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Long-term results of liver resection for hepatocellular carcinoma in noncirrhotic liver

Published:November 02, 2012DOI:https://doi.org/10.1016/j.surg.2012.09.015

      Background

      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.
      • Parkin D.M.
      • Bray F.
      • Ferlay J.
      • Pisani P.
      Estimating the world cancer burden: Globocan 2000.
      • Parkin D.M.
      • Bray F.
      • Ferlay J.
      • et al.
      Global cancer statistics, 2002.
      Liver cirrhosis is the strongest predisposing factor, and most HCC cases in Western countries develop in cirrhotic livers.
      • Colombo M.
      Risk groups and preventive strategies.
      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.
      • Ardiles V.
      • Sánchez Clariá R.
      • Mazza O.M.
      • et al.
      Prognostic factors after resection of hepatocellular carcinoma in the non-cirrhotic liver: presentation of 51 cases.
      • Smoot R.L.
      • Nagorney1 D.M.
      • Chandan V.S.
      • et al.
      Resection of hepatocellular carcinoma in patients without cirrhosis.
      • Verhoef C.
      • De Man R.A.
      • Zondervan P.E.
      • et al.
      Good outcome after resection of large hepatocellular carcinoma in the noncirrhotic liver.
      • Dupont-Bierre E.
      • Compagnon P.
      • Raoul J.L.
      • et al.
      Resection of hepatocellular carcinoma in non cirrhotic liver: analysis of risk factors for survival.
      • Nagasue N.
      • Ono T.
      • Yamanoi A.
      • et al.
      Prognostic factors and survival alter hepatic resection for hepatocellular carcinoma without cirrhosis.
      • Alkofer B.
      • Lepennec V.
      • Chiche L.
      Hepatocellular carcinoma in the non-cirrhotic liver.
      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
      • Llovet J.M.
      • Bruix J.
      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.
      • Ardiles V.
      • Sánchez Clariá R.
      • Mazza O.M.
      • et al.
      Prognostic factors after resection of hepatocellular carcinoma in the non-cirrhotic liver: presentation of 51 cases.
      • Smoot R.L.
      • Nagorney1 D.M.
      • Chandan V.S.
      • et al.
      Resection of hepatocellular carcinoma in patients without cirrhosis.
      • Verhoef C.
      • De Man R.A.
      • Zondervan P.E.
      • et al.
      Good outcome after resection of large hepatocellular carcinoma in the noncirrhotic liver.
      Liver transplantation is not an accepted treatment for patients with HCC without cirrhosis because of impaired long-term survival rates in early studies.
      • Iwatsuki S.
      • Starzl T.E.
      • Sheahan D.G.
      • et al.
      Hepatic resection versus transplantation for hepatocellular carcinoma.
      • Neuhaus P.
      • Jonas S.
      • Bechstein W.O.
      • et al.
      Liver transplantation for hepatocellular carcinoma.
      • Neuhaus P.
      • Jonas S.
      • Bechstein W.O.
      Hepatoma of the liver: resection or transplantation?.
      • Pichlmayr R.
      • Weimann A.
      • Oldhafer K.J.
      • et al.
      Role of liver transplantation in the treatment of unresectable liver cancer.
      • Houben K.W.
      • McCall J.L.
      Liver transplantation for hepatocellular carcinoma in patients without underlying liver disease: a systematic review.
      Recently, however, Mergental et al
      • Mergental H.
      • Porte R.J.
      Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.
      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).
      Table IIntraoperative data
      Resection grade, n (%)
       1 segment and less32 (21.6)
       Left lateral hemihepatectomy15 (10.1)
       Left hemihepatectomy14 (9.5)
       Right hemihepatectomy39 (26.4)
       More than hemihepatectomy48 (32.4)
      Duration of operation (min)
      Median value (range).
      225 (85 to 429)
      Need for blood transfusion per patient
      Median value (range).
      0 (0 to 8)
      Patients requiring blood transfusion, n (%)32 (21.6)
      Need for transfusion of fresh frozen plasma per patient
      Median value (range).
      0 (0 to 15)
      Patients requiring fresh frozen plasma, n (%)50 (33.8)
      Need for transfusion of platelets per patient
      Median value (range).
      0 (0 to 2)
      Patients requiring platelet transfusion, n (%)2 (1.4)
      Median value (range).
      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
      ValueRecurrence-free survivalCumulative survival
      PExp(B)LowerUpperPExp(B)LowerUpper
      Gender.610.8820.5471.421
      Age.011.0271.0061.048
      Operative time<.011.0051.0021.007.011.0041.0011.007
      Blood
      Intraoperative.
      <.011.3071.1531.481.011.1711.0361.322
      Fresh frozen plasma
      Intraoperative.
      <.011.1181.0401.202.081.0760.9921.168
      Intensive care unit stay.051.0141.0001.027.011.0171.0041.030
      In-hospital stay<.011.0121.0041.021.011.0121.0031.021
      Aspartate aminotransferase
      Preoperative.
      .101.0021.0001.004
      AP
      Preoperative.
      .011.0021.0011.004.001.0031.0011.005
      GGT
      Preoperative.
      <.011.0021.0011.003.001.0031.0021.004
      Tumor size<.011.0071.0041.011.001.0081.0041.013
      Multiple nodes.010.5920.3930.891.000.4880.3100.769
      Vascular invasion<.010.5270.3570.779.000.4980.3220.768
      Steatosis.102.1380.8635.300
      Possible alcohol anamnesis.030.4550.2230.927
      Tumor grading.02.03
       G1.010.3080.1350.707.010.2440.0840.707
       G2.220.7570.4871.177.650.8930.5481.457
       G3ReferenceReference
      Tumor stage
      TNM classification of malignant tumors.18
      <.01.00
       I<.010.3680.1850.732.000.2780.1320.585
       II.010.4170.2120.818.000.2950.1430.610
       IIIA.800.9220.4941.720.380.7520.3981.419
       IIIB and IIICReferenceReference
      The following parameters were for recurrence free survival not significant (P > .1): Gender, patient age, platelets, alpha fetoprotein,
      Preoperative.
      albumin,
      Preoperative.
      alanine aminotransferase,
      Preoperative.
      bilirubin,
      Preoperative.
      quick,
      Preoperative.
      creatinine,
      Preoperative.
      urea,
      Preoperative.
      positive margin, steatosis, body mass index, fibrosis grade,
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      and resection grade. The following parameters were for cumulative survival not significant (P > .1): Gender, platelets, alpha fetoprotein,
      Preoperative.
      albumin,
      Preoperative.
      alanine aminotransferase,
      Preoperative.
      aspartate aminotransferase,
      Preoperative.
      bilirubin,
      Preoperative.
      quick,
      Preoperative.
      creatinine,
      Preoperative.
      urea,
      Preoperative.
      positive margin, body mass index, positive alcohol anamnesis, fibrosis grade,
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      and resection grade.
      GGT, Gamma-glutamyl transferase.
      Intraoperative.
      Preoperative.
      TNM classification of malignant tumors.
      • Sobin L.H.
      • Wittekind C.
      UICC: TNM classification of malignant tumors.
      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.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      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)
      • Sobin L.H.
      • Wittekind C.
      UICC: TNM classification of malignant tumors.
      (Table III).
      Table IIIHistologic characteristics
      Tumor size
      Median (range).
      (mm)
      90 (5–250)
      Positive tumor margin25 (16.9%)
      Vascular invasion52 (35.1%)
      Multiple tumor nodules43 (29.1%)
      Tumor grading
       G119 (12.8%)
       G297 (65.5%)
       G332 (21.6%)
      American Joint Committee on Cancer/International Union Against Cancer (2002) tumor stage
      TNM classification of malignant neoplasms.18
       I50 (33.8%)
       II36 (24.3%)
       IIIA48 (32.4%)
       IIIB9 (6.1%)
       IIIC5 (3.4%)
      Fibrosis grade
      Fibrosis score according to the classification system of Desmet and Scheuer.17
       042 (28.4%)
       164 (43.2%)
       242 (28.4%)
      Median (range).
      TNM classification of malignant neoplasms.
      • Sobin L.H.
      • Wittekind C.
      UICC: TNM classification of malignant tumors.
      Fibrosis score according to the classification system of Desmet and Scheuer.
      • Desmet V.J.
      • Gerber M.
      • Hoofnagle J.H.
      • et al.
      Classification of chronic hepatitis: diagnosis, grading and staging.
      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).
      Figure thumbnail gr1
      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.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications.
      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).
      Table IVClinical course
      Intensive care unit stay
      Median value (range).
      (days)
      1 (0–133)
      In-hospital stay
      Median value (range).
      (days)
      15 (5–161)
      Clavien grade
       I8 (5.4%)
       II17 (11.5%)
       IIIa13 (8.8%)
       IIIb16 (10.8%)
       IVa2 (1.4%)
       V7 (4.7%)
      Intraoperative death0 (0.0%)
      Median value (range).

      Survival

      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.
      Figure thumbnail gr2
      Fig 2Cumulative overall survival and cumulative disease-free survival. (Color version of figure is available online.)
      Figure thumbnail gr3
      Fig 3Cumulative survival after liver resection. (Color version of figure is available online.)
      Table VCumulative survival after liver resection
      Tumor stage0 years (n)1 years (n)3 years (n)5 years (n)
      I50184
      II36282018
      IIIA4832146
      IIIB and IIIC14742
      Cumulative1481065630
      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.
      Figure thumbnail gr4
      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.)
      Figure thumbnail gr5
      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.
      • Ardiles V.
      • Sánchez Clariá R.
      • Mazza O.M.
      • et al.
      Prognostic factors after resection of hepatocellular carcinoma in the non-cirrhotic liver: presentation of 51 cases.
      • Smoot R.L.
      • Nagorney1 D.M.
      • Chandan V.S.
      • et al.
      Resection of hepatocellular carcinoma in patients without cirrhosis.
      • Verhoef C.
      • De Man R.A.
      • Zondervan P.E.
      • et al.
      Good outcome after resection of large hepatocellular carcinoma in the noncirrhotic liver.
      • Dupont-Bierre E.
      • Compagnon P.
      • Raoul J.L.
      • et al.
      Resection of hepatocellular carcinoma in non cirrhotic liver: analysis of risk factors for survival.
      • Nagasue N.
      • Ono T.
      • Yamanoi A.
      • et al.
      Prognostic factors and survival alter hepatic resection for hepatocellular carcinoma without cirrhosis.
      • Alkofer B.
      • Lepennec V.
      • Chiche L.
      Hepatocellular carcinoma in the non-cirrhotic liver.
      Our study highlights this important topic.
      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.
      • Dupont-Bierre E.
      • Compagnon P.
      • Raoul J.L.
      • et al.
      Resection of hepatocellular carcinoma in non cirrhotic liver: analysis of risk factors for survival.
      • Bège T.
      • Le Treut Y.P.
      • Hardwigsen J.
      • et al.
      Prognostic factors after resection for hepatocellular carcinoma in nonfibrotic or moderately fibrotic liver. A 116-case European series.
      • Lang H.
      • Sotiropoulos G.C.
      • Brokalaki E.I.
      • et al.
      Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers.
      Bismuth et al
      • Bismuth H.
      • Chiche L.
      • Castaing D.
      • et al.
      Surgical treatment of hepatocellular carcinoma in non-cirrhotic liver: experience with 68 liver resections.
      showed that tumor size was a poor prognostic factor for survival and the recurrence rate. Nagasue et al
      • Nagasue N.
      • Ono T.
      • Yamanoi A.
      • et al.
      Prognostic factors and survival alter hepatic resection for hepatocellular carcinoma without cirrhosis.
      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.
      • Dupont-Bierre E.
      • Compagnon P.
      • Raoul J.L.
      • et al.
      Resection of hepatocellular carcinoma in non cirrhotic liver: analysis of risk factors for survival.
      • Laurent C.
      • Blanc J.F.
      • Nobili S.
      • et al.
      Prognostic factors and longterm survival after hepatic resection for hepatocellular carcinoma originating from noncirrhotic liver.
      • Capussotti L.
      • Muratore A.
      • Amisano M.
      • et al.
      Liver resection for large-size hepatocellular carcinomas in 47 non-cirrhotic patients — no mortality and long-term survival.
      Furthermore, some authors reported a lesser cumulative survival in male patients, while other authors did not observe such an association.
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      • D'Intino P.E.
      • Caraceni P.
      • et al.
      Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients.
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      • Goodman Z.D.
      • Ishak K.G.
      Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients.
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      • Cescon M.
      • Ravaioli M.
      • et al.
      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.
      • Chang C.H.
      • Chau G.Y.
      • Lui W.Y.
      • et al.
      Long-term results of hepatic resection for hepatocellular carcinoma originating from the noncirrhotic liver.
      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.
      • Nagasue N.
      • Ono T.
      • Yamanoi A.
      • et al.
      Prognostic factors and survival alter hepatic resection for hepatocellular carcinoma without cirrhosis.
      • Grando-Lemaire V.
      • Guettier C.
      • Chevret S.
      Hepatocellular carcinoma without cirrhosis in the west: epidemiological factors and histopathology of non-tumorous liver.
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      • et al.
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      • Bouvier A.M.
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      • et al.
      Treatment and prognosis of hepatocellular carcinoma: a population based study in France.
      The 1-, 3-, 5-, and 7-year survival rates were 75.4%, 54.7%, 38.9%, and 31.8%, respectively, and were comparable with previously published data.
      • Dupont-Bierre E.
      • Compagnon P.
      • Raoul J.L.
      • et al.
      Resection of hepatocellular carcinoma in non cirrhotic liver: analysis of risk factors for survival.
      • Alkofer B.
      • Lepennec V.
      • Chiche L.
      Hepatocellular carcinoma in the non-cirrhotic liver.
      • Bège T.
      • Le Treut Y.P.
      • Hardwigsen J.
      • et al.
      Prognostic factors after resection for hepatocellular carcinoma in nonfibrotic or moderately fibrotic liver. A 116-case European series.
      • Lang H.
      • Sotiropoulos G.C.
      • Brokalaki E.I.
      • et al.
      Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers.
      • Bismuth H.
      • Chiche L.
      • Castaing D.
      • et al.
      Surgical treatment of hepatocellular carcinoma in non-cirrhotic liver: experience with 68 liver resections.
      • Laurent C.
      • Blanc J.F.
      • Nobili S.
      • et al.
      Prognostic factors and longterm survival after hepatic resection for hepatocellular carcinoma originating from noncirrhotic liver.
      • Capussotti L.
      • Muratore A.
      • Amisano M.
      • et al.
      Liver resection for large-size hepatocellular carcinomas in 47 non-cirrhotic patients — no mortality and long-term survival.
      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
      • Lang H.
      • Sotiropoulos G.C.
      • Brokalaki E.I.
      • et al.
      Survival and recurrence rates after resection for hepatocellular carcinoma in noncirrhotic livers.
      and Smoot et al.
      • Smoot R.L.
      • Nagorney1 D.M.
      • Chandan V.S.
      • et al.
      Resection of hepatocellular carcinoma in patients without cirrhosis.
      In accordance with our data, Young et al
      • Young A.L.
      • Adair R.
      • Prasad K.R.
      • et al.
      Hepatocellular carcinoma within a noncirrhotic, nonfibrotic, seronegative liver: surgical approaches and outcomes.
      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.
      • Abdel-Wahab M.
      • El-Husseiny T.S.
      • El Hanafy E.
      • et al.
      Prognostic factors affecting survival and recurrence after hepatic resection for hepatocellular carcinoma in cirrhotic liver.
      • Yeh C.N.
      • Chen M.F.
      • Lee W.C.
      • et al.
      Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis.
      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.
      • Yeh C.N.
      • Chen M.F.
      • Lee W.C.
      • et al.
      Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis.
      • Lise M.
      • Bacchetti S.
      • Da Pian P.
      • et al.
      Prognostic factors affecting long term outcome after liver resection for hepatocellular carcinoma: results in a series of 100 Italian patients.
      • Llovet J.M.
      • Fuster J.
      • Bruix J.
      • et al.
      Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.
      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.
      • Yeh C.N.
      • Chen M.F.
      • Lee W.C.
      • et al.
      Prognostic factors of hepatic resection for hepatocellular carcinoma with cirrhosis: univariate and multivariate analysis.
      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,
      • Poon R.T.
      • Fan S.T.
      • Lo C.M.
      • et al.
      Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years.
      • Fong Y.
      • Sun R.L.
      • Jarnagin W.
      • et al.
      An analysis of 412 cases of hepatocellular carcinoma at a Western center.
      • Hanazaki K.
      • Kajikawa S.
      • Shimozawa N.
      • et al.
      Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma.
      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
      • Iwatsuki S.
      • Starzl T.E.
      • Sheahan D.G.
      • et al.
      Hepatic resection versus transplantation for hepatocellular carcinoma.
      reported a 5-year survival rate of 26%. Schlitt et al
      • Schlitt H.J.
      • Neipp M.
      • Weimann A.
      • et al.
      Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation.
      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
      • Neuhaus P.
      • Jonas S.
      • Bechstein W.O.
      • et al.
      Liver transplantation for hepatocellular carcinoma.
      • Neuhaus P.
      • Jonas S.
      • Bechstein W.O.
      Hepatoma of the liver: resection or transplantation?.
      • Pichlmayr R.
      • Weimann A.
      • Oldhafer K.J.
      • et al.
      Role of liver transplantation in the treatment of unresectable liver cancer.
      • Houben K.W.
      • McCall J.L.
      Liver transplantation for hepatocellular carcinoma in patients without underlying liver disease: a systematic review.
      ; in contrast, Mergental et al
      • Mergental H.
      • Porte R.J.
      Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.
      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.

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