Hepatoblastoma

Summarize

1. General remarks

Overview: Hepatoblastoma (HB) is the most common malignant liver tumor in children, often because parents touch a mass in the abdomen when bathing or changing clothes.

Who is most likely to develop it: 80-90% occur in children under the age of 5.

Manifestation: In the early stage, there are no symptoms, and children often seek medical treatment because of accidental abdominal masses.

Treatment: Chemotherapy and surgery are the main treatments.

Prognosis: The overall survival rate of hepatoblastoma is currently 80%.

2. Disease definition

Hepatoblastoma is the most common malignant liver tumor in childhood, accounting for 90% of primary malignant liver tumors in children. Hepatoblastoma develops from hepatocellular precursor cells.

Epidemiological

epidemiology

Hepatoblastoma accounts for 90% of primary malignant liver tumors in children, with an incidence of about 0.7/1 million to 1/1 million, and 80-90% occur in children under 5 years old. The male to female ratio is 1.5-2:1.

Etiology & Risk Factors

1. General remarks

The cause of hepatoblastoma is not clear. Some genetic diseases and congenital factors are associated with the risk of hepatoblastoma, such as Bev syndrome, familial adenomatous polyposis, and hemiatrophy.

2. Basic causes

Hepatoblastoma develops from hepatocyte precursor cells. However, the exact cause of the disease is not clear.

3. Triggering factors

Some genetic diseases and congenital factors are associated with the risk of hepatoblastoma, including:

● Beckwith-Wiedemann syndrome (BECKWITH-WIEDMAN syndrome): This genetic disorder is caused by abnormalities in genes that control growth and development. It can cause excessive growth in various parts of the body and is associated with an increased risk of many tumors, including hepatoblastoma.

● Familial adenomatous polyposis (FAP): This is a rare hereditary gastrointestinal disease associated with an increased risk of hepatoblastoma.

● Hemihypertrophy: This disease is characterized by excessive growth on one side of the body (left or right), and children with this condition have a higher risk of hepatoblastoma.

● Children infected with the hepatitis B virus are also at increased risk of developing hepatoblastoma.

Classification & Staging

Type of disease

(1) Histological classification

According to histological classification, it can be divided into epithelial type and epithelial and mesenchymal mixed type.

● Epithelial tumors are composed of liver epithelial components at different developmental stages and are divided into:

● Fetal type, further divided into:

● Well-differentiated fetal type (simple fetal type with low mitotic activity, <2/10 high power field): This subtype is completely composed of 1-2 layers of tumor cells similar to fetal hepatocytes, arranged in a fine beam, and does not contain any other tumor components of the subtypes. The prognosis of this subtype is good.

● Congested fetal type (active nuclear division, more than 2/10 high power field): In this subtype, the case samples were arranged in crowded cells under the microscope, with less glycogen content, active nuclear division and obvious nucleolus, and may contain some well-differentiated fetal tumor cells.

● Polymorphic fetal type (differentiated poorly): This subtype of tumors has characteristics similar to those of the fetal or embryonic types, but with irregular nuclear shapes, rough chromatin, and prominent nucleoli. The mitotic figures are more frequent. This subtype is less common and is often observed in post-chemotherapy cases or metastatic lesions of hepatoblastoma. The presence of this subtype does not necessarily indicate a poor prognosis.

● Transformed fetal type (obvious enlargement of nucleus, deep staining, with polymorphism)

● Embryonic type: This subtype is characterized by some tumor cells arranged in sheets and clusters. These cells are small, measuring 10 to 15 μm in diameter, and can be round or irregularly angular. The cytoplasm is sparse, and the nuclear-to-cytoplasmic ratio is significantly increased. Tumor cells often form structures resembling glands, acini, or pseudoglands. This subtype is typically found mixed with fetal-type tumor cells.

● Small cell undifferentiated (SUC): This subtype of tumors contains small, undifferentiated cells. These cells are arranged in bundles or nests, slightly larger than lymphocytes, with a diameter of about 7-8 μm. They have minimal cytoplasm, fine chromatin, and indistinct nucleoli. Additionally, these cells express CK8/18 and vimentin but do not express alpha-fetoprotein (AFP) or Glypican-3, which means that the alpha-fetoprotein levels in children with this subtype may not be elevated. This subtype can be further classified into INl1-positive and INl1-negative types, and overall, the prognosis is less favorable compared to other subtypes.

● Coarse large lamellar type: the arrangement of tumor cells shows obvious coarse lamellar structure, usually the thickness of the lamellar is more than 6 layers of tumor cells, and a certain number of fetal or embryonic hepatoblastoma areas can be seen in the tumor.

● Biliary cell type: Some tumor cells of this type show biliary differentiation and express biliary epithelial markers (such as CK7, CK19, etc.).

● Epithelial and mesenchymal mixed tumors, which consist of not only liver epithelial components, but also other sources of epithelial and mesenchymal tumor components. This type is further divided into:

● Mixed type with teratoma-like features: this subtype of tumor is mixed with non-hepatic epithelial components, such as primitive endoderm, neural tube-like structures, melanin, squamous epithelium and glandular epithelium and other heterogenous components.

● Mixed type of mesenchymal origin (without teratoma-like features): In addition to the epithelial component, various mature or immature mesenchymal components can be seen in this subtype of tumor. The most common mesenchymal components are osteoid tissue, cartilage tissue and striated muscle tissue.

(2) Disease staging

Hepatoblastoma is currently staged according to two staging systems: pretreatment staging (PRETEXT) and preoperative staging after chemotherapy (POST-TEXT), and the improved COG Evans staging system.

● Pre-text staging before treatment and pre-text staging before surgery 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-TEXTI: The tumor was confined to one liver region, and the other three adjacent liver regions were not invaded by the tumor.

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

PRETEXT/POST-TEXTⅲ: 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.

● Improved COG Evans staging system

Ia stage: complete tumor resection, histopathological type was simple fetal type.

Ib stage: complete tumor resection with histopathological types other than simple fetal type.

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

Stage iii: the mass has visible residue; or basic resection with positive lymph nodes; or tumor rupture or peritoneal bleeding;

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

(3) Disease risk grouping

Currently, the treatment of hepatoblastoma in China is based on PRETEXT staging, COG staging, the level of alpha-fetoprotein (AFP) at diagnosis, pathological subtypes, and the presence of distant metastasis. These factors are combined with the risk stratification criteria from the SIOPEL and COG collaborative groups, taking into account the specific conditions in China. Children diagnosed with hepatoblastoma are categorized into four groups: extremely low-risk, low-risk, intermediate-risk, and high-risk.

● Extremely low risk group: postoperative COG stage I, and histopathological type of well-differentiated simple fetal type.

● The low-risk group meets any one or more of the following:

● Patients with serum alpha-fetoprotein levels of ≥100 ng/ml at PRETEXTI stage I or II, excluding the following conditions: invasion of the portal vein (P+), inferior vena cava or hepatic veins (V+), distant metastasis (M+), extrahepatic intra-abdominal disease (E+), tumor rupture or peritoneal hemorrhage (H+), and lymph node involvement (N+).

● Postoperative COG stage was stage I or II, and histopathological type was non-simple fetal type and non-small cell undifferentiated type.

● The intermediate risk group meets any one or more of the following criteria:

● PRETEXT stage III before surgery.

● Postoperative COG stage was stage I or II, and histopathological type was undifferentiated small cell.

● Postoperative COG stage was stage III.

● The high-risk group meets one or more of the following criteria:

● Serum alpha-fetoprotein <100 ng/ml.

● PRETEXT IV stage before surgery.

● Postoperative COG stage was IV.

● Invasion of the portal vein (P+) and inferior vena cava or hepatic veins (V+).

Clinical Manifestations

1. General remarks

The symptoms of hepatoblastoma are related to the size of the tumor and whether it has metastasized. In the early stage, there are no symptoms, and children often seek medical attention because of an accidental abdominal mass.

2. Typical symptoms

The early symptoms of hepatoblastoma are not obvious, and the child usually looks well. Some may have mild anemia, but there are usually no other symptoms. After that, the tumor grows rapidly, and abdominal mass may appear, which is the most common symptom of hepatoblastoma, and is the reason why most children seek medical attention.

Other clinical manifestations include abdominal distension, abdominal pain, loss of appetite, dizziness, vomiting, etc. In the late stage of the disease, jaundice, ascites, fever, anemia, weight loss may occur, and dilated veins may appear on the abdominal wall.

3. Accompanying symptoms

In a small number of patients, there may be signs of precocious puberty due to the secretion of human chorionic gonadotropin. If the tumor compresses the nerves, it may also cause back pain. In advanced stages, if the abdominal tumor is large, it may cause breathing difficulties

Clinical Department

1. General remarks

The early symptoms of hepatoblastoma are not obvious, and when there are obvious symptoms (such as abdominal mass), the tumor is usually already large. Therefore, once related symptoms are found, you should seek medical attention as soon as possible. Early detection and early treatment.

The diagnostic criteria for hepatoblastoma are:

● Children with abdominal masses, typical imaging manifestations of hepatoblastoma and abnormal elevation of serum alpha-fetoprotein.

● Typical imaging findings: Abdominal CT scans reveal a single or multiple solid masses primarily composed of soft tissue within the liver, with abundant blood supply. These masses can invade major blood vessels and show calcification foci and cystic necrosis. Abdominal ultrasound shows a single solid mass; in some cases, multiple lesions may be present, with clear margins and slightly enhanced echogenicity.

The diagnosis of hepatoblastoma is based on the results of pathological examination after tumor resection or puncture sampling.

2. Department of treatment

Oncology, pediatrics, pediatric surgery

Examination & Diagnosis

(1) Laboratory tests

● Serum alpha-fetoprotein (AFP) level test: Most children with hepatoblastoma show abnormally elevated serum AFP levels, which correlate with the severity of their clinical condition. Additionally, detecting serum AFP isotypes aids in diagnosing hepatoblastoma and is valuable for differentiating residual lesions from newly formed liver tissue.

● Other hematological biochemical tests: liver function (alanine transaminase, direct bilirubin), kidney function (urea nitrogen, creatinine, uric acid), creatinine clearance rate, blood/urine β2 microglobulin, electrolyte series, serum lactate dehydrogenase (LDH), ferritin, myocardial enzyme spectrum, coagulation function.

● routine blood test

● Urinalysis and stool analysis

● Viral infection detection: hepatitis B, hepatitis C, cytomegalovirus (CMV), EB virus (EBV), infectious disease screening before blood transfusion (in addition to hepatitis B and hepatitis C antibodies, syphilis and HIV tests should also be carried out).

● Immunological function (IgG, IgM, IgA, peripheral blood T cells, B cells and NK cell subpopulation ratio and absolute value) can be checked when necessary.

(2) Imaging examination

● Abdominal ultrasound examination: can determine the size, structure and nature of the mass, and understand whether there is tumor thrombus formation in the portal vein and hepatic vein.

● Chest CT (plain scan or enhanced): can be used to determine whether there is lung metastasis.

● Abdominal 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 MRI (MRI, stages III and IV) and a whole body bone scan may also be required if necessary.

(3) Pathological examination

Pathological analysis is essential for the definitive diagnosis of hepatoblastoma, aiding in the classification and staging of the disease. Samples are typically obtained through biopsy, either surgically or by puncture. For smaller tumors that can be completely resected, surgical removal followed by pathological examination is common. For larger tumors, a biopsy is usually performed first (using a coarse needle, open surgery, or laparoscopic surgery) to confirm the diagnosis, stage the cancer, and assess the risk level before proceeding with chemotherapy and subsequent surgical removal. Specific tests include:

● Histomorphological observation under microscope.

● Detect alpha-fetoprotein (AFP), phosphatidylinositol proteoglycan 3, β-linked protein, glutamine synthetase (GS), waveform protein, hepatocyte antigen, integrase interaction factor (INI1).

● Detection of CK7, CK19, CD34 and Ki-67 can help to indicate whether the tumor is differentiated into cholangiocellular cells, clarify the number of hepatocyte cords between hepatic sinusoids and the proliferation index of tumor cells.

(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

(1) Hepatocellular carcinoma

Hepatocellular carcinoma is more common in older children (mostly aged 10-14), and it represents a lower proportion of primary malignant liver tumors in children. When the hepatitis B virus test is positive, it is particularly important to differentiate hepatoblastoma. Hepatoblastoma typically features alternating light and dark structures, cells of similar size and shape, and extramedullary hematopoiesis between cells. In contrast, hepatocellular carcinoma cells exhibit significant differences, lacking alternating light and dark structures and extramedullary hematopoiesis. The coarse trabecular type of hepatocellular carcinoma can be easily confused with the coarse large trabecular type of hepatoblastoma. Although both types of tumors show a clear coarse trabecular structure, a closer examination reveals that the coarse large trabecular type of hepatoblastoma contains typical fetal or embryonic areas, which are absent in the coarse trabecular type of hepatocellular carcinoma.

(2) Infantile hepatic angioendothelioma

Infantile hepatic angiosarcoma is a common benign liver tumor in children, particularly in infants under 6 months old. Common symptoms include diffuse abdominal distension, abdominal swelling, an abdominal mass, jaundice, and respiratory distress, which can be easily confused with hepatoblastoma. It can typically be differentiated through a plain CT scan, and serum alpha-fetoprotein (AFP) levels can also serve as an auxiliary diagnostic tool.

(3) Liver germ cell tumor

Liver germ cell tumors primarily include teratomas, yolk sac tumors, and choriocarcinomas. Primary liver germ cell tumors in children are extremely rare. Symptoms may include abdominal distension, nausea, vomiting, and sometimes jaundice. Some patients may also experience elevated serum alpha-fetoprotein levels, which can be confused with hepatoblastoma. These conditions can be differentiated through pathological examination.

(4) Hepatic mesenchymal hamartoma

Hepatic mesenchymal hamartoma is a rare benign liver tumor that primarily affects children under 5 years old, with most cases diagnosed in children under 2. The primary symptoms include abdominal distension, and some patients may experience jaundice, breathing difficulties, nausea, and vomiting. These symptoms can be confused with those of hepatoblastoma. However, hepatic mesenchymal hamartomas typically do not cause elevated serum alpha-fetoprotein levels, and their histopathology differs significantly from that of hepatoblastoma, aiding in differentiation.

(5) Cholangiocarcinoma

Cholangiocarcinoma is rare in children. Common symptoms include jaundice, skin itching, weight loss, decreased appetite, and fever. It can sometimes be confused with cholangiocoblast hepatoblastoma. The tissue of cholangiocarcinoma typically exhibits typical adenocarcinoma features, with significant fibrous proliferation, which helps to differentiate it from cholangiocoblast hepatoblastoma.

(6) Liver metastasis of other malignant tumors

The liver metastasis of some malignant tumors is easy to be confused with undifferentiated small cell hepatoblastoma, such as neuroblastoma, lymphoma, Ewing's sarcoma, embryonal rhabdomyosarcoma and small round cell tumor of connective tissue hyperplasia. It can be identified by the following aspects:

● Site of tumor occurrence. If the imaging can clearly identify the tumor in the liver, the possibility of hepatoblastoma is high.

● Traces of hepatocyte differentiation. If a small amount of cytoplasmic glycogen, lipid vacuoles or bilirubin can be found in the sample, the possibility of hepatoblastoma is high.

● If extramedullary hematopoietic cells can be found, the possibility of hepatoblastoma is high.

● Immunohistochemistry, electron microscopy and other tests can also be used to assist in diagnosis.

Clinical Management

1. General remarks

The treatment for hepatoblastoma primarily involves a combination of surgery and chemotherapy. If the patient is suitable for immediate surgery (refer to the 'Surgical Indications for Initial Surgical Resection' section below), surgery can be performed first, followed by chemotherapy as needed. For patients who are not suitable for immediate surgery (refer to the 'Indications for Delayed Surgery' section below), chemotherapy should be administered first, followed by delayed surgery if necessary. In rare cases, liver transplantation or interventional treatments may be required.

Liver cell carcinoma must be comprehensively evaluated before treatment. If the patient has distant metastasis, chemotherapy should be given first.

2. Surgery

If the patient's condition meets the indications for initial surgical resection, surgery can be performed first and chemotherapy can be carried out as needed. If the patient's condition does not meet the indications for initial surgical resection, neoadjuvant chemotherapy can be performed first, and then surgery can be performed after the tumor meets the indications for delayed surgical resection.

(1) Indications for surgical resection at first diagnosis

● American Society of Anesthesiologists rating 1 to 2.

● After imaging evaluation, the residual liver tissue is greater than 35% of the original volume and the function can meet the metabolic needs.

● Pretexti, single tumor lesions in stage II, with sufficient gap (≥1 cm) from important blood vessels.

● Residual under the microscope (COG II) is expected and no second surgery is required.

(2) Indications for delayed surgery

● For patients in stage III and IV, the surgery will be postponed after neoadjuvant chemotherapy is performed after a definitive diagnosis is made by biopsy.

● For patients who are assessed as POST-TEXT I, II, or POST-TEXT III without major blood vessels (portal vein or inferior vena cava) involved after chemotherapy, hepatic resection or segmental resection may be performed.

● For children who are assessed as POST-TEXT stage III after PRETEXT IV and chemotherapy, with inferior vena cava (V+) or portal vein (P+) involvement, they should be transferred to hospitals with the ability to perform complex hepatic resection or liver transplantation as soon as possible.

● For patients with residual lung or brain metastases after chemotherapy, surgical resection of residual lesions can be performed.

3. Chemotherapy

Patients were treated in groups according to different risk levels, and the efficacy was evaluated regularly, and the treatment regimen was adjusted when necessary.

● Children in the extremely low-risk group did not receive chemotherapy after surgery and were closely followed up.

● Chemotherapy regimen for low-risk group: C5V regimen (cisplatin +5-fluorouracil + vincristine). Each chemotherapy cycle is 21 days, and the total course of treatment is 4 ~ 6 cycles.

● Chemotherapy regimen for the intermediate risk group: C5VD regimen (cisplatin +5-fluorouracil + vincristine). Each chemotherapy cycle is 21 days, and elective surgery is performed after 2 ~ 4 cycles of chemotherapy. The total course of treatment is 6 ~ 8 cycles.

● Chemotherapy regimen for the high-risk group: Each chemotherapy cycle lasts 21 days, with three cycles of cisplatin and doxorubicin. After these three cycles, an evaluation is conducted. For patients who are suitable for surgical resection, postoperative chemotherapy is continued with a carboplatin and doxorubicin regimen, with a total course of 6 to 10 cycles. For patients who are not suitable for surgical resection, the regimen is changed to ifosfamide, carboplatin, and etoposide, with a total course of 8 to 10 cycles.

4. Liver transplantation

If the patient is assessed as POST-TEXT stage IV or POST-TEXT stage III after neoadjuvant chemotherapy and is accompanied by important vascular involvement such as hepatic vein or inferior vena cava, and cannot be operated, liver transplantation can be considered.

5. Other treatments

The following treatments can be tried for patients who do not achieve complete remission after standard treatment:

(1) Interventional therapy (TACE)

Interventional therapy involves injecting chemotherapy drugs into the liver through an artery to increase the local concentration of drugs and kill more effectively. The following children can be considered for interventional therapy:

● The most suitable children for interventional treatment are those with PRETEXT stage III or above and/or lung metastasis who cannot be surgically removed after standard treatment.

● Children waiting for liver transplantation. Interventional treatment can control the progression of tumors during the waiting period;

● After 3 cycles of systemic chemotherapy, new lesions appeared in imaging, and the tumor did not shrink significantly or the degree of shrinkage was less than 50%.

It is important to note that if the patient has any of the following conditions, interventional therapy should not be performed: a positive iodine allergy test or a significant allergic constitution; poor overall health with severe heart, liver, or kidney failure; Child-Pugh C grade with a main portal vein tumor thrombus (PVTT); severe systemic infection or inflammation at the puncture site; intrahepatic arteriovenous fistula; or coagulation disorders.

(2) Radiofrequency ablation therapy (RFA)

Radiofrequency ablation can be tried for multiple hepatoblastomas that cannot be operated after chemotherapy.

(3) High intensity focused ultrasonic knife therapy

High intensity ultrasound focused knife can also be used for refractory multifocal children who have not undergone liver transplantation or residual after surgery.

Prognosis

1. General remarks

At present, the overall survival rate of hepatoblastoma is about 80%. The factors affecting the prognosis are:

● Pre-treatment staging (PRETEXT): PRETEXTI, II and III stages have a better prognosis than stage IV.

● The following characteristics and prognosis are relatively poor before treatment: invasion of portal vein (P+), invasion of inferior vena cava or hepatic vein (V+), distant metastasis (M+), extrahepatic abdominal disease (E+), multiple tumors (F+), tumor rupture (R+).

● COG stage: The prognosis of children with COG stage Ia is better.

● Tumor resection: children with complete tumor resection have a relatively good prognosis.

● Fetal alpha-fetoprotein (AFP) level at diagnosis: children with serum AFP <100 ng/mL (100-1000 ng/mL for infants) at diagnosis (high-risk group) have a relatively poor prognosis.

● Pathological subtypes: well-differentiated fetal type (simple fetal type with low mitotic activity, <2/10 high power field) has a better prognosis, while poorly differentiated small cell type (SUC) has a relatively poor prognosis.

● Age: The prognosis of children aged 6 months to 5 years is relatively good. The prognosis is poor for those older than 8 years, and they are listed as high-risk groups for chemotherapy.

● Whether there is metastasis at diagnosis: children with metastasis at diagnosis have a relatively poor prognosis.

2. Complications

(1) Tumor rupture and bleeding

In rare cases, hepatoblastoma may spontaneously rupture and bleed, or rupture and bleed due to iatrogenic puncture. This can be a serious threat to the patient

The safety of the baby.

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, accelerated heart rate, and in severe cases, hemorrhagic shock manifestations.

For treatment, surgical hemostasis or interventional therapy can be chosen. If the child cannot undergo surgery, medical treatment can be administered, including activity restriction and abdominal band compression dressing. In cases of hemorrhagic shock, immediate anti-shock treatment should be provided, which may involve the infusion of coagulation factors, plasma, and hemostatic drugs.

(2) Cardiotoxicity

Aminoglycoside chemotherapy drugs, such as doxorubicin, 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 irreversible congestive heart failure, which is associated with the cumulative dose of the drug.

Therefore, when using anthracycline drugs, it is essential to closely monitor cardiac function, including myocardial enzyme levels, troponin, brain natriuretic peptide, and echocardiography. When the cumulative dose of doxorubicin reaches or exceeds 400 ng/m2, caution is advised when using anthracycline drugs. If the medication causes cardiac dysfunction, the drug should be discontinued. Additionally, based on the dose of the anthracycline drugs or the severity of myocardial damage, treatments such as dexpanthenolamine and L-carnitine may be considered.

(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 recommended every 4 to 8 weeks; for children without specific symptoms, testing can be done 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 isotopic renal scan.

(6) Hearing impairment

Platinum-based chemotherapy drugs, such as cisplatin and carboplatin, can cause approximately 60% of infants to experience varying degrees of bilateral permanent, progressive high-frequency hearing loss. Therefore, it is essential to conduct hearing tests before the first chemotherapy session, every two treatment cycles, and at the end of the chemotherapy 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 medications 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.

(7) 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 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.

(8) Anemia

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

(9) Thrombocytopenia

Platelet transfusion should be given when the 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.

(10) Prevent Pneumocystis infection

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

3. Recurrence

There are few cases of recurrence of hepatoblastoma. The criteria for diagnosis and recurrence are as follows: biopsy confirmed, clear imaging evidence, and serum alpha-fetoprotein (AFP) increased for three consecutive times within 4 weeks.

At present, there is no standard therapy for recurrent hepatoblastoma. It is usually combined with surgery, chemotherapy, liver transplantation, radiofrequency ablation (RFA) and other methods. The prognosis is related to the recurrence site, the treatment of the primary tumor and the specific condition of the child.

Follow-up & Review

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Daily Care

1. General remarks

Follow the doctor's advice to complete the treatment and maintain a good living habit. After the end of the treatment, regular follow-up should be conducted to monitor the recurrence and long-term effect. At the same time, in daily life, children should be provided with a balanced diet, encouraged to do moderate activities, and given positive encouragement in emotion.

2. Follow-up

First year after treatment: monthly physical examination and serum alpha-fetoprotein (AFP) level, chest X-ray and abdominal MRI or abdominal B-ultrasound every 3 months.

2-3 years after treatment: physical examination every 6 months, serum alpha-fetoprotein (AFP) level, chest X-ray and abdominal MRI or abdominal B-ultrasound.

In the 4th to 5th year after treatment, a physical examination every 12 months is recommended, along with serum alpha-fetoprotein (AFP) tests, chest X-rays, and abdominal B-ultrasound. If the child has lung metastasis during treatment, a chest CT scan is required. The schedule is as follows: once every 3 months in the first year, once every 4 months in the second year, and once every 6 months in the third to fourth years.

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) Rest and exercise

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'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.

(2) 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.

4. Special Precautions

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

5. Daily disease surveillance

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.

6. Prevention

Because the cause of hepatoblastoma is not known, there is no specific prevention. However, certain diseases have been linked to an increased risk of hepatoblastoma (see "Risk factors"). Therefore, if a child has one of these conditions, regular screening for hepatoblastoma should be performed.

At the same time, because the early symptoms of hepatoblastoma are not obvious, and when there are obvious symptoms, the tumor is usually already larger, so once related symptoms are found, they should be treated as soon as possible for early diagnosis and treatment.

Cutting-edge therapeutic and clinical Trials

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References

1.https://www.stanfordchildrens.org/en/topic/default?id=hepatoblastoma-90-P02728

2.https://www.chop.edu/conditions-diseases/hepatoblastoma-liver-cancer

3. Treatment of pediatric liver cancer PDQ Professional edition: https://www.cancer.gov/types/liver/hp/child-liver-treatment-pdq#_581_toc

4. Pediatric liver cancer treatment PDQ patient version: https://www.cancer.gov/types/liver/patient/child-liver-treatment-pdq

5. Expert Group for the Preparation and Review of the Diagnosis and Treatment Guidelines for Hepatoblastoma in Children (2019 Edition). Diagnosis and treatment guidelines for hepatoblastoma in children (2019 edition). Journal of Clinical Hepatology and Biliary Diseases. 2019,35(11):2431-2434.

6. Chinese Anti-Cancer Association Pediatric Tumor Professional Committee and the Oncology Group of the Chinese Medical Association's Pediatric Surgery Branch. Expert Consensus on Multidisciplinary Diagnosis and Treatment of Pediatric Hepatoblastoma (CCCG-HB-2016). Chinese Journal of Pediatrics. 2017,38(10):733-738.

7. Pediatric Pathology Group of the Chinese Medical Association's Pathology Branch, and the Pathology Professional Committee of the Fuchang Children's Medical Development Research Center. Expert consensus on hepatoblastoma pathology. Chinese Journal of Pathology. 2019,48(3):176-181.

8.https://rarediseases.info.nih.gov/diseases/9331/childhood-hepatocellular-carcinoma

9. Zhou Ying, Gu Xiaohong, Xi Wenhua, Zhu Ming. CT manifestations of infantile hepatic hemangioendothelioma. 2009.15:64-67.

10. Wang Hongbo, Liang Hongyuan, and Lu Zaiming. CT and MR diagnosis and differential diagnosis of pediatric hepatic mesenchymal hamartoma. Chinese Journal of Clinical Medical Imaging. 2015.26(7):483-486.