Pulmonary Hypertension Complicating Hepatocellular Carcinoma

Transcription

1 GASTROENTEROLOGY 1984;87: Pulmonary Hypertension Complicating Hepatocellular Carcinoma I. R. WILLETT, R. C. SUTHERLAND, M. F. O'ROURKE, and F. J. DUDLEY Gastroenterology Service, Alfred Hospital, Melbourne; and Medical Professorial Unit, St. Vincent's Hospital, Sydney, Australia A case of primary liver cell carcinoma is presented in which tumor emboli to the pulmonary microvasculature resulted in pulmonary hypertension, documented by clinical, radiologic, electrocardiographic, and cardiac catheter studies. Emboli arose from tumor invading the portal vein and passed via a patent splenorenal shunt to the systemic venous and pulmonary arterial microvasculature. Despite a prolonged clinical course (20 mo) there was no radiologic evidence of pulmonary metastases and, histologically, tumor emboli were seen to undergo organization and recanalization. Primary liver cell carcinoma is a highly invasive tumor. The lungs and regional lymph nodes are the most frequent sites of extrahepatic metastases, and invasion into both the hepatic and portal vein is common (1-3). The high incidence of pulmonary metastases is related to invasion of the hepatic venous system by tumor and subsequent embolization of tumor cells to the lungs (1-8). Although usually silent, tumor embolization can result in symptoms of respiratory and pulmonary infarction (1-8). When clinically apparent, the tumor emboli almost always occlude a major or lobar pulmonary artery. This case report concerns a patient with cryptogenic cirrhosis and portal hypertension treated by a splenorenal shunt, who presented with pulmonary hypertension as the initial feature of a primary liver cell carcinoma. The pulmonary hypertension was caused by recurrent tumor emboli from the portal vein via a patent splenorenal shunt. Received August 11, Accepted June 1, Address requests for reprints to: Dr. 1. R. Willett, Alfred Hospital, Commercial Road, Prahran, 3181, Melbourne, Australia. This work was supported by a grant from the Alfred Hospital Whole Time Medical Specialist Private Practice Fund by the American Gastroenterological Association /84/$3.00 Case Report A 48-yr-old white woman presented in severe respiratory, with a history of progressively increasing dyspnea over an 18-mo period. The presence of splenomegaly was first documented at age 22 yr. At 31 she presented with an upper gastrointestinal hemorrhage, and a barium swallow demonstrated esophageal varices. There had been no past history of jaundice, hepatitis, blood transfusion, or exposure to potentially hepatotoxic agents. Family history was unremarkable. Liver tests were normal and liver biopsy revealed inactive macronodular cirrhosis. Splenoportography demonstrated a patent splenic and portal vein, and an elective splenorenal shunt was performed. The patient remained well until she presented again at the age of 46 yr, with persistent respiratory tract symptoms. Examination revealed jaundice, palmar erythema, and leukonychia. Laboratory tests disclosed the following values: serum bilirubin 67 p,molil (normal <23), serum albumin 33 gil (normal 35-52)' alkaline phosphatase 288 U/L (normal )' aspartate aminotransferase 120 U/L (normal <50), and alanine aminotransferase 51 U/L (normal <50). A liver scan revealed a liver of normal size with patchy uptake of isotope and increased bone marrow uptake. Tests for antimitochrondrial, smooth muscle, and antinuclear antibody and for hepatitis B surface antigen were negative, as was screening for Wilson's disease. Serum iron, transferrin, O'-fetoprotein, and O'rantitrypsin levels were normal. Over the next 18 mo the patient's exercise tolerance, wheeze, and exertional dyspnea worsened, until she required hospital admission. Examination revealed clinical evidence of pulmonary hypertension. There was a pronounced right ventricular heave, a loud pulmonary component to the second heart sound, and a long diastolic murmur in the pulmonary area radiating down the left sternal edge. Her chest was clear. The liver was palpable 2 cm below the right costal margin in the midclavicular line and hepatojugular reflux was present. Chest x-ray, electrocardiography, and echocardiography were consistent with pulmonary hypertension. Respiratory function studies did not reveal any pulmonary cause for her pulmonary hypertension. Right heart catheterization was performed. Pulmonary arterial and right ventricu-

2 November 1984 PULMONARY HYPERTENSION AND HEPATOMA 1181 Figure 1. Postmortem radiograph of formalin-inflated lungs perfused with barium sulfate showing poor perfusion of the smaller pulmonary arteries with larger vessels unaffected. lar pressures were greatly elevated at 132/44 and 130/20. respectively. The pulmonary arteriogram showed marked dilatation and tortuosity of the main pulmonary artery and its first four to five divisions. with attenuation of more peripheral vessels. 'There was no evidence of any localized vascular obstruction in the major arteries. The appearances were consistent with primary pulmonary hypertension. Total serum bilirubin was 131 /LmoIlL. alkaline phosphatase 440 u/l. aspartate aminotransferase 271 U/L. alanine aminotransferase 120 u/l. lactic acid dehydrogenase 1545 U/L. serum albumin 22 gil. and prothrombin time 50%. Serum a-fetoprotein was not increased. Liver scan at this time showed further impairment of hepatic uptake especially in the right lobe. The right ventricular failure was temporarily controlled by digitalization and diuretic therapy. but hepatocellular function continued to deteriorate and signs of progressive hepatic encephalopathy developed. The patient died some 20 mo after her first presentation with dyspnea and wheeze. Autopsy Findings Macroscopic Significant findings were confined to the liver. splanchnic venous bed. heart. and lungs. Bulging from the inferior surface of the right lobe of a macronodular cirrhotic liver was a large primary liver cell carcinoma. Tumor had spread into and occluded the intra- and extrahepatic portal vein. The splenic vein. splenorenal anastomosis. renal vein. major hepatic veins. and inferior vena cava were patent. The heart was enlarged due to right atrial and ventricular hypertrophy and dilatation. There was no evidence of congenitai heart disease. No thrombus or tumor was identified in the dilated pulmonary arteries or their major branches. After perfusion of the pulmonary arteries with a barium sulfate mixture. the lungs were inflated with formalin. Radiography of the inflated lungs (Figure 1) revealed poor perfusion of the smaller pulmonary arteries and capillaries. especially of the right lower lobes. but no definite obstruction of the pulmonary arterial branches could be identified. A single lo5-cm-diameter area of hemorrhagic infarction was present in the periphery of the right lobe. Microscopic Histology of the liver revealed a macronodular cirrhosis and a primary liver cell carcinoma with

3 1182 WILLETT ET AL. GASTROENTEROLOGY Vol. 87, No.5 Figure 2. Tumor emboli in small pulmonary arteriole showing canalization and endothelialization. evidence of bile secretion by the tumor cells. Invasion of both intrahepatic bile ducts and vessels by tumor was demonstrated microscopically, and the portal vein was blocked by tumor cells and associated fibrinous and platelet thrombus. Occlusion of the majority of the smaller pulmonary arteries and arterioles by intravascular tumor cells was evident. The intravascular tumor cells were morphologically identical to those in the liver and could occasionally be identified as producing bile. In many of the tumor emboli there was evidence of organization and recanalization with endothelial cells (Figure 2). Invasion of the vessel wall by tumor cells was rare. In summary, the autopsy findings revealed macronodular cirrhosis of the liver with a complicating primary liver cell carcinoma that had invaded and occluded the portal vein. Tumor emboli almost certainly arising from the portal vein, and passing to the lung via a patent splenorenal anastomosis, had led to occlusion of the pulmonary microvasculature, pulmonary hypertension, and right heart failure. Discussion Extrahepatic metastases commonly complicate the clinical course of patients with primary hepatocellular carcinoma (1-3). Hematogenous seeding of tumor cells into the pulmonary vasculature is the most common form of spread to the lungs and can result in extensive vascular occlusion without roentgenologic evidence of pulmonary parenchymal involvement. Winterbauer (1). in a review of the incidence and clinical significance of tumor embolization, found evidence of microscopic tumor embolization to the lungs in 60 of 79 patients with primary hepatocellular carcinoma. In 72.5% of these cases, tumor embolization was classified as an incidental finding. In 15 % of patients, the finding of pulmonary vascular involvement by tumor was considered only contributory to their symptoms of respiratory in that there was also evidence of pulmonary parenchymal involvement or a second primary cardiopulmonary problem. Only in 12.5% of patients was tumor embolization thought to be the primary cause of respiratory and a major

4 November 1984 PULMONARY HYPERTENSION AND HEPATOMA 1183 Table 1. Summary of Clinical Findings in Five Cases of Hepatocellular Carcinoma and Complicating Pulmonary Hypertension due to Tumor Emboli Case Clinical findings report Survival Pulmonary Right Investigations reference Clinical from Pulmonary hypertension heart Pulmonary No. Age Sex presentation presentation infarction (mmhg) failure Chest x-ray Lung scan angiogram 1 61 M Respiratory 12 wk disease 2 58 M Recurrent 9 wk pulmonary infarction 3 60 M Respiratory 10 wk 4 63 M Respiratory 13 mo Present 48 F Respiratory 20 mo case a LUL. left upper lobe. 50/10 plus Lung fields Multiple Occlusion clinical clear defects of lobar arteries right and left lobes Clinical plus Decreased Not done Not done serial ECGs vascular marking in the lower one-third of the right lung and entire left lung 35/? plus Lung fields Multiple Diffuse obclinical clear defects struction of pulmonary artery tree. relative sparing LUL" 45/10 Lung fields Normal Inadequate clear 132/44 Lung fields Normal Distal clear pruning of pulmonary arteries contributing factor to death in that these patients died with respiratory failure in the absence of significant pulmonary parenchymal, lymphatic, or pleural metastases. In only 1 patient was pulmonary hypertension a chronic problem (6 mol. In the remaining patients the pulmonary embarrassment was acute, varying from 6 h to 7 wk from onset to death. The usual mode of spread of tumor emboli to the lungs from primary hepatocellular carcinoma is via the hepatic veins, inferior vena cava, and right heart. In this case, as there was no involvement of a major hepatic vein by tumor, it is likely that tumor cells invading the portal vein were the major source of emboli to the pulmonary microvasculature via the patent splenorenal shunt. Pulmonary emboli originating from a non tumor thrombus in the portal vein and reaching the lungs via a patent surgical shunt is a rare but well-documented cause of pulmonary hypertension (9-12). We, however, are unaware of any previous reports of tumor emboli rising from the portal vein resulting in pulmonary hypertension. Despite the documented frequency of pulmonary arterial involvement with tumor emboli in primary liver cell carcinoma, there are only 4 reported cases of associated pulmonary hypertension (Tables 1 and 2). In 3 of these cases, the clinical course was brief, the pulmonary hypertension was moderate, and there was clinical evidence of pulmonary infarction. Tumor emboli involved the large and small pulmonary arteries and arterioles, and the emboli arose from tumor involvement of a major hepatic vein. The fourth patient's clinical course was very similar to that of the present case. Symptoms of respiratory continued over a period of months and tumor emboli occluded only the more peripheral pulmonary microvasculature. Pulmonary infarction was not evident clinically and no major hepatic vein was invaded by tumor. All tumor emboli should not necessarily be regarded as metastases because there is good evidence that the majority of such tumor fragments are destroyed or contained within the vessel's lumen without any

5 1184 WILLETT ET AL. GASTROENTEROLOGY Vol. 87. No.5 Table 2. Summary of Autopsy Findings in Five Cases of Hepatocellular Carcinoma and Complicating Pulmonary Hypertension due to Tumor Emboli Tumor Main Case report involvement or reference of major lobar No. hepatic vein artery 1 RHV RA 2 RHV 3 HV 4 Present case Autopsy data Tumor occlusion Segmental or s u bsegmen ta I artery Small pulmonary artery or arteriole (occlusion of 80% vascular bed) HV, hepatic vein;, illferior vena cava; RA, right atrium; RHV, right hepatic vein. Autopsy evidence of pulmonary infarction Right ventricular hypertrophy evidence of parenchymal invasion. In the present case, multiple tumor emboli undergoing organization and recanalization were evident throughout the pulmonary microvasculature with little evidence of tumor invasion. Schmidt (13) in 1903 investigated 45 patients with abdominal malignancy and found that 15 of these patients hap multiple small tumor emboli to the lung. In 5 of these cases there were no pulmonary metastases. He noted that tumor emboli were commonly associated with thrombus and that during the organization of the thrombus, tumor cells became fewer in number and degenerative in appearance without tumor invasion. It was postulated that the associated thrombus and local factors in the vessel wall inhibit tumor growth and invasion. This may explain why massive pulmonary metastases were not found in the present case as would have been predicted from consideration of tumor doubling times in a patient with a 20-mo history of tumor emboli to the lung. References 1. Winterbauer RH, Elfenbein IB, Ball CB. Incidence and clinical significance of tumor embolization to the lungs. Am I Meci 1968;45 : Storey PB, Goldstein W. Pulmonary embolization from primary hepatic carcinoma. Arch Intern Med 1962;110: Tumulty PA. Clinicopathologic conference: case presentation (JHH ). Johns Hopkins Med j 1967;121: Brisbane IV, Howell DA, Bonkowsky J-IL. Pulmonary hypertension as a presentation of hepatocarcinoma. Am j Med 1980;68: DeVita VT, Trujillo NP. Blackman AH, Ticktin HE. Pulmonary manifestations of primary hepatic carcinoma. Am I Med Sci 1965;250: Benner EM, Labby DH. Hepatoma: clinical experience with a frequently bizarre tumor. Ann Intern Med 1961 ;54: Greenspan EB. Carcinomatous endarteritis of the pulmonary vessels resulting in failure of the right ventricle. Arch Intern Mec\ 1934;54: Kane RD, Hawkins HK, Miller JA, Noce PS. Microscopic pulmonary tumor emboli associated with dyspnoea. Cancer 1975;36: Brill IC, Robertson TO. Subacute cor p ulmonale. Arch Intern Med 193 7;60: Naeye RL. 'Primary' pulmonary hypertension with coexisting portal hypertension. Circulation 1960;22: Lal S, Fletcher S. Pulmonary hypertension and portal venous thrombosis. Br Heart J 1968;30: Sail am M, Watson we. Pulmonary hypertension due to micro-thromboembolism from splenic and portal veins after porta-caval anastomosis. Br Heart I 1970;32: Schmidt MB. Die Verbreitungswege der Karcinome und di e Beziehung generalisierter Sarcome zu den leukamischen Neubildungen. jena, Germany: G. Fischer, 1903.