ANTICANCER RESEARCH 37 : 1381-1386 (2017) doi:10.21873/anticanres.11459

Post-hepatectomy Refractory Ascites in Cirrhotic Patients with Hepatocellular Carcinoma : Risk Factor Analysis to Overcome this Problematic Complication SHINJI ITOH 1,2 , HIDEAKI UCHIYAMA 1, YASUHARU IKEDA 1, KAZUTOYO MORITA 1, NOBORU HARADA 1, KEISHI SUGIMACHI 1, HIROFUMI KAWANAKA 1, DAISUKE KORENAGA 1, TOMOHARU YOSHIZUMI 2, KENJI TAKENAKA 1 and YOSHIHIKO MAEHARA 2

1Department of Surgery, Fukuoka City Hospital, Fukuoka, Japan; 2Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Abstract. Background: Refractory ascites is a serious post- hepatectomy refractory ascites. Surgeons should avoid hepatectomy complication in cirrhotic patients with extensive dissection of these ligaments in order to avoid this hepatocellular carcinoma (HCC). In order to avoid this detrimental complication. complication, surgeons should preserve as much liver parenchyma as possible in performing hepatectomy in such Hepatocellular carcinoma (HCC) is the sixth most prevalent patients. However, we still occasionally encounter refractory cancer worldwide and the third most common cause of ascites even after limited or small hepatectomy. The aim of cancer related death (1, 2). Hepatectomy has been this study was to identify risk factors for post-hepatectomy established as one of the most effective treatment for HCC, refractory ascites in cirrhotic patients, focusing on limited and is often performed in patients with cirrhosis (3-5). or small hepatectomy. Patients and Methods: The data of 73 However, the incidence of postoperative complications cirrhotic patients with HCC who underwent limited or small after hepatectomy is still high (6-8). Cirrhotic patients have hepatectomy were analyzed. Limited or small hepatectomy elevated portal venous pressures, decreased function of the was defined as hepatectomy equal to or of less than reticuloendothelial system and impaired regeneration and subsegmentectomy. We compared the clinicopathological coagulopathy (9). Therefore, hepatectomy in cirrhotic factors between patients with and without postoperative patients is usually accompanied by more problems than refractory ascites. Results: Fourteen cirrhotic patients non-cirrhotic patients, including ascites, pleural effusion, suffered postoperative refractory ascites. Total cholesterol, septic complications, and post-hepatectomy liver failure duration of operation, duration of Pringle maneuver, (10). We previously reported that cirrhosis and resection of segment VII, intraoperative blood loss, and intraoperative blood loss are risk factors for developing intraoperative blood transfusion were found to be significant postoperative complications after hepatectomy (8). Limited risk factors for postoperative refractory ascites in univariate hepatic resection and subsegmentectomy of the liver for analyses. Multivariate analysis revealed that resection of cirrhotic patients with HCC have been indicated to preserve segment VII was an independent risk factor. Conclusion: liver tissue and avoid a liver failure after hepatectomy (11- Resection of segment VII necessitates extensive dissection of 13). Various technical methods for parenchymal transection the right triangular or coronary ligaments, which could have been developed to reduce intraoperative blood loss explain that it was an independent risk factor for post- (14, 15). So far, there have been only restricted number of published reports about post-hepatectomy complication in cirrhotic patients with HCC (16, 17). However, to the best Correspondence to: Shinji Itoh, MD, Ph.D., Department of Surgery of our knowledge, there are no previous data on post- and Science, Graduate School of Medical Sciences, Kyushu hepatectomy refractory ascites focused on restricted University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. hepatectomy including subsegmentectomy or limited Tel: +81 926425466, Fax: +81 926425482, e-mail: itoshin@ surg2.med.kyushu-u.ac.jp resection for cirrhotic patients with HCC. The objectives of this study were to identify risk factors for refractory ascites Key Words: Refractory ascites, cirrhosis, hepatocellular carcinoma after limited or small hepatectomy to treat HCC in cirrhotic hepatectomy. patients.

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Patients and Methods Table I. Postoperative complications after limited or small hepatectomy in 19 out of the 73 cirrhotic patients with hepatocellular carcinoma. Patients. 73 cirrhotic patients that underwent limited or small hepatectomy (subsegmentectomy or less) for primary HCC at our Complications Number of patients the Department of Surgery, Fukuoka City Hospital, between April 2000 and May 2012. Patient’s clinical, surgical, and pathological Refractory ascites 14 data were collected retrospectively from the institute’s database, as Pleural effusion 4 Local wound complications 4 well as from each patient’s medical chart. Cirrhosis was confirmed Intra-abdominal infection 2 by the histological specimens (18). The study protocol was carried Bile leakage 2 out in accordance with the Code of Ethics of the World Medical Gastrointestinal bleeding 1 Association (19). All of the patients were evaluated at a multidisciplinary tumor board conference of surgical oncologists, medical oncologists and interventional radiologists (20). The indication and the extent of hepatectomy were decided by tumor location, tumor size and conventional liver function tests. Liver Table II. Limited or small hepatectomy for each segment of the liver. transection was performed using an ultrasonic dissection aspirator (SONOP; ALOKA, JAPAN). Inflow vascular control was performed Segment Number of Number of Number of Number of with hepatic pedicle occlusion (Pringle maneuver) for 15 min and patients limited subsegmentectomy refractory then releasing the occlusion for 5 min (21). Postoperative resection ascites complication was graded in accordance with the Dindo-Clavien I 1 1 0 0 (0.0%) classification (22). In this study, post-hepatectomy complications of II 6 6 0 1 (16.7%) Clavien’s grade II or more were analyzed. Post-hepatectomy III 6 5 1 1 (16.7%) refractory ascites was defined as ascites that required the IV 9 9 0 1 (11.1%) administration of intravenous albumin or paracentesis in this study. V 10 4 6 1 (10.0%) Operative mortality was defined as a patient death within 30 days VI 11 5 6 2 (18.2%) after surgery. VII 12 9 3 5 (41.7%) VIII 18 13 5 3 (20.0%) Statistical analysis. Continuous variables are presented as a median (range) and compared using the Mann-Whitney U-test. Categorical variables were compared using a χ2 test or Fisher’s exact test. Logistic regression analysis was performed to identify independent variables for post-hepatectomy refractory ascites. Differences were considered significant at p<0.05. All statistical analyses were performed using the There were no significant differences between two groups StatView 5.0 (Abacus Concepts, Berkeley, CA, USA). regarding liver function. In univariate analysis, total cholesterol, duration of operation, duration of Pringle Results maneuver, resection of segment VII, intraoperative blood loss, intraoperative blood transfusion were significant risk Nineteen of the 73 cirrhotic patients (26.0%) suffered factors for postoperative refractory ascites after limited or postoperative complications, as detailed in Table I. Refractory small hepatectomy in the cirrhotic patients with HCC. ascites was the most commonly encountered postoperative Logistic regression analysis of factors including total complication after limited or small hepatectomy in cirrhotic cholesterol, duration of operation, duration of Pringle patients. There was no mortality nor hospital death. maneuver, resection of segment VII, intraoperative blood The segmental locations of the 73 hepatectomies included loss, intraoperative blood transfusion, all of which were one located in the segment I, six in the segment II, six in the judged as a statistically significant risk factor in univariate segment III, nine in the segment IV, ten in the segment V, analysis, revealed that only resection of segment VII (Table eleven in the segment VI, twelve in the segment VII and IV) was an independent risk factor. eighteen in the segment VIII, as defined by Couinaud (23) (Table II). Five out of the 12 hepatectomies of the segment Discussion VII (41.7%) had post-hepatectomy refractory ascites. Ultrasonography guided paracentesis was performed in 5 Ascites is generally considered a consequence of cirrhotic patients with post-hepatectomy refractory ascites. The liver, and patients with refractory ascites may have a higher median postoperative hospital stay in patients with post- risk of mortality (24, 25). Resection of a cirrhotic liver may hepatectomy refractory ascites (28 days, range: 17-74 days) lead to decreased liver function and elevate portal pressure was significantly longer than that in patients without ascites because of the decrease of the hepatic vascular bed, which (18 days, range: 12-46 day; p< 0.001). may result in refractory ascites and patient mortality. The clinicopathological data for the cirrhotic patients with Although several published studies have been described the vs . without refractory ascites are compared in Table III. risk factors for ascites after hepatectomy in patients with

1382 Itoh et al : Refractory Ascites After Minor Hepatectomy in Cirrhotic Patients

Table III. Comparison of cirrhotic patients with hepatocellular carcinoma after limited or small hepatectomy with and without postoperative refractory ascites.

Variables With ascites Without ascites p-Value (n=14) (n=59)

Age (years) 64 (47-80) 66 (41-80) 0.574 Gender (male/female) 9/5 40/19 >0.999 HBs-Ag positive 2 (14.3 %) 13 (22.0 %) 0.719 HCV-Ab positive 10 (71.4 %) 39 (66.1 %) >0.999 Child Pugh (A/B) 11/3 54/5 0.174 Portal hypertension 9 (64.3 %) 29 (49.2 %) 0.380 Diabetes mellitus 5 (35.7 %) 19 (32.2 %) >0.999 Albumin (g/dl) 3.5 (3.1-4.3) 3.8 (2.7-4.8) 0.211 Total bilirubin (mg/dl) 1.0 (0.5-2.0) 1.0 (0.4-2.2) 0.700 Prothrombin time (%) 82 (65-109) 87 (65-137) 0.131 ICGR15 (%) 23 (5-33) 19.5 (3-55) 0.588 Platelets (x104/mm3) 9.3 (5.1-22.7) 10.3 (2.6-24.1) 0.113 AST (IU/l) 71 (24-117) 50 (17-155) 0.079 ALT (IU/l) 54 (8-85) 47 (11-164) 0.293 Total cholesterol (mg/dl) 142 (94-223) 170 (79-256) 0.039 Creatinine (mg/dl) 0.7 (0.5-1.0) 0.8 (0.5-2.0) 0.066 Tumor size (cm) 3.0 (1.5-5.2) 2.6 (1.2-8.0) 0.305 Duration of operation (min) 248 (198-421) 215 (97-345) 0.001 Duration of Pringle maneuver (min) 70 (30-160) 45 (15-115) 0.024 Limited resection/subsegmentectomy 9/5 43/16 0.526 Resection of segment VII 5 (35.7%) 7 (11.8%) 0.030 Blood loss (ml) 1329 (155-2991) 604 (10-2305) 0.005 Blood transfusion 5 (35.7 %) 3 (5.1 %) 0.005 Mortality 0 (0.0 %) 0 (0.0 %) >0.999

HBs-Ag, Hepatitis B surface antigen; HCV-Ab, hepatitis C virus antibody; ICGR15, indocyanine green dye retention at 15 min; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Values are expressed as a percentage in parentheses or a median (range).

HCC (26-28), to the best of our knowledge, predictors for Table IV. Multivariate analysis of the risk factors for postoperative ascites after limited or small hepatectomy preserving as refractory ascites after limited or small hepatectomy in cirrhotic much liver tissue as possible ( i.e. , limited resection or patients with hepatocellular carcinoma. subsegmentectomy) remained to be elucidated. Therefore, we Variables Odds ratio (95% CI) p-Value retrospectively investigated the risk factors for postoperative refractory ascites after limited or small hepatectomy in Total cholesterol 0.979 (0.95-1.00) 0.107 cirrhotic patients with HCC. Duration of operation 1.013 (0.99-1.03) 0.210 In this study, we found that resection of segment VII was Duration of Pringle maneuver 1.013 (0.97-1.05) 0.502 Resection of segment VII 11.8 (1.83-76.7) 0.009 a risk factor for developing postoperative refractory ascites Intraoperative blood loss 1.00 (1.00-1.00) 0.179 after limited or small hepatectomy in cirrhotic patients by the Intraoperative blood transfusion 3.77 (0.36-38.6) 0.263 multivariate analysis. In general, the hepatic lymphatic system falls into three categories depending on their location; CI, Confidence interval. portal, sublobular, and superficial lymphatic vessels (29, 30). Superficial lymphatic vessels in human liver form a very dense network and their efferent vessels travel in several directions (31, 32). Some of the lymphatic vessels coming drain into those along the inferior vena cava. Under cirrhosis, from the central area run in the falciform ligament toward the hepatic lymphatic system is developed, these flow are the diaphragm, others pass downward into the lymph nodes increased, and superficial lymphatic vessels are well of porta hepatis. The lymphatic vessels from the lateral area observed. Liver must be mobilized by sectioning the of the liver convexity advance in the triangular ligament falciform, triangular and coronary ligaments in some of the toward the diaphragm and lead into the pancreaticolienal hepatectomy. In patients undergoing resection of the segment lymph nodes. The lymphatic vessels in the coronary ligament VII, the right triangular and the coronary ligaments, which

1383 ANTICANCER RESEARCH 37 : 1381-1386 (2017) are including the superficial lymphatic vessels, must be more the right liver, seems to be associated with the development extensively dissected to mobilize the right liver than the of postoperative refractory ascites. We recommend that other segments. Therefore, the leakage of lymph into the mobilization of cirrhotic liver be restricted in order to peritoneal space would be enhanced and formed as prevent this detrimental complication. postoperative ascites. In order to prevent the leakage of lymph we must take into consideration the postoperative References refractory ascites after limited or small hepatectomy for segment VII and refrain from the mobilization of a cirrhotic 1 Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. liver as much as possible. Lancet 379 : 1245-1255, 2012. Recently, we reported that pure laparoscopic partial 2 El-Serag HB: Epidemiology of viral hepatitis and hepatocellular 142 hepatectomy could be safely performed and useful in carcinoma. Gastroenterology : 1264-1273, 2012. 3 Takenaka K, Kawahara N, Yamamoto K, Kajiyama K, Maeda T, cirrhotic liver using a newly-developed vessel sealing Itasaka H, Shirabe K, Nishizaki T, Yanaga K and Sugimachi K: device, BiClamp (33). According to Ikeda et al. (34), pure Results of 280 liver resections for hepatocellular carcinoma. laparoscopic liver resection in the semiprone position Arch Surg 131 : 71-76, 1996. could be performed for resected tumors located in the 4 Shirabe K, Takeishi K, Taketomi A, Uchiyama H, Kayashima H segment VI, VII, or VIII. Moreover, pure laparoscopic and Maehara Y: Improvement of long-term outcomes in hepatitis partial hepatectomy seemed to reduce postoperative C virus antibody-positive patients with hepatocellular carcinoma complication. A further study is needed in order to after hepatectomy in the modern era. World J Surg 35 : 1072-1084, 2011. compare surgical outcomes between open and pure 5 Itoh S, Morita K, Ueda S, Sugimachi K, Yamashita Y, Gion T, laparoscopic limited or small hepatectomy for the segment Fukuzawa K, Wakasugi K, Taketomi A and Maehara Y: Long- VII in cirrhotic patients. term results of hepatic resection combined with intraoperative In this study, we found that prolonged Pringle maneuver local ablation therapy for patients with multinodular and low total cholesterol level were significant risk factors hepatocellular carcinomas. Ann Surg Oncol 16 : 3299-3307, 2009. for developing postoperative refractory ascites by univariate 6 Shimada M, Takenaka K, Fujiwara Y, Gion T, Shirabe K, Yanaga analyses. However, they did not reach statistical significance K and Sugimachi K: Risk factors linked to postoperative morbidity in patients with hepatocellular carcinoma. Br J Surg in the multivariate analysis. The Pringle maneuver is an 85 : 195-198, 1998. effective and simple means for reducing blood loss during 7 Taketomi A, Kitagawa D, Itoh S, Harimoto N, Yamashita Y, liver transection, and has been widely used during Gion T, Shirabe K, Shimada M and Maehara Y: Trends in hepatectomy. However, Pringle maneuver inherently results morbidity and mortality after hepatic resection for hepatocellular in some degree of ischemia/reperfusion injury of the liver carcinoma: An Institute’s experience with 625 patients. J Am (35, 36). Sugiyama et al. reported that parameters of hepatic Coll Surg 204 : 580-587, 2007. functional reserve were significantly impaired by the use of 8 Itoh S, Shirabe K, Taketomi A, Morita K, Harimoto N, Tsujita Pringle maneuver in cirrhotic patients with HCC (37). Total E, Sugimachi K, Yamashita Y, Gion T and Maehara Y: Zero mortality in more than 300 hepatic resections: validity of cholesterol and its fractions, such as serum albumin, are preoperative volumetric analysis. Surg Today 42: 435-440, 2012. markers of nutritional status (38). In cirrhotic patients, there 9 Tobe T: Hepatectomy in patients with cirrhotic liver: clinical and was a significant decrease in total cholesterol serum level basic observation. Surg Annu 121 : 515-521, 1984. compared to non-cirrhotic patients and the decrease was 10 Fan ST: Problems of hepatectomy in cirrhosis. related to the severity of the liver disease (39). Taken Hepatogastroenterology 45(Suppl 3) : 1288-1290, 1998. together, the duration of Pringle maneuver and the 11 Kanematsu T, Takenaka K, Matsumata T, Furuta T, Sugimachi preoperative level of total cholesterol might also influence K and Inokuchi K: Limited hepatic resection is effective for selected cirrhotic patients with primary liver cancer. Ann Surg on the incidence of postoperative ascites in cirrhotic patients. 199 : 51-56, 1984. Selection of this study population was intended to 12 Makuuchi M, Hasegawa H and Yamazaki S: Ultrasonically guided maximize homogeneity. Thus, the study comprised highly subsegmentectomy. Surg Gynecol Obstet 161 : 346-350, 1986. selected patients who not only underwent limited or small 13 Yamashita Y-i, Taketomi A, Itoh S, Kitagawa D, Kayashima H, hepatectomy for HCC but also had a cirrhotic liver. We Harimoto N, Tsujita E, Kuroda Y and Maehara Y: Longterm would like to underline that this is the first clinical study to Favorable results of limited hepatic resections for patients with assess the risk factors for postoperative refractory ascites hepatocellular carcinoma. J Am Coll Surg 205 : 19-26, 2007. after selected limited or small hepatectomy in cirrhotic 14 Uchiyama H, Itoh S, Higashi T, Korenaga D and Takenaka K: A Two-Step Hanging Maneuver for a Complete Resection of patients with HCC. Couinaud’s Segment I. Dig Surg 29 : 202-205, 2012. In conclusion, the present study is the first to evaluate risk 15 Itoh S, Fukuzawa K, Shitomi Y, Okamoto T, Kinoshita T, factors for postoperative refractory ascites after limited or Taketomi A, Shirabe K, Wakasugi K and Maehara Y: Impact of small hepatectomy in cirrhotic patients with HCC. Resection the VIO system in hepatic resection for patients with of the segment VII, which needs extensive mobilization of hepatocellular carcinoma. Surg Today 42 : 1176-1182, 2012.

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