Prognosis of Patients With HCC in the Non-cirrhotic Liver
Prognosis of Patients With HCC in the Non-cirrhotic Liver
Most of the characteristics reported in the literature over the last decades were confirmed in our analysis, but we also identified some differences compared to published data.
In 14% of our study population HCC has been detected in NCL. Patients with HCC in NCL presented at an older age than patients with HCC in LC and this differs from some of the previous reports. We confirmed a larger proportion of female patients with HCC in NCL. In both cohorts of patients, with and without LC, more than 50% of patients initially presented with symptoms and impaired performance status. A previous study from Germany states that 47% of patients present with tumor symptoms leading to the initial diagnosis of HCC, but 86% of patients with HCC in NCL are not restricted in their daily activities at all.
For the majority of patients with HCC in NCL the etiology was most likely related to the metabolic syndrome. Even though non-alcoholic fatty liver disease (NAFLD) was diagnosed in a small proportion of patients, factors of the metabolic syndrome were frequent in our cohort, especially in the subgroup of patients in whom no other risk factor was identified. NAFLD, the hepatic manifestation of the metabolic syndrome, is frequently underdiagnosed in the general population but is recognized to be a frequent cause for HCC. The incidence of cirrhosis, on the other hand, in patients with HCC and NAFLD is low in comparison to patients with other causes of HCC, and patients with HCC and NAFLD exhibit more features of the metabolic syndrome. Vice versa, about 75% of obese patients suffer from NAFLD, and obesity alone has been shown to be a risk factor for HCC with an OR of 1.39 to 4.52.
Several cohort studies have demonstrated that diabetes mellitus is an independent risk factor for hepatocellular carcinoma. An analysis within the SEER-database found a 2.9 fold risk for diabetic patients to develop HCC. This risk factor was present in more than 70% of our patients with HCC in NCL.
It is suggested that tumor suppressor genes play an important role in the development of steatosis, induce liver cell damage and therefore promote the formation of HCC in the absence of cirrhosis in combination with other complex dysregulated mechanisms and pathways in fatty liver disease.
It is striking that, although a direct hepatocarcinogenic role of alcohol has not been proven so far, 15% of patients with HCC in NCL reported a significant intake of alcohol as risk factor for liver disease. This goes along with data previously reported in which 12% to 21.4% of patients with HCC in NCL abused alcohol. This suggests that cirrhosis is not a condition sine qua non in alcoholic liver disease for HCC development. It is not known whether in these patients the inflammation alone is sufficient or whether fibrosis needs to develop before HCC can arise. A Swedish study demonstrated a 2.4 fold risk for hepatocellular carcinoma in patients with alcohol abuse in comparison to the general population that increased to a 22.4 fold risk in the presence of cirrhosis. An interaction between alcoholic liver disease and other risk factors is likely to occur. Hence, obesity and the metabolic syndrome are factors which favor the progression of alcoholic liver disease and increase hepatocellular carcinoma (HCC) incidence and mortality. Similarly, a synergism has been shown for viral hepatitis and heavy alcohol consumption. Viral hepatitis played a minor role in our cohort.
Since we did not take biopsies from non-tumorous liver tissue as part of the standard work-up of patients with HCC, the number of patients with histology from non-tumorous tissue is rather small. Patients without any hepatic damage of the tissue surrounding the tumor were few and this may indicate the possibility of direct hepatocarcinogenesis in the healthy liver (e.g. adenoma-carcinoma sequence). Most patients showed histological features of chronic liver damage. Chronic liver disease thus may not have been recognized in advance of hepatocellular carcinoma and therefore no surveillance has been offered. This is probably the reason why diagnosis is made in advanced tumor stages in these patients.
Consistent with previous studies almost every second patient with HCC in NCL was diagnosed with a single tumorous nodule but of larger size. The proportion of patients with extrahepatic metastases in our cohort exceeded 25% and was strikingly larger than reported in other cohorts with up to 15%.
The BCLC staging system, although developed for patients with LC, correlates with patients' survival. The CLIP score was less suitable to predict survival of patients with HCC in NCL. Patients in intermediate stage HCC according to BCLC in NCL show a trend towards prolonged survival in comparison to patients with LC. This is most likely because curative treatment can be offered to these patients even if the tumor load exceeds the Milan criteria.
Survival of patients with HCC in NCL mainly depends on tumor related factors such as tumor size, existence of satellite lesions, existence of a tumor capsule, vascular invasion, grading, R0 resection and the amount of intraoperative blood transfusions. Analyses from mixed surgically and medically treated cohorts of patients identified tobacco consumption, clinical performance status, siderosis of non-tumorous tissue, tumor stage according to BCLC and the initial treatment to be relevant for survival. Our study confirms tumor related factors to exert a significant influence on patients' outcome in univariate explorative analyses (portal vein thrombosis, existence of extrahepatic tumor manifestations). Tumor size and number of intrahepatic HCC nodules had not statistically significant impact on survival. Ongoing hepatic inflammation, mirrored in elevation of ASAT, reduced hepatic synthesis capacity mirrored in prolonged PTT and low platelets (probably a consequence of portal hypertension caused by portal vein thrombosis or by large hepatic tumor load) were negative predictive for survival for patients with HCC in NCL. At multivariate analysis solely the presence of metastases and low platelets were significant factors influencing survival.
Although the proportion of patients who presented at an early tumor stage was rather small, it was evident that in addition to patients in BCLC A some patients at an intermediate tumor stage (BCLC B) also qualified for treatment in curative intent. A modification of current treatment algorithms for patients with HCC in NCL is desirable.
Our study has some limitations due to the retrospective design and the small number of patients in some of the univariate analyses might lead to insignificant findings in the statistical analyses. The mixed cohort of patients does not permit to address surgical aspects.
Discussion
Most of the characteristics reported in the literature over the last decades were confirmed in our analysis, but we also identified some differences compared to published data.
In 14% of our study population HCC has been detected in NCL. Patients with HCC in NCL presented at an older age than patients with HCC in LC and this differs from some of the previous reports. We confirmed a larger proportion of female patients with HCC in NCL. In both cohorts of patients, with and without LC, more than 50% of patients initially presented with symptoms and impaired performance status. A previous study from Germany states that 47% of patients present with tumor symptoms leading to the initial diagnosis of HCC, but 86% of patients with HCC in NCL are not restricted in their daily activities at all.
For the majority of patients with HCC in NCL the etiology was most likely related to the metabolic syndrome. Even though non-alcoholic fatty liver disease (NAFLD) was diagnosed in a small proportion of patients, factors of the metabolic syndrome were frequent in our cohort, especially in the subgroup of patients in whom no other risk factor was identified. NAFLD, the hepatic manifestation of the metabolic syndrome, is frequently underdiagnosed in the general population but is recognized to be a frequent cause for HCC. The incidence of cirrhosis, on the other hand, in patients with HCC and NAFLD is low in comparison to patients with other causes of HCC, and patients with HCC and NAFLD exhibit more features of the metabolic syndrome. Vice versa, about 75% of obese patients suffer from NAFLD, and obesity alone has been shown to be a risk factor for HCC with an OR of 1.39 to 4.52.
Several cohort studies have demonstrated that diabetes mellitus is an independent risk factor for hepatocellular carcinoma. An analysis within the SEER-database found a 2.9 fold risk for diabetic patients to develop HCC. This risk factor was present in more than 70% of our patients with HCC in NCL.
It is suggested that tumor suppressor genes play an important role in the development of steatosis, induce liver cell damage and therefore promote the formation of HCC in the absence of cirrhosis in combination with other complex dysregulated mechanisms and pathways in fatty liver disease.
It is striking that, although a direct hepatocarcinogenic role of alcohol has not been proven so far, 15% of patients with HCC in NCL reported a significant intake of alcohol as risk factor for liver disease. This goes along with data previously reported in which 12% to 21.4% of patients with HCC in NCL abused alcohol. This suggests that cirrhosis is not a condition sine qua non in alcoholic liver disease for HCC development. It is not known whether in these patients the inflammation alone is sufficient or whether fibrosis needs to develop before HCC can arise. A Swedish study demonstrated a 2.4 fold risk for hepatocellular carcinoma in patients with alcohol abuse in comparison to the general population that increased to a 22.4 fold risk in the presence of cirrhosis. An interaction between alcoholic liver disease and other risk factors is likely to occur. Hence, obesity and the metabolic syndrome are factors which favor the progression of alcoholic liver disease and increase hepatocellular carcinoma (HCC) incidence and mortality. Similarly, a synergism has been shown for viral hepatitis and heavy alcohol consumption. Viral hepatitis played a minor role in our cohort.
Since we did not take biopsies from non-tumorous liver tissue as part of the standard work-up of patients with HCC, the number of patients with histology from non-tumorous tissue is rather small. Patients without any hepatic damage of the tissue surrounding the tumor were few and this may indicate the possibility of direct hepatocarcinogenesis in the healthy liver (e.g. adenoma-carcinoma sequence). Most patients showed histological features of chronic liver damage. Chronic liver disease thus may not have been recognized in advance of hepatocellular carcinoma and therefore no surveillance has been offered. This is probably the reason why diagnosis is made in advanced tumor stages in these patients.
Consistent with previous studies almost every second patient with HCC in NCL was diagnosed with a single tumorous nodule but of larger size. The proportion of patients with extrahepatic metastases in our cohort exceeded 25% and was strikingly larger than reported in other cohorts with up to 15%.
The BCLC staging system, although developed for patients with LC, correlates with patients' survival. The CLIP score was less suitable to predict survival of patients with HCC in NCL. Patients in intermediate stage HCC according to BCLC in NCL show a trend towards prolonged survival in comparison to patients with LC. This is most likely because curative treatment can be offered to these patients even if the tumor load exceeds the Milan criteria.
Survival of patients with HCC in NCL mainly depends on tumor related factors such as tumor size, existence of satellite lesions, existence of a tumor capsule, vascular invasion, grading, R0 resection and the amount of intraoperative blood transfusions. Analyses from mixed surgically and medically treated cohorts of patients identified tobacco consumption, clinical performance status, siderosis of non-tumorous tissue, tumor stage according to BCLC and the initial treatment to be relevant for survival. Our study confirms tumor related factors to exert a significant influence on patients' outcome in univariate explorative analyses (portal vein thrombosis, existence of extrahepatic tumor manifestations). Tumor size and number of intrahepatic HCC nodules had not statistically significant impact on survival. Ongoing hepatic inflammation, mirrored in elevation of ASAT, reduced hepatic synthesis capacity mirrored in prolonged PTT and low platelets (probably a consequence of portal hypertension caused by portal vein thrombosis or by large hepatic tumor load) were negative predictive for survival for patients with HCC in NCL. At multivariate analysis solely the presence of metastases and low platelets were significant factors influencing survival.
Although the proportion of patients who presented at an early tumor stage was rather small, it was evident that in addition to patients in BCLC A some patients at an intermediate tumor stage (BCLC B) also qualified for treatment in curative intent. A modification of current treatment algorithms for patients with HCC in NCL is desirable.
Our study has some limitations due to the retrospective design and the small number of patients in some of the univariate analyses might lead to insignificant findings in the statistical analyses. The mixed cohort of patients does not permit to address surgical aspects.