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Epidemiology or primary liver cancer in Singapore.

Primary Liver Cancer occurs with high frequency in most parts of the East and South East Asia. The age standarised rates for most Western countries are below 2 per 100,000 per year for males and below 1 for females. In Singapore, the rate is 29.1 for males and 7.7 for females. There is a male preponderance in Singapore by a ratio of male to female of 3.8 in age standardised incidence rates. The peak incidence is the 6th decade (30.1% of cases) and in the 7th decade (31.7% of cases). The Chinese have the highest incidence amongst the different ethnic races. Epidemiological studies done on migrant population strongly suggest that environmental factors are more important than genetic factors in the aetiology of liver cancer.

Aged↗

Epidemiology of liver cancer in Europe.

Liver cancer (LC) ranks fifth in frequency in the world, with an estimated 437,000 new cases in 1990. The estimates are different when LC frequency is analyzed by sex and geographical areas. In developed areas, the estimates are 53,879 among men and 26,939 among women. In developing areas, the estimates are 262,043 in men and 93, 961 in women. Areas of highest rates include Eastern and South Eastern Asia, Japan, Africa and the Pacific Islands (LC age-adjusted incidence rates [AAIRs] ranging from 17.6 to 34.8). Intermediate rates (LC AAIRs from 4.7 to 8.9 among men) are found in Southern, Eastern and Western Europe, Central America, Western Asia and Northern Africa. Low rates are found among men in Northern Europe, America, Canada, South Central Asia, Australia and New Zealand (LC AAIRs range from 2.7 to 3.2). In Europe, an excess of LC incidence among men compared with women is observed, and the age peak of the male excess is around 60 to 70 years of age. Significant variations in LC incidence among different countries have been described and suggest differences in exposure to risk factors. Chronic infection with the hepatitis B virus (HBV) and hepatitis C virus (HCV) in the etiology of LC is well established. In Europe, 28% of LC cases have been attributed to chronic HBV infection and 21% to HCV infection. Other risk factors such as alcohol consumption, cigarette smoking and oral contraceptives may explain the residual variation within countries. Interactions among these risk factors have been postulated. New laboratory techniques and biological markers such as polymerase chain reaction detection of HBV DNA and HCV RNA, as well as specific mutations related to LC, may help to provide quantitative estimates of the risk related to each these factors.

Adolescent↗

Role and limitations of magnetic resonance imaging in the diagnostic work-up of patients with liver cancer.

The main objectives of liver imaging are detection and characterization of focal liver lesions. There is a wide range of imaging modalities available for the work-up of patients with liver cancer. In the current environment of cost containment, the most appropriate modality should be chosen to answer the clinical question. Contrast-enhanced computed tomography is currently the modality of choice for liver imaging for routine applications. Until recently magnetic resonance imaging was used only as a problem solving technique for lesions that were equivocal after contrast-enhanced computed tomography. However magnetic resonance with the use of tissue specific contrast agents, has already challenged the role of computed tomography portography in preoperative staging of liver cancer, and may soon completely replace this technique. It is also the primary modality for screening patients with cirrhosis for hepatocellular carcinoma. This review describes the role of magnetic resonance imaging, in the evaluation of patients with liver cancer, and outlines a rational approach for the diagnostic work-up of these patients.

Contrast Media↗

The relationship of hepatitis history and pathological diagnosis of primary liver cancer.

During the analysis of risk factors in relation to primary liver cancer, we noticed an association between the confirmed (as opposed to probable) pathologic diagnosis of liver cancer and a positive history of hepatitis. This report pursues the observation using data from the Selected Cancers Study. Study subjects included 168 men who lived in areas covered by eight cancer registries in the U.S., and were pathologically diagnosed with confirmed or probable primary liver cancer during 1984-1988. The results showed that men with confirmed primary liver cancer were six times more likely to have a hepatitis diagnosed within 3 years before liver cancer detection, compared with those with probable primary liver cancer. Further analyses showed that men with a confirmed primary liver cancer or with a recent hepatitis more likely had a tissue specimen obtained from a surgery, and less likely had one from an aspiration. Upon adjustment for type of specimen, the association between pathological confirmation of primary liver cancer and recent hepatitis persisted. The results raised questions whether recent hepatitis and its pathologic changes influence choice of tissue-collecting procedure and ultimate pathological diagnosis of primary liver cancer. Other factors that might be related to the findings also need to be examined in future studies.

Adolescent↗

Computed tomography and magnetic resonance imaging evaluation of liver cancer.

Focal liver lesions occur commonly and with varying histology, each requiring radically different management. There are a multitude of imaging modalities currently being used for detecting and characterizing focal liver neoplasms. The primary modalities include ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and rarely, angiography. CT and MRI have benefited from rapid technologic advances, and MRI, in particular, from the advent of new contrast agents.

Adenoma, Liver Cell↗

[Multidisciplinary treatment of unresectable liver cancer].

From January 1984 to December 1987, 63 unresectable liver cancers (22 hepatocellular carcinoma and 41 metastatic liver cancer) were treated with multidisciplinary therapy: partial resection of liver, hepatic arterial infusion, coagulation therapy using microwave tissue coagulator and intratumoral injection of the liver. The median survival period was 5-7 months, and the clinical response rate was 21.6% in these therapies, but there was no statistically significant difference between the treatments. Recently, we usually use degradable starch microspheres (DSM) with anticancer agents in hepatic arterial infusion. Adriamycin + DSM was administered for hepatocellular carcinoma, and Mitomycin C + DSM was used for metastatic liver cancer. The regimens were used for 12 cases, 6 of hepatocellular carcinoma and 6 of metastatic liver cancer, with a response rate of 50%, respectively. We also undertook chemosensitivity tests for liver cancer. The coincidence of clinical response with results of chemosensitivity tests was above 50%. In future, we shall use the most effective anticancer agents for individual tumors with DSM in arterial infusion.

Adult↗

Trends in liver cancer, Sa Kaeo Province Thailand.

OBJECTIVE: To determine liver cancer trends in Sa Kaeo Province, Thailand. METHODS: Death certificate (1993-2003) and hospital records (1999-2003) were reviewed and compared to national averages and other provinces. RESULTS: According to data from death certificates, liver cancer mortality in Sa Kaeo Province increased from 3.1 to 26.1 per 100,000 population between 1993 and 2003. In Thailand overall rates increased from 9.0 to 19.8 per 100,000 population between 1996 and 2003. According to electronic hospital records, the total number of patient encounters (in-patient admissions and out-patient visits) for liver cancer in the two main hospitals in Sa Kaeo Province increased 56% (14% annually) between 1999 and 2003. The number of cases of hepatocellular carcinoma increased from 42 in 2001 to 73 in 2003, while the number of cases of cholangiocarcinoma showed little change. CONCLUSIONS: Thailand as a whole and Sa Kaeo Province specifically have a high burden of liver cancer, which appears to have increased substantially in the past 10 years. Demonstrating the impact of ongoing strategies aimed at reducing risk factors for liver cancer, such as universal hepatitis B vaccination of infants, will require reliable data describing liver cancer disease burden and etiology. Rapid investigations using available data from death certificates, electronic admissions records, and patient charts can provide valuable insights on disease burden and trends.

Adolescent↗

The accuracy of liver cancer as the underlying cause of death on death certificates.

Studies of liver cancer mortality are subject to confusion attributable to the changes in categories by which liver cancer is identified in successive revisions of the International Classification of Diseases. To determine the effects of these changes, diagnoses of 2,388 cases of primary liver cancer in the years 1973-80 were compared to the underlying causes of death recorded on the death certificates, using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Results showed that only 53 percent of the deaths were attributed on death certificates to primary liver cancer. In a reverse comparison of 2,977 death certificates from the years 1973-85 with an underlying cause of death of primary liver cancer, 83 percent had been diagnosed as liver cancer. However, among the certificates that specified cancer of the liver, not specified as primary or secondary, as the cause of death, only 40 percent had been diagnosed originally as liver cancer. The mortality of liver cancer can be either underestimated or overestimated depending on which disease classification categories are used.

Cause of Death↗

[Trans-arterial embolization or transarterial infusion of anti-cancer drugs suspended in a lipid contrast medium against unresectable metastatic liver cancer].

We had 84 patients with unresectable metastatic liver cancer from May, 1980 to December 1987 in the National Matsudo Hospital. Eighteen of them had no treatment; 26 of them had serial transarterial embolization (TAE) with or without infusion of anti-cancer drug dispersed in lipiodol; 7 of them had only serial trans-arterial infusion (L-TAI) of an anticancer drug suspended in lipiodol. A significant survival advantage of patients with TAE or L-TAI was noted when compared with no treatment, but there was no difference between the survival rate of patients with TAE and L-TAI. There were some 82 patients with unresectable metastatic liver cancer from October 1984 to March 1988 in Kyto Prefectural University of Medicine Hospital. Thirteen of them had L-TAI using one anti-cancer drug (one-drug group); 8 of them had L-TAI using two drugs (two-drug group); 22 of them had L-TAI with three drugs (three-drug group). The survival rate of the three-drug group was superior to the one- and two-drug groups. It was concluded that TAE was not necessary for metastatic liver cancer, but L-TAI must be undertaken, because combined cancer chemotherapy enhanced the effect of L-TAI.

Antineoplastic Combined Chemotherapy Protocols↗

Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro.

The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.

Animals↗

Primary liver cancer: worldwide incidence and trends.

Estimates from the year 2000 indicate that liver cancer remains the fifth most common malignancy in men and the eighth in women worldwide. The number of new cases is estimated to be 564,000 per year, including 398,000 in men and 166,000 in women. In high-risk countries, liver cancer can arise before the age of 20 years, whereas, in countries at low risk, liver cancer is rare before the age of 50 years. Rates of liver cancer in men are typically 2 to 4 times higher than in women. The incidence of primary liver cancer is increasing in several developed countries, including the United States, and the increase will likely continue for some decades. The trend is a result of a cohort effect related to infection with hepatitis B and C viruses, the incidence of which peaked in the 1950s to 1980s. In selected areas of some developing countries, the incidence of primary liver cancer has decreased, possibly as a result of the introduction of hepatitis B virus vaccine. The geographic variability in incidence of primary liver cancer is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.

Adolescent↗

Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer.

OBJECTIVE: To assess the validity and cost of a screening test for primary liver cancer using combined serum alpha fetoprotein testing and ultrasonography. SETTING: An urban community in Shanghai, China. METHODS: 9373 subjects aged 35 to 59 with positive hepatitis B surface antigen (HBsAg) or chronic hepatitis were studied. Outcome measures were detection rate, false positive rate, and positive predictive value, the cost for each primary liver cancer detected, and the average cost of detecting each additional primary liver cancer by the combined method. The number of small primary liver cancers detected was used for the economic evaluation. RESULTS: 20,294 screening examinations were carried out. Primary liver cancer was detected in 51 subjects, 36 of whom had small primary liver cancer. When alpha fetoprotein and ultrasonography were used in parallel the detection rate, false positive rate, and positive predictive value were 92%, 7.5%, and 3.0%, respectively; the cost for each primary liver cancer detected was 30,206 RMB (Chinese currency, $3639). When ultrasonography was used alone the detection rate, false positive rate, and positive predictive value were 84%, 2.9%, and 6.6%, respectively; the cost for each primary liver cancer detected was 16,451 RMB ($1982). When the alpha fetoprotein test was used alone the detection rate, false positive rate, and positive predictive value were 69%, 5.0%, and 3.3%, respectively; the cost for each primary liver cancer detected was 25,139 RMB ($3029). CONCLUSION: The combination of both screening methods results in a relatively small increase in detection but a considerably higher false positive rate, increasing the costs. The combined test may be the best choice for primary liver cancer screening in developed areas of China, but otherwise, ultrasonography alone is the method of choice.

Adult↗

[Preliminary observations on effect of selenium yeast on high risk populations with primary liver cancer].

Two populations with high risk primary liver cancer (PLC), one of 226 cases with HBsAg carriers and another of 3849 first-relatives in the pedigree with high incidence of PLC, were randomly divided into the supplementing selenium group (selenium yeast 200 g Se1Tab/day) and the control group (common yeast 1 Tab/day), and were followed-up for four years and two years respectively. In the population with HBsAg carriers, no liver cancer occurred in the supplementing selenium group; where as the liver cancer incidence rate was 1573.03/10(5) in the control group. Among the first relatives. The liver cancer incidence rate in the supplementing selenium group was 219.37/10(5); and 553.15/10(5) in the control group. The results showed that the incidence of PLC in the supplementing selenium group was significantly lower than in the control group. This study indicates that selenium has distinct anti-PLC effect.

Adolescent↗

[Experimental analysis of postoperative early recurrence of liver cancer].

The author suspected that the high incidence of early recurrence after macroscopically curative operation in human liver cancers correlated with the production of liver regeneration factor which was induced following partial hepatectomy (PH). The author therefore analyzed whether PH enhanced the growth of liver cancers or not, and the relevant mechanism involved, using rats subcutaneously injected with hepatocellular carcinoma (KDH-8, AH-66) cells. Primarily, it proved that PH significantly enhanced the growth of liver cancers injected in rats. The effect of this enhancement of liver cancer growth appeared as an abrupt increase in tumor volume within 24 hours following PH, which fact was supported by the mitotic indices of the hepatocellular carcinoma (KDH-8) cells. However PH did not affect rats injected with mammary carcinoma (SST-2) cells without estrogen receptor (E2R) or fibrosarcoma (KMT-75) cells. Secondly, based on this result, the author tried to analyze the mechanism of enhanced growth of liver cancers following PH, from the standpoints of; changes in postoperative immunity, expression of cytosol E2R in liver cancer cells or liver regeneration factor, using KDH-8 cells. The changes in postoperative immunity (NK-activity and Blastogenesis) did not correlate with the changes in liver cancer growth. Although serum estradiol (E2) increased significantly after PH, E2R was not detected in the KDH-8 cells used in this experiment. Serum was obtained from healthy rats 24 hours after PH, and 20 mg of serum, as calculated from total protein, was eluted into 50 fractions by high liquid chromatography (column; TSK G3000 SW). When the author examined which fractions stimulated both the growth of primarily cultivated hepatocytes and KDH-8 cells, only the fraction Fr. 30, the molecular weight of which was about 100 Kd, enhanced both. Furthermore, the author performed an in vivo assay to determine the number of days needed for tumor appearance: PHs were carried out 2 months, 5 days and 1 day before, at the same day of, and 1 day and 5 days after KDH-8 cell (500 cells/100 microliters, sc) inoculation. The author also noticed from these in vivo tests that PHs which were performed 1 day before, at the same day of, and 1 day and 5 days after the KDH-8 cell inoculation enhanced significantly the growth of liver cancers.

Animals↗

Increase in incidence of disease due to diagnostic drift: primary liver cancer in Denmark, 1943-85.

OBJECTIVE: To examine the extent to which changes in diagnostic methods and classification are responsible for the striking increase in incidence of primary liver cancer in Denmark since 1943. DESIGN: Analysis of the time trends in sex specific, age standardised incidence of primary liver cancer and unspecified liver cancer (either secondary without known primary cancer or not specified as primary cancer) in the entire population from 1943 to 1985. By review of the 727 notifications from three periods of 5 years (1948-52, 1963-7, and 1978-82) the changes in histological diagnosis and classification were assessed. SETTING: Denmark. SUBJECTS: Notifications of liver cancer to the Danish cancer registry. RESULTS: Concomitant with the increase in primary liver cancer, the incidence of the unspecified liver cancer declined. The proportion of histologically diagnosed primary liver cancer rose from 85% to 98%, whereas the proportion for unspecified liver cancer rose from 12% to 51%. When the proportion of primary versus unspecified liver cancer obtained by histological diagnosis was extrapolated to all cases, the annual incidence of primary liver cancer was 4.4 rather than 1.6 per 100,000 population in 1948-52 and 6.0 rather than 5.5 per 100,000 in 1978-82. CONCLUSION: The increase in the incidence of primary liver cancer may be much smaller than the numbers of registered cases indicate. This example emphasises the need to consider diagnostic drift in time trend studies of disease incidence.

Denmark↗

Multi-Omics Biomarker Signatures for Precision Diagnosis and Prognosis in Primary Liver Cancer: A Literature Review.

Primary liver cancer (PLC) is a biologically heterogeneous group of malignancies dominated by hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and a smaller subset of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and its clinical burden remains high because current diagnostic and prognostic tools do not adequately capture molecular diversity. Conventional imaging, serum markers, and histopathological assessment remain insufficient for precise early diagnosis, subtype-resolved classification, and outcome stratification, while tissue and liquid biopsy approaches have expanded the range of analytes available for clinical assessment. Recent studies have identified candidate biomarker signatures across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and circulating layers, suggesting that integrated multi-omics profiling may better represent tumor lineage, clonal evolution, immune context, and therapeutic vulnerability than isolated molecular readouts. However, these layers are not equally mature for clinical use: genomic testing is closest to routine therapeutic application in iCCA, plasma methylation assays are advancing for HCC surveillance augmentation, and many proteomic or metabolomic panels remain validation-stage tools. Their clinical value remains constrained by sampling bias, biospecimen-dependent signal loss, assay standardization, cost, and the need for prospective validation across clinically diverse populations. This narrative review critically synthesizes current evidence on multi-omics biomarker signatures for precision diagnosis and prognosis in primary liver cancer and argues that clinically useful signatures should be question-specific, stage-aware, and specimen-aware rather than universal multi-analyte panels.

Humans↗

Diabetes mellitus and the risk of primary liver cancer.

The relationship between diabetes mellitus and primary liver cancer was investigated in a case-control study conducted in Italy between 1984 and 1996 on 428 cases with incident, histologically confirmed hepatocellular carcinoma, 59 with gallbladder and bile duct cancer, and 1,502 control subjects in the hospital for acute non-neoplastic diseases. Sixty-four cases of hepatocellular carcinoma vs. 87 controls reported a history of diabetes, corresponding to an odds ratio (OR) of 2.3 after allowance for age, sex and area of residence, and of 2.1 [95% confidence interval (CI) = 1.4-3.2] after further allowance for alcohol and tobacco consumption, history of hepatitis and liver cirrhosis, body mass index and history of liver cancer in first-degree relatives. The ORs were similar both for subjects diagnosed with diabetes below age 45, who most likely had insulin-dependent diabetes, and for those diagnosed later, who were likelier to have non-insulin-dependent diabetes. The OR was 2.3 for subjects whose diabetes was diagnosed <5 years before diagnosis of liver cancer, 1.9 for those diagnosed 5-9 years in advance and 2.2 for those diagnosed since 10 years or more. Five cases of gallbladder and bile duct cancer reported a history of diabetes: the corresponding OR was 1.2 (95% CI 0.5-2.9). The OR of hepatocellular carcinoma was 2.4 for males and 2.0 for females, 3.0 for subjects diagnosed with liver cancer under age 60 and 1.8 for those diagnosed at age 60 or over. None of the other covariates considered, including education, history of hepatitis, liver cirrhosis and alcohol drinking showed any meaningful modifying effect or interaction. The potential pathogenic mechanisms include liver alteration-and consequent cell proliferation-in subjects with diabetes. Thus a history of diabetes mellitus could explain about 8% (95% CI 5-11) of cases of liver cancer in this population.

Adult↗