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Japanese Journal of Clinical Oncology Advance Access originally published online on August 27, 2008
Japanese Journal of Clinical Oncology 2008 38(10):683-688; doi:10.1093/jjco/hyn082
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© The Author (2008). Published by Oxford University Press. All rights reserved

Epidemiology and Survival of Hepatocellular Carcinoma in Turkey: Outcome of Multicenter Study

Ahmet Alacacioglu1, Isil Somali1, Ilkay Simsek2, Ibrahim Astarcioglu3, Metin Ozkan4, Cemalettin Camci5, Necati Alkis6, Aziz Karaoglu7, Oktay Tarhan1, Tugba Unek1 and Ugur Yilmaz1

1 Dokuz Eylul University, Institute of Oncology, Izmir
2 Department of Gastroenterology, Faculty of Medicine, Dokuz Eylul University, Izmir
3 Department of General Surgery, Faculty of Medicine, Dokuz Eylul University, Izmir
4 Department of Medical Oncology, Faculty of Medicine, Erciyes University, Kayseri
5 Department of Medical Oncology, Faculty of Medicine, Gaziantep University, Gaziantep
6 Ankara Oncology Hospital, Ankara
7 Department of Medical Oncology, Firat University Faculty of Medicine, Elazig, Turkey

For reprints and all correspondence: Ugur Yilmaz, Dokuz Eylul University, Institute of Oncology, Balcova, 35340, Izmir, Turkey. E-mail: dralaca2000{at}yahoo.com

Received June 5, 2008; accepted July 23, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 References
 
Objective: Hepatocellular cancer (HCC) is one of the important health problems in Turkey. We aimed to determine the clinical and demographic features of HCC in the Turkish population and to evaluate the prognostic and survival features.

Method: Two hundred and twenty-one patients with HCC from five hospitals in Turkey are included in this study.

Results: In 44.4% of the 221 patients with hepatitis B virus and in 21.3% of the 221 patients with hepatitis C virus were found to be responsible for HCC etiology. It has been shown that HCC developed on cirrhosis basis in 74.2% of the patients. HCC was presented with single solitary nodule in 69.2% of the patients. Non-liver metastasis was present in 12.5% of the patients. In 21.7% of the patients, {alpha}-fetoprotein (AFP) levels were above the diagnostics level of 400 ng/ml. The median overall survival (OS) of 221 patients was 14 months. The median OS of the patients with Child-Pugh A class was significantly longer than that with Child-Pugh B and C classes. The OS of the individuals with normal AFP levels was also longer than that with high AFP levels. The OS of the patients with Stage I HCC according to tumor node metastasis (TNM) classification, the female patients and the treated patients group was found to be significantly good.

Conclusions: In conclusion, the viral etiology (hepatitis B and C infections) in Turkish population is found to be an important factor in HCC development. The Child-Pugh classification, AFP levels, TNM classification, being female and treatment were determined to be important prognostic factors in HCC patients.

Key Words: hepatocellular cancer • HCC • prognosis • Turkey


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 References
 
Hepatocellular cancer (HCC) is one of the most common cancers in the world. It is the fifth most common malignancy in men and the eighth most common malignancy in women worldwide (1). The incidence and the etiology of HCC vary according to the geographic region. Eastern Asia and Southeast Africa have high incidence for HCC (2).

The cirrhosis is the most important risk factor for HCC. The hepatitis B and C infections are the predominant causes of chronic liver disease and cirrhosis (1). Therefore, the incidence of HCC is parallel with the incidence of viral hepatitis B and C. The other risk factors are aflatoxin exposure and hereditary hemachromatosis.

Turkey is a hepatitis B endemic country with a hepatitis B carrier rate of 5–10%. The incidence of hepatitis C in the Turkish population is 1.5% (3). The HCC incidence was 0.83/100 000 according to 2003 Ministry of Health report in Turkey. The annual incidence of HCC in Turkey was similar between 2000 and 2003 (0.80/100 000 at 2000, 0.87/100 000 at 2001, 1.1/100 000 at 2002 and 0.87/100 000 at 2003).

The prognosis of HCC is very poor. The cure and long-term survival are possible only when tumors can be resected completely.

In this multicenter study, we evaluated epidemiologic characteristics, prognostic factors and survival of HCC in Turkish patients.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 References
 
Two hundred and twenty-one patients with HCC were included in this study consecutively from five hospitals in Turkey (158 patients from Dokuz Eylul University in Izmir, 34 patients from Erciyes University in Kayseri, 10 patients from Firat University in Elazig, nine patients from Gaziantep University and 10 patients from Ankara Oncology Hospital). All centers reviewed the medical records of their HCC cases in the period of 1994–2007 retrospectively.


   DATA COLLECTION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 References
 
Medical records were included gender, age at diagnosis, symptoms, etiologic factors (hepatitis B or C virus, alcohol, cirrhosis, etc), laboratory data [hemoglobin, white blood cell counts, platelet counts, albumin, bilirubin, alanine-aminotransferases (ALT) and aspartate-aminotransferases (AST), prothrombin time (PT), alkaline phosphatase (ALP), gama-glutamyl transpeptidase (GGT)], degree of hepatic disease (Child-Pugh score), sizes of tumor, types of tumor (uninodular, multinodular or diffuse), {alpha}-fetoprotein (AFP) and the methods of HCC diagnosis, treatment of HCC [surgical resection, liver transplantation, arterial chemoembolization (ACE), percutaneous alcohol injection (PAI), radiofrequency ablation (RFA), chemotherapy (CT), hormonotherapy (HT) or no treatment].


   STATISTICAL ANALYSIS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
RESULTS
 DISCUSSION
 References
 
All statistical analysis was performed using the SPSS 10.0 statistical package. Numerical variables were summarized by their median, mean and range. Categorical variables were described by counts and relative frequencies. Overall survival (OS) was defined as the time between diagnosis and death (due to any causes) or end of follow-up (censored observations). The univariate analysis to identify predictors of survival was performed using the Kaplan–Meier method and was compared with the Mantel log-rank test. P < 0.05 was considered as significant. Multivariate analysis was performed by Cox regression analysis.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
DISCUSSION
 References
 
A total of 221 patients with HCC were included this study. The characteristics of patients were presented in Table 1. The median age of HCC patients was 62 ± 11.3 (range: 15–84) years. There were 170 males (76.9%) and 51 females (22.3%).


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  		Table 1. The characteristics of patients with HCC

 
Among the 221 HCC patients, 11 were asymptomatic at presentation. The other HCC patients had different symptoms, such as anorexia, malaise, abdominal pain, abdominal discomfort, nausea and vomiting, loss of weight, gastrointestinal bleeding and icterus.

The laboratory data of HCC patients were given in Table 2.


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  		Table 2. Laboratory data of HCC patients

 
The etiologic risk factors for HCC were hepatitis B (98 patients; 44.4%) (five of them had alcohol abuse and two patients had hepatitis D also), hepatitis C (47 patients; 21.3%) (five of them also had alcohol abuse), hepatitis B and C (11 patients; 5%), chronic alcohol abuse (more than 10 years) (13 patients; 5.9%) and cryptogenic cirrhosis (nine patients; 4.1%). No etiologic cause could be identified in 43 patients (19.5%).

One hundred and sixty-four of 221 HCC patients (74.2%) were diagnosed as cirrhosis clinically and/or histologically. In 57 patients, there was no evidence of cirrhosis. Fourteen of the 57 patients had chronic hepatitis.

The distribution of the 164 patients with cirrhosis was as follows: Child A, 49 (29.8%) patients; Child B, 41 (25%) patients; Child C, 74 (45.2%) patients.

The biopsy (histologic or cytologic) in 141 (63.8%) patients and imaging (ultrasonography, computerized tomography, magnetic resonance imaging and angiography) in 80 (36.2%) patients were used for the diagnosis of HCC.

The characteristics of tumors were presented in Table 3. The single nodule was the dominant tumor pattern (in 153 patients, 69.2%). The most common tumor diameter was <5 cm in 100 (45.2%) patients. Extra hepatic metastasis (lung, bone and adrenal gland) was present in 12 (5%) patients. Stage IV tumor according to TNM classification was present in 58 patients. The HCC patients with HBV had mostly Stage 3 and 4 disease (41.8 and 26.5%, respectively), whereas HCC patients with HCV had shown mostly similar distributions according to disease stage (Stage 1, 12.8%; Stage 2, 29.8%; Stage 3, 27%; Stage 4, 29.7%). The AFP levels were >400 ng/dl in 48 (21.7%) patients, which was considered as diagnostic for HCC.


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  		Table 3. The characteristics of tumors and treatment in HCC patients

 
Only 31 (14%) patients received surgical therapy (resection, liver transplatation). One hundred and ninety (86%) patients received palliative (PAI, RFA, ACE, CT and HT) therapy or no therapy (Table 3).

The OS was 14 months (Fig. 1). Patients aged <60 and female patients had longer survival compared with those aged >60 and male patients (median OS: 15 versus 12.6 months, P = 0.619 and 17.6 versus 11.7 months, P = 0.057, respectively). The OS of patients with cirrhosis and non-viral hepatitis was shorter survival with respect to these with no cirrhosis and non-viral hepatitis (median OS: 13.9 versus 19.1 months, P = 0.286 and 10.7 versus 15.3 months, P = 0.797) although it did not show any statistical significance.


Figure 1
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  		Figure 1. Overall survival of hepatocellular cancer (HCC) patients.

 
Child-Pugh class had a significant effect on survival. Child-Pugh A class had a longer survival with respect to Child-Pugh B and C (median OS: 26.8 versus 15.3 and 8 months, P = 0.045) (Fig. 2). TNM classification systems were found to be significantly predictive for OS. The median OS of patients with AFP level ≤20 ng/ml was better than that of patients with AFP level >20 ng/ml significantly (median OS: 23.8 versus 8.5 months, P = 0.003) (Fig. 3).


Figure 2
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  		Figure 2. Survival of HCC patients according to Child-Pugh class.

 

Figure 3
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  		Figure 3. Survival of HCC patients according to {alpha}-fetoprotein levels.

 
There were significant differences in prognosis between subgroups (P = 0.025) (Fig. 4). Stages I and II patients showed the best prognosis in TNM classification (Table 4). The effect of treatment on OS was studied in HCC patients. The patients received some treatment were a longer survival with respect to patients received no treatment (median OS: 23.8 versus 3.3 months, P < 0.0001) (Fig. 5). The OS of the patients who underwent surgery were longer compared with patients who underwent other treatment options (P < 0.0001) (Fig. 6).


Figure 4
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  		Figure 4. Survival of HCC patients according to TNM classification.

 

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  		Table 4. Prognostic factors affecting survival (univariate analysis)

 

Figure 5
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  		Figure 5. Survival of HCC patients according to treatment.

 

Figure 6
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  		Figure 6. Survival of HCC patients according to treatment options. CT, chemotherapy; HT, hormonotherapy; PAI, percutaneous alcohol injection; RFA, radiofrequency ablation; ACE, arterial chemoembolization.

 
Multivariate analysis showed that being female, TNM Stage I disease and low titer AFP were independent risk factors for better survival (Table 5).


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  		Table 5. Prognostic factors affecting survival (multivariate analysis)

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
References
 
We determined in this multicenter study that the hepatitis B infection is the primary risk factor (44.4%) for HCC development in the Turkish population. In the epidemiologic studies of Uzunalimoglu et al. (3), it has been shown that the hepatitis B infection is the most important risk factor in Turkey. In both studies, hepatitis C infection has been found to be the secondary risk factor. In Europe and the other countries of the Mediterranean, it has been reported that viral etiology, especially the hepatitis C virus infection, is the most important risk factor responsible for HCC development (4–6).

In our study, the median survival of the patients was 14 months. Sakar et al. (7) reported that the median OS in Turkish patients with cirrhosis was 16.9 months, whereas Borzio et al. (4) reported that the median survival rate was 19.7 months in the Italian population.

Median survival was longer in female patients (6) than in males (17.6 versus 11.6 months, P = 0.05). In the studies of Dohmen et al. (8), the longer survival rate of female patients has been emphasized.

In our patients, the presence or absence of cirrhosis (13.9 versus 19.1 months, P = 0.28) had no significant impact on median survival. In the patient group with cirrhosis, the Child-Pugh classification has been determined to be an important prognostic factor. The median survival of the Child-Pugh A class patients has been statistically determined to be longer than that of the Child-Pugh B and C classes (26.8 versus 15.8 versus 8 months, P = 0.04). Also in the studies of Sakar et al. (7) and Borzio et al. (4), it is reported that the Child-Pugh classification is an independent prognostic factor and that the survival of Child-Pugh A class patients is significantly longer.

Serum AFP levels being >400 ng/ml is considered to be diagnostic for HCC diagnosis (6). Only 21.7% (48) of our patients have been determined to have an increase above the AFP diagnostic value. In the Italian study (6) in 18% of the patients and in 20% of the Far East study, a value above the AFP diagnostic value was determined. Our study, just like the other studies, shows a low sensitivity of the AFP diagnostic value in the Turkish population. However, high AFP value has been determined to be a prognostic factor. The median survival of patients with an AFP of ≤20 ng/ml is significantly higher than that of patients with an AFP of >20 ng/ml (23.8 and 8.5 months, P = 0.003).

In various studies in the literature, AFP is stated as an important prognostic factor (9–12). In the studies of Sakar et al. (7), in the Turkish population, they have reported that the AFP level is a prognostic factor.

In our study, it has been determined that the TNM classification is also an important prognostic factor. The median survival of stage I patients was high. While the stage of the disease was increasing, the median survival of patients significantly decreased (29.3, 19.1, 14.1 and 5.4 months, P = 0.025).

Median survival has been found to be significantly higher in the treated patient group compared with that in untreated patients (23.8 versus 3.3 months, P < 0.0001). In the other studies, it has been emphasized that the treatment has a significant contribution to median survival (4,7). Especially in patients with a surgical treatment, survival difference was more evident. There is still no any screening program for HCC in Turkey. Owing to this, our patients had been caught mostly at advanced or inoperable stage. So, the median survival was poor in our patients.

As a conclusion, in this multicenter retrospective study, it has been determined that the viral etiology (hepatitis B and C infection) in the Turkish population is an important factor in HCC development. In HCC patients, Child-Pugh classification, AFP level, TNM classification, being female and treatments were shown as important prognostic factors.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 DATA COLLECTION
 STATISTICAL ANALYSIS
 RESULTS
 DISCUSSION
 References
 
1 Monto A, Wright TL. The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol (2001) 28:441–9.[CrossRef][Web of Science][Medline]

2 Sewart BW, Kleihues P. World Cancer Report. (2003) Lyon: IARC Pres. 11–9.

3 Uzunalimoglu O, Yurdaydin C, Cetinkaya H, Bozkaya H, Sahin T, Colakoglu S, et al. Risk factors for hepatocellular carcinoma in Turkey. Dig Dis Sci (2001) 46:1022–8.[CrossRef][Web of Science][Medline]

4 Borzio M, Colloredo G, Pioltelli P, Quagliuolo M. Epidemiology and outcome of hepatocellular carcinoma in Lombardy. Dig Liver Dis (2007) 39:1011–7.[CrossRef][Web of Science][Medline]

5 Markovic S, Gadzijev E, Stabuc B, Croce LS, Masutti F, Surlan M, et al. Treatment options in Western hepatocellular carcinoma: a prospective study of 224 patients. J Hepatol (1998) 29:650–9.[CrossRef][Web of Science][Medline]

6 Stroffolini T, Andreone P, Andriulli A, Ascione A, Craxi A, Chiaramonte M, et al. Characteristics of hepatocellular carcinoma in Italy. J Hepatol (1998) 29:944–52.[CrossRef][Web of Science][Medline]

7 Sakar B, Ustuner Z, Karagol H, Aksu G, Camlica H, Aykan NF. Prognostic features and survival of inoperable hepatocellular carcinoma in Turkish patients with cirrhosis. Am J Clin Oncol (2004) 27:489–93.[CrossRef][Web of Science][Medline]

8 Dohmen K, Shigematsu H, Irie K, Ishibashi H. Longer survival in female than male with hepatocellular carcinoma. J Gastroenterol Hepatol (2003) 18:267–72.[CrossRef][Web of Science][Medline]

9 Wang BE, Ma WM, Sulaiman A, Noer S, Sumoharjo S, Sumarsidi D, et al. Demographic, clinical, and virological characteristics of hepatocellular carcinoma in Asia: survey of 414 patients from four countries. J Med Virol (2002) 67:394–400.[CrossRef][Web of Science][Medline]

10 Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg (1999) 229:790–800.[CrossRef][Web of Science][Medline]

11 Purtilo DT, Kersey JH, Hallgren HM, Fox KR, Yunis EJ. Alpha-fetoprotein: diagnostic and prognostic use in patients with hepatomas. Am J Clin Pathol (1973) 59:295–9.[Web of Science][Medline]

12 Stuart KE, Anand AJ, Jenkins RL. Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer (1996) 77:2217–22.[CrossRef][Web of Science][Medline]


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This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
38/10/683    most recent
hyn082v1
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