What Is Metastatic Hepatocellular Carcinoma

What Are The Risk Factors For Liver Cancer Is Liver Cancer Hereditary

Incidence rates of hepatocellular cancer are rising in the United States due to increasing prevalence of cirrhosis caused by chronic hepatitis C and steatohepatitis .

Cirrhosis of the liver due to any cause is a risk factor for liver cancer. The risk factors for liver cancer in cirrhosis are being male, age 55 years or older, Asian or Hispanic ethnicity, family history in a first-degree relative, obesity, hepatitis B and C, alcohol use, and elevated iron content in the blood due to hemochromatosis.

Chronic hepatitis B infection even without cirrhosis is a risk factor for liver cancer.

Isolated Metastases Of Hepatocellular Carcinoma In The Right Atrium: Case Report And Review Of The Literature

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Abstract

Introduction

Hepatocellular carcinomas frequently invadethe vascular system at points such as the portal and hepatic veins.The results of autopsy studies indicate a 2.74.1% incidence ofatrial metastases of HCC . Acorrect diagnosis is important in the clinical setting sincecardiac metastases are able to induce sudden cardiac arrest. Themajority of metastases develop as continuous extensions of a tumorthrombus in the hepatic vein. However, isolated cardiac metastasesare extremely rare. The present study describes a 66-year-oldfemale with an isolated right atrial metastasis of a HCC andreviews previous published studies, treatments and outcomes insimilar patients. Written informed consent was obtained from thepatients family.

Case report

Abdominal sonography and computed tomography imaging revealed a large mass reaching from the right to the leftlobe and a tumor thrombus in the main portal vein . Angiography revealed ahypervascular tumor in the right lobe exhibiting the thread andstreak sign. No metastases were identified in the right atrium or inferior vena cava prior to starting intraarterialchemotherapy with cisplatin, 5-fluouracil, adriamycin andmitomycin.

Discussion

What Is The Prognosis For Hepatocellular Carcinoma

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Overall prognosis for survival is poor, with a 5-year relative survival rate of 18.4%. By stage, the relative 5-year survival is 32.6% in patients diagnosed with localized disease, 10.8% with regional disease, and 2.4% with distant disease. Length of survival depends largely on the extent of cirrhosis in the liver cirrhotic patients have shorter survival times and more limited therapeutic options. Portal vein occlusion, which occurs commonly, portends an even shorter survival. As many patients die of liver failure as from tumor progression.

The influence of diabetes, obesity, and glycemic control continues to be evaluated in studies of the etiology and outcomes of HCC. For example, in a study of patients who had undergone curative resection for solitary HCV-related HCC, the tumor-free survival rate at 3 years was more than twice as high in patients in patients who had a normal hemoglobin A1c than in those whose hemoglobin A1c was 6.5% or higher .

References

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A Rare Case Of Metastatic Hepatocellular Carcinoma Masquerading As A Forehead Hematoma

Kimberly Sanders

1Department of Internal Medicine, University of Florida College of Medicine Jacksonville, Jacksonville, FL, USA

2Department of Pathology, University of Florida College of Medicine Jacksonville, Jacksonville, FL, USA

Academic Editor:

Abstract

Hepatocellular carcinoma is the most common primary liver cancer and can arise from any form of chronic liver disease or cirrhosis. With increasing rates of metabolic syndrome and obesity, it is not surprising that NASH is quickly becoming a leading cause of chronic liver disease and HCC in the western hemisphere . Metastasis is usually found in advanced stages of the disease, owing to its poor prognosis. The lung, bone, and lymph nodes are the most frequent sites of metastasis . On the other hand, metastasis to the skin and cranium is relatively rare. Literature review reveals less than 10 reported cases in the last 10 years. Herein, we report an unusual case of a forehead hematoma leading to the formal diagnosis of metastatic HCC.

1. Introduction

2. Case Presentation

××

Exosomal S100a4 Is A Key Enhancer Of Metastatic Potential In Hcc Cells

In order to identify the element via which HMH-exosomes work to enhance the metastatic potential of low metastatic HCC cells, we adopted iTRAQ mass spectrum screening for HMH-exosomes and LMH-exosomes. Results showed that 116 proteins were significantly up-regulated in HMH-exosomes group while 43 down-regulated . Proteins were clustered at the 2-fold changes with a p value less than 0.05. The volcano plots revealed that 4 protein families, Apo, PSM, EEF/EIF, and S100 calcium binding protein family, were clustered. After reviewing literatures, we focused on four members of S100 calcium binding protein family with the most differentiated expression, S100A4 , followed sequentially by S100A11 , S100A10 , and S100A6 . Furthermore, we conducted comparison of the expression abundance of S100A4, S100A6, S100A10, and S100A11 in 5 HCC cells lines, as well as the abundance of S100A4 in exosomes derived from these cell lines. Results were consistent with the iTRAQ data . Immunohistochemistry staining of S100A4 in nude mice tumor models also confirmed that S100A4 was significantly more highly expressed in MHCC97-H derived tumors . Therefore, we hypothesized that S100A4 may be one of the most potentially functional factors in HMH-exosomes and we selected it for further analyses.

Fig. 3

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What Is The Follow

Patients are advised to follow up with the doctor for lab tests and office visits. Patients with chronic liver disease should avoid alcohol and any drugs that can harm the liver. Patients with liver transplants will need to take anti-rejection drugs for the rest of their life to prevent their body from rejecting the new liver.

Systemic Chemotherapy For Hcc Has Been Disappointing In The Past But In The Future Can Be Promising

Neither complete response nor partial response was observed using paclitaxel for unresectable HCC. However, a phase II study with cisplatin, doxorubicin, 5-fluorouracil, and IFN-alpha in advanced unresectable HCC demonstrated that complete pathological remission was possible, partial response rate was 26%, no viable tumor cells were found in four out of nine resected specimens. Based on the study of the expression of drug resistance-related genes in three human hepatoma cell lines, it was demonstrated that IFN-alpha modulated the mechanism of resistance to cisplatin in liver cancer. Individual patient with complete remission of multiple HCC associated with HCV-related decompensated liver cirrhosis by oral administration of enteric-coated tegafur/uracil has been reported.

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Systemic Therapies For Hcc

• A commonly used type of advanced liver cancer treatment
• Some work to cut off blood and nutrients from reaching the tumor
• Some use other targets to help keep the cancer from growing and spreading
• May also affect healthy cells

• Helps the immune system see cancer cells
• Designed to help find and fight the cancer
• May also affect healthy cells

Discover the benefits of TECENTRIQ

Important Safety Information and Indication

Indication

TECENTRIQ is a prescription medicine used to treat adults with:

A type of liver cancer called hepatocellular carcinoma . TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:

• has spread or cannot be removed by surgery, and
• you have not received other medicines by mouth or injection through your vein to treat your cancer.

It is not known if TECENTRIQ is safe and effective in children.

What is the most important information about TECENTRIQ?TECENTRIQ can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended.

Lung problems

• swollen lymph nodes

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

• chills or shaking
• fever
• back or neck pain

Regional Cancer Therapy For Hcc Is One Of The Nonsurgical Therapies That Develops Recently

Based on the advances of early detection and medical imaging, more HCCs can be diagnosed with small and localized lesions. As a result, regional cancer therapies have developed in the recent decades. Unfortunately, the number of RCTs was insufficient to make any conclusion as yet.

Percutaneous ethanol injection is a treatment choice of unresectable small HCC. The 4-year survival rate was 39% in 47 small HCC patients with cirrhosis, however, the 4-year recurrence rate was as high as 79%. Local recurrence depends predominantly on the biologic characteristics of the tumor , regardless of the efficacy of PEI. For large HCC, PEI performed in a single session under general anesthesia was an alternative. In a series of 108 patients, the 4-year survival rates were 44% for single encapsulated HCC , 18% for single infiltrating HCC or multiple HCC and 0% for advanced disease, the mortality was 0.7% and major complications 4.6%. A RCT study comparing 50% acetic acid and PEI indicated that local recurrence rate was lower and 2-year survival rates higher with acetic acid.

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X Protein Of Hbv Is One Of The Target Of How Hbv Induces Hcc

The incidence of HCC was as high as 86% in a HBV-X transgenic mice. It was also found that the structure of the X gene is modified in the majority of tumorous livers, suggesting a potential role of mutated X proteins in HBV-related liver oncogenesis. Moreover, HBV-X might play a role in hepatic inflammation by up-regulating interleukin-6 production, which can eventually lead to HCC. Transactivation of transforming growth factor alpha gene by HBV preS1 was observed which provides a clue for understanding viral hepatocarcinogenesis. Synergy between TGF-alpha and HBsAg in hepatocellular proliferation and carcinogenesis was also reported.

All of these indicate a multifactorial and multistep development of HCC. Interaction among HBV/HCV, aflatoxin, alcohol, and genetic susceptibility might be important.

The Molecular Basis Of Hcc Invasiveness Is Similar To That Of Other Solid Cancers Its Complexity Represents As Multi

Numerous papers have been published concerning the molecular basis of HCC invasiveness in the literature. At the authors institution, studies concerning HCC invasiveness could be summarized into the followings: a Factors that positively related to invasiveness included: p16 and p53 mutation, H-ras, c-erbB-2, mdm2, TGF, epidermal growth factor receptor , matrix metalloproteinase-2 , urokinase-type plasminogen activator , its receptor and inhibitor , intercellular adhesion molecule-1 , vascular endothelial growth factor , platelet-derived endothelial cell growth factor , basic fibroblast growth factor , etc. On the other hand, factors that negatively related to HCC invasiveness included: nm23-H1, Kai-1, tissue inhibitor of metalloproteinase-2 , integrin 5, E-cadherin, etc. b The biological characteristics of small HCC was slightly better than that of large HCC c The following blood test have been tried with potential clinical implication: thrombomodulin, ICAM-1, PAI-1, VEGF, bFGF, etc. Serum ICAM-1 content was higher in patients with metastasis than those without metastasis. Loss of heterozygosity at D14S62 and D14S51 in plasma DNA were also related to metastatic recurrence. The combination of several items that mentioned above increased sensitivity.

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Isolation And Identification Of Exosomes Released And Up

Exosomes were extracted from supernatant of HCC cells by ExoQuick reagent kit. Then morphological observation was performed by transmission electron microscope and shapes of exosomes were observed . Furthermore, we utilized nanoparticle tracking analysis to determine exosomes diameters, which were mostly ranged between 40 and 200ânm . Relatively specific exosomal markers, CD63, CD9, and Alix, were detected by Western blot in six HCC cell lines . In order to verify the reliability of extracted exosomes, we adopted methylated-β-Cyclodextrin treatment, which can destruct exosomal lipid membrane. After MβCD treatment, exosomal markers were much less detected by Western blot, which further verified the reliability and purity of exosomes extracted by ExoQuick reagent kit . Next, we used DIO green to separately dye exosomes released by highly metastatic HCC cells and low metastatic HCC cells . We also observed with laser scanning confocal microscope that both green coated HMH-exosomes and LMH-exosomes could be up taken efficiently by lowly metastatic HCC cells, MHCC97-L, and HepG2 . These indicate that we have successfully isolated and purified exosomes form HCC cells, and demonstrated that they can be up-taken by the other HCC cells.

Fig. 1

Hepatocellular Carcinoma Or Hepatoma

A primary cancer that begins in the hepatocytes, the cells that make up the main functional part of the liver. Approximately three out of four primary liver cancers are hepatocellular carcinoma , sometimes referred to as hepatoma. Some hepatocellular carcinomas begin as a single tumor that grows and later spreads to other parts of the liver. In other cases, hepatomas begin as many small tumors scattered throughout the organ. This cancer may spread elsewhere in the body.

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Exosomal S100a4 Activates Opn Transcription Via Stat3 Phosphorylation

Next, we attempted to elucidate the mechanism of exosomal S100A4 on metastatic potential and stemness. First, we selected 21 cancer stemness-related genes, OPN, OCT4, NANOG, SOX2, HIF1α, BMI1, ABCG2, CK19, NOTCH1, KLF4, CD44, CD90, CD133, CD117, CD24, EPCAM, TCF3, TCL, CTNNB1, HEY1, and C-MYC. Then we downloaded a GEO datasheet of HCC samples for correlation analyzes. Among those 21 stemness-related genes, S100A4 was positively correlated with OPN, HIF1α, BMI1, CK19, NOTCH1, KLF4, CD44, CD90, TCL, HEY1, and C-MYC . We further determined the expression levels of these 11 genes in Huh7, PLC, and HepG2 cells with S100A4 overexpression , as well as HCC-LM3 and MHCC97-H cells with S100A4 knockdown . We found that only the expressions of OPN and its downstream genes, HIF1α and BMI1, were correspondent with S100A4 expressions in all these four cell lines. OPN is a key promoter of HCC metastasis and stemness, but the mechanism of how exosomal S100A4 regulates OPN in HCC is unclear.

Fig. 4Fig. 5Fig. 6

Angiogenesis Is Closely Related To Hcc Invasiveness

Vascular endothelial growth factor gene and protein expression are involved in the progression of HCC, and that VEGF 121 and 165 isoforms play a critical role in angiogenesis of HCC. However, some author reported that VEGF might be associated with the angiogenic process of the cirrhotic liver, but not with the angiogenesis of HCC. VEGF level increased after TACE, indicating that VEGF may be a marker for tumor ischemia. Angiogenesis in HCC depends on the net balance between human macrophage metalloelastase and VEGF gene expressions. Platelet-derived endothelial cell growth factor , another angiogenic factor, is also involved in HCC progression. The enhanced gene expression of angiopoietin-2 may also contribute to the hypervascular phenotype. Angiogenesis in HCC can be evaluated by CD34 immunohistochemistry. At authors institution, using CD34 staining to measure microvessel density , we found that MVD was only useful for small HCC resection, the 5-year survival after resection of hypovascular type small HCC was double to that of hypervascular type, being 74.6% versus 34.7%. As small HCCs increase in size and become increasingly dedifferentiated, the number of portal tracts apparently decreases and intratumoral arterioles develop. These findings may reflect changes in the hemodynamics as the HCC develops.

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Viral Hepatitis B And/or C Aflatoxin And Alcohol Are Major Risk Factors Of Hcc

However, the importance of these different factors varies in different geographic areas. HBV is more predominant in Chinese, Southeast Asian and African patients with HCC, whereas HCV is common in HCC patients in developed countries . The prevalence of hepatitis B surface antigen and antibody to HCV in HCC patients were reported to be 63.2% and 11.2% respectively in China, which was similar to that reported in the past.Prospective studies showed that there is an additive effect of HCV and HBV infection on HCC development. Cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. An association was found between high serum alanine aminotransferase levels and more rapid development and high incidence rate of HCC in patients with HCV-associated cirrhosis. In a transgenic mice, it was found that the core protein of HCV induces HCC.

Barcelona Clinic Liver Cancer Staging System

Currently, the BCLC staging classification is the most accepted staging system for HCC and is useful in the staging of early tumors. Evidence from an American cohort has shown that BCLC staging offers better prognostic stratification power than other staging systems.

The BCLC staging system attempts to overcome the limitations of previous staging systems by including variables related to the following:

• Tumor stage.
• Functional status of the liver.
• Physical status.
• Cancer-related symptoms.

Five stages are identified based on the variables mentioned above. The BCLC staging system links each HCC stage to appropriate treatment modalities as follows:

• Patients with early-stage HCC may benefit from curative therapies .
• Patients with intermediate-stage or advanced-stage disease may benefit from palliative treatments .
• Patients with end-stage disease who have a very poor life expectancy are offered supportive care and palliation.

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Other Risk Factors Have Also Been Reported

In Japan, alcohol consumption and cigarette smoking were also risk factors of HCC, and synergism between them was observed. In Italy, for attributable risk of HCC, heavy alcohol intake ranked first , HCV second and HBV third . The risk of dietary iron overload was 4.1 for HCC in black Africans, which is similar to that of haemochromatosis in Caucasians. A role of family history independent from and interacting with known risk factors for HCC was also reported, the odds ratio was reported to be 2.4.

North America And Western Europe

The most common malignant tumors in the liver represent metastases from tumors which originate elsewhere in the body. Among cancers that originate from liver tissue, HCC is the most common primary liver cancer. In the United States, the US surveillance, epidemiology, and end results database program, shows that HCC accounts for 65% of all cases of liver cancers. As screening programs are in place for high-risk persons with chronic liver disease, HCC is often discovered much earlier in Western countries than in developing regions such as sub-Saharan Africa.

Acute and chronic hepatic porphyrias and tyrosinemia type I are risk factors for hepatocellular carcinoma. The diagnosis of an acute hepatic porphyria should be sought in patients with HCC without typical risk factors of hepatitis B or C, alcoholic liver cirrhosis, or hemochromatosis. Both active and latent genetic carriers of acute hepatic porphyriasare at risk for this cancer, although latent genetic carriers have developed the cancer at a later age than those with classic symptoms. Patients with acute hepatic porphyrias should be monitored for HCC.

The incidence of HCC is relatively lower in the Western Hemisphere than in Eastern Asia. However, despite the statistics being low, the diagnosis of HCC has increased since the 1980s and it is continuing to increase, making it one of the rising causes of death due to cancer. The common risk factor for HCC is hepatitis C, along with other health issues.

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