Childhood Hepatocellular Carcinoma

Summarize

1. General remarks

● Overview: Hepatocellular carcinoma in children is a malignant epithelial tumor originating from liver cells, which occurs most frequently in children aged 10-14 years and less frequently in children under 5 years of age.

● Symptoms: abdominal mass, abdominal distension and pain, weight loss, loss of appetite, jaundice, vomiting, fever, skin itching and anemia.

● Treatment: surgery, chemotherapy or liver transplantation are the main treatment methods.

● Prognosis: The prognosis of hepatocellular carcinoma in children is not ideal, and the overall survival rate is less than 30%.

2. Disease definition

Hepatocellular carcinoma (HCC) is a malignant epithelial tumor originating from liver cells. It usually occurs in the right lobe of the liver and is the second most common malignant liver tumor in children, but it is very rare overall.

Epidemiological

epidemiology

Childhood hepatocellular carcinoma accounts for less than 0.5% of all childhood cancers, predominantly affecting children and adolescents aged 10 to 14, and is relatively rare in children under 5 years old. In the United States, the annual incidence of hepatocellular carcinoma among children aged 14 and under is 0.8 cases per 1 million people, and among adolescents aged 15 to 19, it is 1.5 cases per 1 million people. Compared to the United States, children in Asian regions with higher rates of hepatitis B virus infection have a higher incidence of hepatocellular carcinoma. According to statistics from Taiwan, China, before the widespread vaccination against hepatitis B, the incidence was approximately 5.4 cases per 1 million people; after the vaccine became widely available, the incidence dropped to 2 cases per 1 million people. The age of diagnosis for childhood hepatocellular carcinoma is typically between 12 and 14 years, with males being more frequently affected, and the male-to-female ratio among patients ranges from 2.1 to 13.3:1.

Etiology & Risk Factors

1. General remarks

The exact cause of hepatocellular carcinoma in children is not clear. Unlike adult hepatocellular carcinoma, hepatocellular carcinoma in children may occur in individuals without underlying liver disease. The tumor occurs due to genetic variations that lead to abnormal cell growth and proliferation, resulting in the formation of tumors.

2. Basic etiology

The exact cause of hepatocellular carcinoma in children is still unknown. Mutated genes associated with hepatocellular carcinoma in children include CTNNB1, NFE2L2 and TERT.

3. Triggering factors

Some underlying diseases that lead to liver dysfunction and congenital or hereditary diseases affecting the liver may increase the risk of hepatocellular carcinoma in children. It is important to note that susceptibility factors and disease are not the same.

1) Alagille syndrome

Alagille syndrome, an autosomal dominant genetic disorder, is typically caused by mutations or deletions in the JAG1 gene. This syndrome affects the bile ducts of the liver, blood vessels in the heart, brain, and kidneys. It can also lead to bile duct abnormalities, causing scar formation in the liver, which increases the risk of hepatocellular carcinoma in patients compared to the general population. Patients with Alagille syndrome often have a distinctive facial appearance, characterized by a broad and prominent forehead, deep-set eyes, and a small, protruding chin.

2) Hepatitis B or C virus infection

In children, hepatocellular carcinoma is associated with perinatal acquired hepatitis B virus infection, and hepatitis B immunization can reduce the risk of hepatocellular carcinoma. Compared to adults, a small number of children with this type of hepatocellular carcinoma have a very short latency period from hepatitis virus infection to the development of hepatocellular carcinoma, possibly due to mutations in the Met/hepatocyte growth factor receptor gene.

HCV infection is associated with the development of cirrhosis and hepatocellular carcinoma, although this process typically takes decades to occur and is therefore less common in children. Compared with adult cirrhosis, children with cirrhosis are less likely to develop hepatocellular carcinoma, occurring in only 20 to 35 per cent of children with hepatocellular carcinoma.

3) Tyrosineemia

This is a rare genetic disorder caused by mutations in genes responsible for producing enzymes essential for tyrosine breakdown. Hyperthyrosinemia, characterized by high levels of tyrosine in the blood, can lead to harmful accumulation of tyrosine and other substances in body tissues and organs, particularly the liver, kidneys, and nervous system, potentially increasing the risk of liver cancer.

4) Progressive familial intrahepatic cholestasis

It is a rare genetic disease characterized by the accumulation of bile in the liver. Symptoms include jaundice, itching and growth retardation that begin in infancy and progress to portal hypertension and liver failure.

5) Glycogen storage disease

This is a genetic disorder caused by abnormal storage and use of glycogen in the body. Glycogen storage diseases come in many types and can cause problems in different parts of the body, including the liver, muscles, kidneys and heart.

6) Family history of hepatocellular carcinoma

If a child's parents or siblings have hepatocellular carcinoma, the child is more likely to develop hepatocellular carcinoma than the average child.

Classification & Staging

Type of disease

1) Pathological classification

According to the 2019 classification of digestive system tumors by the World Health Organization (WHO), hepatocellular carcinoma can be categorized into non-specific and several variant types. These variants include fibrous platelet, sclerosing, clear cell, fatty hepatitis, coarse beam, dyschromatosis, neutrophilic, and lymphocytic types. In children, the most common subtypes are non-specific and fibrous platelet.

Non-specific (NOS) hepatocellular carcinoma, also known as transitional hepatocellular tumor (TLCT) or hepatocellular carcinoma with elements of hepatoblastoma, is a rare tumor that exhibits characteristics of both hepatoblastoma and hepatocellular carcinoma. It is typically found in older children and adolescents, with features that lie between those of hepatoblastoma and hepatocellular carcinoma. These tumors are usually solitary, and their response to chemotherapy remains unclear, although they are generally considered similar to hepatocellular carcinoma.

Fibrous platelet-like hepatocellular carcinoma, also known as fibrous platelet-like cancer, primarily affects older children and young adults. A key feature is the fusion gene resulting from a 400kb genomic segment deletion on chromosome 19. In 2019, the World Health Organization (WHO) established DNAJB1-PRKACA gene susceptibility as a classification criterion for this subtype.

2) Disease staging

Childhood hepatocellular carcinoma is currently staged according to two staging systems: pre-treatment staging (PRETEXT) and preoperative staging after chemotherapy (POST-TEXT), the COG Evans staging system.

● Pre-textual staging before treatment and post-textual preoperative staging after chemotherapy

The pre-treatment staging (PRETEXT) is based on the extent of liver involvement before treatment, primarily to assess the feasibility of complete surgical resection at the initial diagnosis. The post-treatment staging (POST-TEXT) is based on the extent of liver tumor involvement after neoadjuvant chemotherapy, mainly to evaluate the feasibility of complete surgical resection at a later stage. The definitions for each stage are as follows:

PRETEXT/POST-TEXT I: The tumor was confined to one liver region, and the other three adjacent liver regions were not invaded by the tumor.

PRETEXT/POST-TEXT ⅱ: The tumor involved one or two liver areas, and the adjacent other two liver areas were not invaded by the tumor.

PRETEXT/POST-TEXT ⅲ: 2 or 3 liver areas are affected, and another adjacent liver area is not affected.

PRETEXT/POST-TEXT ⅳ: The tumor involved all four liver regions.

● COG Evans staging system

The COG Evans staging system can be used to develop a treatment plan for children with liver tumors, but it has been less used in recent years.

Stage I: complete tumor resection.

Stage II: the tumor is basically removed with microscopic residue.

Stage iii: there is no distant metastasis of the tumor, but the tumor cannot be removed and there is gross residual tumor after surgery; or there is no distant metastasis of the tumor, but the lymph node metastasis is positive.

Stage iv: distant metastasis occurs at the time of diagnosis, regardless of whether the primary lesion is completely resected.

Clinical Manifestations

1. General remarks

Symptoms of hepatocellular carcinoma in children are usually abdominal masses and pain. Other common symptoms include abdominal swelling and discomfort, weight loss, loss of appetite, fever, vomiting and yellowing of the skin and eyes (jaundice).

2. Typical symptoms

About 80 to 99 percent of patients have abdominal pain, liver enlargement and elevated alpha-fetoprotein levels, and about 30 to 79 percent have fatigue, liver necrosis, portal vein thrombosis and vomiting.

3. Accompanying symptoms

Large masses may rupture at times, causing symptoms and signs of acute abdomen.

Clinical Department

1. General remarks

The main diagnostic criteria for hepatocellular carcinoma in children are medical history, physical examination, serum alpha-fetoprotein, hepatitis B virus, imaging and histopathology, among which histopathology is the gold standard for diagnosis, but usually combined with hepatitis B virus test results.

2. Department of treatment

Pediatric oncology, pediatric oncology surgery, hepatobiliary surgery, oncology surgery.

Examination & Diagnosis

coherence check

1) Laboratory tests

At present, there is no specific tumor marker for hepatocellular carcinoma in children, but the alpha-fetoprotein (AFP) of most children is elevated, and the serum β-human chorionic gonadotropin (β-hCG) of some children is elevated, and the hepatitis B or C virus test is positive.

In addition, routine blood tests and biochemical examinations are required, including liver function (ALT, direct bilirubin), kidney function (urea nitrogen, creatinine, uric acid), creatinine clearance rate, serum and urine β2 microglobulin, electrolyte levels, serum lactate dehydrogenase (LDH), ferritin, myocardial enzyme spectrum, and coagulation function. Sometimes, a Ÿ routine urine test and stool test are also necessary.

When necessary, immune function (IgG, IgM, IgA, peripheral blood T cells, B cells and NK cell subpopulation ratio and absolute value) should be checked.

2) Imaging examination

● Abdominal ultrasound examination: Abdominal ultrasound can be used to examine large blood vessels, and preliminarily determine the location, size and relationship with surrounding tissues of tumors.

● Chest/abdomen CT (plain or enhanced): can be used to determine whether there is metastasis to the lungs or abdominal organs.

● Abdominal magnetic resonance imaging (MRI): used to examine and determine the density of the mass, whether there is calcification and ossification, and the relationship with surrounding tissues. In cases of hypersensitivity to MRI contrast agents, inability to sedate, or other special circumstances, abdominal CT can be considered as an alternative to abdominal MRI.

● A cranial magnetic resonance imaging (MRI) and a whole body bone scan may also be required if necessary.

3) Pathological examination

The American Collaborative Group on Childhood Oncology (COG) surgical guidelines recommend that for PREXTI stage tumors and PREXTT II stage tumors with imaging margins greater than 1 cm in the superior vena cava, middle hepatic vein, and portal vein, direct tumor resection can be performed to ensure a clear pathological diagnosis. For patients who cannot undergo complete surgical resection, a biopsy can be performed. However, if the patient has liver cirrhosis, a biopsy is not recommended. Instead, a comprehensive assessment based on imaging findings, alpha-fetoprotein levels, and hepatitis B virus tests is typically conducted.

4) Other tests

It includes electrocardiogram, color Doppler echocardiography, cardiac function and hearing examination. Bone marrow cytology examination is required if necessary.

4. Differential diagnosis

When hepatitis B virus is positive, it is necessary to differentiate between hepatocellular carcinoma and hepatoblastoma in children. Hepatoblastoma mostly occurs in children under 5 years old, while hepatocellular carcinoma rarely occurs before 5 years old. Moreover, the histopathological characteristics of the two are different, which can be used for differential diagnosis.

Clinical Management

1. General remarks

The treatment of hepatocellular carcinoma in children depends on several factors: whether the tumor has metastasized, whether the tumor is associated with hepatitis B virus infection, whether the tumor can be completely removed, and how the tumor responds to chemotherapy.

If the child's hepatocellular carcinoma is associated with hepatitis B virus infection, antiviral therapy should be administered. If it is not associated with viral infection, treatment options are selected based on the specific condition of the tumor.

For children with hepatocellular carcinoma that may be completely resected, the current treatment is mainly surgery, which can be combined with neoadjuvant chemotherapy before surgery or adjuvant chemotherapy after surgery. However, due to the low incidence of hepatocellular carcinoma in children and limited research, there is no reliable evidence that chemotherapy can improve survival in this group of patients.

For tumors that have not metastasized but cannot be completely removed, chemotherapy is initially administered. Once the tumor has shrunk, complete removal is considered. If the tumor remains inoperable after chemotherapy, options such as liver transplantation, transarterial chemoembolization (TACE), or complete removal or liver transplantation following TACE may be considered.

At present, there is no effective treatment for metastatic hepatocellular carcinoma in children. The chemotherapy regimen of cisplatin combined with doxorubicin is effective in some children, which can reduce the tumor and facilitate complete resection.

2. Chemotherapy

1) Chemotherapy regimen

I) Intravenous chemotherapy

Intravenous chemotherapy is a traditional method of cancer treatment. Currently, there is no standardized intravenous chemotherapy regimen for pediatric hepatocellular carcinoma. However, several chemotherapy regimens can be considered: the PLADO regimen (platinum + doxorubicin), the extended PLADQ regimen (platinum + carboplatin + doxorubicin), the ICE regimen (ifosfamide + carboplatin + etoposide), and the C5VD regimen (platinum + vincristine + 5-fluorouracil).

ii) Transarterial embolization chemotherapy (TACE)

Catheter arterial embolization chemotherapy is an interventional chemotherapy technique that involves inserting a catheter into the hepatic artery. Chemotherapy drugs are then selectively injected into the artery. This method kills tumor cells by delivering high concentrations of chemotherapy locally and also blocks the blood vessels supplying the tumor, thereby interrupting its blood supply and enhancing the effectiveness of the treatment.

In children with hepatocellular carcinoma, studies have shown that the combined use of cisplatin, doxorubicin and mitomycin in catheter arterial embolization chemotherapy has certain effect and good tolerance. However, overall, the current research is limited.

2) Adverse reactions

Common adverse reactions to chemotherapy include anemia, thrombocytopenia and/or neutropenia, nausea and vomiting, increased risk of infection, ototoxicity, nephrotoxicity, cardiotoxicity, and elevated transaminase.

Catheter arterial embolization chemotherapy may also cause embolization syndrome and arterial spasm.

3. Surgical treatment

1) Surgical treatment of hepatocellular carcinoma in children

Complete resection of the tumor is very important for the treatment of hepatocellular carcinoma in children. The standard for surgical resection is to achieve a residual liver volume/body mass ratio of more than 0.6-0.8 mL/kg.

2) Postoperative complications

Children, especially newborns, have not fully developed liver and are prone to postoperative liver insufficiency. In addition, complications such as bleeding, bile leakage, infection and biliary obstruction may occur after hepatectomy.

4. Liver transplantation

Given the rarity of hepatocellular carcinoma in children, there is currently insufficient research data on the impact of liver transplantation on prognosis. However, there are successful clinical cases reported. In 2013, a retrospective study from Seattle Children's Hospital in the United States found that the 5-year survival rate after liver transplantation for children with hepatocellular carcinoma was 85.3%, significantly higher than the 5-year survival rate after liver resection (53.4%). In 2014, the American Association for the Study of Liver Diseases (AASLD), the American Society of Transplantation (AST), and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) jointly released guidelines stating that the indications for liver transplantation in adult hepatocellular carcinoma may not apply to children. For children with hepatocellular carcinoma, transplantation should be considered based on individual conditions, and it is recommended that children without extrahepatic metastasis or major vascular invasion should consider liver transplantation as soon as possible.

5. Frontier treatment

In adult hepatocellular carcinoma, the combination of targeted drug sorafenib (Sorafenib) and chemotherapy has certain effect. In children with hepatocellular carcinoma, there are cases of effective combination of sorafenib and chemotherapy, but the current research is limited.

In adult hepatocellular carcinoma, in addition to sorafenib, several other targeted drugs are under investigation, including bevacizumab, brivanib, sunitinib, erlotinib, everolimus, tivantinib, cabozantinib, and nivolumab (commonly known as 'O drug'). Due to the rarity of hepatocellular carcinoma in children, no related research has been conducted.

Prognosis

1. General remarks

According to a U.S. follow-up study of 218 children and adolescents under the age of 20 with hepatocellular carcinoma (HCC) between 1973 and 2009, the 5-year overall survival rate was 24%, the 10-year overall survival rate was 23%, and the 20-year overall survival rate was 8%. Among these patients, those with complete tumor resection had a 5-year overall survival rate of 60%, while those who could not have their tumors completely removed had a 5-year overall survival rate of 0%. For children with HCC who underwent liver transplantation, the 1-year, 5-year, and 10-year overall survival rates were 86%,63%, and 58%, respectively.

Factors that influence the prognosis include: tumor stage (early-stage cases generally have a better prognosis), metastasis at diagnosis (cases without metastasis generally have a better prognosis), whether the tumor can be completely removed (cases where the tumor can be completely removed generally have a better prognosis), the tumor's response to chemotherapy (tumors that respond well to chemotherapy generally have a better prognosis), and the presence of hepatitis B virus infection.

2. Aftereffects

Platinum-based chemotherapy drugs, such as cisplatin and carboplatin, can cause varying degrees of bilateral permanent, progressive high-frequency hearing loss in children. Therefore, it is essential to conduct hearing tests before the first chemotherapy session, every two cycles, and at the end of the treatment to monitor the child's hearing. If hearing damage is detected, the dosage of cisplatin and carboplatin should be reduced based on the severity of the damage, and other drugs or regimens should be considered if necessary.

After the end of chemotherapy, hearing should be tested every six months until five years after the cessation of medication.

3. Complications

1) Tumor rupture and bleeding

In rare cases, large hepatocellular carcinoma may spontaneously rupture and bleed, or rupture and bleed due to iatrogenic puncture. This can seriously threaten the life of children.

The symptoms of tumor rupture and bleeding are related to the amount of bleeding and the site of bleeding. When the tumor is bleeding inside, the symptoms are mild; when the tumor capsule ruptures and bleeds, it can be manifested as severe abdominal pain, peritoneal irritation signs, anemia appearance, increased heart rate, and in severe cases, hemorrhagic shock manifestations.

2) Cardiac toxicity

Aminoglycoside chemotherapy drugs, such as doxorubicin and epirubicin, can cause cardiac toxicity, potentially leading to acute myocardial injury and chronic heart function impairment. Acute myocardial injury is a transient and reversible localized myocardial ischemia, which may present with symptoms like palpitations, shortness of breath, chest tightness, and discomfort in the chest area. Chronic heart function impairment is an irreversible condition characterized by congestive heart failure, which is associated with the cumulative dose of the drug.

Therefore, when using anthracyclines, cardiac function (cardiac enzyme spectrum, troponin, brain natriuretic peptide, echocardiography) should be closely monitored. If the drug causes abnormal cardiac function, the drug should be stopped. At the same time, treatment should be carried out according to the dose of anthracyclines or the degree of myocardial injury.

3) Liver toxicity

During the treatment process, it is necessary to monitor the child's liver function based on clinical conditions, but the frequency of these tests should not be overly frequent. Before each chemotherapy session, a liver function test is typically required to ensure the child can undergo chemotherapy on schedule. During the maintenance phase, tests are conducted every 4 to 8 weeks; if there are no special symptoms, tests can be performed every 12 weeks.

4) Neurotoxicity

Cervicovirine has neurotoxic effects, and a single dose should not exceed 2 mg. Common mild symptoms include jaw pain, constipation, and diminished deep tendon reflexes. Occasionally, it may cause voice disorders. Symptoms of poisoning include persistent abdominal cramps, unsteady gait, severe pain, or syndrome of inappropriate antidiuretic hormone secretion (SIADH). If these symptoms occur, the dose of cervicovirine should be reduced or discontinued.

5) Kidney toxicity

When a child has kidney dysfunction, it can lead to delayed excretion of platinum-based drugs (such as cisplatin and carboplatin), thereby exacerbating their toxic side effects. Therefore, if the child's serum creatinine level is greater than 100 μmol/L or more than twice the normal value, the child should be given hydration through oral or intravenous routes. After hydration, the endogenous creatinine clearance rate (CCR) should be tested, or the glomerular filtration rate (GFR) can be measured using an isotope renal scan.

6) Neutropenia with fever

Chemotherapy can lead to a deficiency of neutrophils in children. If the absolute neutrophil count in peripheral blood is less than or equal to 1.0×10^9/L 24 hours after chemotherapy, granulocyte colony-stimulating factor (G-CSF, commonly known as white blood cell enhancer) or granulocyte-macrophage colony-stimulating factor (GM-CSF) can be administered. This treatment is also suitable for patients who are expected to experience a prolonged neutropenia.

At the same time, children with neutropenia may develop infections that lead to fever, which usually progresses quite rapidly and requires timely and appropriate treatment of the infection. Initial empirical treatment should be given immediately while identifying the pathogen, and targeted treatment should be given after the pathogen is identified.

7) Anemia

Anemia may occur in children during treatment and can generally be relieved by transfusion of red blood cells. If the hemoglobin level is below 60 g /L, transfusion is required.

8) Thrombocytopenia

Platelet transfusion should be given when platelet count is less than 20 x 109 /L, and the indications for transfusion can be relaxed appropriately when there are obvious bleeding symptoms or signs of infection.

9) Pneumocystis infection

Children under treatment are advised to take compound sulfamethoxazole (SMZco) for a long time to prevent Pneumocystis infection until 3 months after chemotherapy.

4. Recurrence

Due to the low incidence of hepatocellular carcinoma in children, there are currently no precise statistics on recurrence rates. In a 2007 study by American scientists, the recurrence rate for children with completely resected and negative margin hepatocellular carcinoma was 45%. In 2010, Finnish scientists published a small, single-center report showing that the recurrence rate for children with hepatocellular carcinoma after liver transplantation was 17%.

At present, there is no particularly effective treatment for recurrent pediatric hepatocellular carcinoma.

Follow-up & Review

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Daily Care

1. General remarks

After the end of treatment, children need regular follow-up to monitor recurrence and long-term effects.

2. Review

Within one year after surgery, liver function should be reviewed monthly, serum alpha-fetoprotein (AFP) level should be checked, B-ultrasound and chest X-ray should be performed, and CT or magnetic resonance imaging (MRI) scan should be performed if necessary. One year after surgery, the above indicators should be reviewed every three months.

Children need to undergo electrocardiogram and echocardiography for 2 years after discontinuation of the drug. Those who use platinum need to undergo hearing examination for 2 years after discontinuation of the drug.

3. Daily life management

1) Diet

It is recommended to provide patients with a nutrient-rich and balanced diet, ensuring the intake of high-quality proteins such as meat, eggs, dairy, poultry, fish, shrimp, soybeans and soy products, and quinoa. Additionally, patients should consume more whole grains, vegetables, and fruits to ensure adequate intake of other essential nutrients. During treatment, patients 'immune systems may weaken, so it is important to avoid expired, spoiled, unclean, or potentially unsafe food. For specific dietary recommendations, consult the hospital's nutritionist.

2) Movement

If the patient's physical condition allows, encourage and assist the patient to do some simple activities. Moderate exercise is helpful in preventing muscle atrophy, enhancing physical strength and endurance, and promoting appetite.

3) Lifestyle

It is important to ensure that patients get enough sleep, as regular and quality sleep can help with recovery and immunity. A suitable sleep environment (usually dark, quiet, and at a comfortable temperature) may help improve the quality of sleep.

If the patient is caused by treatment of neutropenia, attention should be paid to prevent infection. Pay attention to personal and living environment hygiene, do not approach patients with infectious diseases, and do not go to crowded places.

If the treatment causes a decrease in platelets, be careful to avoid bleeding. Stay away from sharp, spiky toys and objects, and avoid strenuous activities such as jumping, soccer, or basketball.

4. Daily disease monitoring

Postoperative complications, chemotherapy side effects (such as hair loss, fatigue, vomiting, etc.), tumor metastasis and recurrence, growth and development problems and other problems should be paid attention to. When fever, worsening symptoms, new symptoms and treatment side effects occur, consult your doctor in time.

5. Special Precautions

All medical records of the child should be kept for future review and reference.

6. Prevention

Hepatitis B virus infection is one of the inducing factors of hepatocellular carcinoma in children. It is necessary to timely vaccinate mothers and children with hepatitis B virus to avoid hepatitis B virus infection.

In addition to hepatitis B virus infection, the causes of hepatocellular carcinoma in children are not well understood and therefore no specific prevention methods are available. However, certain diseases have been identified as associated with an increased risk of hepatocellular carcinoma in children (see "Risk factors"). Therefore, if a child has one of these conditions, liver tumor screening should be considered.

At the same time, once the child is found to have related symptoms, they should seek medical treatment as soon as possible for early diagnosis and treatment.

Cutting-edge therapeutic and clinical Trials

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References

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Audit specialists

Yuan Xiaojun, director of pediatric Hematology and Oncology Department, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine

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