Aims
The scirrhous variant of hepatocellular carcinoma (S‐HCC) and fibrolamellar HCC (FL‐HCC) are less common subtypes of HCC that are characterized by abundant fibrous stroma. Here, we aimed to ...investigate differences in the tumour microenvironment and the tumour epithelial cell characteristics of S‐HCC and FL‐HCC.
Methods and results
Whole tissue sections of 17 S‐HCCs and 9 FL‐HCCs were subjected to immunohistochemical stains for keratin 7 (K7), K19, EpCAM, CD56/NCAM, CD163, CD68, pSTAT3, FAP, CCN2 and Ki‐67. FL‐HCC patients were younger than S‐HCC patients (P < 0.001), and chronic liver disease was seen in the background of 88.2% of S‐HCC and in none of the FL‐HCC. CD68 and CD163‐positive tumour‐infiltrating macrophages, and FAP‐positive cancer‐associated fibroblasts (CAFs) were more abundant in the stroma of S‐HCCs compared to FL‐HCCs (all P < 0.05). Tumour epithelial K19 expression was more frequent in S‐HCCs compared to FL‐HCCs (P = 0.023). Significant positive correlations were seen between pSTAT3 expression status in tumour epithelial cells and CAFs, the extent of stromal CAF and macrophage infiltration and K19 expression status. No significant differences were seen for K7, EpCAM, CD56/NCAM, CCN2 expression and Ki‐67 labelling index between S‐HCCs and FL‐HCCs.
Conclusion
S‐HCC and FL‐HCC are subtypes of HCC with extensive fibrosis, and the nature of the fibrous stroma differs between them. While the stroma of FL‐HCC is composed of dense lamellated collagenous bands with sparse cellular components, S‐HCC demonstrates more abundant CAF and tumour‐infiltrating macrophages and stemness‐related marker expression, suggesting the presence of a complex tumour microenvironment that may influence the aggressive behaviour of S‐HCCs.
Abstract Objective We correlated dietary profile and markers of visceral and somatic obesities in non-alcoholic fatty liver disease. Methods Patients with histologically proven fatty infiltration of ...the liver ( n = 25, 52 ± 11 y of age, 64% women) underwent abdominal computed tomography, bioelectrical impedance, and anthropometric measurements. Insulin resistance was evaluated (homeostasis model assessment) and dietary intake of macronutrients was estimated by 24-h recall. Main outcome measurements were correlation of carbohydrate and fat ingestion with liver histology. Results Metabolic syndrome was present in 72% of the population, and increased waist circumference and low high-density lipoprotein cholesterol occurred in 66%. Total body fat (bioimpedance) and dietary intake of lipids were higher in patients with non-alcoholic steatohepatitis ( P < 0.05), but not in diabetic subjects who exhibited more steatosis than non-alcoholic steatohepatitis. Waist circumference exhibited a good correlation with homeostasis model assessment, total energy intake, and ingestion of specific fatty acids. Body mass index correlated well with somatic and visceral adiposities. Conclusion Energy intake and visceral adiposity were predisposing factors for fatty liver disease. Lipid input correlated with non-alcoholic steatohepatitis in the entire group and after stratification for diabetes. These findings suggest that lipid intake may play a greater role in non-alcoholic steatohepatitis than hitherto suspected.
Background/Aims Hepatocellular carcinoma (HCC) is a well recognized complication of advanced NASH (non-alcoholic steatohepatitis). We sought to produce a rat model of NASH, cirrhosis and HCC. Methods ...Adult Sprague–Dawley rats, weighing 250–300 g, were fed a choline-deficient, high trans-fat diet and exposed to DEN in drinking water. After 16 weeks, the animals underwent liver ultrasound (US), sacrifice and assessment by microscopy, immunohistochemistry and transmission electron microscopy (TEM). Results US revealed steatosis and focal lesions in 6 of 7. All had steatohepatitis defined as inflammation, advanced fibrosis and ballooning with Mallory–Denk bodies (MDB) with frank cirrhosis in 6. Areas of more severe injury were associated with anti-CK19 positive ductular reaction. HCC, present in all, were macro-trabecullar or solid with polyhedral cells with foci of steatosis and ballooned cells. CK19 was positive in single or solid nests of oval cells and in neoplastic hepatocytes. TEM showed ballooning with small droplet fat, dilated endoplasmic reticulum and MDB in non-neoplastic hepatocytes and small droplet steatosis in some cancer cells. Conclusions This model replicated many features of NASH including steatohepatitis with ballooning, fibrosis, cirrhosis and hepatocellular carcinoma. Oval cell proliferation was evident and the presence anti-CK 19 positivity in the cancer suggests oval cell origin of the malignancy.
AbstractBackground and aim. The lack of information about hepatocellular carcinoma (HCC) in Brazil weakens health policy in preventing deaths from the illness. The aim of this study was to establish ...the cumulative incidence and the risk factors for hepatocellular carcinoma development in patients under a surveillance program. Material and methods. 884 patients with compensated cirrhosis were prospectively followed up for at least five years, from August 1998 until August 2008, with at least one annual ultrasonography liver examination and serum alpha fetoprotein (AFP) measurement. Results. Among 884 patients, 72 (8.1%) developed a tumor with a median follow up of 21.4 months. In the hepatocellular carcinoma group, hepatitis C virus infection was the major etiological factor (65.3%), 56.9% (41/72) were male and the mean average age was 57 ± 10 years. The annual incidence of hepatocellular carcinoma was 2.9%. 79.2% (57/72) of HCCs were detected within Milan Criteria, and the mean survival time was 52.3 months, significantly higher than for those outside Milan, with a mean time of 40.6 months (p = 0.0003). Conclusion. The annual incidence of HCC among this large series of Brazilian cirrhotic patients was around 2.9% with a detection rate of 8.1%, or a cumulative incidence rate over five years of 14.3%. The three variables related to HCC risk were low serum albumin HR: 0.518 (0.46-0.78), high AFP > 20 ng/mL HR: 3.16 (1.86-5.38), and ethnicity (Brazilian-East Asian descendants vs. other mixed Brazilian ethnicities) HR: 2.86 (1.48-5.53).
Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma ...continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone.
Aims
The clinical spectrum of yellow fever (YF) ranges from asymptomatic to fulminant hepatitis. During the sylvatic YF epidemic in the metropolitan area of São Paulo, Brazil in 2018, seven ...orthotopic liver transplantations (OLTs) were performed in our institution to treat fulminant YF hepatitis. Three patients recovered, while four patients died following OLT. The autopsy findings of all these cases are presented herein as the first description of YF in transplanted patients.
Methods and results
All patients were men, aged 16–40 years, without vaccination to YF virus (YFV). All organs were examined, with tissue sampling for histopathological analysis. Detection of YF virus antigens (YFV Ag) was performed with two primary antibodies (mouse polyclonal anti‐YFV antibody directed to wild strain and a goat anti‐YF virus antibody), and RT–PCR assays were utilised to detect YFV‐RNA. All the cases depicted typical findings of YF hepatitis in the engrafted liver. The main extrahepatic findings were cerebral oedema, pulmonary haemorrhage, pneumonia, acute tubular necrosis and ischaemic/reperfusion pancreatitis. Of the four cases, the YVF Ag was detected in the heart in one case, liver and testis in three cases, and the kidney and spleen in all four cases. All four cases had YF virus RNA detected by RT–PCR in the liver and in other organs.
Conclusions
Infection of the engrafted liver and other organs by YFV, possibly combined with major ischaemic systemic lesions, may have led to the death of four of the seven patients undergoing OLT.
Background and objective:
The ideal margin width for surgical resection of colorectal liver metastases has been extensively studied, but not sufficiently in accordance with other pathological ...factors. The aim of this study was to assess for the first time the prognostic impact of margin widths according to different prognostic pathological factors in colorectal liver metastasis.
Methods:
We evaluated 101 patients with a single resected metastasis. Slides stained by HE were assessed for the presence of poorly differentiated clusters, peritumoral inflammatory infiltrate, tumor pseudocapsule, and tumor borders pattern. Overall survival, disease-free survival, and hepatic recurrence were evaluated. The pathologic factors prognostic impact was evaluated according to a (< or ⩾) 10-mm margin size.
Results:
Factors independently associated with a shorter overall survival were absence of tumor pseudocapsule (p < 0.001) and infiltrative tumor border pattern (p = 0.019). The absence of tumor pseudocapsule was the only factor independently associated with shorter disease-free survival (p < 0.001). Hepatic recurrence was associated with infiltrative tumor border and absence of pseudocapsule. Margin width ⩾10 mm did not impact overall survival independently of the studied histological prognostic factors.
Conclusions:
In colorectal liver metastasis resection, the absence of tumor pseudocapsule was significantly associated with shorter overall survival and disease-free survival and hepatic recurrence. However, margins larger than 10 mm did not offer survival benefit when other pathologic negative prognostic factors were concomitantly analyzed, reinforcing the idea that biology, rather than margin size, is crucial for prognosis.
Hepatitis C virus (HCV) infection affects approximately 3 % of the world population. HCV targets hepatic tissue, and most infected patients develop a chronic infection. Currently, studies have ...demonstrated an association between HCV-RNA replication and miR-122, the most abundant microRNA in the liver. Our aim was to evaluate liver and serum expression of miR-122 in patients infected with HCV genotypes 1 and 3, and to identify possible associations between miR-122 expression and lipid profiles, HCV viral load, apolipoproteins and liver enzymes. MicroRNAs were isolated from blood and liver tissue, and miR-122 expression was quantified by real-time PCR. HCV viral load was quantified by real-time PCR and HCV genotype, and serum biomarkers were obtained from medical report. The levels of miR-122 were higher in liver than those in blood from individuals infected with HCV genotypes 1 and 3 (
p
< 0.0001). The tissue levels of miR-122 were higher in subjects infected with HCV genotype 3 (6.22-fold,
p
< 0.001). A positive correlation was observed between the blood and hepatic levels of miR-122 in patients infected with HCV genotype 1 (
r
= 0.302,
p
= 0.026); in these patients, an inverse correlation was observed between serum apolipoprotein A-II (ApoA-II) levels and the blood (
r
= −0.330;
p
= 0.014) and hepatic (
r
= −0.311;
p
= 0.020) levels of miR-122. In patients infected with HCV genotype 3, there was a positive correlation between the hepatic miR-122 and the high-density lipoprotein—HDL (
r
= 0.412,
p
= 0.036) and insulin (
r
= 0.478,
p
= 0.044). Lipid metabolism proteins and miR-122 expression levels have different relations in HCV-3- and HCV-1-infected patients.
Summary
Objective
LIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic ...role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs).
Patients and methods
LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let‐7 family, mir‐9, mir‐30 and mir‐125 in 28 carcinomas.
Results
LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease‐free survival in ACC patients (P = 0·01), but for overall survival only a trend was detectable (P = 0·117). In the multivariate analysis, only Ki67 index ≥10% (HR 4·6, P = 0·000) and weak LIN28 protein expression (HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir‐9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs 2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011 and was highly associated with reduced overall (P = 0·01) and disease‐free survival (P = 0·01). However, mir‐9 prognostic role should be further evaluated in a larger cohort.
Conclusion
Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir‐9, a negative LIN28A regulator, was associated with poor outcome.
Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the ...clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival.
We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed.
The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had “pure fibrolamellar hepatocellular carcinoma,” whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having “mixed fibrolamellar hepatocellular carcinoma.” The median overall survival was 36 months. The presence of “mixed fibrolamellar hepatocellular carcinoma” and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery.
Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival.
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