- Email: [email protected]
Role of splenectomy in hepatic resection for hepatocellular carcinoma associated with severe cirrhosis and hypersplenism
Hepatology Research 14 (1999) 35 – 48
Role of splenectomy in hepatic resection for hepatocellular carcinoma associated with severe cirrhosis and hypersplenism Naofumi Nagasue *, Hitoshi Kohno, Akira Yamanoi, Haruki Ohmori, Dipok Kumar Dhar, Yoshinari Makino, Takeo Kimoto, Mitsuo Tachibana Shimane Medical Uni6ersity, Second Department of Surgery, Izumao 693 -8501, Japan Received 29 June 1998; received in revised form 15 October 1998; accepted 26 October 1998
Abstract The incidence of hepatocellular carcinoma (HCC) associated with severe cirrhosis has been increasing due to better management of chronic liver disease. This study prospectively aimed to elucidate whether splenectomy is beneficial or detrimental when performed simultaneously with hepatic resection in patients with HCC and hypersplenism due to severe cirrhosis. Splenectomy and subsequent partial hepatectomy were concomitantly performed on 26 patients with Child–Turcotte class B (n= 17) or C (n= 9) cirrhosis, HCC and hypersplenism. Portal pressure was measured before and after splenectomy in 21 cases. Endothelin-1 (ET-1) levels in splenic venous blood were estimated in eight cases. The splenectomy reduced portal venous pressure by 20%. The ET-1 level in splenic venous blood was significantly higher than that in systemic blood indicating the release of ET-1 from the spleen into the portal circulation. Operative morbidity and mortality rates were 23.1 and 11.5%. Child’s class C was improved to class B or A in half of the patients. The 1-, 3-, and 5-year survival rates were 61.5, 42.3 and 16.5%. These results were compared with those of 36 patients with Child’s class B (n= 29) or class C (n= 7) cirrhosis and HCC in whom concomitant splenectomy had not been performed because of weak or no hypersplenism. The
* Corresponding author. Tel.: + 81-853-20-2230; fax: + 81-853-20-229; e-mail: [email protected]. 1386-6346/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 3 8 6 - 6 3 4 6 ( 9 8 ) 0 0 1 0 4 - 1
36
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
extent of hypersplenism and hepatic dysfunction was more severe and the estimated blood loss during surgery was larger in the splenectomy group. Despite such background differences, there were no significant differences between the two groups in postoperative morbidity and mortality rates, causes of late death, and long-term survival rate. Concomitant splenectomy during hepatic resection seems to be beneficial in the treatment of HCC and hypersplenism associated with severe cirrhosis. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Liver cirrhosis; Hypersplenism; Portal hypertension; Hepatic resection; Splenectomy; Endothelin-1
1. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and its incidence is increasing world-wide [1,2]. The main cause of this tumor is chronic infection with hepatitis B and C viruses and the latter is currently recognized as the major cause of HCC [3–5]. The infection with hepatitis C virus is usually insidious and chronic, and finally induces cirrhosis of the liver and HCC. The association between cirrhosis and HCC has been known for many years. The recent advance in treatment methods of chronic liver disease has brought about a higher incidence of HCC associated with advanced cirrhosis. Liver transplantation may be best indicated for patients with advanced cirrhosis complicating small HCCs in the absence of active viral replication [6,7]. However, it was not feasible in our country and transcatheter chemoembolization or percutaneous ethanol injection have been used alternatively. Since the report of Banti [8], the relationship between the liver and the spleen has been extensively disputed. However, there is a traditional belief that splenectomy when performed at an early stage of Banti’s syndrome may prevent the progression of liver disease [9] or that splenectomy frequently improves not only hematologic data but also the general status in patients with advanced cirrhosis [10–13]. In fact, recent investigations in animals have elucidated that splenectomy enhances liver regeneration after partial hepatectomy [14,15], ameliorates hepatic injury induced by endotoxin [16,17] and ischemia-reperfusion [18], and inhibits or suppresses hepatic fibrosis [19,20]. Thus, the spleen seems to play an important role in various pathologic conditions of the liver possibly through such mechanisms as modified responses of immunology and cytokines. During the past 11 years, we prospectively performed splenectomy simultaneously with hepatic resection on 26 patients with severe cirrhosis, HCC and hypersplenism with the hope that the splenectomy would improve not only the hematologic data but hepatic functions in such patients. The results of these patients were compared with those of 36 similar patients on whom concomitant splenectomy had not been performed because of weak or no hypersplenism.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
37
2. Materials and methods During the past 11 years, 292 patients with primary HCC were hospitalized in our department. Curative hepatic resection was carried out on 210 patients (71.9%). In 26 patients with Child – Turcotte class B or C cirrhosis who had splenomegaly and hypersplenism, splenectomy was performed simultaneously with hepatic resection. The indication criteria for splenectomy was principally leucocytopenia less than 3000 mm − 3 and/or thrombocytopenia less than 50 000 mm − 3 associated with splenomegaly and esophageal varices. In total 36 patients with Child’s class B or C cirrhosis in whom splenectomy had not been performed served as control. The clinical data for these patients is shown in Table 1. The incidence of women was significantly higher in the splenectomy group. Other associated conditions are summarized in Table 2. The incidence of esophageal varices was higher in the splenectomy group (73%) than in the control group (33%). The grade of the varices was only slight or moderate in most patients but two patients in the former group with a history of variceal bleeding had received endoscopic injection sclerotherapy before the current admission. Diabetes mellitus was diagnosed by the WHO criteria after ingestion of 75 g glucose. Preoperative hematologic and hepatic functional data are shown in Table 3. Leucocytopenia and thrombocytopenia were more common and liver functions were poorer in the splenectomy group.
2.1. Operati6e procedures In all cases of the splenectomy group, splenectomy was performed first followed by hepatic resection. Thereafter, other additional operations were carried out. Liver resections performed were Couinaud’s one segmentectomy with one wedge resection in one patient, Couinaud’s one segmentectomy in three patients, two wedge resections in four patients, and one wedge resection in 18 patients. In addition to splenectomy, ligation of spontaneous portosystemic shunts was performed in five patients; splenorenal shunt in three and Cruveilheir–Baumgarten syndrome (patent umbilical vein) in two. Cholecystectomy was carried out on all of the eight patients with gallstones. Other concomitant operations included Nissen’s fundoplication for hiatal hernia performed on one patient and distal pancreatectomy for pancreatic cyst on one patient also. In the non-splenectomy group, the types of hepatic resection included extended right lobectomy in one, right lobectomy in two, left lobectomy in one, Couinaud’s two segmentectomy in four, Couinaud’s one segmentectomy in four, two wedge resections in one, and one wedge resection in 23 patients. Cholecystectomy was carried out on five patients with gallstones. Spontaneous splenorenal shunt was ligated in one.
2.2. Intraoperati6e measurements Portal venous pressure was manometrically measured before and after splenectomy in 21 patients. In the recent eight cases, endothelin-1 (ET-1) and big ET-1 levels were measured for the plasma taken from the splenic vein, superior mesen-
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
38
teric vein and systemic vein. The RIA double antibody method for ET-1 and the enzyme immunoassay for big ET-1 were the assay methods used. Portal pressure was estimated before and after hepatic resection in 11 patients of the non-splenectomy group.
2.3. Postoperati6e follow-up After discharge from the hospital, the patients were monitored at 2-week intervals for the first 6 months and monthly thereafter. Child’s class was re-evaluTable 1 Clinical data of 62 patients who underwent hepatic resection with or without splenectomy Data
Splenectomy (n=26)
Non-splenectomy (n = 36)
P value
Age (years) Younger than 50 50–65 Older than 65
4 12 10
4 19 13
0.8316
Sex Man Woman
15 11
31 5
0.0257
Alcohol abuse Yes No
11 15
11 25
0.4930
History of li6er disease (years) Less than 10 16 10–20 8 More than 20 2
19 8 9
0.2037
Child–Turcotte class B C
17 9
29 7
0.2923
Cause of cirrhosis HBVa HCVb HBV+HCV Non-B, non-C Unknown
7 10 3 4 2
7 19 1 3 6
0.3462
Preoperati6e TAE c Yes No
6 20
15 21
0.2097
Postoperati6e chemotherapy Yes 8 No 18
12 24
0.9504
a
HBV, hepatitis B virus. HCV, hepatitis C virus. c TAE, transcatheter arterial embolization. b
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
39
Table 2 Preoperative associated conditions Condition
Splenectomy (n =26)
Non-splenectomy (n =36)
P value
Esophageal varices Diabetes mellitus Cholelithiasis Gastric ulcer Hiatal hernia Pancreatic cyst Splenic infarction
19 16 8 3 1 1 1
12 17 5 2 0 0 0
0.0148 0.7062 0.2896 0.8372 0.4482 0.4482 0.4482
ated 3 to 6 months postoperatively. After 5 years, the follow-up interval was prolonged to 3 months. Imaging studies with ultrasonography and computed tomography were repeated every 3 months. When tumor recurrence was suspected, the patient was hospitalized for angiography and treatment.
2.4. Statistical methods All deaths within 1 month after operation were considered operative death. The end-point was the patients death. Clinicopathologic data were compared by the chi-square or Fischer’s exact test. Mean values were compared by the Student t-test. All patients were included in overall survival rates which were obtained using the Kaplan – Meier method and compared by the log-rank test. All the analyses were two-sided and differences with P values of less than 0.05 were considered statistically significant.
3. Results
3.1. Blood loss and operation time The estimated blood loss during surgery ranged from 500 to 4800 g (mean9 S.D., 15489954) in the splenectomy and from 150 to 4010 g (9689 845) in the non-splenectomy group (P =0.0182). The mean operation time was 1589 37 min (range 100 – 250) in the former and 1359 37 min (range 60–235) in the latter group.
3.2. Portal pressure Changes in portal venous pressure after splenectomy are shown in Fig. 1. The pressure was reduced in all cases but two (P= 0.0069). The mean reduction rate was 20 912%. On the other hand, the pressure was elevated from 288 9 55 mm of saline to 3149 58 mm following hepatic resection in the 11 non-splenectomized patients.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
40
3.3. Endothelin-1 le6els The mean values of plasma ET-1 for the peripheral vein (systemic), superior mesenteric vein (SMV), and splenic vein (SPV) were 3.739 1.52 pg ml − 1 (range 1.16 – 5.78), 4.62 9 1.70 pg ml − 1 (range 2.06–7.89), and 5.64 9 l.92 pg ml − 1 (range 2.68 – 8.96), respectively (Fig. 2). The difference was significant between the systemic and SPV (P = 0.0446). There were no differences in big ET-1 levels between the three sites.
Table 3 Preoperative laboratory data Data
Splenectomy (n= 26)
Non-splenectomy (n =36)
P value
Hemoglobin (g dl−1) Less than 10 10–13 More than 13
2 14 10
3 22 11
0.8091
White blood cell (mm−3) Less than 3000 7 3000–4000 12 More than 4000 7
2 9 25
0.0024
Platelet (×10 3 mm−3) Less than 50 7 50–100 14 More than 100 5
0 16 20
0.0005
Bilirubin (mg dl−1) Less than 1 1–2 More than 2
5 16 5
24 12 0
0.0002
Albumin (g d1−1) Less than 3 3–3.5 More than 3.5
8 16 2
7 29
0.1152
ICG R15 (%) a Less than 20 20–40 More than 40
5 8 13
9 20 7
0.0360
BSP R30 (%) b Less than 20 20–40 More than 40
0 11 15
4 22 10
0.0267
a b
ICG R15, indocyanine green retention rate at 15 min (normal: 0–10). BSP R30, bromosulphalein retention rate at 30 min (normal: 0–10).
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
41
Fig. 1. Changes in portal venous pressure after splenectomy in 21 patients with HCC and hypersplenism. Hepatic resection was subsequently performed. The difference was significant (P=0.0069).
3.4. Operati6e morbidity and mortality In the splenectomy group, postoperative complications occurred in six patients (23.1%); these included subphrenic abscess followed by liver failure, retroperitoneal bleeding of unknown origin, generalized peritonitis, postoperative bleeding, intraabdominal abscess, and gastroduodenal ulcers, respectively. The former three patients (11.5%) died within 1 month of the operation. In total nine patients (25.0%) had postoperative complications in the non-splenectomy group. Two (5.6%) of them died within 1 month due to liver failure and intraabdominal sepsis, respectively.
3.5. Pathological data Histopathologic data of the tumor and liver is shown in Table 4. The maximal diameter of the tumor was taken as the tumor size. In cases of multiple HCC, the size of the largest tumor was considered. Surgical margin less than 5 mm was defined as surgical margin positive. Although there were no significant differences in the tumor-related factors between the groups, the rate of macronodular cirrhosis judged by the WHO criteria was significantly higher in the splenectomy group. The
42
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
splenic weight ranged from 150 to 1060 g averaging 3309 205. Histologically, sinus hyperplasia and chronic congestion were found in most cases and hemorrhage and/or hemosiderosis (Gamna – Gandy bodies) were observed in one third of the patients.
3.6. Changes in Child’s class Among 22 patients of the splenectomy and 30 patients of the non-splenectomy group in whom Child’s class could be evaluated 3–6 months postoperatively, the class was improved in nine (40.0%) versus 12 (40.0%), unchanged in ten (45.4%) versus 16 (53.3%), and deteriorated in three (13.6%) versus two (6.7%) as shown in Fig. 3. In total four of the five patients in whom spontaneous portosystemic shunts had been occluded showed an improvement of Child’s class. Half of the Child’s class C patients showed an improvement after splenectomy, but of the five Child C patients in the non-splenectomy group only one with occlusion of spontaneous sprenorenal shunt had an improvement of Child’s class.
Fig. 2. Endotheli-1 (ET-1) levels in plasma taken from the peripheral vein (Systemic), superior mesenteric vein (SMV), and splenic vein (SPV). The ET-1 level in splenic venous blood was significantly higher than that in systemic blood (P =0.0446), but there were no differences in big ET-1 levels among the three sites.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
43
Table 4 Histopathologic date of HCC and liver Data
Splenectomy (n = 26)
Non-splenectomy (n =36)
P value
Number of tumor Solitary Multiple
20 6
32 4
0.3606
Tumor size (cm) Smaller than 3 3–5 Larger than 5
9 12 5
16 12 8
0.5864
Capsule Present Absent
17 9
27 9
0.5894
9 9 8
19 10 7
0.3441
Surgical margin Positive Negative
15 115
15 215
0.3229
Type of cirrhosis Micronodular Macronodular Mixed type
2 17 7
15 7 14
0.0004
Vascular in6asion Present Absent Unknown
3.7. Patient sur6i6al and cause of late death At present, seven patients are alive in each group. One patient in the splenectomy group was lost for follow-up 21 months after operation. The causes of late death are shown in Table 5. There were no differences in the incidence of each cause. Overall survival rates including operative deaths are shown in Fig. 4. Although the preoperative liver function had been significantly worse in the splenectomy group, there was no difference in the long-term survival rate between the two groups.
4. Discussion In this prospective study of 62 patients, partial hepatectomy was performed with curative intent for the treatment of HCC associated with Child–Turcotte class B or C cirrhosis. In 26 patients with hypersplenism and splenomegaly, splenectomy was carried out simultaneously with liver resection. Clinicopathological results were compared between the 26 splenectomized and 36 non-splenectomized patients. Although both groups included only Child’s class B or C patients, the extent of hypersplenism and hepatic dysfunction was significantly worse and therefore the
44
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
estimated blood loss during surgery was significantly higher in the splenectomy group. Despite such background differences, there were no significant differences between the two groups in postoperative morbidity and mortality rates, causes of late death, and long-term survival rate. The splenectomy reduced portal pressure by approximately 20%. The ET-1 level in patients with hypersplenism was significantly higher in splenic venous blood than in systemic blood. When judged 3–6 months postoperatively, Child’s class C was improved to class B or A in four of eight splenectomized patients while such a phenomenon was rare in the non-splenectomy group.
Fig. 3. Changes in Child–Turcotte class. The postoperative Child’s class was evaluated 3 – 6 months after operation. The closed circle indicates the patients in whom spontaneous portosystemic shunts had been occluded.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
45
Table 5 Causes of late death Cause
Splenectomy (n = 23)
Non-splenectomy (n =34)
Level of significance
Cancer Liver failure Variceal bleeding GI bleeding Infection Lost in follow-up
10 2 2 1 0 1
18 4 2 1 2 0
nsa ns ns ns ns ns
a
ns, not significant.
The main purpose of this study was to discover if splenectomy was beneficial or detrimental when performed simultaneously with hepatic resection in the treatment of HCC associated with severe cirrhosis and hypersplenism. Since the beginning of this century, a number of previous reports indicated that splenectomy improves hepatic function or stops the progression of liver disease in Banti’s syndrome as well as cirrhosis [9 – 13]. In the study of 64 patients with Banti’s syndrome by Sato et al. [9], a splenectomy improved liver functions in most patients and histologic findings of the liver disease in 43%. Although there was a lot of controversy as to whether the spleen releases toxic substances for the liver in Banti’s syndrome and liver cirrhosis, previous workers observed a beneficial effect of splenectomy on the liver in selected patients without knowing the underlying mechanisms [8–13]. Since the first report of Maddison [21], embolization of the splenic artery has been widely used for the treatment of hypersplenism as an alternative method to splenectomy or splenic artery ligation [22]. Most reports, however, focus on the effect on hematology or complications of this treatment method. Among them,
Fig. 4. Survival rates including operative deaths in 26 splenectomized and 36 non-splenectomized patients. There was no significant difference (P =0.4437, log-rank test).
46
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
several papers describe patients with cirrhosis in whom hepatic function has improved following the embolization [23,24] and attribute the effect to increased hepatic arterial flow [25]. On the other hand, recent studies in animals have shown that the spleen plays an important role in hepatic injury induced by various stimuli [16–20]. Several authors assume that hepatic injury induced by endotoxin may be due to tumor necrosis factor (TNF) or oxygen free radicals released by activated macrophages [16,17]. Since the epoch-making report by Higgins and Priestly [14], it has been assumed that the spleen releases substances which inhibit liver regeneration [15,26–28]. Furthermore, it has recently been reported that hepatic fibrosis is inhibited or suppressed by splenectomy in rat models with carbon tetrachloride [19] and porcine serum [20]. Of late, the pathogenetic role of ET-1 in portal hypertension has been extensively discussed and reviewed [29 – 31]. Up until now, a number of studies have reported elevated plasma ET-1 levels in cirrhotic patients [32–36]. Although ET-1 is overexpressed in cirrhotic livers [37], the origin of ET-1 in systemic blood is obscure [32– 36]. In this study, we measured ET-1 levels in plasma taken from the systemic, splenic venous, and superior mesenteric venous blood in eight patients with splenomegaly and hypersplenism. Although there were no differences in big ET-1 levels among the three sites, the ET-1 level in the splenic venous blood was significantly higher than that in the systemic blood indicating that ET-1 is released from the enlarged spleen. As ET-1 is known to cause contraction of hepatic stellate cells (Ito cells or lipocytes) thus decreasing the sinusoidal flow and elevating portal pressure [29 – 31], it may be assumed that the splenectomy counteracted the release of ET-1 from the spleen and improved the sinusoidal perfusion in our patients. Furthermore, it is theoretically considered that reduced TNF production by splenectomy may also contribute to the improvement of hepatic function as cirrhotic patients have more or less endotoxemia which induces the production of TNF by not only the Kupffer cells but macrophages in the spleen [16,17]. Finally, the spleen contains about 25% of the T-lymphocyte pool and 10–15% of the B-lymphocyte pool. Among the various functions of the spleen, its immunologic action is assumed to be most important in various clinical states. The spleen captures, processes, and concentrates antigens in the white pulp where T- and B-cell interaction can produce antibodies. It can also produce opsonins and recruit complements. The increased risk of infection after splenectomy is attributed to the ablation of such functions of the spleen [38]. In such a context, the role of the spleen in tumor cell surveillance has been suggested by several workers [39,40]. In the present study, the incidence of infectious complications during the immediate and late postoperative periods was not increased by splenectomy. Moreover, the splenectomy did not influence the tumor recurrence rate. However, it is obvious that only a prospective randomized study with sophisticated parameters can elucidate the genuine immunologic effect of splenectomy in patients with HCC complicating severe cirrhosis.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
47
References [1] Okuda K, Fujimoto I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 1987;47:4967–72. [2] Kacrynski J, Hansson G, Norkrans G, Wallerstedt S. Lack of correlation between hepatitis B virus infection and the increasing incidence of primary liver cancer in Sweden. Acta Oncol 1991;30:311 – 3. [3] Colombo M, De Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675 – 80. [4] Tsukama H, Hiyama T, Tanaka S, Nakao M, Yabauchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797– 801. [5] Benvegnu L, Alberti A. Risk factors and prevention of hepatocellular carcinoma in HCV infection. Dig Dis Sci 1996;41:49–55. [6] Iwatsuki S, Gordon RD, Shaw BW Jr., Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985;202:401–7. [7] Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. [8] Banti G. Splenomegalie mit Leberzirrhose. Beitr Pathol Anat 1898;24:21 – 33. [9] Sato T, Takahashi M, Suda Y, Watanabe T. Effect of splenectomy on histopathology and functions of the liver in Banti’s syndrome. Tohoku J Exp Med 1963;81:17 – 45. [10] Deaver JB. Splenic enlargement with cirrhosis of the liver. Ann Surg 1928;88:355 – 60. [11] Mayo WJ. A review of 500 splenectomies with special reference to mortality and end results. Ann Surg 1928;88:409–15. [12] Larrabee RC. Chronic congestive splenomegaly and its relationship to Banti’s disease. Am J Med Sci 1934;188:745–60. [13] Rousselot LM. The role of congestion (portal hypertension) in so-called Banti’s syndrome: a clinical and pathologic study of thirty-one cases with the late results following splenectomy. J Am Med Assoc 1936;107:1788–93. [14] Higgins GM, Priestley JT. Experimental pathlogy of the liver-VI. Restoration of the liver in white rats after partial removal and splenectomy. Arch Pathol 1932;13:573 – 83. [15] Ohira M, Umeyama K, Taniura M, Yamashita T, Morisawa S. An experimental study of a splenic inhibitory factor influencing hepatic regeneration. Surg Gynecol Obstet 1987;164:438 – 44. [16] Shiratori Y, Tanaka M, Hai K, Kawase T, Shiina S, Sugimoto T. Role of endotoxin-responsive macrophages in hepatic injury. Hepatology 1990;11:183 – 92. [17] Suzuki S, Nakamura S, Serizawa A, Sakaguchi T, Konno H, Muro H, et al. Role of Kupffer cells and the spleen in modulation of endotoxin-induced liver injury after partial hepatectomy. Hepatology 1996;24:219–25. [18] Okuaki Y, Miyazaki H, Zeniya M, Ishikawa T, Ohkawa Y, Tsuno S, et al. Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat. Liver 1996;16:188 – 94. [19] Hashimoto H, Taruya E, Yamashita T, Ishikawa T, Taniura M, Umeyama K. The effect of splenectomy in the experimental liver injury induced by carbon tetrachloride. Acta Hepatol Jpn 1984;25:907–14. [20] Miyazaki H, Sata H, Kawabe T, Okuyama S, Takahashi H, Negishi M, et al. Role of the spleen on liver fibrogenesis in experimental liver fibrosis. Acta Hepatol Jpn 1988;29:703 – 4. [21] Maddison FE. Embolic therapy of hypersplenism. Invest Radiol 1973;8:280 – 1. [22] Witte CL, Witte MH, Renert W, O’Mara RE, Lilien DL. Splenic artery ligation in selected patients with hepatic cirrhosis and in Sprague-Dawley rats. Surg Gynecol Obstet 1976;142:1 – 12. [23] Hirai K, Kawazoe Y, Yamashita K, Arima N, Hino K, Eguchi S, et al. A case of liver cirrhosis with hypersplenism undertaken transcatheter splenic arterial embolization (TSAE). Acta Hepatol Jpn 1985;26:1681–5.
48
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
[24] Tashiro K, Akagi K, Azuma K, Ikeda K, Nomiyama K, Sakino I, et al. Efficacy of partial splenic embolization for the treatment of liver cirrhosis with hypersplenism: a case report. Acta Hepatol Jpn 1996;37:513–9. [25] Porter BA, Frey CF, Link DP, Lantz BM, Pimstone NR. Splenic embolization monitored by the video dilution technique. Am J Roentgenol 1983;141:1063– 5. [26] Perez-Tamayo R, Romero R. Role of the spleen in regeneration of the liver: an experimental study. Lab Invest 1958;7:248–57. [27] Sakai A, Taha M, Kashiwabara H, Pfeffermann R, Kountz SL. On the origin of the regeneration factor. Surg Gynecol Obstet 1977;145:889 – 94. [28] Miyata S, Kihara H. Selective inhibition of DNA synthesis by a protein released from spleen cells. J Cell Physiol 1982;110:315–7. [29] Housset CN, Rockey DC, Friedman SL, Bissell DM. Hepatic lipocytes: a major target for endothelin-1. J Hepatol (Suppl 2) 1995;22:55 – 60. [30] Mallat A, Lotersztajn S. Multiple hepatic functions of endothelin-1: physiopathological relevance. J Hepatol 1996;25:405–13. [31] Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25:2 – 5. [32] Uchihara M, Izumi N, Sato C, Marumo F. Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology 1992;16:95 – 9. [33] Asbert M, Gines A, Gines P, Jimenez W, Claria J, Salo J, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993;104:1485– 91. [34] Moller S, Emmeluth C, Henriksen JH. Elevated circulating plasma endothelin-1 concentrations in cirrhosis. J Hepatol 1993;19:285–90. [35] Gerbes AL, Moller S, Gulberg V, Henriksen JH. Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: role of splanchnic and renal passage and liver function. Hepatology 1995;21:735–9. [36] Bernardi M, Gulberg V, Colantoni A, Trevisani F, Gasbarrini A, Gerbes AL. Plasma endothelin-1 and -3 in cirrhosis: relationship with systemic hemodynamics, renal function and neurohumoral systems. J Hepatol 1996;24:161–8. [37] Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, et al. Endothelin-1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996;110:534–48. [38] Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991;78:1031 – 8. [39] Jessup JM, Pellis NR, Kahan BD. The spleen as a source of nonspecific suppressor cells in the tumor-bearing mouse. J Surg Res 1980;28:460 – 5. [40] Meyer JD, Argyris BF, Meyer JA. Splenectomy, suppressor cell activity, survival in tumor bearing rats. J Surg Res 1980;29:527–32.
.
Role of splenectomy in hepatic resection for hepatocellular carcinoma associated with severe cirrhosis and hypersplenism Naofumi Nagasue *, Hitoshi Kohno, Akira Yamanoi, Haruki Ohmori, Dipok Kumar Dhar, Yoshinari Makino, Takeo Kimoto, Mitsuo Tachibana Shimane Medical Uni6ersity, Second Department of Surgery, Izumao 693 -8501, Japan Received 29 June 1998; received in revised form 15 October 1998; accepted 26 October 1998
Abstract The incidence of hepatocellular carcinoma (HCC) associated with severe cirrhosis has been increasing due to better management of chronic liver disease. This study prospectively aimed to elucidate whether splenectomy is beneficial or detrimental when performed simultaneously with hepatic resection in patients with HCC and hypersplenism due to severe cirrhosis. Splenectomy and subsequent partial hepatectomy were concomitantly performed on 26 patients with Child–Turcotte class B (n= 17) or C (n= 9) cirrhosis, HCC and hypersplenism. Portal pressure was measured before and after splenectomy in 21 cases. Endothelin-1 (ET-1) levels in splenic venous blood were estimated in eight cases. The splenectomy reduced portal venous pressure by 20%. The ET-1 level in splenic venous blood was significantly higher than that in systemic blood indicating the release of ET-1 from the spleen into the portal circulation. Operative morbidity and mortality rates were 23.1 and 11.5%. Child’s class C was improved to class B or A in half of the patients. The 1-, 3-, and 5-year survival rates were 61.5, 42.3 and 16.5%. These results were compared with those of 36 patients with Child’s class B (n= 29) or class C (n= 7) cirrhosis and HCC in whom concomitant splenectomy had not been performed because of weak or no hypersplenism. The
* Corresponding author. Tel.: + 81-853-20-2230; fax: + 81-853-20-229; e-mail: [email protected]. 1386-6346/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 3 8 6 - 6 3 4 6 ( 9 8 ) 0 0 1 0 4 - 1
36
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
extent of hypersplenism and hepatic dysfunction was more severe and the estimated blood loss during surgery was larger in the splenectomy group. Despite such background differences, there were no significant differences between the two groups in postoperative morbidity and mortality rates, causes of late death, and long-term survival rate. Concomitant splenectomy during hepatic resection seems to be beneficial in the treatment of HCC and hypersplenism associated with severe cirrhosis. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Liver cirrhosis; Hypersplenism; Portal hypertension; Hepatic resection; Splenectomy; Endothelin-1
1. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and its incidence is increasing world-wide [1,2]. The main cause of this tumor is chronic infection with hepatitis B and C viruses and the latter is currently recognized as the major cause of HCC [3–5]. The infection with hepatitis C virus is usually insidious and chronic, and finally induces cirrhosis of the liver and HCC. The association between cirrhosis and HCC has been known for many years. The recent advance in treatment methods of chronic liver disease has brought about a higher incidence of HCC associated with advanced cirrhosis. Liver transplantation may be best indicated for patients with advanced cirrhosis complicating small HCCs in the absence of active viral replication [6,7]. However, it was not feasible in our country and transcatheter chemoembolization or percutaneous ethanol injection have been used alternatively. Since the report of Banti [8], the relationship between the liver and the spleen has been extensively disputed. However, there is a traditional belief that splenectomy when performed at an early stage of Banti’s syndrome may prevent the progression of liver disease [9] or that splenectomy frequently improves not only hematologic data but also the general status in patients with advanced cirrhosis [10–13]. In fact, recent investigations in animals have elucidated that splenectomy enhances liver regeneration after partial hepatectomy [14,15], ameliorates hepatic injury induced by endotoxin [16,17] and ischemia-reperfusion [18], and inhibits or suppresses hepatic fibrosis [19,20]. Thus, the spleen seems to play an important role in various pathologic conditions of the liver possibly through such mechanisms as modified responses of immunology and cytokines. During the past 11 years, we prospectively performed splenectomy simultaneously with hepatic resection on 26 patients with severe cirrhosis, HCC and hypersplenism with the hope that the splenectomy would improve not only the hematologic data but hepatic functions in such patients. The results of these patients were compared with those of 36 similar patients on whom concomitant splenectomy had not been performed because of weak or no hypersplenism.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
37
2. Materials and methods During the past 11 years, 292 patients with primary HCC were hospitalized in our department. Curative hepatic resection was carried out on 210 patients (71.9%). In 26 patients with Child – Turcotte class B or C cirrhosis who had splenomegaly and hypersplenism, splenectomy was performed simultaneously with hepatic resection. The indication criteria for splenectomy was principally leucocytopenia less than 3000 mm − 3 and/or thrombocytopenia less than 50 000 mm − 3 associated with splenomegaly and esophageal varices. In total 36 patients with Child’s class B or C cirrhosis in whom splenectomy had not been performed served as control. The clinical data for these patients is shown in Table 1. The incidence of women was significantly higher in the splenectomy group. Other associated conditions are summarized in Table 2. The incidence of esophageal varices was higher in the splenectomy group (73%) than in the control group (33%). The grade of the varices was only slight or moderate in most patients but two patients in the former group with a history of variceal bleeding had received endoscopic injection sclerotherapy before the current admission. Diabetes mellitus was diagnosed by the WHO criteria after ingestion of 75 g glucose. Preoperative hematologic and hepatic functional data are shown in Table 3. Leucocytopenia and thrombocytopenia were more common and liver functions were poorer in the splenectomy group.
2.1. Operati6e procedures In all cases of the splenectomy group, splenectomy was performed first followed by hepatic resection. Thereafter, other additional operations were carried out. Liver resections performed were Couinaud’s one segmentectomy with one wedge resection in one patient, Couinaud’s one segmentectomy in three patients, two wedge resections in four patients, and one wedge resection in 18 patients. In addition to splenectomy, ligation of spontaneous portosystemic shunts was performed in five patients; splenorenal shunt in three and Cruveilheir–Baumgarten syndrome (patent umbilical vein) in two. Cholecystectomy was carried out on all of the eight patients with gallstones. Other concomitant operations included Nissen’s fundoplication for hiatal hernia performed on one patient and distal pancreatectomy for pancreatic cyst on one patient also. In the non-splenectomy group, the types of hepatic resection included extended right lobectomy in one, right lobectomy in two, left lobectomy in one, Couinaud’s two segmentectomy in four, Couinaud’s one segmentectomy in four, two wedge resections in one, and one wedge resection in 23 patients. Cholecystectomy was carried out on five patients with gallstones. Spontaneous splenorenal shunt was ligated in one.
2.2. Intraoperati6e measurements Portal venous pressure was manometrically measured before and after splenectomy in 21 patients. In the recent eight cases, endothelin-1 (ET-1) and big ET-1 levels were measured for the plasma taken from the splenic vein, superior mesen-
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
38
teric vein and systemic vein. The RIA double antibody method for ET-1 and the enzyme immunoassay for big ET-1 were the assay methods used. Portal pressure was estimated before and after hepatic resection in 11 patients of the non-splenectomy group.
2.3. Postoperati6e follow-up After discharge from the hospital, the patients were monitored at 2-week intervals for the first 6 months and monthly thereafter. Child’s class was re-evaluTable 1 Clinical data of 62 patients who underwent hepatic resection with or without splenectomy Data
Splenectomy (n=26)
Non-splenectomy (n = 36)
P value
Age (years) Younger than 50 50–65 Older than 65
4 12 10
4 19 13
0.8316
Sex Man Woman
15 11
31 5
0.0257
Alcohol abuse Yes No
11 15
11 25
0.4930
History of li6er disease (years) Less than 10 16 10–20 8 More than 20 2
19 8 9
0.2037
Child–Turcotte class B C
17 9
29 7
0.2923
Cause of cirrhosis HBVa HCVb HBV+HCV Non-B, non-C Unknown
7 10 3 4 2
7 19 1 3 6
0.3462
Preoperati6e TAE c Yes No
6 20
15 21
0.2097
Postoperati6e chemotherapy Yes 8 No 18
12 24
0.9504
a
HBV, hepatitis B virus. HCV, hepatitis C virus. c TAE, transcatheter arterial embolization. b
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
39
Table 2 Preoperative associated conditions Condition
Splenectomy (n =26)
Non-splenectomy (n =36)
P value
Esophageal varices Diabetes mellitus Cholelithiasis Gastric ulcer Hiatal hernia Pancreatic cyst Splenic infarction
19 16 8 3 1 1 1
12 17 5 2 0 0 0
0.0148 0.7062 0.2896 0.8372 0.4482 0.4482 0.4482
ated 3 to 6 months postoperatively. After 5 years, the follow-up interval was prolonged to 3 months. Imaging studies with ultrasonography and computed tomography were repeated every 3 months. When tumor recurrence was suspected, the patient was hospitalized for angiography and treatment.
2.4. Statistical methods All deaths within 1 month after operation were considered operative death. The end-point was the patients death. Clinicopathologic data were compared by the chi-square or Fischer’s exact test. Mean values were compared by the Student t-test. All patients were included in overall survival rates which were obtained using the Kaplan – Meier method and compared by the log-rank test. All the analyses were two-sided and differences with P values of less than 0.05 were considered statistically significant.
3. Results
3.1. Blood loss and operation time The estimated blood loss during surgery ranged from 500 to 4800 g (mean9 S.D., 15489954) in the splenectomy and from 150 to 4010 g (9689 845) in the non-splenectomy group (P =0.0182). The mean operation time was 1589 37 min (range 100 – 250) in the former and 1359 37 min (range 60–235) in the latter group.
3.2. Portal pressure Changes in portal venous pressure after splenectomy are shown in Fig. 1. The pressure was reduced in all cases but two (P= 0.0069). The mean reduction rate was 20 912%. On the other hand, the pressure was elevated from 288 9 55 mm of saline to 3149 58 mm following hepatic resection in the 11 non-splenectomized patients.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
40
3.3. Endothelin-1 le6els The mean values of plasma ET-1 for the peripheral vein (systemic), superior mesenteric vein (SMV), and splenic vein (SPV) were 3.739 1.52 pg ml − 1 (range 1.16 – 5.78), 4.62 9 1.70 pg ml − 1 (range 2.06–7.89), and 5.64 9 l.92 pg ml − 1 (range 2.68 – 8.96), respectively (Fig. 2). The difference was significant between the systemic and SPV (P = 0.0446). There were no differences in big ET-1 levels between the three sites.
Table 3 Preoperative laboratory data Data
Splenectomy (n= 26)
Non-splenectomy (n =36)
P value
Hemoglobin (g dl−1) Less than 10 10–13 More than 13
2 14 10
3 22 11
0.8091
White blood cell (mm−3) Less than 3000 7 3000–4000 12 More than 4000 7
2 9 25
0.0024
Platelet (×10 3 mm−3) Less than 50 7 50–100 14 More than 100 5
0 16 20
0.0005
Bilirubin (mg dl−1) Less than 1 1–2 More than 2
5 16 5
24 12 0
0.0002
Albumin (g d1−1) Less than 3 3–3.5 More than 3.5
8 16 2
7 29
0.1152
ICG R15 (%) a Less than 20 20–40 More than 40
5 8 13
9 20 7
0.0360
BSP R30 (%) b Less than 20 20–40 More than 40
0 11 15
4 22 10
0.0267
a b
ICG R15, indocyanine green retention rate at 15 min (normal: 0–10). BSP R30, bromosulphalein retention rate at 30 min (normal: 0–10).
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
41
Fig. 1. Changes in portal venous pressure after splenectomy in 21 patients with HCC and hypersplenism. Hepatic resection was subsequently performed. The difference was significant (P=0.0069).
3.4. Operati6e morbidity and mortality In the splenectomy group, postoperative complications occurred in six patients (23.1%); these included subphrenic abscess followed by liver failure, retroperitoneal bleeding of unknown origin, generalized peritonitis, postoperative bleeding, intraabdominal abscess, and gastroduodenal ulcers, respectively. The former three patients (11.5%) died within 1 month of the operation. In total nine patients (25.0%) had postoperative complications in the non-splenectomy group. Two (5.6%) of them died within 1 month due to liver failure and intraabdominal sepsis, respectively.
3.5. Pathological data Histopathologic data of the tumor and liver is shown in Table 4. The maximal diameter of the tumor was taken as the tumor size. In cases of multiple HCC, the size of the largest tumor was considered. Surgical margin less than 5 mm was defined as surgical margin positive. Although there were no significant differences in the tumor-related factors between the groups, the rate of macronodular cirrhosis judged by the WHO criteria was significantly higher in the splenectomy group. The
42
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
splenic weight ranged from 150 to 1060 g averaging 3309 205. Histologically, sinus hyperplasia and chronic congestion were found in most cases and hemorrhage and/or hemosiderosis (Gamna – Gandy bodies) were observed in one third of the patients.
3.6. Changes in Child’s class Among 22 patients of the splenectomy and 30 patients of the non-splenectomy group in whom Child’s class could be evaluated 3–6 months postoperatively, the class was improved in nine (40.0%) versus 12 (40.0%), unchanged in ten (45.4%) versus 16 (53.3%), and deteriorated in three (13.6%) versus two (6.7%) as shown in Fig. 3. In total four of the five patients in whom spontaneous portosystemic shunts had been occluded showed an improvement of Child’s class. Half of the Child’s class C patients showed an improvement after splenectomy, but of the five Child C patients in the non-splenectomy group only one with occlusion of spontaneous sprenorenal shunt had an improvement of Child’s class.
Fig. 2. Endotheli-1 (ET-1) levels in plasma taken from the peripheral vein (Systemic), superior mesenteric vein (SMV), and splenic vein (SPV). The ET-1 level in splenic venous blood was significantly higher than that in systemic blood (P =0.0446), but there were no differences in big ET-1 levels among the three sites.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
43
Table 4 Histopathologic date of HCC and liver Data
Splenectomy (n = 26)
Non-splenectomy (n =36)
P value
Number of tumor Solitary Multiple
20 6
32 4
0.3606
Tumor size (cm) Smaller than 3 3–5 Larger than 5
9 12 5
16 12 8
0.5864
Capsule Present Absent
17 9
27 9
0.5894
9 9 8
19 10 7
0.3441
Surgical margin Positive Negative
15 115
15 215
0.3229
Type of cirrhosis Micronodular Macronodular Mixed type
2 17 7
15 7 14
0.0004
Vascular in6asion Present Absent Unknown
3.7. Patient sur6i6al and cause of late death At present, seven patients are alive in each group. One patient in the splenectomy group was lost for follow-up 21 months after operation. The causes of late death are shown in Table 5. There were no differences in the incidence of each cause. Overall survival rates including operative deaths are shown in Fig. 4. Although the preoperative liver function had been significantly worse in the splenectomy group, there was no difference in the long-term survival rate between the two groups.
4. Discussion In this prospective study of 62 patients, partial hepatectomy was performed with curative intent for the treatment of HCC associated with Child–Turcotte class B or C cirrhosis. In 26 patients with hypersplenism and splenomegaly, splenectomy was carried out simultaneously with liver resection. Clinicopathological results were compared between the 26 splenectomized and 36 non-splenectomized patients. Although both groups included only Child’s class B or C patients, the extent of hypersplenism and hepatic dysfunction was significantly worse and therefore the
44
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
estimated blood loss during surgery was significantly higher in the splenectomy group. Despite such background differences, there were no significant differences between the two groups in postoperative morbidity and mortality rates, causes of late death, and long-term survival rate. The splenectomy reduced portal pressure by approximately 20%. The ET-1 level in patients with hypersplenism was significantly higher in splenic venous blood than in systemic blood. When judged 3–6 months postoperatively, Child’s class C was improved to class B or A in four of eight splenectomized patients while such a phenomenon was rare in the non-splenectomy group.
Fig. 3. Changes in Child–Turcotte class. The postoperative Child’s class was evaluated 3 – 6 months after operation. The closed circle indicates the patients in whom spontaneous portosystemic shunts had been occluded.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
45
Table 5 Causes of late death Cause
Splenectomy (n = 23)
Non-splenectomy (n =34)
Level of significance
Cancer Liver failure Variceal bleeding GI bleeding Infection Lost in follow-up
10 2 2 1 0 1
18 4 2 1 2 0
nsa ns ns ns ns ns
a
ns, not significant.
The main purpose of this study was to discover if splenectomy was beneficial or detrimental when performed simultaneously with hepatic resection in the treatment of HCC associated with severe cirrhosis and hypersplenism. Since the beginning of this century, a number of previous reports indicated that splenectomy improves hepatic function or stops the progression of liver disease in Banti’s syndrome as well as cirrhosis [9 – 13]. In the study of 64 patients with Banti’s syndrome by Sato et al. [9], a splenectomy improved liver functions in most patients and histologic findings of the liver disease in 43%. Although there was a lot of controversy as to whether the spleen releases toxic substances for the liver in Banti’s syndrome and liver cirrhosis, previous workers observed a beneficial effect of splenectomy on the liver in selected patients without knowing the underlying mechanisms [8–13]. Since the first report of Maddison [21], embolization of the splenic artery has been widely used for the treatment of hypersplenism as an alternative method to splenectomy or splenic artery ligation [22]. Most reports, however, focus on the effect on hematology or complications of this treatment method. Among them,
Fig. 4. Survival rates including operative deaths in 26 splenectomized and 36 non-splenectomized patients. There was no significant difference (P =0.4437, log-rank test).
46
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
several papers describe patients with cirrhosis in whom hepatic function has improved following the embolization [23,24] and attribute the effect to increased hepatic arterial flow [25]. On the other hand, recent studies in animals have shown that the spleen plays an important role in hepatic injury induced by various stimuli [16–20]. Several authors assume that hepatic injury induced by endotoxin may be due to tumor necrosis factor (TNF) or oxygen free radicals released by activated macrophages [16,17]. Since the epoch-making report by Higgins and Priestly [14], it has been assumed that the spleen releases substances which inhibit liver regeneration [15,26–28]. Furthermore, it has recently been reported that hepatic fibrosis is inhibited or suppressed by splenectomy in rat models with carbon tetrachloride [19] and porcine serum [20]. Of late, the pathogenetic role of ET-1 in portal hypertension has been extensively discussed and reviewed [29 – 31]. Up until now, a number of studies have reported elevated plasma ET-1 levels in cirrhotic patients [32–36]. Although ET-1 is overexpressed in cirrhotic livers [37], the origin of ET-1 in systemic blood is obscure [32– 36]. In this study, we measured ET-1 levels in plasma taken from the systemic, splenic venous, and superior mesenteric venous blood in eight patients with splenomegaly and hypersplenism. Although there were no differences in big ET-1 levels among the three sites, the ET-1 level in the splenic venous blood was significantly higher than that in the systemic blood indicating that ET-1 is released from the enlarged spleen. As ET-1 is known to cause contraction of hepatic stellate cells (Ito cells or lipocytes) thus decreasing the sinusoidal flow and elevating portal pressure [29 – 31], it may be assumed that the splenectomy counteracted the release of ET-1 from the spleen and improved the sinusoidal perfusion in our patients. Furthermore, it is theoretically considered that reduced TNF production by splenectomy may also contribute to the improvement of hepatic function as cirrhotic patients have more or less endotoxemia which induces the production of TNF by not only the Kupffer cells but macrophages in the spleen [16,17]. Finally, the spleen contains about 25% of the T-lymphocyte pool and 10–15% of the B-lymphocyte pool. Among the various functions of the spleen, its immunologic action is assumed to be most important in various clinical states. The spleen captures, processes, and concentrates antigens in the white pulp where T- and B-cell interaction can produce antibodies. It can also produce opsonins and recruit complements. The increased risk of infection after splenectomy is attributed to the ablation of such functions of the spleen [38]. In such a context, the role of the spleen in tumor cell surveillance has been suggested by several workers [39,40]. In the present study, the incidence of infectious complications during the immediate and late postoperative periods was not increased by splenectomy. Moreover, the splenectomy did not influence the tumor recurrence rate. However, it is obvious that only a prospective randomized study with sophisticated parameters can elucidate the genuine immunologic effect of splenectomy in patients with HCC complicating severe cirrhosis.
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
47
References [1] Okuda K, Fujimoto I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 1987;47:4967–72. [2] Kacrynski J, Hansson G, Norkrans G, Wallerstedt S. Lack of correlation between hepatitis B virus infection and the increasing incidence of primary liver cancer in Sweden. Acta Oncol 1991;30:311 – 3. [3] Colombo M, De Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675 – 80. [4] Tsukama H, Hiyama T, Tanaka S, Nakao M, Yabauchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797– 801. [5] Benvegnu L, Alberti A. Risk factors and prevention of hepatocellular carcinoma in HCV infection. Dig Dis Sci 1996;41:49–55. [6] Iwatsuki S, Gordon RD, Shaw BW Jr., Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985;202:401–7. [7] Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. [8] Banti G. Splenomegalie mit Leberzirrhose. Beitr Pathol Anat 1898;24:21 – 33. [9] Sato T, Takahashi M, Suda Y, Watanabe T. Effect of splenectomy on histopathology and functions of the liver in Banti’s syndrome. Tohoku J Exp Med 1963;81:17 – 45. [10] Deaver JB. Splenic enlargement with cirrhosis of the liver. Ann Surg 1928;88:355 – 60. [11] Mayo WJ. A review of 500 splenectomies with special reference to mortality and end results. Ann Surg 1928;88:409–15. [12] Larrabee RC. Chronic congestive splenomegaly and its relationship to Banti’s disease. Am J Med Sci 1934;188:745–60. [13] Rousselot LM. The role of congestion (portal hypertension) in so-called Banti’s syndrome: a clinical and pathologic study of thirty-one cases with the late results following splenectomy. J Am Med Assoc 1936;107:1788–93. [14] Higgins GM, Priestley JT. Experimental pathlogy of the liver-VI. Restoration of the liver in white rats after partial removal and splenectomy. Arch Pathol 1932;13:573 – 83. [15] Ohira M, Umeyama K, Taniura M, Yamashita T, Morisawa S. An experimental study of a splenic inhibitory factor influencing hepatic regeneration. Surg Gynecol Obstet 1987;164:438 – 44. [16] Shiratori Y, Tanaka M, Hai K, Kawase T, Shiina S, Sugimoto T. Role of endotoxin-responsive macrophages in hepatic injury. Hepatology 1990;11:183 – 92. [17] Suzuki S, Nakamura S, Serizawa A, Sakaguchi T, Konno H, Muro H, et al. Role of Kupffer cells and the spleen in modulation of endotoxin-induced liver injury after partial hepatectomy. Hepatology 1996;24:219–25. [18] Okuaki Y, Miyazaki H, Zeniya M, Ishikawa T, Ohkawa Y, Tsuno S, et al. Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat. Liver 1996;16:188 – 94. [19] Hashimoto H, Taruya E, Yamashita T, Ishikawa T, Taniura M, Umeyama K. The effect of splenectomy in the experimental liver injury induced by carbon tetrachloride. Acta Hepatol Jpn 1984;25:907–14. [20] Miyazaki H, Sata H, Kawabe T, Okuyama S, Takahashi H, Negishi M, et al. Role of the spleen on liver fibrogenesis in experimental liver fibrosis. Acta Hepatol Jpn 1988;29:703 – 4. [21] Maddison FE. Embolic therapy of hypersplenism. Invest Radiol 1973;8:280 – 1. [22] Witte CL, Witte MH, Renert W, O’Mara RE, Lilien DL. Splenic artery ligation in selected patients with hepatic cirrhosis and in Sprague-Dawley rats. Surg Gynecol Obstet 1976;142:1 – 12. [23] Hirai K, Kawazoe Y, Yamashita K, Arima N, Hino K, Eguchi S, et al. A case of liver cirrhosis with hypersplenism undertaken transcatheter splenic arterial embolization (TSAE). Acta Hepatol Jpn 1985;26:1681–5.
48
N. Nagasue et al. / Hepatology Research 14 (1999) 35–48
[24] Tashiro K, Akagi K, Azuma K, Ikeda K, Nomiyama K, Sakino I, et al. Efficacy of partial splenic embolization for the treatment of liver cirrhosis with hypersplenism: a case report. Acta Hepatol Jpn 1996;37:513–9. [25] Porter BA, Frey CF, Link DP, Lantz BM, Pimstone NR. Splenic embolization monitored by the video dilution technique. Am J Roentgenol 1983;141:1063– 5. [26] Perez-Tamayo R, Romero R. Role of the spleen in regeneration of the liver: an experimental study. Lab Invest 1958;7:248–57. [27] Sakai A, Taha M, Kashiwabara H, Pfeffermann R, Kountz SL. On the origin of the regeneration factor. Surg Gynecol Obstet 1977;145:889 – 94. [28] Miyata S, Kihara H. Selective inhibition of DNA synthesis by a protein released from spleen cells. J Cell Physiol 1982;110:315–7. [29] Housset CN, Rockey DC, Friedman SL, Bissell DM. Hepatic lipocytes: a major target for endothelin-1. J Hepatol (Suppl 2) 1995;22:55 – 60. [30] Mallat A, Lotersztajn S. Multiple hepatic functions of endothelin-1: physiopathological relevance. J Hepatol 1996;25:405–13. [31] Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25:2 – 5. [32] Uchihara M, Izumi N, Sato C, Marumo F. Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology 1992;16:95 – 9. [33] Asbert M, Gines A, Gines P, Jimenez W, Claria J, Salo J, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993;104:1485– 91. [34] Moller S, Emmeluth C, Henriksen JH. Elevated circulating plasma endothelin-1 concentrations in cirrhosis. J Hepatol 1993;19:285–90. [35] Gerbes AL, Moller S, Gulberg V, Henriksen JH. Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: role of splanchnic and renal passage and liver function. Hepatology 1995;21:735–9. [36] Bernardi M, Gulberg V, Colantoni A, Trevisani F, Gasbarrini A, Gerbes AL. Plasma endothelin-1 and -3 in cirrhosis: relationship with systemic hemodynamics, renal function and neurohumoral systems. J Hepatol 1996;24:161–8. [37] Pinzani M, Milani S, De Franco R, Grappone C, Caligiuri A, Gentilini A, et al. Endothelin-1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 1996;110:534–48. [38] Holdsworth RJ, Irving AD, Cuschieri A. Postsplenectomy sepsis and its mortality rate: actual versus perceived risks. Br J Surg 1991;78:1031 – 8. [39] Jessup JM, Pellis NR, Kahan BD. The spleen as a source of nonspecific suppressor cells in the tumor-bearing mouse. J Surg Res 1980;28:460 – 5. [40] Meyer JD, Argyris BF, Meyer JA. Splenectomy, suppressor cell activity, survival in tumor bearing rats. J Surg Res 1980;29:527–32.
.