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Occurrence of portal vein tumor thrombus in hepatocellular carcinoma affects prognosis and survival.
Hepatology Research 24 (2002) 50 – 59
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Occurrence of portal vein tumor thrombus in hepatocellular carcinoma affects prognosis and survival. A retrospective clinical study of 150 cases Gianluigi Giannelli a,*, Francesca Pierri a, Paolo Trerotoli b, Felice Marinosci a, Gabriella Serio b, Oronzo Schiraldi a, Salvatore Antonaci a a
Department of Internal Medicine, Immunology and Infectious Disease, Section of Internal Medicine, Uni6ersity of Bari Medical School, Bari, Italy b Department of Internal Medicine and Public Health, Section of Medical Statistics, Uni6ersity of Bari Medical School, Bari, Italy Received 7 July 2001; received in revised form 1 February 2002; accepted 15 February 2002
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Despite improvements in diagnostic and therapeutic interventions, prognosis and survival are still poor. To identify factors influencing survival, we retrospectively examined 150 consecutive patients with HCC from the time of first diagnosis of cirrhosis to death. In a multivariate analysis, we found that patients with larger HCC lesions had shorter survival, while other pathologic features had no predictive value. The most important and reliable prognostic factor was the occurrence of tumor thrombus of the portal vein (PB0.01). Child’s stage of underlying liver disease was relevant only in the univariate, but not in the multivariate analysis. The survival of patients with HCC is mainly affected by the biological ability of cancer cells to invade surrounding tissue and vessels. More studies are needed to elucidate the mechanisms that modulate tumor cell motility, in order to design more effective therapies. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Hepatocellular carcinoma; Metastasis; Prognostic factors; Tumor invasion; Blood vessel metastasis; Multivariate analysis
1. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. In Eu* Corresponding author. Address: Dipartimento di Medicina Interna Immunologia e Malattie Infettive, Clinica Medica II, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. Tel.: +39-80-5592-573; fax: +39-80-5478-670 E-mail address: [email protected] (G. Giannelli).
ropean countries, it develops most often in patients with chronic liver disease, as a natural evolution or a complication of the illness [1]. The Hepatitis C virus (HCV) has been found to be strongly associated with the development of HCC, although the issue as to whether it is directly responsible for liver cancer development is still controversial [2,3]. Prospective epidemiologic studies suggest that the number of patients with HCC will increase in the upcoming years as a
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consequence of HCV-related cirrhosis [3]. Although imaging modalities and therapeutic approaches have been greatly improved, long-term survival is still unsatisfactory [3– 6]. Therapeutic strategies such as hepatectomy, cryosurgery, radio frequency ablation, and in suitable cases, liver transplantation have not yet solved the problem of tumor recurrence, which is the most important factor for poor prognosis [7– 9]. Although the appearance of distant metastases in patients with HCC is a relatively rare event, neither the type of hepatectomy performed nor the various different pharmacological approaches can prevent tumor recurrence, which remains to be a serious consequence of the disease [7– 9]. In view of the above circumstances, the need to identify accurate prognostic factors has become even more compelling. In other types of cancer, a number of prognostic factors are available, which allow for staging of tumor status. In the case of HCC, the reliability and the clinical significance of known prognostic factors are poor. Several studies have reported that biochemical markers such as a-fetoprotein, or routine tests of liver functionality are not helpful in either staging or early detection of the disease [10,11]. Tumor growth rate has been investigated by ultrasonography with unsatisfactory results in terms of prognosis, whereas it was useful as an effective tool for early detection of the tumor [6,12]. Many authors have reported that the underlying disease is the most important index of prognosis and survival of patients with HCC. Therefore, Child’s classification of cirrhosis was initially thought to be the most effective parameter for predicting long-term survival, but on the basis of this classification highly variable survival rates have been reported in the literature in the various different studies [12,13]. Finally, only a few studies, which employed multivariate analyses, have reported that the invasion of the portal vein is an important prognostic factor for HCC [10,14]. Overall, it is generally agreed that HCC is a very difficult tumor to stage, and predict in terms of its clinical prognosis, mainly because of the large number of complications deriving from the underlying liver disease, which can affect long-term survival [3]. In this study, we analyzed 150 cases of HCC, evalu-
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ating the prognostic significance of the main biochemical, histopathological and clinical features.
2. Patients and methods We followed 150 consecutive patients affected by HCC, who were referred to our Unit at the Clinica Medica II Policlinico di Bari, over the last 10 years, from the time of first diagnosis of cirrhosis to death. Demographic information such as age, sex, and ethnicity was recorded at the time of initial presentation. The diagnosis of HCC was based on ultrasound and computed tomography examinations, and confirmed by histology. From the time of diagnosis of HCC, patients underwent frequent ultrasound examinations, every 3 months, to monitor changes of size and number of neoplastic lesions. As a control group, we sampled 100 patients with liver cirrhosis, to assess the relevance of liver damage in patients with HCC as a risk factor for survival. Patients underwent routine biochemical blood tests of liver and kidney function. The presence of hepatitis B surface antigen (HBsAg) was detected by an enzyme monoclonal immunoassay, Auszyme, Abbott laboratories (Abbott Park, IL); and anti-HCV antibodies were determined by a third-generation enzyme-linked immunosorbent assay, Ortho Diagnostic Systems (Raritan, NY). Other possible etiologies commonly associated with liver diseases were extensively investigated. Survival analyses were performed as described by Kaplan and Meier. To compare different groups, the Wilcoxon test was used, and the confidence level was set at 95%. Univariate Cox’s regression was used to evaluate the association between survival and each risk factor. Stepwise Cox’s regression was applied to select the principal risk factors in a multivariate model; the significance level for entry of the variables was 0.05. Categorical variables were transformed into dummy variables. The baseline metastatic risk was assessed as the complete absence of metastasis, whereas other two dummy variables, linearly correlated, identify the presence of tumor thrombus of the portal vein and the presence of metastasis in another site. The
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serum level of a-fetoprotein was transformed into a category variable by selecting an appropriate cut-off level for HCC risk. This was defined as a value 4-fold that of the reference value recommended by the laboratory. The association between categorical variables was performed using the 2 test, and means for continuous variables were compared using the student t-test.
3. Results The patients were divided into two groups: 150 had cirrhosis with HCC, and 100 had only cirrhosis (CH), according to the histological and/or clinical findings. Mean age of patients with HCC was 65 years and with CH 59 years (P B 0.01); males accounted for 67.43% of HCC patients vs 42.67% in the CH group ( 2 =13.41; P B 0.01). Other clinical features are reported in Table 1. A significant difference was found between the two groups of HCC vs CH patients in terms of Child’s stage ( 2 =22.084; P B0.01). Child’s A was observed in 61.00% of CH patients, while Child’s B was observed in 36.00% of the same group, and Child’s C in only one patient. In Table 1 Demographic and clinical features of patients examined Patients’ characteristics HCC (n= 150)
CH (n= 100)
n
%
n
%
32 118
21.33 78.67
43 57
43.00 57.00
Age Age 065 years Age \65 years Missing
64 80 6
42.67 53.33 4.00
71 16 3
71.00 16.00 3.00
Child stage A B C Missing
59 64 27 –
39.33 42.67 18.00
61 36 1 2
61.00 36.00 1.00 2.00
132 18
88.00 12.00
92 8
92.00 8.00
Sex Female Male
Etiology Viral Other
comparison, 18% of HCC patients were classified in Child’s C stage vs 42.67 and 39.33% in Child’s B and Child’s A stage, respectively. A viral etiology was observed in 88% of HCC patients vs 92% of CH patients, but this difference was not statistically significant ( 2 = 1.03; P=0.31). Anti-HCV antibodies were found in 68% of the HCC patients and in 87% of the CH patients. Histological data were not available for 63.1% of the HCC group. In the others, a differentiated tumor was diagnosed in 19.1% of patients and an undifferentiated tumor in 17.8%, this type of classification was used to render the available data more homogeneous and ensure statistically meaningful numbers. Metastases were found in 33% of the HCC patients, the most frequent site being intrahepatic (15.4%), 12.7% of which had tumor thrombus of the portal vein. Extrahepatic metastases affected the lung (6.7%), the local lymph nodes (5.3%), and other sites (5.6%); these findings are consistent with those in previous studies [15]. Intrahepatic metastases were defined in accordance with radiological and clinical criteria as already reported [16]. The evaluation of survival had two goals: (1) to compare the survival curves of HCC vs CH patients referring to the whole period from diagnosis of cirrhosis to the final event (death); (2) to identify the principal factors that play a role in the survival function of the HCC group. In these patients, we also evaluated the period from diagnosis of HCC to death. With regard to the first point, the survival function, estimated using the Kaplan and Meyer method, was statistically different for the HCC and CH groups (Wilcoxon= 25.83; PB 0.01) as was expected. The median of survival in the HCC group was 8 years, whereas median survival had not yet been reached in the CH group. This difference was entirely due to the occurrence of HCC, since the development of malignancy caused a dramatic decline in the survival curve, while CH patients had a relatively high life expectancy. The absence of data on median survival in the CH group is due to the long survival of these patients, who often fail to undergo serial controls in the same clinical unit. It is therefore sometimes difficult to keep track of the clinical conditions or exitus of patients in a retrospective study, and this explains the high
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Table 2 Variables influencing survival, from diagnosis of hepatocarcinoma until death Variable
Findings
Number of patients
Number of events
Median (months)
P
Number of therapies
None One More than 1
63 64 14
55 54 10
12 24 66
B0.01
Alfafeto protein
E28 UI B28 UI
67 67
63 51
12 24
B0.05
Neoplasm dimension
E5 cm B5 cm
25 91
24 73
12 24
B0.01
Child stage
A B C
56 61 26
41 55 24
24 12 7
B0.01
Tumor invasion
Portal vein Extrahepatic Absence
17 28 98
17 28 75
3 14 24
B0.01
The among subgroups were evaluated with log-rank test.
number of truncated data, that also include patients lost to follow-up. In addition, we evaluated the role of the Child’s stage on survival time of HCC and CH patients. In the CH group, we considered only the stratification for Child’s A and Child’s B stage, since there was only one subject in Child’s C. A statistically significant difference was found between strata (log-rank=5.13; P B 0.05), but the estimate of median time was biased because of the high number of truncated data (89.47%). No statistically significant difference was observed between strata for the HCC group (log-rank= 1.29; P = 0.52); the median time of survival was 7 years for patients classified as Child’s A stage, 6 years for patients with Child’s B stage and 7 years for Child’s C patients. We analyzed the role of viral etiology as a prognostic factor. In the CH group, it was impossible to estimate its influence on survival time because of the low number of events without viral etiology, and the high number of truncated data (87.62%). On the contrary, in HCC patients the truncated data accounted for 16.08% and the difference between the two curves was statistically significant (log-rank= 9.32; P B 0.01). The median survival in patients with a viral etiology of their liver disease was 3 years, compared to 7
years in patients with other etiologies. Using a univariate Cox’s regression model, we then analyzed the effect of ‘risk’ factors on the survival of HCC patients, considering the time elapsing from initial diagnosis of cancer to death. The results are shown in Tables 2 and 3. With regard to viral etiology, once HCC was diagnosed, no significant difference was found between patients with viral and other causes of their liver disease (Fig. 1); the median time observed was 1 year for both groups and the risk associated with this factor was not statistically significant (Score= 0.47; P =0.49). This appears to contrast with the result obtained when considering the whole period from diagnosis of hepatitis to death. We then investigated the time lapse from the diagnosis of hepatitis vs other etiologies to that of HCC. Patients with a viral etiology contracted cancer later than patients with other etiologies: 7 years vs 1 year, respectively (log-rank= 8.76; PB 0.01; Fig. 2). There was an effect for Child’s stage in the univariate Cox’s analysis, where two dummy variables were created to evaluate the risk of mortality: one for the presence of Child’s B stage and one for the presence of Child’s C stage, while Child’s A was considered as baseline. A significant model was obtained (Score= 13.16; P B 0.01) with a risk of 1.6 for Child’s B stage
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( 2 =5.08; P B 0.05) and a risk of 2.35 for Child’s C ( 2 =12.2; PB0.01). Our data suggest that the risk increases progressively with the Child’s stage. Furthermore, the median time from appearance of HCC to death was 7 months for patients classified in Child’s C stage, 1 year for Child’s B patients and 2 years for those in Child’s A. The respective survival curves were significantly different (log-rank=16.43; PB 0.01; Fig. 3). In our study, as in others, the size of the primary HCC also plays a role in predicting survival. It seems that lesions larger than 5 cm shorten survival by a median of 1 year, (logrank =6.46; P B0.01). Moreover, in patients with large lesions, the risk of dying was 1.7 times higher than that of patients with lesions smaller than 5 cm. Another important finding was the effect of the presence of metastases (Fig. 4). This variable was transformed into two dummy values (the presence of intrahepatic metastasis with tumor thrombus of the portal vein, and the presence of extrahepatic metastasis), with the absence of metastasis as baseline. The estimated survival time from diagnosis of HCC to death was 3 months for patients with tumor thrombus of the portal vein, 14
months for patients with other metastases and 24 months for patients without metastases. Comparing the survival curves, we observed a statistically significant difference (log-rank= 50.2; PB 0.01). The Cox’s model with the two dummy variables described as above was statistically significant (Score: 34.07; PB 0.01). It also demonstrated the significance of tumor thrombus of the portal vein, which posed a 4.4-fold increased risk of death ( 2 = 29.21; PB0.01) above baseline, while the risk at other sites was 1.38 ( 2 = 2.05; P= 0.15). Finally, to evaluate the combined effect of the different risk factors on death, a multivariate regression stepwise Cox’s model was used. The factors considered were: age, sex, presence/ absence tumor thrombus of the portal vein, size of the tumor, therapy, viral hepatitis, and Child’s stage. The results are shown in Table 3. The variables demonstrating statistical significance in the overall model (Score: 49.77; PB 0.01) were vascular invasion (OR= 3.67; PB 0.01), and presence of metastases in other sites (OR= 2.24; PB 0.01). Using a univariate analysis, only metastases, both intrahepatic and extrahepatic, were found to be a relevant factor that influenced survival.
Table 3 Results of univariate and multivariate Cox regression for each factor influencing survival with related risk and 95% confidence interval Variable
Univariate analysis Parameter
P
Multivariate analysis OR
CI 95%
Parameter
Age E65 years Sex (Female = 1; male=0)
0.108 0.115
0.567 0.613
1.11 1.12
0.769–1.614 0.717–1.758
Not entered Not entered
Tumor in6asion Portal vein Other sites
1.482 0.323
B0.01 0.152
4.4 1.38
2.57–7.53 0.88–2.15
1.299 0.808
0.377 0.527 0.74 0.024
0.046 0.029 B0.001 0.936
1.46 1.7 2.1 1.03
1.000–2.114 1.056–2.720 1.563–2.818 0.563–1.865
Not entered Not entered 0.976 Not entered
0.49
0.84
0.499–1.399
Not entered
0.024 B0.001
1.62 2.53
1.065–2.450 1.503–4.255
Not entered Not entered
Alfa-feto protein E28 UI Lesion E5 cm Treatment not performed Histology (Undifferenced=1; differenced=0) Viral etiology Child stage B C
−0.18 0.479 0.927
P
OR
CI 95%
B0.01 B0.001
3.67 2.25
1.986–6.777 1.322–3.812
B0.001
2.65
1.854–3.801
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Fig. 1. Survival function of etiology of hepatitis in HCC patients. The follow-up period runs from diagnosis of hepatocarcinoma until death.
The diameter of the tumor did not enter the multivariate model, but was significant in the univariate model. This discrepancy could be linked to the association observed between tumor thrombus of the portal vein and lesions larger than or equal to 5 cm in diameter. In fact, 23% of patients with lesions of this size also had tumor thrombus of the portal vein, while only 9% with lesions smaller than 5 cm presented tumor thrombus of the portal vein ( 2 =7.57; P B0.05). Furthermore, Child’s C stage, which was significant in the univariate Cox’s model, did not enter the multivariate model, but was observed in 36.8% of patients with vascular invasion vs 15.3% without ( 2 =6.14; P B 0.05), showing a significant correlation between Child’s stage and tumor thrombus of the portal vein.
4. Discussion In this retrospective study, we investigated biochemical, histopathological, and clinical data in
150 patients with HCC, using a multivariate analysis to identify prognostic factors affecting patient survival. We found that the most important prognostic factor is the occurrence of tumor thrombus of the portal vein, although the size of the tumor (B 5 cm) was also significantly associated with the final outcome of death. These findings are important for numerous reasons: HCC is one of the most common malignancies in the Mediterranean area; being able to predict survival in patients affected with this condition is important from the standpoint of the increased transmission of HCV infection, and of longer survival of patients with liver cirrhosis [17]. Furthermore, HCC is a unique type of cancer since it develops in an organ that has already been injured by chronic disease. This situation determines a consequent overlapping of clinical outcomes, limits possible and successful therapies, and hampers identification of reliable prognostic factors [3]. For example, in patients with HCC, the main cause of death is liver and/or renal failure, which is also a common cause of death in
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patients affected only by cirrhosis [2,18]. For this reason, some authors have reported that Child’s classification is the most important parameter affecting long term survival of patients with HCC [11,12]. Our data do not confirm this finding, and are in agreement with other studies, which indicate that tumor thrombus of the portal vein is the most important prognostic factor in patients with HCC [10,14]. We believe that a possible explanation for this discrepancy could be the fact that tumor thrombus of the portal vein induces rapid worsening of the clinical outcome and consequently of the Child’s class, leading to death because of liver and/or renal failure. This hypothesis is supported by the following data: (1) survival is shorter in HCC patients than in cirrhotic patients with a similar Child’s class; and (2) the survival of HCC patients declines dramatically after development of tumor thrombus of the portal vein. Therefore, classification of HCC patients according to Child’s stage might be considered as its downstream effect of events such as vascular metastasis, which is more directly related to the malignant HCC phenotype.
We have compared survival between patients with HCC and patients with CH with similar Child’s classes, and our data demonstrate that there is a substantial difference between these two groups of patients in terms of survival. This apparent heterogeneity between groups supports our hypothesis that Child’s classification is not appropriate for predicting survival in patients with HCC, and suggests that its use be limited to patients affected with only cirrhosis. In summary, our data is in accordance with other studies that demonstrate Child’s class is not useful in patients with HCC that have developed vascular metastasis [10]. Our data also show that another important prognostic factor is the size of the tumor. This is a controversial issue because it has been reported by some authors to affect long-term survival, although there are numerous inconsistencies in Refs. [10,14,19]. It has also been reported that tumor growth rate as evaluated by ultrasound is an unreliable prognostic factor, while in the same study, Child’s stage of underlying liver disease
Fig. 2. Survival function of etiology of hepatitis in HCC patients. The follow-up period runs from diagnosis of hepatitis until that of hepatocarcinoma.
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Fig. 3. Survival function of Child stage in HCC patients. The follow-up period runs from diagnosis of hepatocarcinoma until death.
was found to have a significant role [12,13]. Such heterogeneous data could be explained by the biological features of the individual tumor characterised by a more or less aggressive and invasive phenotype. This is also supported by several studies reporting that recurrence of HCC after surgical therapy or even after transplantation is still the main problem during follow-up of HCC patients [3]. It has also been reported that pathologic features of the HCC such as encapsulation and inflammatory infiltrates influence survival [20,21]. In our opinion, the spread of HCC cells could also be favored by the absence of tissue boundaries such as a basement membrane. An intriguing hypothesis is that the invasive HCC phenotype may be modulated by the ability of cancer cells to penetrate the surrounding extracellular matrix proteins and to migrate towards tissues and vessels [22]. However, these findings have been reported on the basis of in vitro studies, while an in vivo demonstration is still lacking. In our experience patients that received more than one therapy showed a better prognosis. In this regard, we cannot rule out the possibility that
such a difference could be caused by a slower biological rate of tumor growth; patients with this pathological type may live longer, and have the opportunity to receive a higher number of treatments. This possibility has been evaluated in other studies, whereby authors measured tumor growth by ultrasound, but obtained contradictory results [12,23]. Alternatively, the tumor growth rate, as well as an aggressive phenotype, may be ascribed to biological features of HCC cells. More studies are needed to further elucidate these aspects. In our experience, cancers with a viral etiology take longer to develop, possibly because these patients receive antiviral therapy such as Interferon, that may slow down the development of cirrhosis and thus of carcinogenesis as already reported by others [24]. Although some differences exist in terms of survival, it is commonly reported that outcome in HCC is better with a surgical rather than a chemotherapeutic approach, probably because of the associated chronic liver damage [3,25]. Improvements in surgery as well as in other forms of therapy (arterial embolization, ethanol injections) have resulted in increased survival for treated
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Fig. 4. Survival function for tumor thrombus of the portal vein, other sites of invasion and absence of metastases. The follow-up period considered runs from diagnosis of hepatocarcinoma until death.
patients, although tumor recurrence still remains the main problem [9,26]. In conclusion, tumor thrombus of the portal vein together with tumor size are the most reliable prognostic factors for survival of HCC patients. The difference in terms of survival of patients with HCC mainly depends on the ability of malignant cells to invade surrounding tissue and to metastasize [27]. This could be facilitated by the absence of tissue boundaries such as the basement membrane, and by the histological features of the liver. A poor knowledge of the biomolecular mechanisms underlying HCC spread and metastasis limits the ability to effectively treat HCC. More studies are needed to elucidate the mechanisms involved in HCC development or metastasis.
Acknowledgements This work was supported by the Bari Univer-
sity Funds for Research (grant to GG, and OS).
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Occurrence of portal vein tumor thrombus in hepatocellular carcinoma affects prognosis and survival. A retrospective clinical study of 150 cases Gianluigi Giannelli a,*, Francesca Pierri a, Paolo Trerotoli b, Felice Marinosci a, Gabriella Serio b, Oronzo Schiraldi a, Salvatore Antonaci a a
Department of Internal Medicine, Immunology and Infectious Disease, Section of Internal Medicine, Uni6ersity of Bari Medical School, Bari, Italy b Department of Internal Medicine and Public Health, Section of Medical Statistics, Uni6ersity of Bari Medical School, Bari, Italy Received 7 July 2001; received in revised form 1 February 2002; accepted 15 February 2002
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. Despite improvements in diagnostic and therapeutic interventions, prognosis and survival are still poor. To identify factors influencing survival, we retrospectively examined 150 consecutive patients with HCC from the time of first diagnosis of cirrhosis to death. In a multivariate analysis, we found that patients with larger HCC lesions had shorter survival, while other pathologic features had no predictive value. The most important and reliable prognostic factor was the occurrence of tumor thrombus of the portal vein (PB0.01). Child’s stage of underlying liver disease was relevant only in the univariate, but not in the multivariate analysis. The survival of patients with HCC is mainly affected by the biological ability of cancer cells to invade surrounding tissue and vessels. More studies are needed to elucidate the mechanisms that modulate tumor cell motility, in order to design more effective therapies. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Hepatocellular carcinoma; Metastasis; Prognostic factors; Tumor invasion; Blood vessel metastasis; Multivariate analysis
1. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. In Eu* Corresponding author. Address: Dipartimento di Medicina Interna Immunologia e Malattie Infettive, Clinica Medica II, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. Tel.: +39-80-5592-573; fax: +39-80-5478-670 E-mail address: [email protected] (G. Giannelli).
ropean countries, it develops most often in patients with chronic liver disease, as a natural evolution or a complication of the illness [1]. The Hepatitis C virus (HCV) has been found to be strongly associated with the development of HCC, although the issue as to whether it is directly responsible for liver cancer development is still controversial [2,3]. Prospective epidemiologic studies suggest that the number of patients with HCC will increase in the upcoming years as a
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G. Giannelli et al. / Hepatology Research 24 (2002) 50–59
consequence of HCV-related cirrhosis [3]. Although imaging modalities and therapeutic approaches have been greatly improved, long-term survival is still unsatisfactory [3– 6]. Therapeutic strategies such as hepatectomy, cryosurgery, radio frequency ablation, and in suitable cases, liver transplantation have not yet solved the problem of tumor recurrence, which is the most important factor for poor prognosis [7– 9]. Although the appearance of distant metastases in patients with HCC is a relatively rare event, neither the type of hepatectomy performed nor the various different pharmacological approaches can prevent tumor recurrence, which remains to be a serious consequence of the disease [7– 9]. In view of the above circumstances, the need to identify accurate prognostic factors has become even more compelling. In other types of cancer, a number of prognostic factors are available, which allow for staging of tumor status. In the case of HCC, the reliability and the clinical significance of known prognostic factors are poor. Several studies have reported that biochemical markers such as a-fetoprotein, or routine tests of liver functionality are not helpful in either staging or early detection of the disease [10,11]. Tumor growth rate has been investigated by ultrasonography with unsatisfactory results in terms of prognosis, whereas it was useful as an effective tool for early detection of the tumor [6,12]. Many authors have reported that the underlying disease is the most important index of prognosis and survival of patients with HCC. Therefore, Child’s classification of cirrhosis was initially thought to be the most effective parameter for predicting long-term survival, but on the basis of this classification highly variable survival rates have been reported in the literature in the various different studies [12,13]. Finally, only a few studies, which employed multivariate analyses, have reported that the invasion of the portal vein is an important prognostic factor for HCC [10,14]. Overall, it is generally agreed that HCC is a very difficult tumor to stage, and predict in terms of its clinical prognosis, mainly because of the large number of complications deriving from the underlying liver disease, which can affect long-term survival [3]. In this study, we analyzed 150 cases of HCC, evalu-
51
ating the prognostic significance of the main biochemical, histopathological and clinical features.
2. Patients and methods We followed 150 consecutive patients affected by HCC, who were referred to our Unit at the Clinica Medica II Policlinico di Bari, over the last 10 years, from the time of first diagnosis of cirrhosis to death. Demographic information such as age, sex, and ethnicity was recorded at the time of initial presentation. The diagnosis of HCC was based on ultrasound and computed tomography examinations, and confirmed by histology. From the time of diagnosis of HCC, patients underwent frequent ultrasound examinations, every 3 months, to monitor changes of size and number of neoplastic lesions. As a control group, we sampled 100 patients with liver cirrhosis, to assess the relevance of liver damage in patients with HCC as a risk factor for survival. Patients underwent routine biochemical blood tests of liver and kidney function. The presence of hepatitis B surface antigen (HBsAg) was detected by an enzyme monoclonal immunoassay, Auszyme, Abbott laboratories (Abbott Park, IL); and anti-HCV antibodies were determined by a third-generation enzyme-linked immunosorbent assay, Ortho Diagnostic Systems (Raritan, NY). Other possible etiologies commonly associated with liver diseases were extensively investigated. Survival analyses were performed as described by Kaplan and Meier. To compare different groups, the Wilcoxon test was used, and the confidence level was set at 95%. Univariate Cox’s regression was used to evaluate the association between survival and each risk factor. Stepwise Cox’s regression was applied to select the principal risk factors in a multivariate model; the significance level for entry of the variables was 0.05. Categorical variables were transformed into dummy variables. The baseline metastatic risk was assessed as the complete absence of metastasis, whereas other two dummy variables, linearly correlated, identify the presence of tumor thrombus of the portal vein and the presence of metastasis in another site. The
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serum level of a-fetoprotein was transformed into a category variable by selecting an appropriate cut-off level for HCC risk. This was defined as a value 4-fold that of the reference value recommended by the laboratory. The association between categorical variables was performed using the 2 test, and means for continuous variables were compared using the student t-test.
3. Results The patients were divided into two groups: 150 had cirrhosis with HCC, and 100 had only cirrhosis (CH), according to the histological and/or clinical findings. Mean age of patients with HCC was 65 years and with CH 59 years (P B 0.01); males accounted for 67.43% of HCC patients vs 42.67% in the CH group ( 2 =13.41; P B 0.01). Other clinical features are reported in Table 1. A significant difference was found between the two groups of HCC vs CH patients in terms of Child’s stage ( 2 =22.084; P B0.01). Child’s A was observed in 61.00% of CH patients, while Child’s B was observed in 36.00% of the same group, and Child’s C in only one patient. In Table 1 Demographic and clinical features of patients examined Patients’ characteristics HCC (n= 150)
CH (n= 100)
n
%
n
%
32 118
21.33 78.67
43 57
43.00 57.00
Age Age 065 years Age \65 years Missing
64 80 6
42.67 53.33 4.00
71 16 3
71.00 16.00 3.00
Child stage A B C Missing
59 64 27 –
39.33 42.67 18.00
61 36 1 2
61.00 36.00 1.00 2.00
132 18
88.00 12.00
92 8
92.00 8.00
Sex Female Male
Etiology Viral Other
comparison, 18% of HCC patients were classified in Child’s C stage vs 42.67 and 39.33% in Child’s B and Child’s A stage, respectively. A viral etiology was observed in 88% of HCC patients vs 92% of CH patients, but this difference was not statistically significant ( 2 = 1.03; P=0.31). Anti-HCV antibodies were found in 68% of the HCC patients and in 87% of the CH patients. Histological data were not available for 63.1% of the HCC group. In the others, a differentiated tumor was diagnosed in 19.1% of patients and an undifferentiated tumor in 17.8%, this type of classification was used to render the available data more homogeneous and ensure statistically meaningful numbers. Metastases were found in 33% of the HCC patients, the most frequent site being intrahepatic (15.4%), 12.7% of which had tumor thrombus of the portal vein. Extrahepatic metastases affected the lung (6.7%), the local lymph nodes (5.3%), and other sites (5.6%); these findings are consistent with those in previous studies [15]. Intrahepatic metastases were defined in accordance with radiological and clinical criteria as already reported [16]. The evaluation of survival had two goals: (1) to compare the survival curves of HCC vs CH patients referring to the whole period from diagnosis of cirrhosis to the final event (death); (2) to identify the principal factors that play a role in the survival function of the HCC group. In these patients, we also evaluated the period from diagnosis of HCC to death. With regard to the first point, the survival function, estimated using the Kaplan and Meyer method, was statistically different for the HCC and CH groups (Wilcoxon= 25.83; PB 0.01) as was expected. The median of survival in the HCC group was 8 years, whereas median survival had not yet been reached in the CH group. This difference was entirely due to the occurrence of HCC, since the development of malignancy caused a dramatic decline in the survival curve, while CH patients had a relatively high life expectancy. The absence of data on median survival in the CH group is due to the long survival of these patients, who often fail to undergo serial controls in the same clinical unit. It is therefore sometimes difficult to keep track of the clinical conditions or exitus of patients in a retrospective study, and this explains the high
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Table 2 Variables influencing survival, from diagnosis of hepatocarcinoma until death Variable
Findings
Number of patients
Number of events
Median (months)
P
Number of therapies
None One More than 1
63 64 14
55 54 10
12 24 66
B0.01
Alfafeto protein
E28 UI B28 UI
67 67
63 51
12 24
B0.05
Neoplasm dimension
E5 cm B5 cm
25 91
24 73
12 24
B0.01
Child stage
A B C
56 61 26
41 55 24
24 12 7
B0.01
Tumor invasion
Portal vein Extrahepatic Absence
17 28 98
17 28 75
3 14 24
B0.01
The among subgroups were evaluated with log-rank test.
number of truncated data, that also include patients lost to follow-up. In addition, we evaluated the role of the Child’s stage on survival time of HCC and CH patients. In the CH group, we considered only the stratification for Child’s A and Child’s B stage, since there was only one subject in Child’s C. A statistically significant difference was found between strata (log-rank=5.13; P B 0.05), but the estimate of median time was biased because of the high number of truncated data (89.47%). No statistically significant difference was observed between strata for the HCC group (log-rank= 1.29; P = 0.52); the median time of survival was 7 years for patients classified as Child’s A stage, 6 years for patients with Child’s B stage and 7 years for Child’s C patients. We analyzed the role of viral etiology as a prognostic factor. In the CH group, it was impossible to estimate its influence on survival time because of the low number of events without viral etiology, and the high number of truncated data (87.62%). On the contrary, in HCC patients the truncated data accounted for 16.08% and the difference between the two curves was statistically significant (log-rank= 9.32; P B 0.01). The median survival in patients with a viral etiology of their liver disease was 3 years, compared to 7
years in patients with other etiologies. Using a univariate Cox’s regression model, we then analyzed the effect of ‘risk’ factors on the survival of HCC patients, considering the time elapsing from initial diagnosis of cancer to death. The results are shown in Tables 2 and 3. With regard to viral etiology, once HCC was diagnosed, no significant difference was found between patients with viral and other causes of their liver disease (Fig. 1); the median time observed was 1 year for both groups and the risk associated with this factor was not statistically significant (Score= 0.47; P =0.49). This appears to contrast with the result obtained when considering the whole period from diagnosis of hepatitis to death. We then investigated the time lapse from the diagnosis of hepatitis vs other etiologies to that of HCC. Patients with a viral etiology contracted cancer later than patients with other etiologies: 7 years vs 1 year, respectively (log-rank= 8.76; PB 0.01; Fig. 2). There was an effect for Child’s stage in the univariate Cox’s analysis, where two dummy variables were created to evaluate the risk of mortality: one for the presence of Child’s B stage and one for the presence of Child’s C stage, while Child’s A was considered as baseline. A significant model was obtained (Score= 13.16; P B 0.01) with a risk of 1.6 for Child’s B stage
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G. Giannelli et al. / Hepatology Research 24 (2002) 50–59
( 2 =5.08; P B 0.05) and a risk of 2.35 for Child’s C ( 2 =12.2; PB0.01). Our data suggest that the risk increases progressively with the Child’s stage. Furthermore, the median time from appearance of HCC to death was 7 months for patients classified in Child’s C stage, 1 year for Child’s B patients and 2 years for those in Child’s A. The respective survival curves were significantly different (log-rank=16.43; PB 0.01; Fig. 3). In our study, as in others, the size of the primary HCC also plays a role in predicting survival. It seems that lesions larger than 5 cm shorten survival by a median of 1 year, (logrank =6.46; P B0.01). Moreover, in patients with large lesions, the risk of dying was 1.7 times higher than that of patients with lesions smaller than 5 cm. Another important finding was the effect of the presence of metastases (Fig. 4). This variable was transformed into two dummy values (the presence of intrahepatic metastasis with tumor thrombus of the portal vein, and the presence of extrahepatic metastasis), with the absence of metastasis as baseline. The estimated survival time from diagnosis of HCC to death was 3 months for patients with tumor thrombus of the portal vein, 14
months for patients with other metastases and 24 months for patients without metastases. Comparing the survival curves, we observed a statistically significant difference (log-rank= 50.2; PB 0.01). The Cox’s model with the two dummy variables described as above was statistically significant (Score: 34.07; PB 0.01). It also demonstrated the significance of tumor thrombus of the portal vein, which posed a 4.4-fold increased risk of death ( 2 = 29.21; PB0.01) above baseline, while the risk at other sites was 1.38 ( 2 = 2.05; P= 0.15). Finally, to evaluate the combined effect of the different risk factors on death, a multivariate regression stepwise Cox’s model was used. The factors considered were: age, sex, presence/ absence tumor thrombus of the portal vein, size of the tumor, therapy, viral hepatitis, and Child’s stage. The results are shown in Table 3. The variables demonstrating statistical significance in the overall model (Score: 49.77; PB 0.01) were vascular invasion (OR= 3.67; PB 0.01), and presence of metastases in other sites (OR= 2.24; PB 0.01). Using a univariate analysis, only metastases, both intrahepatic and extrahepatic, were found to be a relevant factor that influenced survival.
Table 3 Results of univariate and multivariate Cox regression for each factor influencing survival with related risk and 95% confidence interval Variable
Univariate analysis Parameter
P
Multivariate analysis OR
CI 95%
Parameter
Age E65 years Sex (Female = 1; male=0)
0.108 0.115
0.567 0.613
1.11 1.12
0.769–1.614 0.717–1.758
Not entered Not entered
Tumor in6asion Portal vein Other sites
1.482 0.323
B0.01 0.152
4.4 1.38
2.57–7.53 0.88–2.15
1.299 0.808
0.377 0.527 0.74 0.024
0.046 0.029 B0.001 0.936
1.46 1.7 2.1 1.03
1.000–2.114 1.056–2.720 1.563–2.818 0.563–1.865
Not entered Not entered 0.976 Not entered
0.49
0.84
0.499–1.399
Not entered
0.024 B0.001
1.62 2.53
1.065–2.450 1.503–4.255
Not entered Not entered
Alfa-feto protein E28 UI Lesion E5 cm Treatment not performed Histology (Undifferenced=1; differenced=0) Viral etiology Child stage B C
−0.18 0.479 0.927
P
OR
CI 95%
B0.01 B0.001
3.67 2.25
1.986–6.777 1.322–3.812
B0.001
2.65
1.854–3.801
G. Giannelli et al. / Hepatology Research 24 (2002) 50–59
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Fig. 1. Survival function of etiology of hepatitis in HCC patients. The follow-up period runs from diagnosis of hepatocarcinoma until death.
The diameter of the tumor did not enter the multivariate model, but was significant in the univariate model. This discrepancy could be linked to the association observed between tumor thrombus of the portal vein and lesions larger than or equal to 5 cm in diameter. In fact, 23% of patients with lesions of this size also had tumor thrombus of the portal vein, while only 9% with lesions smaller than 5 cm presented tumor thrombus of the portal vein ( 2 =7.57; P B0.05). Furthermore, Child’s C stage, which was significant in the univariate Cox’s model, did not enter the multivariate model, but was observed in 36.8% of patients with vascular invasion vs 15.3% without ( 2 =6.14; P B 0.05), showing a significant correlation between Child’s stage and tumor thrombus of the portal vein.
4. Discussion In this retrospective study, we investigated biochemical, histopathological, and clinical data in
150 patients with HCC, using a multivariate analysis to identify prognostic factors affecting patient survival. We found that the most important prognostic factor is the occurrence of tumor thrombus of the portal vein, although the size of the tumor (B 5 cm) was also significantly associated with the final outcome of death. These findings are important for numerous reasons: HCC is one of the most common malignancies in the Mediterranean area; being able to predict survival in patients affected with this condition is important from the standpoint of the increased transmission of HCV infection, and of longer survival of patients with liver cirrhosis [17]. Furthermore, HCC is a unique type of cancer since it develops in an organ that has already been injured by chronic disease. This situation determines a consequent overlapping of clinical outcomes, limits possible and successful therapies, and hampers identification of reliable prognostic factors [3]. For example, in patients with HCC, the main cause of death is liver and/or renal failure, which is also a common cause of death in
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patients affected only by cirrhosis [2,18]. For this reason, some authors have reported that Child’s classification is the most important parameter affecting long term survival of patients with HCC [11,12]. Our data do not confirm this finding, and are in agreement with other studies, which indicate that tumor thrombus of the portal vein is the most important prognostic factor in patients with HCC [10,14]. We believe that a possible explanation for this discrepancy could be the fact that tumor thrombus of the portal vein induces rapid worsening of the clinical outcome and consequently of the Child’s class, leading to death because of liver and/or renal failure. This hypothesis is supported by the following data: (1) survival is shorter in HCC patients than in cirrhotic patients with a similar Child’s class; and (2) the survival of HCC patients declines dramatically after development of tumor thrombus of the portal vein. Therefore, classification of HCC patients according to Child’s stage might be considered as its downstream effect of events such as vascular metastasis, which is more directly related to the malignant HCC phenotype.
We have compared survival between patients with HCC and patients with CH with similar Child’s classes, and our data demonstrate that there is a substantial difference between these two groups of patients in terms of survival. This apparent heterogeneity between groups supports our hypothesis that Child’s classification is not appropriate for predicting survival in patients with HCC, and suggests that its use be limited to patients affected with only cirrhosis. In summary, our data is in accordance with other studies that demonstrate Child’s class is not useful in patients with HCC that have developed vascular metastasis [10]. Our data also show that another important prognostic factor is the size of the tumor. This is a controversial issue because it has been reported by some authors to affect long-term survival, although there are numerous inconsistencies in Refs. [10,14,19]. It has also been reported that tumor growth rate as evaluated by ultrasound is an unreliable prognostic factor, while in the same study, Child’s stage of underlying liver disease
Fig. 2. Survival function of etiology of hepatitis in HCC patients. The follow-up period runs from diagnosis of hepatitis until that of hepatocarcinoma.
G. Giannelli et al. / Hepatology Research 24 (2002) 50–59
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Fig. 3. Survival function of Child stage in HCC patients. The follow-up period runs from diagnosis of hepatocarcinoma until death.
was found to have a significant role [12,13]. Such heterogeneous data could be explained by the biological features of the individual tumor characterised by a more or less aggressive and invasive phenotype. This is also supported by several studies reporting that recurrence of HCC after surgical therapy or even after transplantation is still the main problem during follow-up of HCC patients [3]. It has also been reported that pathologic features of the HCC such as encapsulation and inflammatory infiltrates influence survival [20,21]. In our opinion, the spread of HCC cells could also be favored by the absence of tissue boundaries such as a basement membrane. An intriguing hypothesis is that the invasive HCC phenotype may be modulated by the ability of cancer cells to penetrate the surrounding extracellular matrix proteins and to migrate towards tissues and vessels [22]. However, these findings have been reported on the basis of in vitro studies, while an in vivo demonstration is still lacking. In our experience patients that received more than one therapy showed a better prognosis. In this regard, we cannot rule out the possibility that
such a difference could be caused by a slower biological rate of tumor growth; patients with this pathological type may live longer, and have the opportunity to receive a higher number of treatments. This possibility has been evaluated in other studies, whereby authors measured tumor growth by ultrasound, but obtained contradictory results [12,23]. Alternatively, the tumor growth rate, as well as an aggressive phenotype, may be ascribed to biological features of HCC cells. More studies are needed to further elucidate these aspects. In our experience, cancers with a viral etiology take longer to develop, possibly because these patients receive antiviral therapy such as Interferon, that may slow down the development of cirrhosis and thus of carcinogenesis as already reported by others [24]. Although some differences exist in terms of survival, it is commonly reported that outcome in HCC is better with a surgical rather than a chemotherapeutic approach, probably because of the associated chronic liver damage [3,25]. Improvements in surgery as well as in other forms of therapy (arterial embolization, ethanol injections) have resulted in increased survival for treated
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Fig. 4. Survival function for tumor thrombus of the portal vein, other sites of invasion and absence of metastases. The follow-up period considered runs from diagnosis of hepatocarcinoma until death.
patients, although tumor recurrence still remains the main problem [9,26]. In conclusion, tumor thrombus of the portal vein together with tumor size are the most reliable prognostic factors for survival of HCC patients. The difference in terms of survival of patients with HCC mainly depends on the ability of malignant cells to invade surrounding tissue and to metastasize [27]. This could be facilitated by the absence of tissue boundaries such as the basement membrane, and by the histological features of the liver. A poor knowledge of the biomolecular mechanisms underlying HCC spread and metastasis limits the ability to effectively treat HCC. More studies are needed to elucidate the mechanisms involved in HCC development or metastasis.
Acknowledgements This work was supported by the Bari Univer-
sity Funds for Research (grant to GG, and OS).
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