A case report of hepatocellular carcinoma within adenomatous hyperplasia: is adenomatous hyperplasia a precancerous lesion or not?

It is controversial whether adenomatous hyperplasia (AH) of the liver progresses to hepatocellular carcinoma. We experienced two hepatic lesions in a patient (73-yr-old male) with cirrhotic liver. One was diagnosed as HCC and the other was AH including a small HCC histologically. To investigate cell kinetics and the ploidy pattern of these lesions, Feulgen DNA-cytofluorometry analysis was performed. The result of this analysis suggested that AH developed into extremely well-differentiated HCC composed of mononuclear diploid cells at first and then was further transformed into clear cell type HCC composed of mononuclear tetraploid cells. The development of human HCC, at least in cirrhotic liver, may therefore be a multi-step process.     

A case report of hepatocellular carcinoma within adenomatous hyperplasia: Is adenomatous hyperplasia a precancerous lesion or not?

It is controversial whether adenomatous hyperplasia (AH) of the liver progresses to hepatocellular carcinoma. We experienced two hepatic lesions in a patient (73-yr-old male) with cirrhotic liver. One was diagnosed as HCC and the other was AH including a small HCC histologically. To investigate cell kinetics and the ploidy pattern of these lesions, Feulgen DNA-cytofiuorometry analysis was performed. The result of this analysis suggested that AH developed into extremely well-differentiated HCC composed of mononuclear diploid cells at first and then was further transformed into clear cell type HCC composed of mononuclear tetraploid cells. The development of human HCC, at least in cirrhotic liver, may therefore be a multi-step process.     

Diagnosis of hepatocellular carcinoma (HCC) in a high-risk patient by using transgastric EUS-guided fine-needle biopsy (EUS-FNA)

Hepatocellular carcinoma (HCC) is the most common primary malignancy arising within the liver and most often affects individuals with chronic hepatitis and/or liver cirrhosis. Patients often present at an advanced stage of disease or with poor liver function, thus limiting treatment options and resulting in a poor prognosis of the disease. Therefore, an early tissue-based diagnosis of HCC is necessary to direct further work-up and treatment. We present the case of a 70-year-old man with alcoholic cirrhosis at stage Child C, in whom a tumor nodule was found incidentally within the left lobe of the liver. Percutaneous biopsy was deemed too dangerous because a deteriorated liver function with coagulopathy was present, and a significant amount of ascites surrounded the small cirrhotic liver. To obtain a conclusive diagnosis, we performed transgastric fine-needle biopsy of the tumor under direct endosonographic guidance (EUS-FNA) without complications. Cytologic examination confirmed the presence of a well differentiated HCC. Based on this finding, super-selective CT-guided angiography and chemoembolization were subsequently performed without complications and the patient remained free of tumor relapse for the 8 months of surveillance. We conclude that EUS-guided fine-needle biopsy and cytologic examination represent a reliable alternative for tissue sampling in HCC, particularly in selected high-risk patients such as those with poor liver function and coagulation disorders; this should be assessed in prospective clinical trials.     

The risk of hepatocellular carcinoma in cirrhotic patients with small liver nodules on MRI

BACKGROUND AND AIM: The presence of hepatocellular carcinoma (HCC) has important implications for patients with cirrhosis. Studies have not compared the risk of cancer in cirrhotic patients with small liver nodules to cirrhotic patients without nodules. Our aim was to determine the risk of HCC in cirrhotic patients with small liver nodules on MRI compared to those without nodules. METHODS: We conducted a prospective study to determine the rate of HCC in cirrhotic patients with and without liver nodules. Cases were patients with liver nodule(s) less than 2 cm on MRI and controls were cirrhotic patients without nodules. Kaplan-Meier estimates and multivariate analysis were performed to estimate the risk of HCC in the two groups. RESULTS: A total of 310 liver transplant candidates with a mean follow-up of 663 days were included in the study and 133 underwent liver transplant during follow-up. The 1-yr incidence of HCC in the liver nodule group and control group was 11% and 0.5%, respectively, p < 0.001. The adjusted risk for HCC in the liver nodule group was 25 times higher compared to the control group, HR = 25.1 [95% CI 8.0, 78.9]. In 133 candidates who underwent transplant with and without liver nodules the rate of HCC was 11 (50%) and 4 (3.6%), respectively, p < 0.001. CONCLUSION: The incidence of HCC in patients with small liver nodules is significantly higher compared to patients with cirrhosis without liver nodules. The presence of small liver nodules warrants increased imaging surveillance for HCC.     

Hepatitis E virus re-infection accelerates hepatocellular carcinoma development and relapse in a patient with liver cirrhosis: A case report and review of literature

BACKGROUNDHepatitis E virus (HEV) superinfection is a suspected promoting factor for hepatocellular carcinoma (HCC) in patients with chronic hepatitis and cirrhosis. However, to date, very few cases of HEV-related HCC have been reported. Nevertheless, the role of HEV re-infection in cirrhotic liver without other chronic hepatitis infections has rarely been explored.CASE SUMMARYA 53-year-old male farmer was diagnosed with liver cirrhosis and splenomegaly in August 2016, accompanied with negative HEV-IgM and positive HEV-IgG. No evidence of hepatitis B virus or hepatitis C virus infection was found. Since then the patient was evaluated for liver function and viral parameters every 3 mo. In June 2017, the patient presented severe fatigue with whole body itching and was diagnosed with HCC. Afterwards this patient experienced quick HCC development, progression, relapse, and metastasis in the following 8 mo, and presented persistent dual positivity of HEV-IgM and HEV-IgG. This patient had a long history of smoking and alcohol consumption.CONCLUSIONThis unique case invokes the importance of HEV surveillance and treatment among cirrhotic patients, HCC cases, and blood donors.     

Hepatocellular carcinoma in a case of Wilson's disease treated with radiofrequency ablation therapy

A 37-year-old Japanese man was diagnosed with liver cirrhosis due to Wilson's disease in 2001 and treated with D-penicillamine. Thereafter, he was admitted to our hospital for further examination of a space occupying lesion in the liver. The patient was diagnosed with hepatocellular carcinoma (HCC) (7th segment, 2.5 cm in diameter) in May 2010 and treated with radiofrequency ablation therapy. Biopsy findings from a non-cancerous area revealed a fatty liver, though cirrhotic nodules were not found. Long-term treatment for Wilson's disease may improve hepatic fibrosis, and careful screening for HCC by abdominal imaging is needed in such cases.     

Coexistence of hepatoma with mantle cell lymphoma in a hepatitis B carrier

The coexistence of hepatocellular carcinoma (HCC) and non-Hodgkin’s lymphoma (NHL) in the liver is rare. Reports show that these patients have cirrhotic livers or hepatitis virus infections before they develop HCC and NHL. We present a patient with hepatitis B virus infection who was transferred to our hospital with a newly detected liver mass; abdominal computed tomography examination showed one hypodense mass of 7 cm in diameter and multiple mesenteric and mediastinal lymph nodes. A liver tumor biopsy showed a hepatoma, and the pathologic findings from an inguinal lymph node excision showed mantle cell lymphoma. An immunohistochemical stain confirmed that the atypical lymphoid cells within the HCC were positive for the CD20, CD5 and cyclin D1 antigens. Taking these findings into account, the hepatic tumor was determined to be a HCC infiltrated by mantle cell lymphoma.     

WJH 6~(th) Anniversary Special Issues(1): Management of hepatocellular carcinoma Management of “very early” hepatocellular carcinoma on cirrhotic patients

Due to the advances in screening of cirrhotic patients, hepatocellular carcinoma(HCC) is being diagnosed in earlier stages. For this reason the number of patients diagnosed of very early HCC(single tumors ≤ 2 cm) is continuously increasing. Once a patient has been diagnosed with this condition, treatment strategies include liver resection, local therapies or liver transplantation. The decision on which therapy should the patient undergo depends on the general patients performance status and liver disease. Anyway, even in patients with similar conditions, the best treatment offer is debatable. In this review we analyze the state of the art on the management of very early HCC on cirrhotic patients to address the best treatment strategy for this patient population.     

Effect of a late evening snack using branched‐chain amino acid‐enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Aim: A late evening snack (LES) is recommended for protein‐energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched‐chain amino acid (BCAA)‐enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75‐g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non‐protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early‐stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA‐enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.     

Advancement in HCC imaging: diagnosis, staging and treatment efficacy assessments

Diagnostic confirmation and assessment of disease extent are crucial for proper management of patients with hepatocellular carcinoma (HCC). Imaging studies play a crucial role in the diagnosis and staging of HCC. The imaging techniques commonly used for the diagnosis of HCC include ultrasound, computed tomography, and magnetic resonance imaging. Currently, improvements in imaging technology make a noninvasive and reliable diagnostic assessment of hepatocellular nodules possible in the cirrhotic liver. Biopsy is infrequently required prior to treatment, and the diagnosis of HCC is strongly dependent on hemodynamic features (arterial hypervascularity and washout in the venous phase) on dynamic imaging. Accurate staging of HCC is important in determining prognosis and in deciding optimal treatment for each patient. In addition, although there is a strong demand for an accurate diagnostic tool to detect smaller tumors, until now, the major challenge for radiologists in imaging cirrhosis is the characterization of small hepatocellular nodules in the cirrhotic liver. Further improvement of imaging technologies including functional imaging such as elastography, perfusion imaging and diffusion imaging, and development of new contrast media will undoubtedly improve the detection and characterization of small tumors. In this article, we present a summary of the most recent information on the diagnosis and staging of HCC.     

New advances in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

Manganese superoxide dismutase activity and incidence of hepatocellular carcinoma in patients with Child-Pugh class A liver cirrhosis: a 7-year follow-up study.

AIMS: To evaluate possible modifications in the manganese superoxide dismutase (MnSOD) activity during neoplastic transformation of a cirrhotic liver and to find out whether its assessment may have predictive value to identify cirrhotic patients at a higher risk of hepatocellular carcinoma (HCC). METHODS: Seventy-one consecutive subjects with Child-Pugh class A liver cirrhosis were recruited. At the time of enrolment, HCC was diagnosed in 20 cirrhotic patients. The 51 cirrhotic patients without HCC were followed up for the occurrence of tumour by 6-monthly screening for 7 years. During follow-up, 16 patients developed HCC. Seventy healthy subjects formed the control group. MnSOD activity was assayed spectrophotometrically. RESULTS: Serum MnSOD activity was significantly lower in 70 healthy subjects compared with 51 cirrhotic patients and 20 cirrhotic patients with HCC. Cirrhotic patients who developed HCC during follow-up showed significantly higher values of MnSOD activity than HCC-free patients. The best cut-off of MnSOD activity was 0.40 U/ml. At this cut-off, chi2 analysis revealed that MnSOD activity was significantly different between the HCC-free cirrhotic patients and cirrhotic patients who developed HCC. CONCLUSION: The present findings suggest that during neoplastic transformation of cirrhotic liver, an increase in MnSOD activity may occur already during the precancerous phase, making this enzyme a probable malignancy-associated parameter.     

Unusual cause of gastrointestinal bleeding in a cirrhotic patient:hepatocellular carcinoma with gastric invasion

BACKGROUND:Upper gastrointestinal(GI)bleeding is a common complication of portal hypertension in cirrhotic patients,and hepatocellular carcinoma(HCC)is the most common tumor in cirrhotic livers.Bleeding from tumor erosion into the GI tract is very rare.A patient with HCC and gastric tumor invasion was described and the previously reported cases were reviewed. METHOD:A patient with upper GI bleeding was treated in a tertiary hospital. RESULTS:A cirrhotic patient with a HCC invading the stomach leading to upp...     

Clinical prognostic variables in young patients (under 40 years) with hepatitis B virus-associated hepatocellular carcinoma

OBJECTIVE: The aim of this study was to determine the impact of hepatocelluar carcinoma (HCC) screening in chronic hepatitis B patients who did not meet the current screening recommendations. METHODS: Patients who were admitted to Bellevue Hospital Center with HCC were assessed for risk factors, cirrhosis and tumor‐specific factors. Eligibility for liver transplantation or resection with favorable outcome was determined by applying Milan criteria. RESULTS: In all 93 patients were diagnosed with hepatitis B virus (HBV)‐associated HCC, 18 of whom were under 40 years. Cirrhosis was infrequently associated with HCC in this group, with most cancers occurring in non‐cirrhotic patients (12/18, 66.7%). No patient developed HCC outside the American Association for the Study of Liver Diseases (AASLD) cancer screening recommendations (young age, non‐cirrhotic) were eligible for liver transplantation or resection with favorable outcomes (within Milan criteria). However, HCC patients who were diagnosed within AASLD screening recommendations did meet Milan criteria in 17.3% (14/81) patients. CONCLUSIONS: Current guidelines for HCC screening in patients with HBV may lead to a delay in diagnosis in non‐cirrhotic patients under 40 years. Consideration should be given to modifying current recommendations to advocate entering HBV patients into a cancer‐screening program at young age.     

Treatment of hepatocellular carcinoma

Opinion statement The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.     

Imaging of hepatocellular carcinoma

Recent improvements in the treatment of hepatocellular carcinoma (HCC) have resulted in a need to identify the disease at an early stage. The wide range of imaging techniques available reflects the difficulty in demonstrating small HCC, particularly in the cirrhotic liver. This article reviews the current imaging techniques available for the diagnosis of HCC.     

Elevation of endoglin (CD105) concentrations in serum of patients with liver cirrhosis and carcinoma

OBJECTIVE: Liver cirrhosis is considered as a premalignant state, as about 80% of hepatocellular carcinoma (HCC) is associated with liver cirrhosis. Although alpha-fetoprotein (AFP) has a high negative predictive value, its sensitivity for detecting HCC is poor. The aim of this study was to evaluate circulating endoglin (CD105) in the serum of patients with liver cirrhosis and at high risk for HCC. METHODS: CD105 and AFP serum concentrations were measured in 70 healthy and 94 nonliver-diseased controls and 130 patients with chronic liver diseases and HCC, respectively. RESULTS: Fifty-seven liver cirrhotic patients, 45 patients with liver cirrhosis plus HCC, 19 liver fibrosis patients and nine patients with HCC only were studied. Serum CD105 is significantly elevated in liver cirrhotic patients compared with healthy (P<0.0001) and nonliver-diseased controls (P<0.0001). Patients with liver cirrhosis and HCC show the highest CD105 concentrations being significantly elevated in comparison to liver cirrhosis (P=0.0006) and HCC only (P=0.0134). A stronger positive correlation exists between CD105 and AFP in the patient group suffering from liver cirrhosis and HCC (r=0.479, P=0.0015) than the obtained correlation between both markers in the group of patients diagnosed with liver cirrhosis alone (r=0.358, P=0.0073). The logistic regression model identified CD105 as an independent marker (P=0.0077, odds ratio 1.3). CONCLUSION: CD105 has the potential to be a novel complementary biomarker that has some important bearing on the risk assessment for development of HCC in cirrhotic patients.     

Successful surgical treatment for hepatocellular carcinoma and concomitant risky esophageal varices

BACKGROUND/AIMS: In our frequent encounters with liver cirrhotic patients with hepatocellular carcinoma (HCC) and concomitant risky esophageal varices, we have found that some of them required endoscopic injection sclerotherapy (EIS) and/or surgical treatment for esophageal variceal bleeding due to increased portal venous pressure after aggressive hepatectomy. In this study, we investigated the short-term effect of aggressive hepatectomy accompanied with left gastric venous caval shunt (Inokuchi's shunt) for esophageal varices and postoperative liver function. METHODOLOGY: Four cirrhotic patients with HCC and concomitant risky esophageal varices underwent hepatectomy with Inokuchi's shunt from 1999 to 2001. The mean age was 58.0 +/- 15.3 years old and all patients were classified in Child grade A or B. We investigated hematochemical data and endoscopic findings before and after surgery. RESULTS: One of the patients experienced disappearance of esophageal varices at discharge. In the others, postoperative endoscopy showed disappearance of CRS and reduced sizes of varices. In one patient, hepatic encephalopathy appeared transiently with bleeding from a duodenal ulcer at one month after surgery. However, the patient improved by conservative treatment. Three of the patients have survived well without recurrence of HCC and esophageal variceal bleeding; the remaining patient died from a recurrence of HCC. CONCLUSIONS: Inokuchi's shunt may be sufficiently effective to treat risky esophageal varices associated with resectable HCC and may be safe even if it is undertaken along with a major hepatectomy.     

Differential vascular endothelial growth factor A protein expression between small hepatocellular carcinoma and cirrhosis correlates with serum vascular endothelial growth factor A and α‐fetoprotein

Background/Aims: Drugs with antivascular endothelial growth factor A (anti‐VEGF‐A) action are under clinical evaluation with encouraging results in advanced hepatocellular carcinoma (HCC). The relative VEGF‐A protein expression in non‐advanced HCC and in the cirrhotic non‐tumoral tissue in the same patient, a variable that could be important for treatment efficacy, has been investigated with conflicting results, only using the cirrhotic tissue surrounding the neoplasm (CS). Methods: We measured, for the first time, VEGF‐A expression in non‐advanced HCC and in the respective CS and cirrhotic tissue at a distance from the tumour (CD), in 24 patients who underwent liver transplantation. Results: VEGF‐A protein was more expressed (P<0.05) in HCC than in CD, while no difference was found between HCC and CS. In HCC patients with a serum α‐fetoprotein (AFP) higher than 20 ng/ml, VEGF‐A protein expression in HCC was higher than in the corresponding CD in 83% of cases and AFP and serum VEGF‐A corrected for the platelet count positively correlated with the differential VEGF‐A protein expression between HCC and CD. Conclusion: Our data provide a rationale for clinical trials involving anti‐VEGF‐A treatments in patients with non‐advanced HCC, and suggest that serum AFP and VEGF‐A are variables to be taken into account in these studies.