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Hepatoblastoma as a Result of APC Gene Mutation

Krawczuk-Rybak, Maryna*; Jakubiuk-Tomaszuk, Anna; Skiba, Elzbieta*; Plawski, Andrzej

Journal of Pediatric Gastroenterology and Nutrition: September 2012 - Volume 55 - Issue 3 - p 334–336
doi: 10.1097/MPG.0b013e318232d4db
Case Reports

*Department of Pediatric Oncology and Haematology

Department of Paediatric Laboratory Diagnostics, Medical University of Bialystok, Bialystok

Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.

Address correspondence and reprint requests to Prof Maryna Krawczuk-Rybak, MD, PhD, Department of Pediatric Oncology and Haematology, Medical University, 15-274 Bialystok, ul.Waszyngtona 17, Poland (e-mail:

Received 26 February, 2011

Accepted 15 August, 2011

The authors report no conflicts of interest.

Hepatoblastoma is a rare early childhood neoplasm occurring in patients with genetic disorders, such as trisomies of chromosomes 18, or inherited predispositions to some neoplastic diseases, including Beckwith-Wiedemann syndrome and familial adenomatous polyposis (FAP) (1). The observed increase in the risk of hepatoblastoma in APC (adenomatous polyposis coli) gene mutation carriers is low, not exceeding 1%, which is associated with APC gene mutation located in the region of codons 459 to 1309, where most mutations identified in families affected by FAP in Poland are found. Tissues obtained from patients with hepatoblastoma but without the diagnosis of FAP show loss of heterozygocity at the locus of APC or MCC (mutated in colorectal cancers) genes. Hepatoblastoma growth is the result of the sequence of changes in genetic material. A major role can be ascribed to the Wnt pathway where somatic mutations have been observed in the genes of B-cathenin (CTNNB1, Cathenin [cadherin-associated protein], β-1.88 kD), and AXIN1 (axis inhibitor 1) (2,3). We present a case of familial hepatoblastoma in a 3-month-old infant with a constitutional mutation in the APC gene.

A female infant ages 3 months (Fig. 1. IV, 4) was admitted to the department for the diagnosis and treatment of abdominal tumor. The index case was born after an uneventful pregnancy with routine antenatal scanning carried out during the pregnancy, which was unremarkable. Parents are healthy and unrelated. This was her mother's fourth pregnancy; the first and third pregnancies ended with miscarriages in 1st trimester (Fig. 1. IV, 1 and 3). Second pregnancy resulted in a girl born at 36th week who died at age 14 months with the diagnosis of multiple congenital defects: congenital hydrocephalus, spina bifida, anorectal malformations, and cardiac anomaly. Her chromosomal analysis was normal: 46, XX (Fig. 1. IV, 2).



On admission, the physical examination revealed a large hard tumor, bulging in the whole abdominal cavity. Additional tests found thrombocythemia (701 × 10−3/μL) and elevated levels of α-fetoproteins (331.000 ng/mL) and β-human chorionic gonadotropin (75.81 mU/mL). The ophthalmic examination showed congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the eye fundus. Computed tomography scan visualized a pathological 120 × 95 × 74-mm mass, visible from the left dome of the diaphragm to the pelvis and from the anterior abdominal integument to the prespinal space, with smooth contours and heterogeneous structure, dislocating the adjacent organs. Distant metastases to other organs were not found. Open biopsy was performed to obtain tumor tissue, as the picture of the disease was equivocal (liver tumor/secreting embryonal tumor). Surgical procedure revealed a large and solid encapsulated tumor, arising from the left hepatic lobe, 526.6 g in mass, which was resected as a whole, together with the second and third liver segments within the normal parenchyma. Hepatoblastoma was diagnosed by histopathological examination, having a predominant fetal form, focally with small fields of the embryonic pattern. The girl was then treated according to the SIOPEL 3 program (cisplatin in monotherapy). Presently, the patient is in remission (1 year).

The analysis of the APC gene was performed, taking into consideration the positive family history: 4 cases of colon cancer in young adults in the 1st and 2nd degree of kinship and hepatoblastoma in a 3-year-old boy (mother's cousin's son–the proband), with diagnosis of APC gene mutation (c.3164–3165delTA) (Fig. 1. IV, 8), who was treated successfully. The proband's father was identified with the same constitutional mutation and experienced colon cancer at age 28 years (Fig. 1. III, 9). Three other members of that family had previously died of colon cancer. They were patient's maternal grandmother (died at age 51), maternal grandmother's brother (died at age 38), and their mother (died at age 45) (Fig. 1. II, 2, 3 and I, 2).

The child was subjected to a genetic test after obtaining an informed consent from her parents. Molecular analysis of the APC gene was conducted on DNA isolated from peripheral blood lymphocytes as described by Plawski et al (4). The carrier state of frame shift mutation (c.3164–3165delTA) was found. The mutation leads to premature termination of the APC gene protein product (5). After the mutation was confirmed, the genetic test was performed on her parents. Constitutional mutation of APC gene was identified in patient's mother. She had the colonoscopy at age 26. It revealed numerous polyps carpeting the entire colon and rectum (Fig. 1. III, 2). Histological examination of biopsied specimens revealed findings of poorly differentiated adenocarcinomas. Further molecular analysis APC gene showed 6 unaffected members, respectively (Fig. 1. III, 1, 3, 6, 11, 12 and II, 7). One member of this family didn’t accept molecular analysis (Fig. 1. III, 8).

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The presented case refers to the development of hepatoblastoma in a child at genetic risk, with a family history of early colon cancer in the course of FAP. FAP is a syndrome associated with high predisposition to neoplastic disease, inherited in a dominant autosomal way, related to APC suppressor gene mutations located on chromosome 5q21. A mutated allele of APC gene increases the risk of the second mutation and thus initiation of the neoplastic disease. Patients with FAP also develop parenteral symptoms, including CHRPE, which was found in the presented case (6). This alteration is observed in >50% of APC gene mutation carriers. CHRPE is associated with mutation locus in the APC gene and does not occur if the product of the mutated gene is <50 kD. Exon 9 is considered borderline between mutations that cause CHRPE and those that do not. Codon 1387 toward the 3′ part of the APC gene is considered borderline of CHRPE. In the presented case, mutation occurs in codon 1055 of the APC gene and is located in the fragment of the gene, in which mutation is related to CHRPE, as described in literature.

Not many cases of hepatoblastoma in children with a family history of FAP have been reported (7–9). Also in the presented case, 2 family members were diagnosed with hepatoblastoma. Based on these data, however, we cannot demonstrate the relation between c.3164–3165delTA and predisposition to hepatoblastoma. The c.3164–3165delTA mutation was described in the German population, but hepatoblastoma was not reported in its carriers (5,10). In the case of our patient, 5 other family members with FAP did not develop hepatoblastoma. Nevertheless, the occurrence of hepatoblastoma in 2 members of FAP-affected family is a rare phenomenon. Also, reproduction failures and death of one of the children at a very young age due to multiple congenital defects should be emphasized.

FAP is associated with an increased risk of hepatoblastoma compared with the general population. The risk is many times higher in APC gene mutation carriers, accounting for 0.42%, whereas the prevalence of hepatoblastoma in the population is estimated to be 1 of 100,000 (0.0001%). This is a few 100-fold increase; however, it is not possible to narrow the risk group. Cases of hepatoblastoma coexisting with FAP have been described in carriers of mutations located at codons 459–1309 of the APC gene. This region has 2 hot sites of mutations in the APC gene, codons 1061 and 1309, and the majority of mutations detected in the APC gene are located in that region.

In the reported case, there remains the problem of the APC gene mutation carrier state. This is associated with a high risk of FAP symptoms and a high risk (100%) of turning malignant. Cases of hepatoblastoma coexisting with FAP are rare and there have been no suggestions of exacerbation or acceleration of polyposis coli symptoms. The diagnosed mutation is located in the region associated with severe FAP. Polyps develop at a mean age of 15 years (11), although they are also found in patients ages 7 to 25 years, the youngest patient being 5 years old (7,11,12). Thus, the definite statement that our patient is at risk should be followed by appropriate prophylaxis, that is, regular examinations to assess the lower segment of the colon (sigmoidoscopy, colonoscopy). According to American Gastroenterological Association, for the children with genetic diagnosis of FAP, it is recommended to introduce annual sigmoidoscopy or colonoscopy within the age of 10 to 12 years. The upper endoscopies (stomach, duodenum) are also indicated (every 6 months–4 years) depending on the polyp burden (11,13). If the polyps are not detected until the age of 25 years, sigmoidoscopy/colonoscopy will be repeated biannually, and as of age 35 years, every third year. Additionally, periodic sonograms for early detection of pancreatic cancer and desmoid tumor as well as thyroid examination are also recommended. Regarding early hepatoblastoma detection in children of FAP parents, some experts propose to examine α-fetoprotein levels and image the liver (sonogram) from the birth up to age 5 to 10 years. To minimize the risk of colorectal cancer in patients with FAP with adenomatosis, the prophylactic, cancer-preventive colorectal surgery (colectomy) is advised (11,13). Genetic counseling is proposed for FAP families; even prenatal diagnosis can be performed (amniocentesis), although identification of gene mutation can lead to psychological problems, such as anxiety and cancer phobia (14).

In summary, we presented a child diagnosed for hepatoblastoma, derived from a family with positive history of colon cancers as well as hepatoblastoma, and the presence of APC gene mutation.

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