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Hepatoblastoma

Hepatoblastomas

Hepatoblastoma (HB) is the most common hepatic tumor in young children. Early detection is of utmost importance to facilitate complete resection of the neoplasia and thus to improve the patient's prognosis. Even if adjuvant chemotherapy is administered, prognosis significantly worsens if the tumor cannot be removed completely.


Presentation

While an important part of children diagnosed with HB does not display any symptoms, patients may also be presented with general symptoms such as anorexia, nausea and emesis, weight loss and impaired development due to overall weakness. Osteopenia is common and frequently leads to pathologic fractures. To a certain degree, the presence of these symptoms does correlate with the tumor's stage. Hence, a significant part of the patients does already have metastasis at the time of diagnosis. The observation of an enlarged abdomen possibly sensitive to pain and a growing abdominal mass should serve as a clear indicator for HB and prompt further diagnostic measures. HB are more often detected in the right lobe of the liver and measure 5 to 25 cm in diameter.

Hemogram and blood chemistry generally reveal anemia, thrombocytosis, an elevated concentration of alpha-fetoprotein and in some cases of human chorionic gonadotrophin.

Icterus and cirrhosis are not common symptoms for HB. Neither is an acute abdomen that may, however, be provoked by tumor rupture. In cases of tumor rupture and consecutive intra-abdominal hemorrhage, severe anemia can be detected.

Certain congenital diseases are associated with an increased risk for HB and may therefore point the physician to this disease. These disorders include trisomy 13 and 18, the Aicardi syndrome, the Beckwith-Wiedemann syndrome, the Fragile X syndrome, the Goldenhar syndrome, the Noonan syndrome, the Prader-Willi syndrome, the Prune belly syndrome, the Sotos syndrome, familial adenomatous polyposis, hemihypertrophy and neurofibromatosis type 1.

Fever
  • Transient symptoms after MWA were fever, abdominal pain, and massive gross hematuria.[ncbi.nlm.nih.gov]
  • Following significant complications from the chemotherapy (neutropenic fever, pneumonia and sepsis), the patient's parents declined further chemotherapy, and the infant was treated with surgical resection and opioid growth factor (OGF)/low dose naltrexone[ncbi.nlm.nih.gov]
  • Only 1 patient developed a fever with temperature 39  C; it lasted 4 days after radiofrequency ablation (RFA) and was resolved by conservative therapy.[ncbi.nlm.nih.gov]
  • What to call the doctor for: Call your surgeon for fevers (greater than 101 Fahrenheit), redness or drainage from the incision or for any vomiting or diarrhea.[eapsa.org]
  • Medicines and other treatments can be used for pain, fever, infection, and nausea and vomiting. With any cancer, how well a child is expected to recover (prognosis) varies.[stlouischildrens.org]
Rigor
  • INTERPRETATION: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare[ncbi.nlm.nih.gov]
  • Response to chemotherapy has not been rigorously studied but is felt to be much like that of hepatocellular carcinoma.[ 31 ] Treatment of Hepatocellular Carcinoma Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:[cancer.gov]
Short Stature
  • Hepatoblastoma was diagnosed in a 4-year-old girl receiving growth hormone substitution therapy for short stature.[ncbi.nlm.nih.gov]
Euthyroid
  • Serum miR‑206 was significantly decreased in patients with hyperthyroidism compared with euthyroid controls.[ncbi.nlm.nih.gov]
Intestinal Atresia
  • A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed.[ncbi.nlm.nih.gov]
Hepatic Mass
  • […] diagnosis of a patient with a congenital PSS and a hepatic mass.[ncbi.nlm.nih.gov]
  • Although Tc red blood cell (RBC) scintigraphy is a very specific method to differentiate a hemangioma from other hepatic masses, several cases of false-positive Tc RBC scintigraphy have been previously reported throughout the literature.[ncbi.nlm.nih.gov]
  • A right lobe hepatic mass classified as PRETEXT III and congenital absence of the portal vein with drainage of the superior mesenteric vein to the inferior vena cava (Abernethy malformation type I) were confirmed by computed tomography and angiography[ncbi.nlm.nih.gov]
  • Diagnostic imaging should include plain radiographs and ultrasonography of the abdomen to characterize the hepatic mass. Ultrasonography can differentiate malignant hepatic masses from benign vascular lesions.[scribd.com]
  • Dear Editor, A 29-day-old infant was evaluated at our center for a hepatic mass found during gestation.[scielo.br]
Hepatomegaly
  • Abdominal magnetic resonance findings revealed hepatomegaly with multiple tumor masses involving nearly all the segments of the liver (PRETEXT IV). The tumor extended through the inferior vena cava and filled 2/3 of the right atrium.[ncbi.nlm.nih.gov]
  • Virtually all patients were infants or young children with hepatomegaly or a mass.[pubs.rsna.org]
  • Fat planes were clear with portal vein and hepatic artery, likely IHH with hepatomegaly [Figure 1].[mmj.eg.net]
  • The presenting symptom of almost all liver tumors in children is abdominal swelling secondary to hepatomegaly. When confronted with this symptom, it is useful to consider the age at which liver tumors tend to occur (see Table 3).[archivesofpathology.org]
  • On examination: hepatomegaly of 5 cm below the costal border, without splenomegaly or ascites. Blood analysis: hemoglobin and liver function test were normal. Alpha-feto-protein (AFP): 1556.30 UI/mL (normal value: 0-10 UI/mL).[scielo.isciii.es]
Joint Stiffness
  • Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain[emedicine.com]
Cryptorchidism
  • Prune belly syndrome (PBS) is a congenital anomaly characterized by the clinical triad of lax abdominal musculature, bilateral cryptorchidism, and abnormalities of the kidney and urinary tract.[ncbi.nlm.nih.gov]
  • EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions.[ncbi.nlm.nih.gov]

Workup

Diagnosis of HB is based on clinical examination, laboratory results and diagnostic imaging. While the clinical examination should point the physician to a possible hepatopathy, thrombocytosis and an elevated serum level of alpha-fetoprotein are findings that support the suspicion of a hepatic neoplasia. Magnetic resonance imaging (MRI) or computed tomography (CT) scans are applied to confirm the presence of a usually solitary mass in the liver of the patient.

In detail, the following diagnostic measures may lead to a correct diagnosis of HB:

  • Hemogram and blood biochemistry. Typical findings include a normochromic normocytic anemia and thrombocytosis. While only some patients show an increase in serum concentrations of liver enzymes, alpha-fetoprotein can be detected in high concentrations (frequently 100,000 to 300,000 mcg/mL)  in virtually all patients suffering from HB, hepatocellular carcinoma and germ cell tumors [3]. Since alpha-fetoprotein is produced by fetal liver cells, embryonal tumors release less alpha-fetoprotein than fetal neoplasias. It is recommended to use age- and laboratory-specific reference values when interpreting alpha-fetoprotein measurements.
  • Diagnostic imaging. The tumor may only measure a few centimeters in size, but may also grow up to 25 cm in diameter. Although the HB is well delimited, its borders generally appear lobulated. Ultrasonography and abdominal radiography can be applied to evaluate the tumor's size and position. In preparation of surgery, ultrasonographic images may also be used to trace bigger vessels. An abdominal MRI or CT scan may be helpful to detect possible involvement of adjacent tissues. In an MRI, HB usually appear T1 hypointense and T2 hyperintens. Both weightings allow for recognition of fibrous septa dividing the tumor into different sections. Patients may benefit from an early diagnosis achieved with the help of positron emission tomography scanning [4]. Diagnostic imaging should furthermore be employed to check for the presence of metastases and later on for possible recurrence. If bone metastases are suspected, radionuclide bone scanning may be indicated.
  • Pathologic assessment. Tissue material is obtained by biopsy or during surgical intervention and analyzed in order to start pharmacological treatment. Histological analysis of HB most often reveals hepatocytes of different subtypes composing the tumor. Among these subtypes, the fetal subtype is found most frequently and is usually arranged in a typical fetal pattern. Embryonal, macrotrabecular and anaplastic patterns can also be detected. Furthermore, it is possible that epithelial and mesenchymal components constitute a mixed type of HB. HB arise from immature liver precursor cells and do thus present morphologic patterns similar to a developing liver. HB may also originate from pluripotent stem cells [5]. Necrosis is common. Immunohistochemistry generally depicts reactivity with the alpha-fetoprotein, the epithelial membrane antigen, cytokeratin and vimentin.
Liver Mass on Ultrasound
  • Case #2 is a child diagnosed with a liver mass on ultrasound at 20 months of age, later biopsy-proven to represent hepatoblastoma.[ncbi.nlm.nih.gov]
Liver Mass on Ultrasound
  • Case #2 is a child diagnosed with a liver mass on ultrasound at 20 months of age, later biopsy-proven to represent hepatoblastoma.[ncbi.nlm.nih.gov]

Treatment

If at all possible, the HB should be completely resected. Partial hepatectomy is required to achieve complete resection, but significantly improves the patient's prognosis.

Chemotherapy is routinely used post-op to prevent recurrences, but may also be of use before surgical intervention to reduce the tumor's size, particularly if the HB is not resectable upon diagnosis. A combined approach of transcatheter arterial chemoembolization and systemic treatment is generally used.  The majority of HB responds to cisplatin treatments. Of note, the kidney function needs to be checked before first cisplatin administration and should be monitored during chemotherapy. If the HB involves all liver segments and does not regress to a resectable size under chemotherapy, a total hepatectomy with a consecutive liver transplantation should be considered.

Treatment recommendations differ depending on tumor stage and further clinical findings (reviewed in [6]). Unifocal, well delimited tumors are considered standard-risk HB. They shall be treated with a cisplatin monotherapy that has been described before [7]. In brief, surgical resection follows four cycles of preoperative chemotherapy and the patient receives two more cycles of chemotherapy after surgery. On the other hand, if a HB is only diagnosed when metastases are already present or the levels of alpha-fetoprotein are below 100 ng/mL, the tumor is defined as a very high-risk HB. Lung metastases are considered to be confirmed if any nodule larger than 10 mm or several nodules with at least one larger than 5 mm are visible in radiographic images. If these criteria are not met, a biopsy should be taken to clarify the nature of doubtful findings. In the case of a very high-risk HB, a weekly induction chemotherapy with cisplatin and doxorubicin is indicated [8]. Any HB that is neither considered standard-risk nor very high-risk, falls into the category of high-risk HB. In these patients, tumor resection is complicated and recurrences are possible. Treatment recommendations have been given elsewhere [9].

Elevated serum levels of alpha-fetoprotein have been named as a clinical sign for HB, but they may also serve to evaluate response to therapy and to detect possible recurrences.

Prognosis

HB shows locally invasive growth and may metastasize to lungs, CNS and other organs. Therefore, the tumor stage at the moment of diagnosis is the most important factor for the patient's prognosis. If the tumor affects several segments of the liver or is ruptured at the time of diagnosis, the prognosis worsens. Results of histological analysis may also affect the outcome with the fetal pattern being associated with a very good prognosis. These cases usually do not require chemotherapy. On the other hand, the macrotrabecular and anaplastic HB entail a poorer prognosis. The probability of metastasis augments in cases of anaplastic HB. Further indicators for an unfavorable outcome are low initial levels of alpha-fetoprotein (<100 ng/ml) and age (older children have a worse prognosis).

Survival rates are high when the tumor is detected in an early stage and a complete resection is possible. Relapses are rare when a complete resection could be achieved. If the HB is not or only partially resectable, the prognosis worsens considerably and the probability of a recurrence increases. Overall survival rates independent from tumor stage at diagnosis and chosen treatment range between 62% and 70% [1].

Etiology

Hepatoblastoma develops due to as of yet unknown causes. Because it mainly affects young children, it may be suspected that noxious agents affecting their mother before conception or during gestation could increase the risk for HB. These noxious agents may then disturb cell proliferation and differentiation in liver development, which gives rise to aberrant proliferation of undifferentiated cells and consecutive tumor growth [1] [2]. This hypothesis may be supported by the fact that HB is sometimes diagnosed in children suffering from hereditary, congenital comorbidities, however, this holds true for only 5% of HB cases. Most cases are sporadic.

Epidemiology

HB is a rare disease with an incidence of approximately 0.5 to 1.5 cases per 1,000,000 children [1]. Other sources report an even lower incidence of 1 case in every 5,000,000 children. HB accounts for about 1% of all pediatric tumors and is the most common pediatric hepatic tumor with percentages ranging from 25% to more than 60%.

Children diagnosed with HB have an average age of somewhat more than 1 year. The vast majority of HB affects children younger than 5 years. Only few cases of HB in adolescents have been reported and even less in adults. Of note, HB cells are occasionally detected in hepatocellular carcinoma. The prognosis of a patient diagnosed with HB worsens with age.

Boys are affected slightly more often than girls and the male to female ratio is about 1.5-2:1 in Europe. Racial differences do exist as the male to female ratio is augmented in Asia (2.9:1) and white children present HB about five times more often than black children. The outcome, however, is usually worse in black children.

Sex distribution
Age distribution

Pathophysiology

If a young child is diagnosed with an intrahepatic mass and does present thrombocytosis and an elevated serum concentration of alpha-fetoprotein, this may be considered pathognomonic for HB [2]. The tumor is generally unifocal and well delimited and does affect the right lobe of the liver more often than the left lobe. Tumor cells may, however, spread through blood vessels beyond the well delimited, pseudoencapsulated tumor. Metastases manifest themselves in the porta hepatis or in the lungs, and while the CNS may be affected, bones rarely are.

A comprehensive classification system for HB has been established based on cellular subtypes, arrangement of cells and molecular markers.

Prevention

No direct cause of HB could be detected so far. Presumably, noxious agents do affect the mother before conception or during gestation and leave the child predisposed to HB. Various risk factors have been discussed as possible triggers (e.g., drugs of different types, alcohol, tobacco, environmental toxins, but also the mother's reproductive history and birth characteristics) but convincing evidence is still missing [10].

Although no direct prevention is possible, efforts need to be made in order to detect possible neoplasias in early tumor stages. A close monitoring of children at risk is the best way to achieve this.

If a family history of any predisposing disease (see chapter Presentation) is suspected or can be confirmed, diagnostic measures should be undertaken regularly up to the age of 4 to detect any possibly developing HB early. These measures involve examination of serum concentrations of alpha-fetoprotein and abdominal ultrasonography every 3 to 6 months. This recommendation also applies to children suffering from chronic hepatitis B and advanced liver damage or any other pathologic condition leading to cirrhosis. Premature babies weighing less than 1,500 g and born between weeks 23 and 25 of gestation comprise another risk group that should be regularly examined [9].

Similar monitoring  actions are indicated in patients who survived a HB.

Summary

Hepatoblastoma (HB) is the most common pediatric hepatic tumor. It generally affects young children, considerably younger than 5 years, but may also be detected in older children. Although there are several congenital disorders associated with an increased risk for HB, no cause at all can be identified in the majority of HB cases. Overall deterioration of health and unspecific symptoms such as anorexia, nausea and emesis are generally the reason for medical consultation. Since these symptoms usually manifest themselves when the cancer has reached an advanced stage, therapy is rather difficult. The treatment of choice is a complete resection of the tumor, a task that may be facilitated by preoperative chemotherapy. Postoperative chemotherapy is used to avoid recurrences. Only if a complete resection of the HB can be achieved, the prognosis is good.

Patient Information

Although HB is the most common hepatic cancer in children, it is still a rare disease. As is the case with many other types of cancer, no direct cause has been identified.

HB generally affects young children, but may occasionally be detected in adolescents. The overall state of health worsens as the disease progresses, but initial symptoms are rather unspecific and involve loss of appetite, nausea and vomiting. Nevertheless, a physician should be consulted to clarify the origin of these symptoms. If the clinical examination reveals a mass in the upper right part of the abdomen, a liver tumor may be suspected. Blood samples are taken to check the child's blood levels of certain tumor markers and diagnostic imaging helps to visualize the liver and its surrounding organs. If the suspicion is corroborated by the physician's findings, a biopsy may be required, i.e. a small amount of tissue needs to be obtained in order to analyze it.

The prognosis strongly depends on the time of diagnosis. If the cancer is diagnosed early, it may be removed completely and the prognosis is very good. However, if metastases are already present upon diagnosis, the prognosis is poor.

References

Article

  1. Perilongo G, Shafford EA. Liver tumours. Eur J Cancer. 1999 Jun;35(6):953-8; discussion 958-9.
  2. Kaur G, Mutum SS. Hepatoblastoma in a low birth weight infant : a case report and review of the literature. Malays J Med Sci. 2001;8(1):69-72.
  3. Ortega JA, Douglass EC, Feusner JH, et al. Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol. 2000 Jul. 18(14):2665-75.
  4. Figarola MS, McQuiston SA, Wilson F, Powell R. Recurrent hepatoblastoma with localization by PET-CT. Pediatr Radiol. 2005 Dec. 35(12):1254-8.
  5. Ruck P, Xiao JC. Stem-like cells in hepatoblastoma. Med Pediatr Oncol. 2002 Nov. 39(5):504-7.
  6. Aronson DC, Czauderna P, Maibach R, Perilongo G, Morland B. The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. J Indian Assoc Pediatr Surg. 2014;19(4):201-207.
  7. Perilongo G, Maibach R, Shafford E, Brugieres L, Brock P, Morland B, de Camargo B, Zsiros J, Roebuck D, Zimmermann A, Aronson D, Childs M, Widing E, Laithier V, Plaschkes J, Pritchard J, Scopinaro M, MacKinlay G, Czauderna P. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med. 2009 Oct 22;361(17):1662-70.
  8. Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, Branchereau S, Aronson D, Rangaswami A, Ronghe M, Casanova M, Sullivan M, Morland B, Czauderna P, Perilongo G; International Childhood Liver Tumours Strategy Group (SIOPEL). Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol. 2013 Aug;14(9):834-42.
  9. Zsíros J, Maibach R, Shafford E, Brugieres L, Brock P, Czauderna P, Roebuck D, Childs M, Zimmermann A, Laithier V, Otte JB, de Camargo B, MacKinlay G, Scopinaro M, Aronson D, Plaschkes J, Perilongo G. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2010 May 20;28(15):2584-90.
  10. Ikeda H, Hachitanda Y, Tanimura M, Maruyama K, Koizumi T, Tsuchida Y. Development of unfavorable hepatoblastoma in children of very low birth weight: results of a surgical and pathologic review. Cancer. 1998 May 1;82(9):1789-96.

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Last updated: 2019-07-11 22:07