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Reprint requests: Wladimir Faber, MD, Department of General, Visceral and Transplantation Surgery, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Hepatocellular carcinoma (HCC) is among the most common malignant neoplasms worldwide. Only few data on HCC in noncirrhotic livers without viral hepatitis in Western countries are available. The purpose of this study was to define the outcomes and potential prognostic factors associated with survival after hepatic resection in patients with HCC in the absence of liver cirrhosis and hepatitis B or C infection.
Patients and Methods
From January 2000 to September 2010, 148 patients without liver cirrhosis and without extrahepatic metastases underwent curative hepatic resection for HCC at the Surgical Department of the Charité, Campus Virchow Klinikum. The outcomes of these patients were retrospectively reviewed. Patients with cirrhosis or severe fibrosis, fibrolamellar HCC, and those positive for hepatitis B or C were excluded.
Results
The cumulative 1-, 3-, 5-, and 7-year survival rates were 75.4%, 54.7%, 38.9%, and 31.8%, respectively. The 1-, 3-, 5-, and 7-year disease-free survival rates were 60.3%, 38.0%, 29.1%, and 18.1%, respectively. In the multivariate analysis, cumulative survival was decreased by patient age, increased operative time, increased preoperative serum gamma-glutamyl transferase (GGT), and tumor stage. In the subgroup with unifocal neoplasms, N0 and R0 status, tumor size >10 cm, and tumor differentiation were highly predictive of lesser survival. Unfavorable survival was observed in patients with multifocal neoplasms, tumor size >10 cm, and/or poor tumor differentiation.
Conclusion
The current TNM staging system is stratified for survival and recurrence. Extension of the current TNM staging system by grading and more exact differentiation of tumor size may increase its prognostic accuracy for predicting outcome. Preoperative increased serum GGT level could be a new poor prognostic factor.
Hepatocellular carcinoma (HCC) is among the most common malignances worldwide with approximately 500,000–1,000,000 new cases annually.
in: Berr F. Briux J. Hauss J. Malignant liver tumors: basic concepts and clinical management. Kluwer Academic Publishers BV and Falk Foundation,
Dordrecht2003: 67-74
Many publications have addressed the characteristics, treatment, and prognosis of HCC in patients with cirrhosis. Liver transplantation and resection are the recommended treatments with a curative intent for patients with HCC in cirrhosis. In contrast, few data on HCC in noncirrhotic livers in patients without viral hepatitis in Western countries are available.
The etiologic factors involved in HCCs in noncirrhotic livers without chronic or previous viral hepatitis are less clear. Most clinical staging systems for HCC do not incorporate a category for patients without cirrhosis
Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.
; however, because of the different clinical course, which is primarily the result of the long-term complications of liver cirrhosis, a direct comparison of the course of HCC arising in normal liver parenchyma to that of patients with HCC in a cirrhotic liver is not possible.
Liver resection has been established as a curative treatment for HCC with improving results owing to advances in operative techniques and perioperative care.
Liver transplantation is not an accepted treatment for patients with HCC without cirrhosis because of impaired long-term survival rates in early studies.
reported very good, long-term results with 5-year survival rates of 50–70% after resection of HCC treatment in noncirrhotic livers in well-selected patients who underwent liver transplantation.
The purpose of this study was to define the outcomes and potential prognostic factors associated with survival after hepatic resection in patients with HCC in the absence of liver cirrhosis and hepatitis B or C infection.
Patients and methods
Patients
From January 2000 to September 2010, 148 patients without liver cirrhosis and without extrahepatic metastases underwent curative-intent hepatic resection for HCC at the Surgical Department of the Charité, Campus Virchow Klinikum. The median age of the 105 men and 43 women at the time of liver resection was 68 years (range, 21–89).
The outcomes of these patients were retrospectively reviewed using a prospective database. Only patients with postoperative histologic assurance of HCC were included in the database. Patients with fibrolamellar HCC and patients positive for hepatitis B or C were excluded. Patients with liver cirrhosis or severe fibrosis (greater than grade 2 fibrosis according to the Desmet-Scheuer score) in the final histologic analysis were also excluded. The median alpha fetoprotein value was 16 ng/mL (range, 1–71,810).
Diagnostic workup
Liver resection was considered the treatment of choice for resectable HCC of the liver based on the number and site of the tumors, the size and function of the future liver remnant, and the general status of the patient. The type of resection was defined by tumor size, number, and location. The abdomen was systematically examined intraoperatively. Every patient underwent intraoperative ultrasonography. Vascular exclusion of the liver was not used.
The diagnosis of HCC was based on ultrasonography, contrast-enhanced, multiphasic computed tomography, and/or magnetic resonance imaging. An increase of alpha fetoprotein levels was used as a supporting factor in the diagnosis of HCC. Preoperative tumor biopsy was performed only in exceptional cases.
Follow-up
Patients were contacted by phone or in person. Alternatively, information regarding patient survival was obtained from the general practitioner and health insurer of the patient. The median follow-up period for the patients after liver resection was 59 months (range, 0–127).
Statistical analysis
Data were analyzed using PASW 18.0 (SPSS Inc, Chicago, IL) software for survival analysis and Kaplan–Meier estimations. Survival data were compared by the log-rank test. Univariate and multivariate associations of factors with patient survival and tumor recurrence were assessed using Cox proportional hazards models. Hazard ratios were presented with 95% confidence intervals. Variables with P < .1 in a univariate analysis were included in the multivariate analysis. Continuous variables were presented as median values and ranges.
Results
Study population and procedural data
A total of 32 patients underwent segmentectomy or wedge resection; 15 patients were treated with a left lateral hemihepatectomy, 14 with a left hemihepatectomy, and 39 with right liver resection. An additional 48 patients underwent extended hemihepatectomies. The median operating time was 225 minutes (range, 85–429). Blood was intraoperatively transfused in 32 patents (21.6%; Table I).
Thirty-seven patients were positive for alcohol abuse. In the univariate analysis, positive alcohol abuse decreased recurrence-free survival (P = .03). Positive alcohol abuse did not influence cumulative survival (P = .54; Table II). In the multivariate analysis, positive alcohol abuse was not a significant predictor for recurrence-free survival.
Table IIUnivariate analysis data for cumulative and recurrence-free survival
The median body mass index was 26.6 kg/m2 (range, 16.9–37.4). Neither recurrence-free survival (P = .74) nor overall survival (P = .13) were significantly influenced by body mass index (Table II).
Pathology
The median tumor size was 90 mm (range, 5–250), and 43 patients had >1 liver lesion. In 52 patients, tumor vascular invasion was found. A positive tumor margin was present in 25 cases. Fibrosis was scored according to the classification of Desmet and Scheuer and was stage 0 in 42 patients, stage 1 in 64, and stage 2 in 42.
Tumor grading was 1 in 19 cases, 2 in 97, and 3 in 32. According to the TNM (TNM-6 American Joint Committee on Cancer/UICC 2002) staging system, patients could be assigned to the following tumor stages: Stage I (n = 50), stage II (n = 36), stage IIIA (n = 48), stage IIIB (n = 9), and stage IIIC (n = 5)
Steatosis, defined as ≥50% fat accumulation, was present in 12 patients (8.1%). Neither recurrence-free survival (P = .13) nor cumulative survival (P = .1) were significantly influenced by steatosis (Table II).
Tumor size correlated with vascular invasion only in patients with a single nodule (P = .01). We divided the patients into 3 groups based on tumor size: <5, 5–10, and >10 cm. Vascular invasion was present in tumors <5 cm in 28.6% of patients, tumors 5–10 cm in 15.0%, and tumors >10 cm in 45.5% of patients (Fig 1).
Fig 1Vascular invasion correlated with tumor size for single node tumors (P = .01). (Color version of figure is available online.)
Tumor size and vascular invasion were not correlated in the subgroup with multiple nodes (P = .8). The number of tumor lesions did not correlate with grade of fibrosis (P = .77) or tumor grading (P = .7). Additionally, the grade of fibrosis was not correlated with vascular invasion (P = .2); in contrast, there was a correlation between grading and vascular invasion in the entire study population (P < .05).
We also compared patients fulfilling the Milan criteria with those who did not and were without lymph node metastases. No differences were observed between these 2 subgroups for vascular invasion (P = .85), tumor grade (P = .37), or recurrence-free survival (P = .63). Cumulative survival showed a strong tendency toward improved survival in the subgroup fulfilling the Milan criteria (P = .06).
Morbidity and mortality
The median in-hospital stay was 15 days (range, 5–161), and the median intensive care stay was 1 day (range, 0–133). Postoperative complications were evaluated according to the Clavien classification.
The overall postoperative morbidity was 37.8% (56 patients); 8 patients developed postoperative complications grade I, 17 grade II, 13 grade IIIa, 16 grade IIIb, and 2 grade IVa. No intraoperative deaths were observed, but 7 patients (5%) died during the hospital stay (Clavien grade V; Table IV).
The median cumulative survival was 25 months (range, 0–133). Figure 3 and Table V show the probability of survival according to TNM stage. The 1-, 3-, 5-, and 7-year survival rates were 75.4%, 54.7%, 38.9%, and 31.8%, respectively.
Fig 2Cumulative overall survival and cumulative disease-free survival. (Color version of figure is available online.)
The results of the univariate analysis for risk factors are summarized in Table II. In the multivariate analysis, cumulative survival decreased with patient age, increased operation time, and increased preoperative gamma-glutamyl transferase (GGT). Tumor stage also influenced cumulative survival.
Increased level of GGT (>50 U/L) correlated with tumor size (P = .01), but not with tumor-free margin (P = .06), grade of neoplasm (P = .55), or operative time (P = .15).
An analysis of risk factors for tumor recurrence was performed in the subgroup of patients with unifocal neoplasms and N0 and R0 status. In this subgroup, T-stage (P = .001) and vascular invasion (P = .009) were predictors of survival. Tumor size >10 cm was highly predictive of decreased survival (P = .002; Fig 4). In contrast, a tumor size >5 cm did not discriminate between a good or poor prognosis (P = .09). In the same subgroup, we also found a significant correlation between tumor grading and survival. Unfavorable survival was observed in patients with a tumor size >10 cm and/or poor tumor differentiation (G3) and in patients with multicentric neoplasms (Fig 5). In the same subgroup who were N0 and R0, a tumor size >5 cm decreased cumulative survival (P = .028). Vascular invasion, grade of tumor, and T stage did not influence survival.
Fig 4Cumulative survival in the subgroup with unifocal neoplasms, N0, and R0, depending on tumor size (<10 and >10 cm; P < .01). (Color version of figure is available online.)
Fig 5Prediction of outcome by grade of tumor and tumor size in patients with N0 and R0 status. Patients with a tumor >10 cm, poor differentiation (G3) or multiple tumor nodules had a particularly unfavorable prognosis. (Color version of figure is available online.)
In the subgroup with fibrosis grade 0 and steatosis <10%, neither tumor size nor grade of tumor influenced survival (P > .05). Only preoperative serum GGT level and tumor size were correlated (P < .01); this subgroup included only 35 patients, limiting the statistical interpretation of the data.
Recurrence
Figure 2 shows the overall survival and disease-free survival (DFS). Tumor recurrence was detected in 58 patients. In 35 patients, tumor recurrence was observed only in the liver remnant or at the resection margin without extrahepatic metastases, whereas 13 patients had synchronous extra- and intrahepatic recurrence. Extrahepatic metastasis (brain, lung, lymph nodes, and others) only were detected in 10 patients during the follow-up period. Tumor recurrence was treated in with second resection (n = 15), chemotherapy (n = 11), high-dose-rate brachytherapy (n = 6), transarterial chemoembolization (n = 5), and other therapeutic options (n = 5); 16 patients were treated by best-supportive therapy.
The median DFS was 14 months. The 1-, 3-, 5-, and 7-year DFS rates were 60.3%, 38.0%, 29.1%, and 18.1%, respectively. The 1-, 3-, 5-, and 7-year recurrence rates were 16.5%, 45.6%, 50.2%, and 60.0%, respectively.
The results of the univariate analysis for risk factors are summarized in Table II. In the multivariate analysis, only in-hospital stay (P = .001), multifocal neoplasms (P = .01), tumor size (P > .01), and vascular invasion (P = .001) decreased recurrence-free survival.
Discussion
HCC in noncirrhotic liver is rare, and the etiologic factors, treatment, and prognostic factors are less clear than for HCC in cirrhotic liver.
Previous studies with only noncirrhotic livers showed a heterogeneous grouping of prognostic factors for recurrence-free and cumulative survival. Berge, Dupont-Bierre, and Lang and their colleagues identified vascular invasion as a poor prognostic factor.
reported that the status of the resection margin, the presence of intrahepatic metastases, and portal vein invasion were independent predictors of poor survival. Other authors showed the negative influence of multicentric neoplasms on prognosis.
Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre.
The aim of the present study was to analyze the outcome of the operative treatment of patients with nonmetastatic HCC in noncirrhotic livers. Patients with viral hepatitis or advanced fibrosis (below grade 2) were excluded for elimination of any influence of concomitant liver disease on the outcome and tumor recurrence based on existing evidence.
In contrast with some previous reports, we did not identify impaired survival with multicentric neoplasms or a positive resection margin in the multivariate analysis. We observed a greater percentage of males in our cohort; however, gender did not influence survival or the recurrence rate. Steatosis, body mass index, and positive alcohol anamnesis did not influence survival or recurrence-free survival in the multivariate analysis (Table II).
A correlation between grade of tumor and survival was previously reported by Lang et al
showed that a tumor size >10 cm decreased survival in a univariate analysis. We analyzed the subgroup of patients with unifocal neoplasms, who had a N0 and R0 resection. The worst survival in this subgroup was observed in patients with a tumor size >10 cm and/or poor tumor differentiation (G3). Both factors can be easily determined before operation, whereas preoperative tumor biopsy increases the risk of cancer cell dissemination.
We identified preoperative in-hospital stay, multifocal neoplasms, tumor size, and vascular invasion as poor prognostic factors for recurrence-free survival. Extended operative time, increased preoperative serum GGT levels, and tumor stage were identified as poor prognostic factors for survival.
Some predictive factors were similar to that for HCC in cirrhotic livers. Multifocal neoplasms and vascular invasion have been reported as poor prognostic factors for DFS in patients with HCC in cirrhotic livers.
Other authors demonstrated that serum levels of aspartate aminotransferase, alanine aminotransferase, AP, and GGT were important factors for DFS in patients with HCC in cirrhotic livers.
A similar situation was found for cumulative survival; serum aspartate aminotransferase, AP, and bilirubin have been reported as significant predictors of decreased cumulative survival for patients with HCC in cirrhotic livers.
A detailed pathologic analysis revealed that the number of tumor nodules did not correlate with the fibrosis grade or the grade of tumor in our collective. Preoperative increased serum levels of GGT could be a new poor prognostic factor, because it was predictive in the entire patient population with HCCs in noncirrhotic livers.
Although we compared subgroups of patients that were inside and outside the Milan criteria, no differences were observed for vascular invasion, grade of tumor, or recurrence-free survival between the 2 groups. Interestingly, the survival rate between these 2 subgroups reached P = .06 (Fig 3). Patients with HCC without cirrhosis in Western countries are often diagnosed with large tumors (median 90 mm in our series) owing to a lack of screening programs, such as those performed on patients with cirrhosis. It is possible that this aspect is not clinically important despite the marked differences in long-term survival.
The current TNM staging system stratified our cohort of patients for survival and recurrence. Tumor stage correlated with progression in most patients. Based on previous reports and our results, the extension of the current TNM staging system by grade of tumor and a more exact differentiation of tumor size in patients with a single nodule and even in patients without vascular invasion may increase the prognostic accuracy for predicting outcome in HCC patients without cirrhosis, because tumor biology and the clinical course might not be directly comparable with patients with cirrhosis.
According to our experience and the literature, liver resection is accepted as the best curative treatment today. Nevertheless, the incidence of intrahepatic tumor recurrence after curative resection is high,
even in patients without liver cirrhosis, as shown in the present analysis (a 50.2% recurrence rate after 5 years). The experience treating HCC in noncirrhotic livers using organ transplantation is disappointing. Iwatsuki et al
showed a greater rate of tumor recurrence after liver transplantation for HCC in noncirrhotic livers compared with patients with liver cirrhosis. Similar experiences were reported by Pichlmayr et al and Houben et al
reported the results of a long-term study with a 5-year survival rate of 50–70% in well-selected patients who underwent liver transplantation.
HCC in a noncirrhotic liver is rare in Western countries. The prognostic factors are less clear than for HCC in a cirrhotic liver. Increased levels of serum GGT preoperatively may prove to be a new, poor prognostic factor. The current TNM staging system is well-stratified for survival and recurrence. Extending the current TNM staging system by grade of tumor and a more exact differentiation of tumor size could increase the prognostic accuracy for predicting outcome. Liver resection is currently the only curative therapy, but the recurrence rate after curative liver resection is high. Further studies are necessary for the identification of other prognostic factors and optional adjuvant therapy.
References
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Pisani P.
Estimating the world cancer burden: Globocan 2000.
in: Berr F. Briux J. Hauss J. Malignant liver tumors: basic concepts and clinical management. Kluwer Academic Publishers BV and Falk Foundation,
Dordrecht2003: 67-74
Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma.
Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre.
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