Brazilian Landscape of Hepatocellular Carcinoma.

The incidence of hepatocellular carcinoma (HCC) is expected to increase in the coming years, and strategies to mitigate the burden of this disease are needed in different regions. Geographic variations in epidemiology and risk factors, such as viral hepatitis and metabolic disease, pose challenges in adopting programs for early detection programs and management of patients with HCC. Brazil, like other countries, has high economic and social inequality, with heterogeneous access to health care. Viral hepatitis is the main risk factor but there is growing awareness of fatty liver disease. Risk factor monitoring and screening programs are unmet priorities because patients are often diagnosed at later stages. Advances in the management of patients with HCC have been made in recent years, including new tools for selecting patients for liver transplantation, sophisticated surgical techniques, and new systemic agents. High-volume academic centers often achieve favorable results through the adoption and application of established treatments, but this is not a reality in most regions of Brazil, because of disparities in wealth and resources. As HCC management requires a coordinated and multidisciplinary team, the role of local referral centers in decentralizing access to treatments and promoting health education in different regions should be encouraged and supported.

Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Immunohistochemical Assessment of Markers of Cancer Cell Metabolism.

INTRODUCTION: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. METHODS: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. RESULTS: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m2; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. CONCLUSION: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.

Hepatocellular carcinoma in patients coinfected with hepatitis B or C and HIV: more aggressive tumor behavior?

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is the 6th cause of cancer and hepatitis C (HCV) and B (HBV) viruses are the most frequent risk factors for HCC. Patients coinfected with HCV or HBV and HIV present a faster progression to liver fibrosis and higher incidence of HCC. The aim of this study was to evaluate the survival and clinical outcomes of coinfected patients with HCC comparing with non-HIV patients. METHODS: We conducted a retrospective cohort study, including 267 HCC patients with HCV or HBV infection with or without HIV. The primary endpoint was overall survival. A Kaplan-Meier curve was presented to assess survival function. Clinical and radiologic variables, according to HIV status, were compared by logistic regression. RESULTS: Among 267 HCC patients, 25 (9.3%) were HIV-positive. In the coinfected group, patients were younger (49.8 vs 61.2 years, P < 0.001), cirrhosis was less predominant (88 vs 96.7%, P = 0.05), a smaller proportion received HCC treatment (60 vs 86.3%, P = 0.001) and the frequency of portal vein tumoral thrombosis was higher (32 vs 11.1%, P = 0.003). The overall mortality rate was higher in the HIV-positive group (92 vs 74.3%), independently of clinical and tumoral variables. CONCLUSION: Coinfected patients with HCC presented higher mortality, tumor diagnosis in a younger age, less underlying cirrhosis and a higher frequency of tumoral thrombosis. Further studies are warranted to better understand the role of HIV in hepatocarcinogenesis, in order to improve the management of those patients, particularly regarding screening programs.

Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort.

BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.

International and multicenter real-world study of sorafenib-treated patients with hepatocellular carcinoma under dialysis.

BACKGROUND & AIMS: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. METHODS: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. RESULTS: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. CONCLUSIONS: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.

Hepatocellular carcinoma in non-alcoholic fatty liver disease (NAFLD) - pathological evidence for a predominance of steatohepatitic inflammatory non-proliferative subtype.

OBJECTIVES: This study evaluated clinical and pathological aspects of patients with hepatocellular carcinoma (HCC) secondary to non-alcoholic fatty liver disease (NAFLD) and related these factors to immunohistochemical markers representative of the proliferative class. METHODS: We evaluated 35 HCC nodules from 21 patients diagnosed with NAFLD undergoing liver resection (n=12) or liver transplantation (n=8) or both (n=1). Demographic, clinical and biochemical data were compared to histological features and to immunohistochemical reactivity for K19 and Ki-67. RESULTS: Cirrhosis was present in 58% of patients. Ages ranged from 50 to 77 years. Sixteen patients (76%) were male and had type 2 diabetes mellitus, 81% had arterial hypertension, and 90% had BMI above 25 kg/m². Alpha-fetoprotein levels were normal in 62% of patients. Twenty-five (70%) nodules were diagnosed as "steatohepatitic HCC". Only 32% of the nodules presented high levels of Ki-67 (>10%) and/or K19 (>5%), although 63% were poorly differentiated (G.3/G.4) according to Edmondson & Steiner grading system. K19 positivity (>5%) was associated with higher degree of intratumoral inflammation (G.2/G.3), and with fibrosis, both at the center of the tumor and at the tumor front, whereas Ki-67 positivity (>10%) was associated with ballooning of neoplastic cells and occurred in more than 70% in non-cirrhotic patients. CONCLUSION: NAFLD-related HCC was found in non-cirrhotic patients in 42% of cases, alpha-fetoprotein level was normal in 63% and "steatohepatitic HCC" was the predominant histological type. Immunoexpression of K19 and/or Ki-67 occurred in 32% of the nodules and were associated with intratumoral inflammation and ballooning, suggesting that HCC in MtS may be preferentially "an inflammatory, non-proliferative subtype of HCC".

Hepatocellular carcinoma recurrence after liver transplantation in a Brazilian multicenter study: clinical profile and prognostic factors of survival.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with unresectable early hepatocellular carcinoma (HCC). Post-LT HCC recurrence rates range from 8 to 20% and still impact on overall survival (OS). The aim of our study was to evaluate the impact of HCC recurrence on post-LT survival and analyze prognostic factors among those patients with recurrence. PATIENTS AND METHODS: We carried out a national, multicenter, retrospective cohort study in Brazil. Medical records of 1119 LT recipients with HCC were collected. Data from patients with post-LT HCC recurrence were analyzed and correlated with post-relapse survival. RESULTS: OS of the 1119 patients included in the study was 63% over 5 years. Post-LT HCC recurrence occurred in 86 (8%) patients. The mean time to recurrence was 12 months. Sites of recurrence were extrahepatic in 55%, hepatic in 27%, and both hepatic and extrahepatic in 18%. Recurrence treatment was performed in 50 (64%) cases, mostly with sorafenib. Post-relapse survival rates were 34% at 1 year and 13% at 5 years. Univariable analysis identified α-fetoprotein more than 1000 ng/ml at relapse, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years as prognostic factors. In multivariable analysis, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years were independent predictors of better survival. CONCLUSION: In a large Brazilian cohort of LT recipients with HCC, post-LT HCC recurrence occurred in 8% and impacted significantly on the OS. Patients with early recurrence presented a worse prognosis. However, treatment of recurrence improved outcomes, highlighting the importance of early diagnosis.

The Impact of Early Dermatologic Events in the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib

ABSTRACT Background and Aims. The presence of dermatologic reaction as an adverse event to sorafenib treatment in patients with unresectable hepatocellular carcinoma has been indicated as a prognostic factor for survival in a recent prospective analysis. To date, this is the only clinical predictor of treatment response, which can be evaluated earlier in the treatment and, therefore, contribute to a better and more individualized patient management. Material and methods. This retrospective study included 127 patients treated with sorafenib under real-life practice conditions in two hepatology reference centers in Brazil. Demographic data, disease/medical history and time of sorafenib administration as well as adverse events related to the medication were recorded in a database. Results. Cirrhosis was present in 94% of patients, 85.6% were Child-Pugh A, 80.3%BCLC-C, 81% had vascular invasion and/or extrahepatic spread and 95% had a performance status 0 to 1.The median duration of treatment was 10.1 months (range: 0.1-47 months).The most common adverse event within the first 60 days of treatment were diarrhea (62.2%) and dermatological reaction (42%).The median overall survival for the cohort was 20 months, and it was higher for patients who developed dermatological reactions within the first 60 days compared to those who did not present this adverse event. Conclusion. This retrospective analysis showed the use of sorafenib in patients selected according to BCLC staging, and it is the first external validation of early dermatologic adverse events as a predictor of overall survival in patients with advanced hepatocellular carcinoma.

The Impact of Early Dermatologic Events in the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND AND AIMS: The presence of dermatologic reaction as an adverse event to sorafenib treatment in patients with unresectable hepatocellular carcinoma has been indicated as a prognostic factor for survival in a recent prospective analysis. To date, this is the only clinical predictor of treatment response, which can be evaluated earlier in the treatment and, therefore, contribute to a better and more individualized patient management. MATERIAL AND METHODS: This retrospective study included 127 patients treated with sorafenib under real-life practice conditions in two hepatology reference centers in Brazil. Demographic data, disease/medical history and time of sorafenib administration as well as adverse events related to the medication were recorded in a database. RESULTS: Cirrhosis was present in 94% of patients, 85.6% were Child-Pugh A, 80.3%BCLC-C, 81% had vascular invasion and/or extrahepatic spread and 95% had a performance status 0 to 1.The median duration of treatment was 10.1 months (range: 0.1-47 months).The most common adverse event within the first 60 days of treatment were diarrhea (62.2%) and dermatological reaction (42%).The median overall survival for the cohort was 20 months, and it was higher for patients who developed dermatological reactions within the first 60 days compared to those who did not present this adverse event. CONCLUSION: This retrospective analysis showed the use of sorafenib in patients selected according to BCLC staging, and it is the first external validation of early dermatologic adverse events as a predictor of overall survival in patients with advanced hepatocellular carcinoma.

Hepatocellular Carcinoma Management in Nonalcoholic Fatty Liver Disease Patients: Applicability of the BCLC Staging System.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) has emerged as an important cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) system is the preferred staging system to evaluate patients with HCC and links prognosis assessment with treatment recommendation. The aim of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD. METHODS: Forty-two patients with HCC related to either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil. Patients were classified according to BCLC staging system. If the proposed HCC therapy could not be applied, the case was considered to represent deviations from the recommended BCLC guideline. Causes of treatment deviations were investigated. RESULTS: There were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the very early (0), early (A), intermediate (B), advanced (C), and terminal (D) BCLC stages, respectively. Thirty-five patients (83%) were treated according to BCLC recommendations. There were 3 cases (of 5) of protocol deviation in BCLC C patients. The 1- and 2-year overall survival rates were 81% and 66%, respectively. CONCLUSIONS: The BCLC system is applied in most cases of NAFLD-related HCC cases. Deviation of BCLC is found more frequently in BCLC C stage patients.

Percutaneous radiofrequency ablation for early hepatocellular carcinoma: risk factors for survival.

AIM: To evaluate outcomes of radiofrequency ablation (RFA) therapy for early hepatocellular carcinoma (HCC) and identify survival- and recurrence-related factors. METHODS: Consecutive patients diagnosed with early HCC by computed tomography (CT) or magnetic resonance imaging (MRI) (single nodule of ≤ 5 cm, or multi- (up to 3) nodules of ≤ 3 cm each) and who underwent RFA treatment with curative intent between January 2010 and August 2011 at the Instituto do Câncer do Estado de São Paulo, Brazil were enrolled in the study. RFA of the liver tumors (with 1.0 cm ablative margin) was carried out under CT-fluoro scan and ultrasonic image guidance of the percutaneous ablation probes. Procedure-related complications were recorded. At 1-mo post-RFA and 3-mo intervals thereafter, CT and MRI were performed to assess outcomes of complete response (absence of enhancing tissue at the tumor site) or incomplete response (enhancing tissue remaining at the tumor site). Overall survival and disease-free survival rates were estimated by the Kaplan-Meier method and compared by the log rank test or simple Cox regression. The effect of risk factors on survival was assessed by the Cox proportional hazard model. RESULTS: A total of 38 RFA sessions were performed during the study period on 34 patients (age in years: mean, 63 and range, 49-84). The mean follow-up time was 22 mo (range, 1-33). The study population showed predominance of male sex (76%), less severe liver disease (Child-Pugh A, n = 26; Child-Pugh B, n = 8), and single tumor (65%). The maximum tumor diameters ranged from 10 to 50 mm (median, 26 mm). The initial (immediately post-procedure) rate of RFA-induced complete tumor necrosis was 90%. The probability of achieving complete response was significantly greater in patients with a single nodule (vs patients with multi-nodules, P = 0.04). Two patients experienced major complications, including acute pulmonary edema (resolved with intervention) and intestinal perforation (led to death). The 1- and 2-year overall survival rates were 82% and 71%, respectively. Sex, tumor size, initial response, and recurrence status influenced survival, but did not reach the threshold of statistical significance. Child-Pugh class and the model for end-stage liver disease score were identified as predictors of survival by simple Cox regression, but only Child-Pugh class showed a statistically significant association to survival in multiple Cox regression analysis (HR = 15; 95%CI: 3-76 mo; P = 0.001). The 1- and 2-year cumulative disease-free survival rates were 65% and 36%, respectively. CONCLUSION: RFA is an effective therapy for local tumor control of early HCC, and patients with preserved liver function are the best candidates.

Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil.

The global hepatocellular carcinoma (HCC) incidence is widely variable, depending on geographic region and the prevalence of major risk factors. In Brazil, two large multicentre retrospective studies were performed to investigate clinical and epidemiological aspects of HCC. In the first study, performed in 1997, HCC was found in cirrhotic livers in 71% of cases. Chronic alcoholism was present in 36% of cases, chronic hepatitis B in 35% and hepatitis C in 25%. In a 2010 survey, cirrhosis was present in 98% of cases and HCV was the main aetiology (54%). Differences in HBV prevalence were found among regions. Selection of HCC treatment depends on tumour burden, liver function and performance status. Liver transplantation (LT) is the best available curative treatment for HCC in its early stage and with compromised liver function. After modifications in priority policy, the number of patients with early HCC submitted for LT has increased in the past 5 years in Brazil. Chemoembolization is the most common initial HCC therapy in early and intermediate stages of HCC in Brazil.

Nodules less than 20 mm and vascular invasion are predictors of survival in small hepatocellular carcinoma.

BACKGROUND: The aims of this study were to analyze the overall survival of patients with cirrhosis and small hepatocellular carcinoma (HCC) and identify independent pretreatment predictors of survival in Brazil. METHODS: Between 1998 and 2003, 74 patients with cirrhosis and small HCC were evaluated. Predictors of survival were identified using the Kaplan-Meier survival curves and the Cox model. RESULTS: The overall survival rates were 80%, 41%, and 17% at 12, 36, and 60 months, respectively. The mean length of follow-up after HCC diagnosis was 23 months (median 22 mo, range: 1 to 86 mo) for the entire group. Univariate analysis showed that model for endstage liver disease (MELD) score (P=0.016), Child-Pugh classification (P=0.007), alpha-fetoprotein level (P=0.006), number of nodules (P=0.041), tumor diameter (P=0.009), and vascular invasion (P<0.0001) were significant predictors of survival. Cox regression analysis identified vascular invasion (relative risk=14.60, confidence interval 95%=3.3-64.56, P<0.001) and tumor size >20 mm (relative risk=2.14, confidence interval 95%=1.07-4.2, P=0.030) as independent predictors of decreased survival. Treatment of HCC was related to increased overall survival. CONCLUSIONS: Identification of HCC smaller than 20 mm is associated with longer survival. Presence of vascular invasion, even in small tumors, maybe associated with poor prognosis. Treatment of small tumors of up to 20 mm diameter is related to increased survival.