Frequency and significance of tumor thrombi in esophageal varices in hepatocellular carcinoma associated with cirrhosis

Histological examination of the wall of the stomach and esophagus in patients with hepatocellular carcinoma associated with cirrhosis demonstrated intravariceal tumor thrombi in 13 (23.6%) of 55 cases studied. There were distant hematogenous metastases in 31 of them, of whom 12 (38.7%) had variceal tumor thrombi. Tumor thrombi were of varying sizes, and tumor cells appeared either intact, degenerated or necrotic. In seven cases, there was a firm adhesion of thrombi onto the vascular wall suggesting possible mural infiltration, but no extravascular metastases were noted grossly. These findings suggest a possibility of metastasis of hepatocellular carcinoma to the stomach and esophagus via the portal vein. It is also suggested that the degree of varices is not increased by tumor thrombus formation per se, and that both varices and tumor thrombi are due to extensive hepatofugal collateral circulation. Considering that 12 of 13 cases of intravariceal tumor thrombi had lung metastases, a portal vein-varices-lung route is possible for lung metastasis beside the established route through the hepatic vein in hepatocellular carcinoma.     

Clinical significance and prediction factors of gastric varices in patients with hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocellular carcinoma is part of the natural history of liver cirrhosis. Gastrointestinal bleeding and hepatic failure are the leading causes of death in hepatocellular carcinoma patients. With gastrointestinal bleeding, variceal bleeding is the most prominent, and most variceal bleeding is of esophageal origin. Gastric varices bleeding is often a massive and severe bleeding episode. The role of gastric varices among patients with hepatocellular carcinoma remains to be clarified. In this study, we aimed to evaluate the prevalence, clinical significance and prediction of gastric varices in patients with hepatocellular carcinoma. METHODOLOGY: From 1998 to 2000, we reviewed 304 patients with hepatocellular carcinoma receiving upper gastrointestinal endoscopic examinations. Patients' clinical characteristics, physical findings, laboratory data, image studies, endoscopic examinations and treatment were reviewed. RESULTS: Among 304 patients with HCC, twenty-one (6.9%) had gastric varices among 304 patients with hepatocellular carcinoma. The location of gastric varices were the posterior wall in 12 (57%), the lesser curvature in 1 (5%), the greater curvature in 4 (19%) and the fundus in 4 (19%). Three (14%) of these 21 patients with hepatocellular carcinoma and gastric varices had clinical evidence of bleeding. One of them died due to uncontrollable bleeding. Child-Pugh classification, hepatic encephalopathy, portal vein or splenic vein dilatation, ascites, splenomegaly, albumin level, prothrombin time and platelet count were significantly different between hepatocellular carcinoma patients with gastric varices and without gastric varices under the univariate analysis. Ascites (Odds ratio: 5.45; 95% confidence interval: 2.12-14.01) and portal vein or splenic vein dilatation (Odds ratio: 4.38; 95% confidence interval: 1.77-10.86) were the two most important predictors under the stepwise logistic regression analysis. CONCLUSIONS: The prevalence of gastric varices in patients with hepatocellular carcinoma is 6.9% and the risk of bleeding is low in this study. The Predictors of gastric varices among hepatocellular carcinoma are related to liver cirrhosis, Child-Pugh classification, hepatic encephalopathy, portal vein or splenic vein dilatation, ascites, splenomegaly, albumin level, prothrombin time and platelet count.     

Advances in the treatment of hepatocellular carcinoma and concomitant esophageal varices

Twenty-four patients with hepatocellular carcinoma (HCC) concomitant with esophageal and/or cardial varices concurrently underwent hepatic resection for HCC and various treatments for varices. All patients had cirrhosis of the liver, and had either blue or white varices with "red color signs" endoscopically. These patients were assigned to two groups. Group A patients simultaneously underwent partial hepatectomy and selective shunt or direct interruption procedures (n = 13). Group B patients underwent hepatic resection and devascularization of the upper half of the stomach and/or preoperative or postoperative endoscopic injection sclerotherapy (n = 11). Seven patients in Group A had a tumor recurrence 4 to 58 months postoperatively, while in Group B, one of 11 patients had a tumor recurrence in the remnant liver. There was one patient in Group A with postoperative rebleeding from esophageal varices, and there was neither variceal bleeding nor variceal recurrence after treatment in Group B. Liver failure was the immediate cause of death in five, including three in-hospital deaths in Group A. Survival rates during the first 5 years in Group A were 75%, 67%, 31%, 21% and 10%, while the four-year survival rate in group B was 100%. In the light of this evidence, the treatment given to Group B is to be preferred.     

Endoscopic injection sclerotherapy versus conservative treatment for patients with unresectable hepatocellular carcinoma and bleeding esophageal varices.

We performed endoscopic injection sclerotherapy (EIS) in the treatment of 37 patients with bleeding esophageal varices due to unresectable hepatocellular carcinoma (HCC). The results were compared with those in another 33 HCC patients treated only conservatively, without EIS, during the same period. A majority of both groups died within 3 weeks after treatment. Comparing the two groups, there was no significant difference in fatal bleeding (66% vs 75%), but significantly fewer of the EIS patients died of the index hemorrhage (43% vs. 83%; p less than 0.01). Also, in the absence of portal vein thrombosis, EIS significantly reduced the risk of fatal bleeding (31% vs. 73%; p less than 0.25). The mean days of survival were 32 +/- 15 (range, 2 to 320) in the EIS group and 10 +/- 14 (range, 2 to 270) in the compared group (p less than 0.001). We conclude that EIS provides temporary control of acute esophageal variceal bleeding in patients with unresectable HCC. The major factors contributing to EIS failure are the lethal propensity of the underlying disease and portal vein thrombosis.     

Treatment and prognostic factors in patients with hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma is a leading cause of death from cancer worldwide. Survival of patients depends on tumor extension and liver function, but yet there is no consensual prognostic model. AIMS: To evaluate the influence on survival of pretreatment parameters (clinico-laboratorial, liver function, tumor extension, Okuda and Cancer of the Liver Italian program (CLIP) staging) and treatment modalities. METHODS: We retrospectively analyzed 207 patients, diagnosed between 1993 and 2003. The initial treatment was: surgery--six patients; radiofrequency ablation--21; percutaneous ethanol injection--29; transarterial chemoembolization--49; tamoxifen--49; supportive care alone--53. Factors determining survival were assessed by Kaplan-Meier method and Cox regression models. RESULTS: Median survival was 24 months. In univariate analysis, Child-Pugh classification and Model for end-stage liver disease (MELD) score, portal vein thrombosis (PVT), tumor size, number of lesions, Okuda and CLIP scores were all associated with prognosis (P < 0.001). Alpha-fetoprotein levels were not predictive of survival. Independent predictors of survival were ascites, bilirubin, PVT and therapeutic modalities (P < 0.001). In early stage hepatocellular carcinoma (HCC), survival was similar for both percutaneous ablation modalities, either radiofrequency or ethanol injection (P = NS). In advanced HCC, survival was better in patients receiving tamoxifen than supportive care alone (P < 0.001). CONCLUSION: This study reinforces the importance of baseline liver function (Child-Pugh classification and MELD score) in the survival of patients with HCC, although staging systems allowed the stratification of patients in different prognostic groups. Ascites, bilirubin and PVT were independent pretreatment predictors of survival. All treatments influenced the patient's outcome, whether in early or advanced stages.     

Prevalence and prognostic value of hepatocellular carcinoma in cirrhotic patients presenting with spontaneous bacterial peritonitis

BACKGROUND/AIMS: This study examined the prognostic power of hepatocellular carcinoma in patients presenting an episode of spontaneous bacterial peritonitis treated with 3rd generation cephalosporins or quinolones, and subsequent prophylaxis with norfloxacin until death or transplantation. METHODS: The study comprises the prospective evaluation of 168 consecutive cirrhosis patients presenting an episode of spontaneous bacterial peritonitis. RESULTS: Hepatocellular carcinoma was diagnosed in 35 out of the 168 (20%) patients included in the study (10 single; 25 advanced tumors). Renal impairment developed in 82 patients. Resolution of infection was achieved in 90% of the cases, the hospital survival being 70%. Renal impairment, advanced tumor stage, albumin, and GGT showed independent prognostic value for hospital mortality. At the end of follow-up 101 patients had died, the 1- and 2-year survival being 36% and 31%, respectively. Four variables independently predicted survival: advanced tumor (OR: 3.9; p=0.00001), renal impairment (OR: 2.1; p=0.00001), bilirubin (OR: 1.6; p=0.02) and creatinine (OR: 1.3; p=0.03). Advanced tumor retained independent predictability in patients surviving hospitalization (OR: 7.5; p=0.0001), the 6-month survival being significantly lower in patients with advanced tumor (12% vs 57%, p<0.00001). CONCLUSION: The prevalence of hepatocellular carcinoma in cirrhotic patients with spontaneous bacterial peritonitis is high, and its presence should be actively sought. Advanced tumor impairs both hospital and long-term survival, and should be considered in the design of future trials.     

Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis

Patients with primary sclerosing cholangitis (PSC) may develop and bleed from esophageal varices. However, the exact prevalence of esophageal varices in patients with PSC remains unknown and potential predictors of esophageal varices in this population have not been identified. Our aim was to determine the prevalence of esophageal varices in patients with PSC and the variables that predict their presence. Data were collected on 283 patients with PSC treated for the first time at the Mayo Clinic (Rochester, MN) during 8 consecutive years. Thirty-six percent (102 of 283) of patients had esophageal varices including 56% (57 of 102) with moderate/large varices. After excluding 28 patients with a history of variceal bleeding, data on 183 patients were analyzed to identify independent predictors of esophageal varices and of moderate/large size varices. Platelet count, albumin level, and advanced histologic disease were independent predictors of esophageal varices (area under the receiver operator characteristic [ROC] curve = 0.88). After controlling for the presence of advanced histologic stage and albumin levels, the odds ratios (OR) of platelet count less than 150 x 10(3)/dL for the presence of esophageal varices was 6.3 (95% CI: 2.6-15.8). The diagnostic accuracy of these results was corroborated by cross-validation of the data in an independent set of 72 patients with PSC (area under the ROC = 0.90). In conclusion, in patients with PSC, noninvasive markers of portal hypertension and of advanced liver disease predict the presence of esophageal varices. Our results suggest a clinically applicable and useful approach to identify patients with PSC who are more likely to benefit from endoscopic screening for esophageal varices.     

The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma

We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73–780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20–122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson’s grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery.     

Endoscopic injection sclerotherapy for esophageal varices prolonged survival of patients with hepatocellular carcinoma complicating liver cirrhosis

BACKGROUND: A prospective controlled study was performed between 1982 and 1991 to evaluate the efficacy of endoscopic injection sclerotherapy (EIS) in patients with esophageal varices complicated by hepatocellular carcinoma and liver cirrhosis. METHODS: The study included 83 patients with esophageal varices, hepatocellular carcinoma, and liver cirrhosis. Forty-three patients (group 1) underwent prophylactic EIS or emergent EIS for bleeding varices. EIS was performed weekly 4 to 6 times until the varices disappeared. The remaining 40 patients (group 2) underwent conservative therapy and did not undergo EIS. Survival rates were compared between the 2 groups. RESULTS: During the 5-year observational period, all patients who did not undergo EIS died. Sixteen in group 2 (40.0%) died of gastrointestinal bleeding including ruptured esophageal varices. In contrast, patients treated with EIS survived significantly longer (p<0.001). Nine patients (20.9%) treated with EIS experienced gastrointestinal bleeding as a result of which 5 (11.6%) died. EIS prolonged survival in patients classified as Child's A or B but did not affect survival in patients with Child's C hepatic function. EIS was effective in prolonging survival in patients with hepatocellular carcinomas smaller than 5 cm. However, EIS had no effect in patients with hepatocellular carcinomas that were larger than 5 cm. EIS prolonged survival only for patients with nodular hepatocellular carcinoma and had no effect in patients with massive and diffuse hepatocellular carcinoma. Further, EIS prolonged survival only for patients who did not have portal vein thrombosis. CONCLUSION: Based on this prospective study, we concluded that EIS was effective in prolonging the survival period of a select subset of patients with hepatocellular carcinoma.     

Endoscopic injection sclerotherapy for esophageal varices in cirrhotic patients with hepatocellular carcinoma: risk factors for survival

GOALS: We previously showed that endoscopic injection sclerotherapy (EIS) prolonged survival in patients with esophageal varices complicated by hepatocellular carcinoma (HCC) and liver cirrhosis. Here, we evaluated risk factors that affect EIS outcomes. Among factors, the difference between prophylactic and emergency EIS was of interest, and we analyzed precisely. STUDY: Subjects were 134 patients with esophageal varices complicated by HCC and liver cirrhosis: 38 underwent emergent therapy for bleeding varices and 96 underwent prophylactic sclerotherapy. RESULTS: During 2-year observation, 22 of the 38 (57.9%) and 38 of the 96 (39.6%) died. Analysis by univariate Cox's proportional hazard model indicated that prognosis of patients receiving emergency EIS was inferior to those with prophylactic EIS. However, multivariate Cox's analysis showed that emergency EIS itself extended survivals of those with esophageal varices complicated by HCC and liver cirrhosis. Patients' hepatic function (Child-Pugh classes) and tumor sizes were also statistically significant factors for survival. Neither prophylactic nor emergency EIS prolonged survival of patients with Child C hepatic function or those with HCCs larger than 5 cm. CONCLUSIONS: The prophylactic sclerotherapy for esophageal varices prolongs long-term survival of patients with liver cirrhosis and HCC, better than emergency therapy. However, EIS itself had no beneficial effect on patients with poor disease status.     

New approaches to hepatocellular carcinoma and concomitant esophageal varices prolong survival

A retrospective study was done on 226 patients with hepatocellular carcinoma and coexisting esophageal varices treated at our institute between 1974 and 1988. The patients were divided into two groups: Group A containing patients treated between 1974 and 1982 (n = 92), and Group B comprising those treated between 1983 and 1988 (n = 134). Surgical treatments were applied to 64 patients (69.6%) and 37 patients (27.6%) in groups A and B, respectively (p less than 0.001). Ninety out of 134 patients (67.2%) in group B were prescribed regional chemotherapy. Forty-nine patients (53.3%) in group A, and 96 (71.6%) in group B had esophageal varices that were about to rupture as indicated endoscopically. Nineteen patients (38.8%) in group A, and 10 (10.4%) in group B were treated surgically (p less than 0.005). The varices in 76 out of 96 patients (79.2%) in group B were treated by endoscopic sclerotherapy. Survival rates during the first 5 years in groups A and B were 28% and 65%, 16% and 43%, 5% and 27%, 4% and 18%, and 4% and 6%, respectively. It would appear that appropriate conservative treatment of the poor surgical candidates will, in general, lead to good clinical results.     

Successful surgical treatment for hepatocellular carcinoma and concomitant risky esophageal varices

BACKGROUND/AIMS: In our frequent encounters with liver cirrhotic patients with hepatocellular carcinoma (HCC) and concomitant risky esophageal varices, we have found that some of them required endoscopic injection sclerotherapy (EIS) and/or surgical treatment for esophageal variceal bleeding due to increased portal venous pressure after aggressive hepatectomy. In this study, we investigated the short-term effect of aggressive hepatectomy accompanied with left gastric venous caval shunt (Inokuchi's shunt) for esophageal varices and postoperative liver function. METHODOLOGY: Four cirrhotic patients with HCC and concomitant risky esophageal varices underwent hepatectomy with Inokuchi's shunt from 1999 to 2001. The mean age was 58.0 +/- 15.3 years old and all patients were classified in Child grade A or B. We investigated hematochemical data and endoscopic findings before and after surgery. RESULTS: One of the patients experienced disappearance of esophageal varices at discharge. In the others, postoperative endoscopy showed disappearance of CRS and reduced sizes of varices. In one patient, hepatic encephalopathy appeared transiently with bleeding from a duodenal ulcer at one month after surgery. However, the patient improved by conservative treatment. Three of the patients have survived well without recurrence of HCC and esophageal variceal bleeding; the remaining patient died from a recurrence of HCC. CONCLUSIONS: Inokuchi's shunt may be sufficiently effective to treat risky esophageal varices associated with resectable HCC and may be safe even if it is undertaken along with a major hepatectomy.     

High-risk esophageal varices in patients treated with locoregional therapy for hepatocellular carcinoma: Assessment with liver computed tomography

AIM:To assess the diagnostic performance of followup liver computed tomography(CT) for the detection of high-risk esophageal varices in patients treated with locoregional therapy for hepatocellular carcinoma(HCC).METHODS:We prospectively enrolled 100 patients with cirrhosis who underwent transcatheter arterial chemoembolization,radiofrequency ablation or both procedures for HCCs.All patients underwent upper endoscopy and subsequently liver CT.Three radiologists independently evaluated the presence of high-risk esophageal varices with transverse images alone and with three orthogonal multiplanar reformation(MPR) images,respectively.With endoscopic grading as the reference standard,diagnostic performance was assessed by using receiver operating characteristic(ROC) curve analysis.RESULTS:The diagnostic performances(areas under the ROC curve) of three observers with transverse images alone were 0.947 ± 0.031,0.969 ± 0.024,and 0.916 ± 0.038,respectively.The mean sensitivity,specificity,positive predicative value(PPV),and negative predicative value(NPV) with transverse images alone were 90.1%,86.39%,70.9%,and 95.9%,respectively.The diagnostic performances,mean sensitivity,specificity,PPV,and NPV with three orthogonal MPR images(0.965 ± 0.025,0.959 ± 0.027,0.938 ± 0.033,91.4%,89.5%,76.3%,and 96.6%,respectively) were not superior to corresponding values with transverse images alone(P 0.05),except for the mean specificity(P = 0.039).CONCLUSION:Our results showed excellent diagnostic performance,sensitivity and NPV to detect high-risk esophageal varices on follow-up liver CT after locoregional therapy for HCC.     

Does the size of esophageal varices have a prognostic significance in alcoholic cirrhosis?

This study was designed to determine whether the size of esophageal varices were of prognostic value in patients with alcoholic cirrhosis. Esophageal varices were classified into 2 groups according to whether their size was larger or smaller than 4 mm. There was a total of 99 patients; 56 had small varices and 43 had large varices. Of the clinical and biological data collected at the time of determination of the size of the esophageal varices, only the duration of cirrhosis and the prevalence of gastrointestinal bleeding were significantly greater in patients with large esophageal varices. The one- and two-year cumulative rates of patients with large esophageal varices were 63 +/- 7 p. 100 and 42 +/- 8 p. 100, respectively; these results were not significantly different from those in patients with small esophageal varices, i.e. 68 +/- 6 p. 100 and 61 p. 100 respectively (p less than 0.5 for one-year survival; p less than 0.08 for two-year survival). Serum bilirubin and albumin as well as the presence of ascite were of significant prognostic value concerning death at two years while the presence of esophageal varices did not significantly increase the prognostic value of the above-mentioned variables (using Cox's regression model). In conclusion, the results of our study suggest that large esophageal varices, in spite of their association with a high incidence of gastrointestinal bleeding, do not influence prognosis at two years for patients with alcoholic liver cirrhosis.