1, vv0, va0, b0)), the other is a diameter of 6 mm (poorly differentiated HCC, im(−), fc(+), fc-inf(+), s0, vp0, vv0, va0, b0)). He was followed up by contrast CT, and CT scan showed intrahepatic recurrence and pelvic metastasis in March 2014. He was treated by radiofrequency ablation for intrahepatic lesion and radiation therapy (total 50 Gy) for pelvic metastasis. After that, sorafenib was introduced. However, his cancer had gradually progressed and CT scan showed a typical pattern of pulmonary lymphangitis carcinomatosa. He complained of fatigue and appetite loss for a week and visited our hospital 2 weeks before admission. He did not complain dyspnoea and chest pain. On physical examination, his heart rate was 37 beats per minute (bpm) (figure 2) and holo inspiratory crackles were audible in both lungs. The ECG showed heart rate of 37 bpm and complete AV block. We stopped administering Ca-blocker and β-blocker, but his heart rate did not improve and after that dyspnoea appeared. He was admitted to our hospital for emergent pacemaker implantation.

Figure 1.

Abdominal contrast CT showed a huge mass with a diameter of 11 cm in lateral segment (arrows).

Figure 2.

ECG on admission showed heart rate as 37 beats per minute and third degree atrioventricular block.

Investigations

On admission day, his vital signs were as follows: blood pressure 117/72 mm Hg, pulse rate 43/min, body temperature 36.8°C, respiratory rate 24/min, oxygen saturation of arterial blood measured by pulse oximetry (SpO₂) 92%. His white cell count was 6.51×10⁹/L, haemoglobin level 13.2 g/dL, serum albumin 3.2 g/dL, total bilirubin 1.0 mg/dL, blood urea nitrogen 15.0 mg/dL, and creatinine 0.73 mg/dL. Aspartate aminotransferase (56 IU/L) was elevated. Alanine aminotransferase (12 IU/L), electrolyte and thyroid hormone were normal. Brain natriuretic peptide (BNP) was 530 pg/mL. Prothrombin time (21.9 s) was prolonged. α-Fetoprotein (81 ng/mL) level and protein induced by vitamin K absence Ⅱ (PIVKAⅡ 3231 mAU/mL) levels were elevated. ECG was performed, which showed heart rate 45 bpm and complete AV block, and ST-segment was not elevated. Chest X-ray on the admission day showed heart enlargement (cardiothoracic ratio 58%), right diaphragm elevation and enlargement of right hilar lymph node (figure 3). The CT scan revealed right pleural effusion, hypertrophy of bronchovascular bundles (figure 4), ground glass opacity and consolidation in both lungs and multiple lymph nodes and dissemination on his peritoneum. And portal vein invasion was suspected.

Figure 3.

Chest X-ray on admission showed cardiac enlargement (cardiothoracic ratio 58%), right diaphragm elevation and enlargement of right hilar lymph node.

Figure 4.

Chest CT scan on admission showed right pleural effusion, hypertrophy of bronchovascular bundles, ground glass opacity and consolidation in both the lungs.

Differential diagnosis

We listed the side effects of sorafenib, liver failure, pulmonary lymphangitis carcinomatosa, cancer cachexia, anaemia, electrolytes imbalance and depression as differential diagnoses for patients with terminal cancer who complain of fatigue. From physical examination, an ECG, a chest X-ray and the elevated BNP levels, we diagnosed that his heart failure had deteriorated due to AV block.

In most cases, the aetiologies of AV block were congenital heart disease, myocardial ischaemia, increased vagal tone, hypothyroidism, hyperkalemia and the adverse effects of various drugs.

Cardiac ischaemia were rare serious adverse events in patients receiving sorafenib. He never had heart operation and had no history of congenital heart diseases. Electrolyte and thyroid hormone levels were normal. The ECG did not show ischaemic changes. The CT scan did not reveal any cause of AV block. We stopped administering antihypertensive drugs, sorafenib, but his heart rate did not improve. The cause of AV block was not apparent.

Treatment

We inserted a DDD pacemaker to improve his heart rate. The operation was successful.

Outcome and follow-up

He expired soon after surgery. Autopsy imaging revealed no significant findings that lead to death. There were no viable HCCs in the liver (figure 5). There were no signs of pericardial effusion. Autopsy finding revealed HCC metastasised to right and left ventricles, ventricular septum, endocardium and epicardium (figure 6). Metastatic lesion was detected around the AV node (figure 7). Histological finding showed that sarcomatous transformation of AV node metastatic lesion (figure 8a,b). The cancer was spread over the pleura and peritoneum.

Figure 5.

Gross appearance of liver section. Tumour thrombus was in the portal vein (arrow). Neoplastic lesion did not remain in the parenchyma of the liver.

Figure 6.

Autopsy findings showed metastatic lesion in the both ventricles and septum (arrow).

Figure 7.

Ventricular septum portion. The atrioventricular conducting system (or atrioventricular nodal pathway) is occupied by metastatic tumour nodule (arrow).

Figure 8.

Histlogical and immunohistological findings of atrioventricular conducting system (or atrioventricular nodal pathway). (A) Proliferation of malignant spindle cells around the atrioventricular nodal artery (arrow) reveals sarcomatoid hepatocellular carcinoma metastasis to the atrioventricular nodal pathway (8a, ×100). (B) Some of the sarcomatoid hepatocellular carcinomas show cytokeratin (CAM5.2) positive staining (8b, ×200).

Discussion

The current case was a case of histologically proved cardiac metastasis of HCC which lead to complete AV block.

In the multiple cardiac lesion as this current case, not only malignant nodules but also non-tumour lesion such as haemangiomas, myxomas or even hydatic cysts should be counted.² In this case, multiple white-yellow solid nodules in the intramyocardial were first detected at the autopsy. Because many solid nodules of cardiac in patients with advanced HCC, we suspect the lesion as cardiac metastasis of HCC. After histological examination, the cardiac metastasis of HCC was histologically confirmed.

According to the previous report, there is an autopsy incidence of cardiac metastases of 2.3% among the general population, while the incidence among autopsies of patients with cancer was 7.1%.³

The common neoplasms associated with cardiac metastases are lung cancer, lymphoma, breast cancer, leukaemia, stomach cancer and melanoma.⁴ As for the predilection sites of cardiac metastasis, the pericardium accounts for 64%–69% of all cases, epicardial involvement is 25%–34% and myocardial involvement is 29%–32%; the endocardium is only 5%.⁵

Cardiac metastasis of HCC is relatively rare (4.96%).⁶

In cardiac metastasis of HCC, first reported by Kato et al in 1971, a large spheric thrombus in the right atrium of the heart was seen.⁷ The autopsy of this case revealed the metastasis to right ventricle, septal, endocardium, epicardium and left ventricle (figure 6); on the other hand, there is no viable tumour in the parenchyma of the liver. It was reported that tumours can spread to the heart through four alternative paths: by direct extension, through the blood stream, through the lymphatic system and by intracavitary diffusion either through the inferior vena cava or the pulmonary veins.⁴ In this case, we speculate that cancer cells metastasised to the heart through the blood stream.

Most of cardiac metastasis of HCC was asymptomatic.¹ But when metastatic lesion invades the cardiac conduction systems, it can cause arrhythmia such as atrial flutter, premature ventricular contraction, and AV block.⁸

Concerning the treatment, surgical management is usually not selected, because cardiac metastasis is usually recognised as a feature of terminal stage widespread metastatic disease at its end stage. In this case, we inserted a pacemaker, but could not save the patient because of the exacerbation of heart failure. It was likely that his fatigue over 2 weeks before admission was due to the exacerbation of heart failure associated with bradycardia. If we inserted the pacemaker earlier, his prognosis would have improved. Therefore, when the patients with malignancies complain the progressive dyspnoea, general fatigue, or the newly emerged arrhythmia was detected, the clinician should consider metastasis to heart as a differential diagnosis.

In this case, the autopsy revealed cardiac metastasis of HCC on AV node. Histological findings showed the proliferation of malignant spindle cells around the AV nodal pathway (figure 8). Furthermore, immunohistological findings showed the positive staining for cytokeratin (CAM5.2) (figure 8) which is classified into epithelial marker. So we suspected the AV nodal pathway lesion as the metastasis from epithelial tumour.

To identify the primary lesion of the metastatic cancer, immunohistochemical analysis was conducted against the metastatic lesion in AV node. None of the hepatocyte marker, including Hep par1, ARG1, glypican 3, alpha fetoprotein (AFP) or HSP70, exhibited positive staining (data not shown). But autopsy findings showed that no other primary lesions except HCC were found. So we diagnosed the AV conducting system tumour as a metastasis from HCC, which represents the feature of sarcomatoid HCC. It was reported that the character of tumour changes especially when it metastasise to the other organ, which is called epithelial mesenchymal transition⁹; it acquired the migratory and invasive properties.¹⁰ The cases that metastasis of lymphoma or melanoma on AV node lead to sick sinus syndrome have been reported. In addition, a case has been reported that AV node metastasis of melanoma resulted in complete AV block.^11–14 However, it was not previously reported that the aetiology of AV block was histologically proven AV node metastasis of HCC. Therefore, we think this case report has significance.

We reported a histologically confirmed case of complete AV block due to cardiac metastasis of HCC.

Learning points.

• Cardiac metastasis of hepatocellular carcinoma (HCC) is rare.

• Cardiac metastasis of HCC occasionally cause complete atrioventricular block.

• Cardiac metastasis of HCC lead to an unfavourable prognosis and early diagnosis is important.

• Treatment for cardiac metastasis may improve prognosis.