Hepatocellular carcinoma (literature review) Текст научной статьи по специальности «Клиническая медицина»

I. ДИАГНОСТИКА И ЛЕЧЕНИЕ

HEPATOCELLULAR CARCINOMA. LITERATURE REVIEW

Kaniyev Sh.A., Nurlanbayev Y.K., Isamatov B.K., Enin E.A., Tadzhibaev T.K., Baiguisova D.Z., Chormanov A.T., Medeubekov U.Sh., Seisembaev M.A., Baimakhanov B.B.

National Scientific Center of Surgery named after A.N.Syzganov, Almaty, Kazakhstan

Abstract

This article presents materials of domestic and foreign authors on hepatocellular carcinoma. The classifications, modern methods of instrumental and laboratory diagnostics, as well as effective treatment tactics are described in detail.

Hepatocellular carcinoma, while remaining a fairly common disease, requires careful research, both clinically and pharmacologically, especially in terms of providing care to patients in regions with limited resources.

Гепатоцелюлярльщ карцинома. Эдебиепчк шолу.

Каниев Ш.А., Нурланбаев Е.К., Исаматов Б.К., Енин Е.А., Тэджiбаев Т.К., Бгуисова Д.З., Чорманов А.Т., Медеубеков ¥. Ш., Сейсембаев М.А., Баймаханов Б.Б.

А.Н.Сь^анов атында™ Улттык гылыми хирургия орталыры, Алматы, Казахстан

кцдата

Бул макалада гепатоцеллюлярлык карцинома бойынша отандык пен шетелд\к авторларыныц материал-дары усынылган. Дертт\ц ж\ктеулер\, диагностикалаудыц курал-саймандар аркылы жэне зертханалык зама-нуи эд1стер1, сондай-ак емдеуд\ц ти1мд1 тактикалары сипатталады. Барынша кец\нен таралган дерт\ бола тура, гепатоцеллюлярлык карцинома калайда клиникалык, сондай-ак фармакологиялык ту,р^ысынан, эфесе ти\ст\ медициналык квмек корсету бойынша шектеул\ корларына ие аймактарда, лайыкты меициналык квмек колжет1мд1 болу уш\н жан-жакты зерттеуд\ талап етед\.

MPHTM 76.29.49

ABOUT THE AUTHORS

Kaniyev Shokan Ahmedbekovich- Surgeon-Department of Hepatopancreatobiliary Surgery and liver Transplantation, JSC NSCS named after A.N. Syzganov. Nurlanbayev Yerik Kumarbekovich-Cand. of Med Sci., Department HPB and LT JSC NSCS named after A.N. Syzganov. Baiguisova Dinara Zulkhanaevna - Doctor of Radiation Diagnostics, Head of the Department of Radiation Methods of Research JSC NSCS named after A.N. Syzganov. ChormanovAlmat Tursynzhanovich -Cand. of Med Sci., Chief Doctor of the JSC NSCS named after A.N. Syzganov. Medeubekov Ulugbek Shalkarovich -Doct. of Med. Sci., Professor, Deputy Chairman of the Board of JSC NSCS named after A.N. Syzganov.

Seisenbayev Manas Ahmedjarovich -

Doct.of Med. Sci., Professor, JSC NSCS named after A.N. Syzganov. Baimakhanov Bolatbek Bimendievich

- Doct. of Med. Sci., Professor, Chairman of the Board JSC NSCS named after A.N. Syzganov.

For correspondence:

Kaniyev Shokan Akhmetbekovich - 62,

Zheltoksan str., Almaty, 050004, Republic of Kazakhstan. Phone: +7-701-294-60-89. E-mail: shokan.kaniyev@gmail.com

Keywords

hepatocellular carcinoma, classification, diagnosis, treatment, liver resection, liver transplantation.

АВТОРЛАР ТУРАЛЫ

Цаниев Шоцан Ахмедбекулы -

«А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» хирург-дэр\гер\. Нурланбаев EpiK Цумарбекулы - м.р.к., А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» хирург-дэр\гер\. Байгуисова Динара Зулхарнацызы - А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» сэуле аркылы диагнстикалау дэр\гер\, зерттеудщ сэуле аркылы эд\стер\ бел\м\н\ц мецгеруш\с\. Чорманов Алмат Турсынжанулы -м.р.к., А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» бас дэрУерг

Медеубеков Улыцбек Шалхарулы -

м.р.д. профессор, А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» баскарма терарасыныц орынбасары. Сейсембаев Манас Ахмеджарулы -м.р.д. профессор, А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» д.м.н, профессор, бас рылыми кызметкер\. Баймаханов Болатбек Бимендеулы -м.р.д. профессор, А.Н.Сызранов атындары Улттык рылыми хирургия орталыры» баскармасынын терарасы. Хат-хабар алмасу уш'м: Цаниев Шоцан Ахмедбекулы - 050004, Алматы к., Желтоксан кеш, 62 уй, Казахстан Республикасы. Тел.: +7-701-294-60-89, E-mail: shokan.kaniyev@gmail.com.

Туйш сездер

гепатоцеллюлярлык карцинома, жктеу, диатностикалау, емдеу, бауырды резекциялау, бауырды ааыстыру.

Гепатоцелюлярная карцинома. Литературный обзор.

ОБ АВТОРАХ

Каниев Шокан Ахмедбекович - врач хирург Национального научного центра хирургии им. А.Н. Сызганова. Досханов Максат Оналбаевич -

врач хирург, заведующий отделением гепатопанкреатобилиарной хирургии и трансплантации печени Национального научного центра хирургии им. А.Н.

Сызганова.

Нурланбаев Ерик Кумарбекович -

к.м.н, врач хирург Национального научного центра хирургии им. А.Н. Сызганова. Байгуисова Динара Зулхарнаевна -врач лучевой диагностики, заведующая отделом лучевых методов исследования Национального научного центра хирургии им. А.Н. Сызганова. Чорманов Алмат Турсынжанович -к.м.н, главный врач Национального научного центра хирургии им. А.Н. Сызганова.

Медеубеков Улугбек Шалкарович -д.м.н, профессор, заместитель председателя правления Национального научного центрахирургии им. А.Н. Сызганова. Сейсембаев Манас Ахмеджарович - д.м.н, профессор, главный научный сотрудник Национального научного центра хирургии им. А.Н. Сызганова. Баймаханов Болатбек Бимендеевич

- д.м.н, профессор, председатель правления Национального научного центра хирургии им. А.Н. Сызганова. Для корреспонденции: Каниев Шокан Ахмедбекович -050004, г. Алматы, ул. Желтоксан, дом 62, Республика Казахстан. Тел.:+7-701-294-60-89, E-mail: shokan.kaniyev@gmail.com.

Ключевые слова

гепатоцеллюлярная карцинома, классификация, диагностика, лечения, резекция печени, трансплантация печени.

Каниев Ш.А., Нурланбаев Е.К., Исаматов Б.К., Енин Е.А., Таджибаев Т.К. Байгуисова Д.З., Чорманов А.Т., Медеубеков У. Ш., Сейсембаев М.А., Баймаханов Б.Б.

Национальный научный центр хирургии им. А.Н. Сызганова, Алматы, Казахстан

Аннотация

В данной статье представлены материалы отечественных и зарубежных авторов по гепатоцеллюлярной карциноме. Описываются классификации, современные методы инструментальной и лабораторной диагностики, а также эффективные тактики лечения.

Гепатоцеллюлярная карцинома, оставаясь достаточно распространенным заболеванием, требует тщательного исследования, как в клиническом, так и фармакологическом плане, особенно в аспекте предоставления помощи пациентам в регионах с ограниченными ресурсами.

Relevant

More than 600.000 people have died worldwide from hepatocellular carcinoma (HCC) [1]

HCC is the sixth of malignant tumor in the world, fifth of men and the eighth of women. HCC is the third of cancer deaths, after lung and stomach cancer and the most frequent malignant formation in some parts of Africa and Asia. [1]

In Kazakhstan, detection frequency of liver cancer is low - 15 ranked. In the death structure liver cancer ranks 8th. The specific gravity of the I-II stages in the diagnosis is 8.7%, the lowest among all cancers. 5-year survival rate is 31.8% - the lowest among all malignant neoplasms. [2].

The purpose

According to international and domestic experience in the hepatocellular carcinoma treatment a literature review based on classification, drug and surgical interventions was conducted.

Materials and methods

This article was used domestic and foreign authors' materials based on the diagnosis and tactics

of hepatocellular carcinoma treatment. The method of investigation is a literary survey. The data was searched using Google Scholar, PubMed, where the data was taken from 2000 to 2017. TNM Classification / AJCC table № 1. [3]. T -Primary tumor

Tx -not enough data for evaluation of primary tumor

T0 - No evidence of primary tumor T1 - solitary tumor without vascular invasion, T2 is up to 5 cm a solitary tumor in the largest measurement with vascular invasion, or up to 5 cm multiple tumors in the largest dimension without vascular invasion.

T3A - multiple tumors more than 5 cm in the largest dimension without vascular invasion,

T3B - solitary tumor or multiple tumors of any size with invasion of the main branches of portal or hepatic veins,

T4 - tumor (s) involves adjacent organs with the exception of the gallbladder, or with the perforation of the visceral peritoneum.

Note: the plane divides the liver into two lobes projected between the gallbladder and the inferior vena cava for classification

Стадия ' Г N M

I 1 0 0

II 2 0 0

IIIA 3 0 0

IIIB 1-3 1 0

IVA 4 Любая 0

IVB Любая Любая 1

Table 1.

Stages of hepatocellular cancer

N - describes whether or not the cancer has reached nearby lymph nodes.

NX - Regional lymph nodes cannot be evaluated NO - No regional lymph node involvement (no cancer found in the lymph nodes)

N1-N3 - Involvement of regional lymph nodes (number and/or extent of spread)

The M category tells whether there are distant metastases (spread of cancer to other parts of the body).

MO - No distant metastasis (cancer has not spread to other parts of the body)

M1 - Distant metastasis (cancer has spread to distant parts of the body)

Nowadays, the most commonly used liver cancer classification is the Barcelona clinic (Table 2), which has taken into account the prevalence of the tumor process, the functional status of the liver, the objective condition of the patient and the estimated effectiveness of treatment.

There are five stages of the disease: from stage 0 (very early) and A (early) to stage D - terminal. The stage of BCLC, along with the prognosis of the disease and the treatment tactics, can change with the progression of the disease, or effective treatment. It should be noted the prognostic significance of classification for patients with HCC without regard to cirrhosis of the liver. An important feature of this classification is that it offers depending on the stage of the disease a treatment algorithm.

• stage 0 (very early stage) means solitary lesion measuring less than 2 cm in diameter

stage A (early stage) means there is a solitary lesion > 2 cm or early multifocal disease characterised by up to 3 lesions measuring less than 3 cm the tumor does not extend to the main vessels of the liver and adjacent anatomical structures; there are no tumor-specific complaints; patients' satisfactory general condition (ECOG 0 point); the liver is working well (Child-Pugh A).

• stage B (intermediate stage) single asymptomatic multifocal disease without macrovas-cular invasion; patients' satisfactory general condition (ECOG 0 point); Child - Pugh A / B.

• stage C (advanced stage) symptomatic tumours, that worsen general condition (ECOG 0-2 points); and invasive and/or metastatic disease Child-Pugh A / B.

• stage D (end-stage disease) Severe symptoms resulting from tumor or decompensation of cirrhosis (Child-Pugh C). according to the «Milan criteria» (solitary lesion <5 cm or no more than 3 foci with the largest size <3 cm) given the small tumor size orthotopic liver transplantation is possible. [3,4]

Diagnostics

Serological test have undergone or are currently underway include the determination of AFP, DCP, also known as prothrombin II, induced by the absence of vitamin K (PIVKA II), the ratio of glycosylated AFP (fraction L3) to total AFP, fucosidase and glypicant 3 for the early diagnosis of HCC[5-6]. AFP is the most widely identified HCC biomarker. A stably high level of AFP is a risk factor for HCC. AFP is mainly determined for diagnostic purposes, and not for screening. This is important, because the value of the method in diagnosis is not equal to the value in the screening. So, as a screening method, the AFP determination is not indicative enough.

Ultrasound diagnosis (UCTT) is applied at the screening stage, for percutaneous biopsy and in-terventional interventions and sometimes for monitoring the effectiveness of treatment. The sensitivity of the method is not high at detecting small-size nodes. According to the world literature, ultrasound reveals 70% of tumors 1 cm size n and 90% of tumors with 5 cm size. Of the diagnosis specificity varies between 48-94%. [7-8]. Computerized and / or magnetic resonance imaging are used for differential diagnosis, estimation of the prevalence of the process, staging of the disease. [9-11].

Methods of objective visualization (multi-phase contrast CT, dynamic contrast MRI or ultrasound with contrast enhancement) allow evaluating the vascular profile of mass lesion, to reveal signs of a typical VC picture of vascularization: amplification into the arterial phase and «washing out» into the portal phase.

In international (AASLD and EASL) guidelines, the diagnosis of hepatocellular carcinoma is considered valid if both methods (dynamic CT and MRI) independently reveal typical vascularization in the tumor. The use of these methods leads to a significant improvement in the diagnosis of HCC: sensitivity increases to 89%, specificity up to 99%. [3,8]

Fig. 2.

Г

Stage 0 PS=0, Child-Pugh A

1

Very early stage (0) 1 neoplasm <2cm Carcinoma in situ

Hepatocellular carcinoma *

Stage A - С PS=0-2, Child-Pugh A-B

-1-

1

Early stage (A) Intermediate stage (B) Advanced stage (C) 1 neoplasm or 2 nodules Multinodular, PS=0 Portal invasion,

<3 cm, PS=0 N1, Ml PS=l-2

Stage D PS>2, Child-Pugh С

I

End stage( D)

1 neoplasm

I

3 neoplasm £3 cm

I

P increased in portal vein/ level of biliiubin

J—Increased

In norm

I

associated diseases

I 4

no yes

I 4

Resection j | Liver transplantation] | PEI/RF

Radical therapies (30%) 5-year survival rate: 40-70%

Chemoembolization

Sorafenib

Palliative care (50%) Survival median 11-20 month

Symptomatic

treatment Survival <3 month

CTA is most commonly usedmethod for refined diagnosis of HCC with obligatory intravenous contrast and evaluation of the features of tumor of the in various (in the arterial, venous and delayed) phase of the study at a recommended rate of injection of a contrast drug 2-4-8 ml / sec (with PKT). Unlike the unaltered unchanged liver parenchyma, which is fed from the portal vein system, hepato-cellular tumors are blood supply mainly from the hepatic artery system, so in typical cases they are characterized by diffuse, heterogeneous «enhancement» to the arterial phase, followed by washing out the contrast drug into the venous and delayed phases, which is considered a classical mapping of the HRC. Features of the mapping of hepatocellular tumors depend both on their size and on the degree of their differentiation. Patients with cirrhosis and impaired liver function, the peak of contrasting parenchyma is difficult to predict. It comes much later - more than 30 - 40 minutes. [9-11].

Positron emission tomography (PET / CT) with glucose is not recommended for routine diagnosis and staging of HCC. PET / CT with choline can be useful for detecting extrahepatic metastases. [9-11].

A biopsy allows obtaining a morphological confirmation of the HCC. In the hands of an experienced surgeon, the frequency of complications of puncture of the liver (bleeding more often) does not exceed 1-2% [9]. Puncture biopsy in receiving a tissue column (cor-biopsy) is preferable to aspiration fine needle biopsy. When detecting (multiphase CT) in cirrhotic liver tumor with characteristic vascular-ization of HCC and confirmation of the diagnosis of contrast MRT morphological verification is not necessary.

A biopsy of the liver tumor is necessary when:

1. The small size of the tumor (<2 cm) and the typical for the HCC blood flow,

2. Atypical vascularization of a node> 2 cm in size,

3. Differences in the description and interpretation of contrasting dynamic studies in combination with a normal or slightly elevated level of AFP,

4. Identification of any tumor formation in the non-cirrhotic liver.

A biopsy of local formation in the cirrhotic liver is not needed if:

1. No treatment is planned for decompensated cirrhosis or other severe pathology;

2. A resection of the liver is planned. [3.9]

Treatment

Liver transplantation.

Liver transplantation with HCC is a simultaneous treatment of both the tumor process and concomitant liver cirrhosis. The MELD (Model for End-stage Liver Disease) classification is used for assess the status of candidates for liver transplantation. Orthotopic liver transplantation is a method of choosing early-stage HCC treatment, in cases not suitable for resection (multiple tumor lesions, cirrhosis, or severe impairment of liver function). The so-called «Milan» criteria are more commonly used: the size of a single tumor is not more than 5 cm or if there are up to 3 foci in the liver with a diameter of the largest node not more than 3 cm, no invasion of the vessels. If the «Milan» criteria are met at the stage of selecting candidates for liver transplantation, the 5-year survival of patients

reaches 70%, the frequency of tumor recurrence is <15%. Several studies indicate an early relapse after transplantation with high AFP (> 400 ng / ml), age> 60 years, and> 20 points on the MELD scale. Patients awaiting liver transplantation can receive both neoadjuvant and antitumor treatment, including ablation, embolization and partial resection of the liver, which increases the likelihood of liver transplantation beyond standard indications. Postoperative staging is performed on the basis of TNM classification taking into account preoperative examination. [4.9]

According to a recent systematic review of 90 studies involving 17,780 patients in 15 years, the Milan criteria are an independent prognostic outcome factor after liver transplantation [6]. The overall 5-year survival of patients with the Milan criteria (65-78%) was similar to the survival of patients without HCC in the European and American registers (ELTR and OPTN, respectively) (65-87%) [6,12-13]. According to ELTR results of more than 12 000 transplants, 10-year survival is about 50% [12]. Due to their success, the Milan criteria were included in the BCLC classification [14-15], as well as the system of pre-transplantation assessment of the stage of the UNOS (United Network for the Distribution of Donor Organisms) in the United States [16] and remain the starting point for all the prognostic criteria proposed to expand the indications to liver transplantation in patients with fcc and cirrhosis [17].

Ablation. Necrosis of the tumor can be caused by chemical ablation (percutaneous injection of ethanol, CHIE), thermoablation (radiofrequency ablation, RFA) or cryoablation. The ablative procedure can be performed percutaneously, laparoscopi-cally or by open access. To date, in the treatment of HCC, RFA and CHE are most commonly used. The safety and efficacy of PI and RFA in the treatment of patients with compensated cirrhosis (class A in Child-Pugh) and HCC meeting the Milan criteria were examined in several randomized controlled trials. Both methods demonstrated a low incidence of complications. RFA showed greater efficacy both in achieving complete response (65.7% vs. 36.2%) and in reducing the number of relapses (within 3 years local tumor recurrence was observed in 14% of patients treated with RFA and 34% , received the PIER,). It has also been shown that RFA requires fewer procedures than CHIE [18-20].

According to published data, the best results were achieved after RFA in a series of patients with HCC, in which 5-year survival was 40-70% [21-22] and even higher in candidates with more stringent selection criteria [23]. The best outcomes were observed in patients with small (usually less than 2 cm) single tumors and Child-Pugh class A [24].

TACE (Transarterial chemoembolization). The procedure consists of introducing through a catheter a mixture of chemotherapeutic and embolizing agents into the hepatic artery. The aim of TACE is to deliver a high dose of chemotherapeutic agent directly to the tumor, to increase the contact time between tumor cells and the agent, while minimizing the systemic effect of the chemotherapeutic agent. Studies have shown a significant benefit of TACH over symptomatic therapy in patients with unresectable HCC. Thus, in one study, survival in the TACE group was: 1 year - 57%, 2 years - 31%, 3 years

- 26%; in the control group: 1 year - 32%, 2 years

- 11%, 3 years -3%. Although death from hepatic insufficiency was somewhat higher in the TACE group, the liver function was statistically significant in the groups did not differ. Frequent complications of TACHE include postembolization syndrome (fever, abdominal pain, vomiting), embolization of non-targeted branches of the hepatic artery, liver failure and cholecystitis [9]. Less common are portal vein thrombosis, bone marrow failure and pancreatitis. The incidence of major serious adverse events varies from study to study, but the incidence of treatment-related deaths is usually less than 5%. The evaluation of the efficacy and safety of TACHE is complicated by various agents used, such as embolizing particles, and chemotherapeutic agents (doxorubicin, cisplatin), as well as a different number of procedures in different patients. These differences were not evaluated in clinical randomized trials. [23,25].

Resection is the method of choice for patients with single tumors and well-preserved liver function (compensated cirrhosis, Class A according to Child-Pugh), normal bilirubin level and either a pressure gradient in the portal vein not more than 10 mm Hg, or a number of tromobocytes not less than 100 * 109 / l. Retrospective studies show a 5-year survival after resection in patients at an early stage of HCC with a preserved liver function at a level of 50-70%. Nevertheless, the recurrence of HCC occurs frequently.

The modern standards of HCC resection in patients with cirrhosis are defined by the expert group as follows: the expected 5-year survival rate of 60%, perioperative mortality 2-3%, the need for blood transfusion less than 10% [26-27].

Clear criteria for the dependence of the feasibility of liver resection on tumor size are not available; However, it should be remembered that the likelihood of vascular invasion increases with the size of the tumor. In one study, a 30% chance of vascular invasion with a tumor diameter of 10 cm or more was demonstrated. According to the national registry conducted in Japan, the five-year post-resection survival depended directly on the tumor size and was 66% for

tumors less than 2cm, 52% for 2-5cm, and for only 37% for tumors greater than 5 cm. A five-year survival rate of more than 50% after resection patients who meet the Milan criteria (no more than 3 foci not larger than 3 cm), but not suitable for liver transplantation. However, the feasibility of liver resection for vascular invasion and / or for multifocal lesion remains to this day unexplored until the end. Preferred is an anatomic resection of the liver with the implementation of Pringle to minimize blood loss. [3-4, 9].

Target therapy

Sorafenib-oral tyrosine kinase inhibitor is the first and so far the only drug that increases the survival rate of patients with late stage HCC. It is indicated to patients with preserved liver function (Child-Pugh class A) and late stage of the tumor (C to BCLC), as well as tumors that progress after locoregional therapy. Patients with Class B in Child-Pugh cannot be given clear recommendations, although cohort studies report a similar safety profile and no decompensation [28-29].

The use of chemotherapy in HCC is problematic due to concomitant cirrhosis of the liver. Because of cirrhosis, the metabolism of chemotherapy drugs is changing and their toxicity is increasing. Systemic therapy with doxorubicin was evaluated in clinical trials in more than 1,000 patients and showed an objective response rate of about 10%. Systemic therapy with other drugs such as gemcitabine, ox-aliplatin, cisplatin and capecitabine, in combination or as monotherapy, showed a different response in uncontrolled studies, ranging from 0 to 18% [30].

Discussion

Today, HCC is by far the most common tumor among primary malignant neoplasms of the liver; its frequency varies depending on geographical and ethnographic features. From a global perspective, the most urgent task is to prevent the development of HCC. The only effective strategy is the primary prevention of viral hepatitis, which in most countries is already carried out in the form of vaccination

against the hepatitis B virus in newborns. Prevention of alcohol abuse and the spread of the hepatitis C virus (HCV), as well as metabolic syndrome, is also very important.

Screening for early detection of HCC is recommended for the following patients at high risk of developing the disease: patients with cirrhosis and patients with chronic viral infections.

The next aim is to increase knowledge among the population to identify risk groups and the possibility of establishing an early diagnosis, followed by resection or ablation of small tumors [1].

Accurate diagnosis of small nodes in the liver is very important. Until 2000, the diagnosis was made based on the results of a biopsy. This approach had a number of disadvantages associated with access to the foci and the risk of complications, such as bleeding and dissemination of the tumor along the needle pathway [31]. As to which imaging method should be used, it should be noted that the radio-logic criterion of HCC is the vascular dynamics of tumor contrast. For non-invasive diagnosis of HCC, CT and MRI of the latest generation are recommended [21].

Treatment options mainly depend on liver function, tumor size and the presence or absence of metastatic lesions or vascular invasion. In most cases, such treatments as resection, radiofrequen-cy ablation or liver transplantation are not feasible, leaving only palliative therapy. The main treatment for HCC is surgical. In well-chosen candidates, liver resection and transplantation provide the best outcomes (5-year survival rates reach 60-80%) and serve as a method of choice in patients with early tumor stage [32-33]. Liver resection is the method of choice in patients with cirrhosis (5% in Western countries, 40% in Asia) [32-33], who have a large resection possible with a low risk of life-threatening complications and acceptable outcomes (5-year survival of 30- 50 %). [4]

There are no apparent and potential conflicts of interest related to the publication of this article.

Source of funding is missing.

References

1. Гепaтoцеллюляpнaя кapцинoмa (ГЦК): глoбaльнaя пеpcпективa. World Gastroenterology Organisation, 2009 crp 3.

2. Нypгaзиев К.Н., Жылкaйдapoвa AX, Нypгaлиев Н.С., Hepce^ A^., Axметжaнoв О.Т., Ишкинин Е.И. Пpoфилaктикa нaибoлее pacпpocтpaненныx злoкaчеcтвенныx нoвooбpaзoвaний. Методиче-а<ие pекoмендaции. Aлмaты 2014г. Crp 16-19

3. Бpедеp В. В., Бaлaxнин П.В., Bиpшке Э.Р., Kocbi-pев В. Ю., Лaзapев C.A., Ледин Е. В. Пpaктиче-акие pекoмендaции no лекapcтвеннoмy лечению

renaTO^MOflflpHoro paKa // 3flOKanecTBeHHbie ony-xoam: npaKTMHecKue peKOMeHfla^M RUSSCO 3s2, 2017 (TOM 7). C. 339-351.

4. EASL-EORTC Clinical Practice Guidelines: Management of Hepatocellular Carcinoma, Journal of Hepa-tology 2012 vol. 56 908-943.

5. Marrero JA, Su GL, Wei W, Emick D, Conjeevaram HS, Fontana RJ, et al. Des-gamma carboxyprothrom-bin can diff erentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology 2003;37:1114-1121.

6. Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, et al. Milan criteria in liver transplantation for HCC: an evidence-based analysis on 15 years of experience. Liver Transpl 2011;17:S44-S57.

7. Colli A. et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review // Am. J. Gastroenterol. - 2006. V. 101. - 3.

- P. 513-523.

8. Lim J.H. et al. Detection of hepatocellular carcinoma: value of adding delayed phase imaging to dual-phase helical CT // Am. J. Roentgenol. - 2002. V. 179. - 1.

- P. 67-73.

9. Клинические рекомендации по диагностике и лечению больных раком печени и внепеченочных желчных протоков. Москва 2014г. 4-7 стр.

10. Balecki ES, Di Bisceglie AM. Diagnosis of hepatocellular carcinoma. YPB (Oxford) 2005; 7, 26-34

11. Saar B, Kellner-Welldon F. Radiological diagnosis of hepatocellular carcinoma. Liver Int. 2008; 28(2), 189-199.

12. ELTR - European Liver Transplant Registry. <www. eltr.org/>; 2011 [accessed 03.11].

13. OPTN - Organ Procurement and Transplantation Network. <http://www. ustransplant.org/annual_reports/ current/>; 2011 [accessed 02.11].

14. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classifi cation. Semin Liver Dis 1999;19:329-338.

15. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Len-cioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711.

16. Freeman Jr RB, Wiesner RH, Harper A, McDiarmid SV, Lake J, Edwards E, et al. UNOS/OPTN Liver Disease Severity Score, UNOS/OPTN Liver and Intestine, and UNOS/OPTN Pediatric Transplantation Committees. Th e new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 2002;8:851-858.

17. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13:e11- e22.

18. Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology 2009;49:453-459.

19. Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgro G, Burroughs AK. Clinical outcomes of radio-frequency ablation, percutaneous alcohol and acetic acid injection for hepatocellular carcinoma: a metaanalysis. J Hepatol 2010;52:380-388.

20. Bouza C, Lopez-Cuadrado T, Alcazar R, Saz-Parkin-son Z, Amate JM. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma. BMC Gastroenterol 2009;9:31.

21. Lencioni R, Cioni D, Crocetti L, Franchini C, Pina CD, Lera J, et al. Earlystage hepatocellular carcinoma in cirrhosis: long-term results of percu

22. Omata M, Tateishi R, Yoshida H, Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation. Gastroenterology 2004;127:S159- S166.

23. N'Kontchou G, Mahamoudi A, Aout M, Ganne-Carrie N, Grando V, Coderc E, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 2009;50:1475-1483.

24. Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justifi ed? Ann Surg 2002;236:602-611.

25. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipi-odol chemoembolization for unresectable hepatocel-lular carcinoma. Hepatology 2002;35:1164-1171.

26. Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, et al. Prevention of hepato-cellular carcinoma recurrence with alpha-interferon aft er liver resection in HCV cirrhosis. Hepatology 2006;44:1543- 1554.

27. Ishizawa T, Hasegawa K, Aoki T Takahashi M, Inoue Y, Sano K, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908- 1916.

28. Kim JE, Ryoo BY, Ryu MH, Chang HM, Suh DJ, Lee HC, et al. Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function. Cancer Chemother Pharmacol 2011;68:1285-1290.

29. Hollebecque A, Cattan S, Romano O, Sergent G, Mourad A, Louvet A, et al. Safety and effi cacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Th er 2011;34:1193-1201.

30. Taieb J, Barbare JC, Rougier P. Medical treatments for hepatocellular carcinoma (HCC): what's next? Ann Oncol 2006;10:308-314.

31. Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK. Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007;33:437-447.

32. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005;25:181-200.

33. Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, et al. Milan criteria in liver transplantation for HCC: an evidence-based analysis on 15 years of experience. Liver Transpl 2011;17:S44-S57.

34. Семендяева М.И., Меркулов И.А., Пастухов А.И., Гайдашева Е.В., Лесняк В.Н., Шутова О.В. Гепа-тоцеллюлярная карцинома - день сегодняшний. Клиническая практика №2, 2013 стр 35-40