Surgery Today Jpn. J. Surg. (1992) 22:474-480

SUI~;ERYTOI)AY © Springer-Verlag 1992

Spontaneous Rupture of Hepatocellular Carcinoma: An Approach with Delayed Hepatectomy SUMIO INOUE, 1 TAKESHI NAGAO,1 TOMO WAKABAYASHI,2YOSHIFUMI BECK,1 KOJI S HIMIZU, 1 KENSHI WATANABE,1 SINJI TOMIKAWA,1 KUNJI MITA, 1 HISAYUKI SUGIMOTO,1 a n d H1SANORI UCHIDA l Departments of ~Organ Transplantation, and 2Pathology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108 Japan

Abstract: Two cirrhotic patients with ruptured hepatocellular carcinoma (HCC), presenting with hemoperitoneum, were successfully treated by elective hepatectomy. Both of these patients, a 67-year-old female and a 76-year-old male, had first been taken to other primary hospitals by ambulance due to hypovolemic shock. They were then found to have a mass of approximately 5 cm in the cirrhotic liver. In the initial management, however, neither any direct hemostasis by surgery nor indirect measures such as transcatheter hepatic arterial embolization were performed in either case. Instead, conservative treatment consisting mainly of fresh blood and plasma transfusions were continued for more than a month until the liver function stabilized. In both hepatectomies, the use of a microwave tissue coagulator resulted in minilnal intra-operative blood loss and an appreciably excellent postoperative course. These cases point to the effectiveness of a "wait and see" policy for selected patients with ruptured HCC. Key Words: hepatocellular carcinoma, spontaneous rupture,

delayed hepatectomy

Introduction

A spontaneous rupture is not such an unusual presentation of hepatocellular carcinoma (HCC), occurring in 11% of patients that succumb to HCC. t The immediate surgical intervention of the hemoperitoneum is often hazardous to patients with an impaired liver function such as coagulopathy, and therefore, an indirect or a non-surgical approach such as hepatic artery ligation2"3 or transcatheter embolization of hepatic artery (TAE) 4'5 has been recommended. In particular, TAE, used alone or as an adjunct to subsequent hepatectomy6 has recently become the treatment of Reprint requests to: S. Inoue (Received for publication on Feb. 1, 1991;.accepted on Jan. 10, 1992)

choice. However, TAE has occasionally been reported to be associated with severe hepatic dysfunction leading to liver failure. 7 Recently, two patients with a ruptured HCC were successfully treated by elective hepatectomy without perioperative TAE.

Case 1

A 67-year-old housewife was admitted, because of a hepatic tumor which was confirmed at a previous laparotomy. She had been well until 13 weeks prior to admission when abdominal pain and subsequent fainting spells developed. She was taken by ambulance to the hospital to receive a blood transfusion and discharged 16 days later, but only 2 days thereafter she was readmitted due to a deterioration of consciousness. She was then transferred to another hospital with a diagnosis of liver cirrhosis and hemoperitoneum. An exploratory laparotomy there revealed a ruptured hepatic tumor, but no active bleeding. Computed tomography (CT) of the liver showed a 5cm round solid mass in the left lateral segment and fluid collection as well (Fig. 1). Then, she was referred to our hospital. On admission, she was found to be hemodynamically stable but had symptoms of mild hepatic encephalopathy. The white cell count was 2,000, hemoglobin 9.8mg/dl, and hematocrit 31.8%. Serum glutamic oxaloacetic transaminase (GOT) was 113 IU/I (normal 10-30), glutamic pyruvic transaminase (GPT) 103 IU/1 (normal 0-30), albumin 3.7mg/dl, and bilirubin 1.5mg/dl. The coagulation factors were decreased; platelet count was 42,000 and prothrombin time was 62% of the control. Indocyanine green (ICG) clearance as assessed by ICG-Rmax8 was markedly reduced to 0.30 (normal 1.4-1.8mg/kg/min), and glucose tolerance was also impaired with normal insulin output.

S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy

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Fig. 1. Abdominal CT performed in Case 1 one month after rupture. A cirrhotic liver surrounded by a large volume of fluid is seen. A low density focal lesion of about 4cm (arrow) is located in the periphery of the enlarged lateral segment

Fig. 2. Hepatic arteriogram taken of case 1 3 months after rupture. A rather weak tumor stain (large arrow) is seen in the lefimost part of the liver, fed by lateral segmental branches. An enlarged spleen is also visible behind (small arrows)

The liver tumor was hypervascular on the angiogram (Fig. 2). CT and ultrasonogram showed a solid mass in contact with the stomach and a small amount of intraperitoneal fluid. An endoscopic examination revealed the presence of non-bleeding esophageal varices, and a compression of the anterior wall of the upper gastric body. The serum alpha-fetoprotein (AFP) was elevated to 12,000 I U / m l (normal < 5 IU/ml). Following a supplementation of fresh plasma and platelet transfusions, elective hepatectomy and splen-

ectomy were p e r f o r m e d 16 weeks after the rupture of the tumor. On laparotomy, there was no evidence of hemoperitoneum but extensive fibrous adhesion around the tumor, anteriorly to the o m e n t u m and posteriorly the stomach wall, was observed. The left lateral segment including the tumor was amputated, using a microwave coagulator, without inflow occlusion (Pringle's maneuver). A prophylactic splenectomy was also performed. The operating time was 4 h 10 min, and 800 ml

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S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy

Fig. 3. The site of rupture in case 1 covered partly by gastric smooth muscle (solid arrow). Note that the thin elastic layer (triangular box) is disrupted with an adjacent granulomatous reaction with hemosiderin deposition, which obscures the fibrous capsule extending from hepatocellular carcinoma (open arrow). (Elastica van Gieson stain, x4)

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of fresh blood was transfused during the operation. A histological examination of the resected specimen showed hepatocellular carcinoma with a trabecular pattern, and the hepatic tissue uninvolved by the t u m o r showed advanced cirrhosis. There was a m a r k e d granulomatous inflammation around the site of the rupture (Fig. 3). The postoperative course was uneventful. The patient was discharged on day 25, and has now been doing well for more than 15 months with no signs of either recurrence or a deterioration of liver function. Serum alpha-fetoprotein sharply fell to 270IU/ml by the time of discharge, and subsequently returned to near normal values (Fig. 4).

Fig. 4. Perioperative liver function tests and alphafetoprotein in case 1. Note that hepatectomy was performed as late as 4 months after rupture, and that the deterioration of the liver function caused by the surgery was transient. After the surgery, the AFP dropped sharply and remained low. The solid squares represent bilirubin, the open circles represent GPT, and the box within a box represents AFP. RUP, rupture; ADM, admission; OPE, operation; DIS, discharge; W, weeks

Case 2

A 76-year-old Buddhist priest was transferred to our hospital, because of h e m o p e r i t o n e u m and a hepatic mass demonstrated on CT (Fig. 5). H e had been well since 6 months earlier when he suddenly experienced a dull pain in his right flank. H e was taken to a nearby hospital and transfused with m o r e than 2,000ml of blood for hypovolemic shock. The hematocrit of the peritoneal tap was 7%. An emergency CT examination of the a b d o m e n revealed a 5 cm solid mass in the upper part of the right liver. Two days later, his condition stabilized and he was transferred to our hospital. On admission to our

S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy

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Fig. 5. Abdominal computed tomography by taken of case 2 the day after rupture. Perihepatic fluid collection is less marked than in case 1. A low density tumor of about 4.5cm is located in the anterior segment of the liver. Apart from a tiny low density nodule in the lateral segment, no other lesions are present

Fig. 6. Hepatic arteriogram, taken of case 2 shortly after rupture. A hypervascular tumor receives a prominent inflow through the arterial branch to anterior superior subsegment. Marginal feeders are partly disrupted presumably at the point of rupture

(arrow)

unit, his white cell count was 6,500, red cell count 415, hemoglobin 13.9, and platelet count 31,000. The prothrombin time was 90% of the control value. Serum G O T was 420IU/1, G P T 187IU/1, albumin 3.6mg/dl, and bilirubin 4.1mg/d. Serum alpha-fetoprotein was 6.7IU/ml. ICG-Rmax was reduced to 0.46 mg/kg/min, and a mild to moderate glucose intolerance was also present. An ultrasound examination showed intraperitoneal fluid collection and two solid lesions in the liver; the larger one in the right lobe was a 5 cm encapsulated mass facing the diaphragma and the smaller lesion,

measuring 1.5cm, was in the medial segment. Angiography visualized only the larger one in the right lobe, which was hypervascular, but failed to depict the small one. T h e r e was no extravasation of contrast material (Fig. 6). The thrombocytopenia was corrected by platelet transfusion, and surgery was performed 4 weeks after rupture. On laparotomy, the peritoneal cavity no longer contained any bloody fluid, but the hepatic dome was partly covered by a thick plaque consisting of clots. Using a microwave coagulator as in case 1, the larger tumor in the right lobe was excised at least a 1.5 cm

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S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy

Fig. 7. Zone of hepatic necrosis in case 2 occurring along the line of dissection produced by microwave. The boundary (triangular box) is sharply demarcated, and is limited to within a short distance from the cut surface. (H&E, ×8)

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away from the tumor. The smaller nodule was left in place, however, since fine needle aspiration biopsy of the lesion was negative for tumor cells. The operating time was 3 h and 10 rain, and no blood transfusion was required. Histologically, the t u m o r was hepatocellular carcinoma with a trabecular pattern, which was separated from the non-cancerous liver tissue by a thick fibrous capsule except at the point of rupture. Looking at the cut end of the specimen, a sharp line of cellular necrosis was created along the cut surface (Fig. 7). The postoperative course was uneventful apart from a transient rise of serum bilirubin with a peak of 2.5 mg/dl on day 3, which then fell to 1.0mg/dl by day 22 when he was discharged from the hospital. The serum transaminases also fell down to normal by the

via hepatectomy to discharge from hospital. Significantly elevated levels of bilirubin and GPT may be attributed to hemolysis of blood from the hemoperitoneum. The sharp and temporary rise in GPT on day 1 was presumably due to extensive tissue injury by the microwave coagulator. In this patient, the serum AFP remained low. For abbreviations see Fig. 4

time of discharge (Fig. 8). For at least 6 months after the surgery, he was well and free of t u m o r recurrence. Thereafter, the remaining lesion in the medial segment started to grow and, in addition, multiple smaller lesions became visible on an ultrasonogram. For m o r e than 12 months, however, there has been no clinical sign of extrahepatic recurrence such as peritoneal spread. The level of alpha-fetoprotein remained below 12 I U / m l throughout the entire course.

Discussion Although newer diagnostic and therapeutic modalities have facilitated the treatment of hepatic tumors, a spontaneous rupture of H C C is still a life-threatening condition, and has been reported to carry a mortality

S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy rate of more than 80% in patients managed conservatively. 2 HCC is not only characterized by hypervascularity which can often lead to fatal hemoperitoneum when ruptured, but is also closely associated with liver cirrhosis which causes disturbance of a hemostasis. Moreover, a rupture of H C C tends to occur during the advanced stage when a tumor often extends to the portal and/or hepatic venous channels, and a good long-term prognosis is therefore unlikely. Replacing the immediate surgical approach such as hepatectomy and hepatic arterial ligation, non-surgical T A E is now becoming a preferred mode of treatment. Although this procedure is a safe and efficient method to temporarily control bleeding, it is likely to cause further ischemic insult to the hepatic parenchyma with an already decreased blood flow. In fact, hepatic failure was reported to be a leading cause of early deaths following T A E for ruptured H C C . 5"7 Among those who died within a month of rupture, 67% of patients (2/3) treated with T A E died of hepatic failure, while it constituted only 30% (4/13) of patients treated conservatively. 7 In another series, 63% (5/8) of patients treated with T A E died of hepatic failure within a month of the first T A E . s T A E has been shown to uniformly reduce the arterial ketone body ratio, which is an excellent prognostic indicator of energy status in liver mitochondria immediately after the procedure. 9 In the presence of liver cirrhosis, such a TAE-induced ischemic insult may further be aggravated, since liver perfusion has been shown to depend more on the hepatic arterial flow relative to the portal flow than that in normal subjects.l° In addition, T A E tends to be non-selective as a treatment of emergent hemostasis in ruptured HCC, where the incidence of extravasation of contrast material has been reported to be as low as 0 % - 1 0 % . 5'7 Thus, before choosing this therapy, it must be both carefully but quickly determined whether direct hemostatic effect outweighs the risk of worsening hepatic function and the resultant increased bleeding tendency. When T A E is considered inappropriate or when surgical measures such as arterial ligation and hepatectomy prove ineffective, providing direct pressure on the bleeding sites can be employed. This may be achieved by surgical packing with gauze, tl by waiting for a thick layer of thrombus to spontaneously form as in case 2, or by the "pressure effect" generated by the accumulation of intraperitoneal blood and fluid. In this regard, an intra-abdominal emergency due to hemoperitoneum should be dealt with differently from a gastrointestinal hemorrhage where there is no spontaneous hemostatic mechanism but there is profound hypotension. The pressure effect, however, may be superficial and temporary, with a possibility of recurrent bleeding even in the short-term.

479 As a stronger measure to control bleeding from ruptured HCC, a microwave coagulator has been successfully applied to the bleeding tumor and adjacent cirrhotic liver tissue. 12 This method has two merits; it can achieve effective tumor necrosis (Fig. 7) as well as hemostasis in the cirrhotic liver without interfering with hepatic blood inflow. This device has been widely used for hepatectomy in cirrhotic patients, in whom operative blood loss has been proven to be a major determinant in the short-term prognosis.~3 Although it seems likely that a spontaneous rupture of tumor would cause a dissemination of tumor cells, 14 there have been few reports of a ruptured HCC resulting in fatal peritoneal dissemination. In our case 2 with a recurrent tumor, there were no clinical signs of peritoneal dissemination of tumor cells at the time of rupture, but the small residual lesion which was left in the liver, presumably resulted in a multiple intrahepatic spread later on. In accordance with the above data as well as the available information, the majority of longterm survivors after a rupture of HCC, although there have been very few so far, consist of those patients who have undergone hepatectomy.~l'~5 Therefore, hepatectomy would be the treatment that offers the best chance of long-term survival to the patients with ruptured HCC, even though in theory it may not be a fully curative procedure. In order to perform a successful hepatectomy on a damaged liver, however, great care must be taken to determine when to operate and how little of the liver to resect so that the risk of posthepatectomy liver failure can be minimized while increasing the chance of cure. In our two cases, the hepatic functional reserves as assessed by ICG Rmax were marginal, and liver function tests on admission were outside the normal range. In both cases, surgery was postponed until liver enzymes and bilirubin levels normalized or were near normal. During hepatectomy, great care was taken to minimize not merely blood loss but also such an ischemic insult to the liver as produced by Pringle's maneuver. Through the strong hemostatic effect, the use of a microwave coagulator has made a limited and nonanatomical hepatectomy on cirrhotic liver much easier and safer. In addition, thanks to the powerful and controlled tissue destruction (as depicted in Fig. 7), the plane of dissection can be set closer to the tumor with a minimal chance of leaving viable tumor tissue in the remaining liver. 12 In previous reports, 4'5'7 the majority of patients with ruptured HCC had large tumors and/or portal vein thrombi in large tributaries, both of which are thought to be major risk factors for performing T A E . Compared with those patients, the two patients presented here, although marginal in hepatic functional reserve as assessed by ICG-Rma×, were fortunately at an earlier

480 clinical s t a g e w h e r e t h e t u m o r was s m a l l e r a n d welll o c a l i z e d a n d t h e r e was no gross t u m o r t h r o m b u s in t h e p o r t a l vein. It is c o n c e i v a b l e t h a t b o t h t u m o r s h a d d e v e l o p e d so n e a r t h e liver surface t h a t t h e y h a d l i k e l y s u r f a c e d e a r l y e n o u g h to cause an " a c u t e a b d o m e n " b e f o r e going into t h e late stages, u n n o t i c e d , a n d which also m a d e s u r g e r y e a s i e r as well. W e feel that, d e l a y e d h e p a t e c t o m y using a m i c r o w a v e c o a g u l a t o r , u n p r e c e d e d b y T A E , is at p r e s e n t a safe a n d effective surgical s t r a t e g y for s e l e c t e d p a t i e n t s with r u p t u r e d h e p a t o c e l l u l a r c a r c i n o m a .

Acknowledgments.

We wish to thank the following doctors for their referral of patients to our department: M. Inada, MD, M. Ishizaki, MD, and T. Kanayama, MD, Department of Surgery, Tokyo Senbai Hospital, Tokyo.

References 1. The Liver Cancer Study Group of Japan: Primary liver cancer in Japan. (1990) Ann Surg 211:277 2. Chearanai O, Plengvanit U, Asavanich C, Damrongsak D, Sindhvananda K, Boonyapisit S (1983) Spontaneous rupture of primary hepatoma: Report of 63 cases with particular reference to the pathogenesis and rationale of treatment by hepatic artery ligation. Cancer 51:1532-1536 3. Lai ECS, Choi TK, Fan ST, Wong J (1989) Spontaneous ruptured hepatocellular carcinoma: An appraisal of surgical treatment. Ann Surg 210:24-28. 4. Satoh Y, Fujiwara K, Furui S, Ogata I, Oka Y, Hayashi S, Ohta Y, Iio M, Oka H (1985) Benefit of transcatheter arterial embolization for ruptured hepatocellular carcinoma complicating liver cirrhosis. Gastroenterology 89:157-159.

S. Inoue et al.: Ruptured HCC and Delayed Hepatectomy 5. Ohtomo K, Furui S, Kokubo T, Yamauchi T, Yashiro N, Itai Y, Iio M (1988) Transcatheter arterial embolization for spontaneous rupture of hepatocellular carcinoma. Radiat Med 6(4): 150-156. 6. Chen MF, Jan YY, Lee TY (1986) Transcatheter hepatic arterial embolization followed by hepatic resection for the spontaneous rupture of hepatocellular carcinoma. Cancer 58:332-335. 7. Ohta H, Nomoto M, Ozaki T, Vemura T, Ichida F, Soga K, Yamada T, Honma A, Shimizu T (1987) A clinical study of ruptured hepatocellular carcinoma (In Japanese). Nippon Shokakibyo Gakkai Zasshi (Jpn J Gastroenterology) 84: 690-697. 8. Rikkers LF, Moody FG (1974) Estimation of functional hepatic mass in resected and regenerating rat liver. Gastroenterology 67:691-699. 9. Tani T, Taki Y, Jikko A, Minematsu S, Yamamoto M, Kamiyama Y, Tobe T, Ozawa K (1986) Short-term changes in blood ketone body ratio in the phase immediately after hepatic artery embolization: Their clinical significance. Am J Med Sci 291:93-100. 10. Gianopalo M (1989) Massimo B, Enzo S, Corrado M. Assessment of liver circulation by quantitative scintigraphy: Evaluation of the relative contribution of the hepatic arterial and portal venous blood flows to liver perfusion. Eur J Nucl Med 15: 211-216. 11. Ong GB, Taw JL (1972) Spontaneous rupture of hepatocellular carcinoma. Br Med J 4:146-149. 12. Tabuse K, Katsumi M (1981) Application of a microwave tissue coagulator to hepatic surgery-the hemostatic effects on spont aneous rupture of hepatoma and tumor necrosis. Arch Jpn Chir 50:571-579. 13. Nagao T, Inoue S, Mizuta T, Saito H, Kawano N, Morioka Y (1985) One hundred hepatic resections-indications and operative results. Ann Surg 202:42-49. 14. Sonoda T, Kanematsu T, Takenaka K, Sugimachi K (1989) Ruptured hepatocellular carcinoma evokes risk of implanted metastases. J Surg Oncol. 41:183-186. 15. Nagasue N, Inokuti K (1979) Spontaneous rupture of hepatoma. Br J Surg 66:248-250.