Hepatoblastoma

Classification according to ICD-10
C22.2	Hepatoblastoma
ICD-10 online (WHO version 2019)

The hepatoblastoma is a malignant (malignant) embryonic tumor of the liver and belongs to the cancer diseases . It is primarily a disease of infancy and early childhood ; Diseases older than 10 years are rare, but do occur.

Epidemiology

Approx. 0.7% of all malignant diseases in children and adolescents are hepatoblastomas. According to US data from the SEER program, the incidence of hepatoblastomas between the ages of 0-15 years is approximately 1.0 / 1,000,000 children. The median age at the onset of hepatoblastoma is 19 months; only 5% of those affected are older than 4 years. Hepatoblastomas are extremely rare in adulthood, but do occur. Men or boys are more frequently affected than women or girls: for every 1.4 to 2.0 male affected there is 1 female affected. An increase in the incidence of hepatoblastoma of about 5% per year has been observed over the past two decades (SEER data: 1972–1992).

causes

The exact cause or the exact causes of the development of hepatoblastomas are currently not fully understood. However, several properties and factors appear to favor the occurrence of hepatoblastomas or to be related to the occurrence of hepatoblastomas.

Prematurity

Japanese studies show a statistical relationship between premature birth and the occurrence of hepatoblastomas. This is especially true for children with a birth weight of less than 1,000 g. It is currently not certain whether this statistical relationship is coincidental or indicates a cause-effect relationship.

Congenital diseases

The Wiedemann-Beckwith syndrome (also known as Beckwith-Wiedemann syndrome or EMG syndrome) is associated with an increased risk of malignant embryonic tumors. Although the most common malignant embryonic tumor in Wiedemann-Beckwith syndrome is nephroblastoma ( Wilms tumor ), the risk of developing hepatoblastoma is significantly increased for people with Wiedemann-Beckwith syndrome. There is also an increased risk of developing hepatoblastoma if there is familial adenomatous polyposis (abbr .: FAP). The statistical relationship has only been shown in small case series . The cause of the increased development of hepatoblastomas in connection with FAP are obviously mutations in the adenomatous polyposis coli gene (APC gene). Hepatoblastomas may be more common in people with Li-Fraumeni syndrome and people with Prader-Willi syndrome ; however, the connection is not considered certain. In contrast to hepatocellular carcinoma (HCC), congenital diseases such as alpha-1-antitrypsin deficiency or hereditary tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency) are not associated with an increased incidence of hepatoblastomas.

Environmental factors

There is evidence of a connection between the occurrence of hepatoblastomas and harmful environmental influences. Exposure to metal fumes in fathers of children with hepatoblastoma is more common than in children without hepatoblastoma. A causal relationship has not yet been established. In contrast to hepatocellular carcinoma (HCC), steroids obviously do not play a role in the development of hepatoblastoma. Likewise, a chronic infection with the hepatitis B virus, in particular, cannot be associated with the occurrence of hepatoblastomas. To what extent the statistical relationship between preterm birth and the likelihood of occurrence of hepatoblastomas can be attributed to environmental influences remains unclear at present.

Genetic changes

The examination of the chromosomes ( karyotyping ) in hepatoblastoma has shown recurring patterns of pathological changes. The most common change is a trisomy (tripling of a chromosome), which can occur either alone or in conjunction with other structural changes in the genetic material. Trisomies 2 and 20 were observed most frequently, followed by trisomy 8. Loss of chromosome parts ( deletions ) also occur. Translocations of chromosome 1q12 to chromosome 4q34 have been observed in only four cases: however, all affected persons were male and all affected persons had high-risk tumors. Genetic changes that can also occur in other embryonic tumors are, for example, the loss of heterozygosity (LOH) on chromosome 11q15 (gene: p57KIP2). Mutations in the APC gene have also been described.

Symptoms

Hepatoblastomas are usually noticeable as a painless swelling of the abdomen. This swelling is discovered either by the parents or by the doctor. In most cases there are no other symptoms; however, abdominal pain or jaundice ( jaundice ) as a result of an obstruction of the biliary tract are possible. Nausea, weight loss and vomiting can also appear as signs of the disease, and in most cases even indicate the presence of an advanced state of the disease. In male patients, due to the disruption of the hormonal balance, puberty can begin earlier (precocious puberty ).

If there is metastasis, further symptoms can occur. Since the most common place of metastasis is the lungs, there may be shortness of breath, irritation of the throat or, rarely, blood spitting. Metastases in the bones, brain and bone marrow are extremely rare, but can occur and manifest themselves in bone pain, broken bones ( pathological fractures ), restricted mobility, seizures, anemia, fatigue and a tendency to bleed.

Diagnosis

The clinical examination usually reveals the swelling in the abdomen. Sonography is usually used as the first imaging method : an increased echogenicity of the mass in the liver usually indicates a malignant disease, but is not a sure sign of this. Using duplex sonography or Doppler sonography , the vascular supply of a liver tumor can also be assessed. The rule here is that evidence of strong blood circulation or evidence of an abnormally pronounced blood vessel supply is an indication of a malignant disease. Either computed tomography (CT) or magnetic resonance imaging (MRI) is required to be able to determine the extent of a hepatoblastoma . Both examinations should be carried out with contrast media. On CT, calcifications in the tumor can indicate a malignant disease. However, no reliable diagnosis of hepatoblastoma can be made with any imaging method.

In the vast majority of cases (more than 90%) hepatoblastomas produce alpha-1-fetoprotein (AFP). This can be detected in the blood as a so-called tumor marker . AFP is not specific for a hepatoblastoma since it is also produced by malignant germ cell tumors or hepatocellular carcinomas, for example ; In combination with the age of the patient and the findings of imaging by sonography, CT and / or MRI, a suspected diagnosis of hepatoblastoma can be further substantiated. Caution is advised when determining the AFP in the first year of life, since AFP is present in very high concentrations in healthy people during childbirth, which decrease to the level of adults in the course of the first year of life. For children in the first year of life, short-term repetitions of the AFP measurement are therefore usually useful, as they show that there is no natural decline in AFP.

In addition to the imaging tests, the diagnosis should also include a blood count and a measurement of liver enzymes and bilirubin . Some hepatoblastomas (approx. 20% of all hepatoblastomas) are associated with thrombocytosis (increase in platelet counts), which is attributed to the formation of thrombopoietin by the hepatoblastoma. Also frequently are mild and asymptomatic forms of anemia ( anemia observed). Both bilirubin and transaminases such as SGOT and SGPT are usually slightly elevated. Occasionally, hepatoblastomas produce beta-human chorionic gonadotropin (beta-HCG) in addition to AFP .

The AFP can then be used as a tumor marker and indirect indicator of the effectiveness of the therapy. After removal of a hepatoblastoma, normalization of the AFP values ​​can be expected: if this does not occur, a relapse or residual tumor can be assumed until proven otherwise. Even with chemotherapy, AFP levels usually drop as a sign of decline in hepatoblastoma.

Anyone with hepatoblastoma should be screened for certain genetic diseases. Enlargement of the tongue (macroglossia), large umbilical hernia at birth (exomphalus) and enlargement of one half of the body ( hemihypertrophy ), for example, suggest the existence of Wiedemann-Beckwith syndrome (EMG syndrome).

A reliable diagnosis can only be made by taking a sample or removing the hepatoblastoma with a subsequent histological (tissue) examination.

If hepatoblastoma is suspected, CT of the lungs should be performed to rule out lung metastases . Furthermore, a skeletal scintigraphy with 99-technetium-phosphonate is useful to rule out bone metastases .

Differential diagnosis

Other malignant and benign liver tumors must be differentiated from hepatoblastoma . A hepatocellular carcinoma usually occurs in patients with an age of over 10 years. Rhabdomyosarcomas of the liver or biliary tract can be difficult to distinguish from hepatoblastoma: typically, rhabdomyosarcomas of the liver or biliary tract more often lead to jaundice. Often the origin of the tumor can also be differentiated from the hepatoblastoma. Hepatomas (benign liver tumors) can hardly be distinguished from hepatoblastomas: however, measuring AFP is helpful in these cases.

therapy

Primarily operable tumors are treated by segmental resections of the liver or hemihepatectomies (removal of the right or left half of the liver) or by atypical resection. After radical resection without leaving any residual tumor tissue, the chances of survival are good. In the case of primarily inoperable hepatoblastomas, chemotherapy containing cisplatin is carried out first. In this way, most tumors can be reduced to such an extent that an operation with a curative (healing) approach can be carried out. Here the 5-year survival rate is 70–75%. Liver transplantation should be considered if the tumor is inoperable. Alternatively, closure of the vessels supplying the tumor should also be considered. Radiation therapy is not effective.

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• PA Pizzo, DG Poplack: Principles and Practice of Pediatric Oncology . 4th edition. Lippincott Williams & Wilkins Publishers, Philadelphia / Baltimore / New York 2001, ISBN 0-7817-2658-1 .
• JM Schnater, SE Köhler, WH Lamers, D. von Schweinitz, DC Aronson: Where do we stand with hepatoblastoma? A review. In: Cancer . 2003 Aug 15; 98 (4), pp. 668-678. Review. PMID 12910509
• CE Herzog, RJ Andrassy, ​​F. Eftekhari: Childhood cancers: hepatoblastoma. In: Oncologist . 2000; 5 (6), pp. 445-453. Review. PMID 11110595
• G. Perilongo, E. Shafford, R. Maibach, D. Aronson, L. Brugieres, P. Brock, M. Childs, P. Czauderna, G. MacKinlay, JB Otte, J. Pritchard, R. Rondelli, M. Scopinaro , C. Staalman, J. Plaschkes: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Pediatric Oncology - SIOPEL 2. In: European Journal of Cancer . 40, (2004), pp. 411-421.

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