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What Is Multifocal Hepatocellular Carcinoma

Multivariate Cox Proportional Hazards Regression Of Disease

Debate 11: Locally-advanced Hepatocellular Carcinoma (HCC) – Surgery is optimal

In the Cox analysis of DSS, before PSM, patients who underwent HR had a significantly longer survival outcome than did those who underwent RFA . Lower tumor differentiation grades, higher alpha-fetoprotein level, bigger tumor size, and higher tumor extension were all significantly correlated with poor prognosis. After PSM, HR was still associated with prolonged survival compared to RFA. Lower tumor differentiation grades, higher alpha-fetoprotein level, bigger tumor size, and higher tumor extension remained significantly associated with worse survival .

Table 2. Multivariate Cox proportional hazards regression for disease-specific survival before and after propensity score matching.

In the Cox analysis of OS, before PSM, patients in the HR group had significantly improved survival than those in the RFA group . Similarly, after PSM, patients treated with HR had a better prognosis than did those treated with RFA . Moreover, tumor differentiation grade, alpha-fetoprotein level, tumor size, and tumor extension were all significantly associated with survival both before and after PSM .

Table 3. Multivariate Cox proportional hazards regression for overall survival before and after propensity score matching.

Tnm Classification For Hepatocellular Carcinoma

Staging systems for hepatocellular carcinoma have not been universally adopted. One system implemented is the American Joint Committee on Cancer tumor/node/metastasis classification system. The TNM classification system takes into account tumor characteristics including size, number, and vascular invasion, as well as lymph node involvement and metastatic disease.

Table 1. TNM Classification for Hepatocellular Carcinoma

Primary tumor

Primary tumor cannot be assessed

No evidence of primary tumor

Solitary tumor < 2 cm, or > 2 cm without vascular invasion

Solitary tumor > 2 cm without vascular invasion

Solitary tumor > 2 cm with vascular invasion or multiple tumors, none > 5 cm

Multiple tumors, at least one of which is > 5 cm

Single tumor or tumors of any size involving a major branch of the portal vein or hepatic vein, or tumor with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum

Regional lymph nodes

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Table 2. Anatomic stage/prognostic groups



Table 4. Barcelona-Clinic Liver Cancer staging system

Table 5. Ishak fibrosis score

  • National Comprehensive Cancer Network. NCCN Hepatobiliary Cancers Clinical Practice Guidelines in Oncology. Available at . Version 4.2019 December 20, 2019 Accessed: March 23, 2020.

  • Stage

    The Role Of Liver Transplant From Living Donor

    Living donor liver transplantation is a practice used mainly in Asia, where orthotopic organs are not readily available. Its use was later extended to other countries, mostly in Europe and North America to compensate for the shortage of organs and the long time on the waiting list which leads to patients death, or dropout for medical reasons or progression of cancer beyond acceptable transplant criteria.

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    What Every Physician Needs To Know:

    Hepatocellular carcinoma is the most common primary malignant tumor of the liver and the third most common cause of cancer-related death worldwide. The incidence of HCC appears relatively static in most endemic regions. Previously considered uncommon in the United States and Europe, its incidence and mortality have increased three-fold in the past two decades, secondary to parallel increases in chronic hepatitis C virus and non-alcoholic steatohepatitis .

    Although surgical resection and liver transplantation are potentially curative therapies, the vast majority of patients present with advanced disease that is not amenable to curative treatment modalities. In addition to patients presenting with advanced tumors, many of these patients also have underlying liver dysfunction which can be a rate-limiting step to initiating treatment.

    The diagnosis and treatment plans should be made in a multi-disciplinary fashion consisting of a team of hepatologists, oncologists, surgeons and radiologists.

    Baseline Demographic And Clinical Characteristics

    Multifocal Hepatocellular Carcinoma (Hepatoma)

    The sample selection procedure was illustrated in Figure 1. Of the 59,914 patients with HCC between 2004 and 2015, we obtained 2,201 patients meeting inclusion criteria for final analysis. Of them, 1,106 cases underwent RFA and 1,095 underwent HR after PSM, there were both 548 cases in RFA and HR groups.

    Figure 1. Flow chart of the sample selection procedure.

    The baseline demographic and clinical data are presented in Table 1. Before PSM, the RFA group contained more young patients had a higher proportion of divorced, widowed, or separated persons had a higher percentage of men, white people, and patients with unknown tumor differentiation grade had a higher level of alpha-fetoprotein were more likely to have liver cirrhosis and smaller tumor size more likely to undergo chemotherapy and had a higher proportion of people with tumor extension 390 and 440 than the HR group. After PSM, all variables were completely balanced between the HR and RFA groups.

    Table 1. Baseline demographic and clinical characteristics before and after propensity score matching.

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    Are You Sure Your Patient Has Hepatocellular Carcinoma What Should You Expect To Find

    The clinical presentation of HCC varies considerably and is often dependent on the degree of hepatic reserve. Many patients with HCC are asymptomatic at the time of diagnosis or have their tumors incidentally discovered on imaging done for unrelated reasons. Given that the vast majority of patients with HCC have concomitant cirrhosis, the first manifestation of HCC can be hepatic decompensation, such as jaundice, hepatic encephalopathy, or ascites.

    In a patient with known cirrhosis, a decline in a patients hepatic function should heighten clinical suspicion for the development of HCC. However, a lack of known chronic liver disease at presentation does not preclude the possibility of HCC. Oftentimes, patients were exposed to one of the inciting risk factors, such as HCV, decades earlier and simply have unrecognized chronic liver disease. In our experience, nearly 40% of patients had HCC as their first presentation of cirrhosis.

    The most common symptoms of HCC upon initial presentation include the following: abdominal pain, weight loss, weakness, abdominal swelling and jaundice. An additional 1-3% of patients initially present with symptoms related to metastatic disease, including body pain to the spine or hips. The most common signs of HCC are hepatomegaly, ascites, fever, splenomegaly, muscle wasting and jaundice.

    Aetiology And Risk Factors

    • 90% of patients with hepatocellular carcinoma have a history of liver cirrhosis. Cirrhosis causes toxic damage to hepatocytes, the release of inflammatory cytokines, prolonged oxidative stress, and increased cell turnover, which ultimately results in DNA damage, mutations and the development of cancer. Tumours can either form a distinct mass or undergo widespread diffuse growth throughout the liver. The incidence of HCC in patients with cirrhosis is 5% per year, which makes the 20-year cancer risk virtually 100%. As many as 30-50% of cases are detected too late for curative treatment, but screening programmes are now in place to try and catch more cancers early.
    • there are many causes of liver cirrhosis, which are associated with variable increases in HCC risk:
    • alcoholic liver disease 5x risk
    • non-alcoholic fatty liver disease 4x risk
    • viral hepatitis: hepatitis B or hepatitis C infection can increase risk up to 60x, responsible for 85% of cases worldwide
    • autoimmune liver diseases such as primary biliary cirrhosis , primary sclerosing cholangitis , and autoimmune hepatitis
    • haemochromatosis some sources say it leads to > 100x risk
    • Wilsons disease
    • cystic fibrosis liver disease
    • porphyria cutanea tarda, hereditary tyrosinaemia and other rare metabolic disorders
    • drug-induced hepatotoxicity
  • amongst patients with cirrhosis, additive factors which further increase risk of HCC include male gender , age > 40, and non-Caucasian ethnic origin
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    What Laboratory And Imaging Studies Should You Order To Characterize This Patient’s Tumor How Should You Interpret The Results And Use Them To Establish Prognosis And Plan Initial Therapy


    HCC can be diagnosed in most cases without the need for a biopsy, provided characteristic radiological features are present in the appropriately completed imaging studies. A four-phase imaging study, either dynamic contrast-enhanced computed tomography or magnetic resonance imaging , consisting of unenhanced , arterial , venous and delayed phase images are necessary to accurately assess for HCC.

    Figure 1.

    Venous phase of CT imaging displaying HCC.

    Figure 4.

    Delayed phase of CT imaging displaying HCC.

    Since HCC tumors typically only contain arterial vascular supply , HCC lesions should enhance compared to the remaining liver on the arterial images. On venous images, the lesion should display washout as the surrounding liver will have a greater portal venous blood flow than the HCC.

    For lesions greater than 1cm in maximum diameter, the presence of arterial enhancement and delayed washout on one imaging study is sufficiently specific for HCC and no further imaging or biopsy is necessary.

    For lesions greater than 1cm without arterial enhancement and delayed washout, a second cross-sectional imaging study should be performed to further characterize the lesion. If the second imaging modality still does not characterize the lesion by the presence of arterial enhancement and delayed washout, or there is a discrepancy in imaging findings, we would then proceed to percutaneously biopsy of the lesion .

    Laboratory Tests
    • viral hepatitis serologies

    Figure 5.

    Etiological Adjunctive Treatment For High

    Hepatocellular Carcinoma Clinical Trial

    While we have discussed above the different treatment modalities available for high-burden HCC, it is also of paramount importance to control the underlying risk factors during treatment. By far, HBV and HCV infections are the most important risk factors for HCC. Together, they account for 80% of the HCC worldwide. The use of antivirals not only reduces the incidence of HCC in viral carriers, it is also effective in reducing HCC recurrence and prolonging survival. This is because viral reactivation is a major complication of HCC treatment. Patients with high-burden HCC are particularly at risk of viral reactivation due to chronic immunosuppression, higher tumor load and poorer liver reserve. Uncontrolled viral reactivation may provoke acute hepatitis, fulminant liver failure and even death.

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    Subgroup Analyses Of Multifocal Tumours Distributed In Different Segments

    For patients with multifocal tumours distributed in different segments, the 1-, 3-, and 5-year OS were 93.8%, 85.2%, and 76.6% in the resection group and 100.0%, 88.6%, and 88.6% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year OS were 89.9%, 84.9%, and 74.3% in the resection group and 100.0%, 95.5%, and 95.5% in the ablation group, respectively . The 1-, 3-, and 5-year RFS were 81.6%, 51.9%, and 42.8% in the resection group and 74.5%, 36.5%, and 26.0% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year RFS were 86.7%, 54.5%, and 42.9% in the resection group and 70.1%, 43.1%, and 25.9% in the ablation group, respectively .

    What Are Liver Cancer Symptoms And Signs

    The medical treatment chosen depends upon how much the cancer has spread and the general health of the liver. For example, the extent of cirrhosis of the liver can determine the treatment options for the cancer. Similarly, the spread and extent of spread of cancer beyond the liver tissue plays an important part in the types of liver cancer treatment options that may be most effective.

    Surgery: Liver cancer can be treated sometimes with surgery to remove the part of liver with cancer. Surgical options are reserved for the smaller sizes of cancer tumors. Complications from surgery may include bleeding , infection, pneumonia, or side effects of anesthesia.

    Liver transplant: The doctor replaces the cancerous liver with a healthy liver from another person. It is usually used in very small unresectable liver tumors in patients with advanced cirrhosis. Liver transplantation surgery may have the same complications as noted above for surgery. Also, complications from medications related to a liver transplant may include possible rejection of the liver transplant, infection due to suppression of the immune system, high blood pressure, high cholesterol, diabetes, weakening of the kidneys and bones, and an increase in body hair.

    Targeted agent: Sorafenib is an oral medication that can prolong survival in patients with advanced liver cancer. Side effects of sorafenib include fatigue, rash, high blood pressure, sores on the hands and feet, and loss of appetite.

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    Indication To Orthotopic Liver Transplantation

    Since 1968 the “European Liver Transplant Registry records all data of liver transplants in 145 centers across Europe. These data give an overview on what is the trend of transplants in Europe during each period.

    Both the number of centers and the number of liver transplants gradually increased, but after an exponential growth until the 80s, they reached a plateau that was maintained as shown by recent data with about 5800 liver transplants performed per year across Europe. Cirrhosis was the most common indication for liver transplantation rate, followed by primary tumors of the liver .

    Indication for liver transplantation have significantly changed over time. Subsequently, the rate of liver transplantation for increased to 20% in late 1990s. Between 2000-2010, two groups of indications have increased: primary tumors of the liver , especially HCC, and cirrhosis , especially alcohol related .

    Transplantation for HCC has thus become a therapeutic approach more commonly used in Europe where it accounted for 25% of all indications for liver transplantation. Improvement of survival of cirrhotic patients given by the pharmacological control of HBV and HCV, has led to an increased rate of survival and lower rate of recurrent HCC. In fact, HCC has gradually become the most common complication in cirrhotic patients. In the last three years the number of patients with HCC in transplant list has grown dramatically: more than 30% in France, 26% in Europe, 34% in the United States .

    Overall Survival And Recurrence

    Multifocal Hepatocellular Carcinoma (Hepatoma)

    During the study period, there were 16.7% all-cause deaths in the resection group and 15.9% all-cause deaths in the ablation group . Before PSM, the 1-, 3-, and 5-year OS were 94.4%, 84.2%, and 72.9% in the resection group and 98.1%, 85.4%, and 77.2% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year OS were 93.5%, 85.8%, and 77.0% in the resection group and 97.4%, 94.6%, and 83.6% in the ablation group, respectively . In terms of tumour recurrence, 48.6% patients in the resection group and 58.7% patients in the ablation group had been observed with relapse . The 1-, 3-, and 5-year RFS were 77.6%, 53.0%, and 43.7% in the resection group and 64.5%, 25.6%, and 18.3% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year RFS were 84.2%, 50.4%, and 40.4% in the resection group and 60.8%, 28.1%, and 16.9% in the ablation group, respectively .

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    Treatment Options For High

    In the literature, a plethora of therapeutic options are available for high-burden HCC. These include surgery, TACE, transarterial radioembolization , radiotherapy and systemic therapy. The choice of therapy depends on the extent of the disease, the liver function and the patients performance status. Each treatment option will be discussed individually here.

    What Therapies Should You Initiate Immediately Ie Emergently

    Spontaneous Rupture

    The major life-threatening complication of HCC is the spontaneous rupture of the tumor with peritoneal hemorrhage. The incidence is 3%-15% in patients with HCC, with a decreasing incidence over the last decade due to earlier diagnosis of the tumor. However, the mortality rate remains high presumably due to a combination of uncontrolled hemorrhage and acute decompensation of liver function.


    Prior to the onset of appropriate treatment the diagnosis of a ruptured HCC must be achieved. This can oftentimes be quite difficult due to the lack of history of known HCC or cirrhosis. Typically, patients present with acute abdominal pain and hemodynamic instability. Confirmation of diagnosis is usually made with a contrast enhanced axial imaging modality that demonstrates hemoperitoneum and presence of tumor .

    Figure 6.

    CT imaging of a ruptured HCC with accompanying hemoperitoneum .


    Depending on local expertise, the least invasive and preferred hemostasis procedure is transarterial embolization . TAE is both diagnostic and therapeutic as the bleeding vessel, typically an arterial source, is identified via celiac trunk angiography and then treated using a variety of embolic materials including gel foam, polyvinyl alcohol or stainless steel coils.

    If the patient becomes hemodynamically stable, a plan for definitive treatment should be implemented.

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    Local Tumour Progression And Intrahepatic Distant Recurrence

    We also explored the relapse patterns after treatment with resection or ablation. During the study period, 6.9% patients in the resection group and 14.3% patients in the ablation group had been observed with LTP . Before PSM, the 1-, 3-, and 5-year LTP rates were 1.6%, 8.9%, and 13.7% in the resection group and 16.4%, 21.8%, and 34.8% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year LTP rates were 2.4%, 12.9%, and 12.9% in the resection group and 18.8%, 24.6%, and 39.7% in the ablation group, respectively . Besides LTP, 40.3% patients in the resection group and 41.3% patients in the ablation group had been observed with IDR . The 1-, 3-, and 5-year IDR rate were 19.7%, 40.7%, and 48.4% in the resection group and 12.8%, 64.3%, and 69.4% in the ablation group, respectively . After PSM, the 1-, 3-, and 5-year IDR rate were 15.6%, 38.4%, and 48.1% in the resection group and 12.6%, 52.6%, and 60.5% in the ablation group, respectively .

    Histopathological Types Of Liver Cancer

    Hepatocellular Carcinoma on the background of CLD || Ultrasound || Case 179
    • ~90% hepatocellular carcinoma
    • fibrolamellar HCC is a rare subtype of hepatocellular carcinoma which tends to occur in young people without a history of cirrhosis or other major risk factors. It has a much better prognosis.
  • ~10% intrahepatic cholangiocarcinoma this will be covered in a separate article soon
  • < 1% sarcomas: angiosarcoma, fibrosarcoma, leiomyosarcoma, undifferentiated embryonal
  • < 1% epithelioid haemangioendothelioma diffuse, multifocal and rarely resectable
  • < 1% primary hepatic lymphoma
  • < 1% hepatoblastoma affects the under 5s and is the commonest liver cancer in children, but is still extremely rare. Fewer than 15 cases are diagnosed each year.
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