Cancer, Hepatoblastoma


Article Author:
Sierra Musick


Article Editor:
Hani Babiker


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
12/1/2018 11:28:26 PM

Introduction

Hepatoblastomas are the most common primary malignant liver tumor in pediatric patients, occurring mostly within the first 2 years of life.[1] The histologic types are subdivided into 2 broad categories: epithelial type and mixed type. Over the last 3 decades, the treatment has advanced with neo-adjuvant chemotherapy now the standard of care for most cases. Neo-adjuvant chemotherapy and surgical resection produce a cure rate of approximately 70%, a vast improvement over the dismal 30% cure rate in the 1970s. Prognosis is based on many factors including alpha-fetoprotein levels, age at the time of diagnosis, completeness of resection, and clinical stage of the disease.[2]

Etiology

Most tumors are sporadic, but one-third of cases may be associated with Beckwith-Weidemann, familial adenomatous polyposis (FAP), Edward syndrome (trisomy 18), nephroblastoma, and Down syndrome.[3] Low birth weight infants are at higher risk of developing a hepatoblastoma and evidence has shown an association with preeclampsia and parental tobacco smoking before and during pregnancy.[3][4] Other factors thought to play a role in pathogenesis include oxygen therapy, certain medication (furosemide), radiation, plasticizers, and total parenteral nutrition (TPN).[2]

The most common genetic mutation involves the Wnt signaling pathway which results in the accumulation of beta-catenin; these mutations are present in a higher proportion of the sporadic cases.[5] By immunohistochemistry, beta-catenin usually shows a membranous staining pattern in the more differentiated fetal types and nuclear staining pattern in the less differentiated histologic types.[6] In aggressive cases, activation of TERT (human telomerase reverse transcriptase) and MYC signaling has been shown[2]

Epidemiology

Hepatoblastoma is a rare tumor comprising approximately 1% of all pediatric tumors.[7] The incidence rate is slowly increasing in North America and Europe, and there is a slight male predominance.[8]

Histopathology

Hepatoblastomas originate from primitive hepatic stem cells that give rise to the epithelial components of the liver. Classically, these tumors are divided into 2 broad categories: epithelial type (E-HB) and mixed epithelial and mesenchymal type (MEM-HB). Revision of this original classification system resulted in the pathology consensus of the pediatric hepatoblastoma classification system, which retained the subdivision of the histologic types into 2 broad categories, as described above. The epithelial type is subdivided into fetal, embryonal, macrotrabecular small cell undifferentiated (SCU), and cholangioblastic variants, while the mixed type is subdivided into stromal derivatives and teratoid variants.

The fetal subtype is further stratified into 4 categories: well-differentiated; crowded or mitotically active; pleomorphic, poorly differentiated; and anaplastic. The well-differentiated variant is characterized by a low power view demonstrating alternating light and dark areas due to variable cytoplasmic glycogen content. Assessment at higher power reveals a uniform population of hepatocytes arranged in trabeculae that are 2to 3 cells thick. Extramedullary hematopoiesis is a typical finding, and mitotic rate is low. Description of the other variants is beyond the scope of this article.

The embryonal subtype is the most commonly encountered subtype and consists of basophilic cells with scant cytoplasm and increased mitotic rate that is arranged in nests, trabeculae, acini, pseudorosettes, or sheets. The macrotrabecular subtype is arranged in trabeculae that are more than ten cells thick. The SCU subtype consists of dyscohesive, uniform round cells arranged in sheets with increased mitotic activity. Some cases of SCU have a loss of INI1, suggesting a possible association with primary rhabdoid tumors of the liver. The cholangioblastic variant has bile ducts, typically located at the periphery of the epithelial sheets.

The mixed subtype contains a variable combination of epithelial and mesenchymal components. Most commonly, the epithelial component is fetal or embryonal, and the mesenchymal component is osteoid. Stromal derivatives include spindle cells, osteoid, skeletal muscle, and cartilage. Teratoid features include primitive endoderm, neural derivatives, melanin, squamous and glandular elements.[2]

History and Physical

Hepatoblastomas usually present with as a single, mildly painful, rapidly enlarging abdominal mass that arises in the right lobe of the liver in 55% to 60% of cases.[9] Rapid enlargement of these tumors rarely results in tumor rupture and hemorrhage. Tumors may reach up to 25 cm in size. Most tumors are solitary; however, up to 15% of tumors are multifocal. Some cases are associated with non-specific symptoms such as weight loss, failure to thrive or anorexia.[7] Significant elevations of alpha-fetoprotein (AFP) are observed in 90% of patients, and rarely, a paraneoplastic syndrome can occur.

Evaluation

Ultrasound (US) and either computed tomography (CT) or magnetic resonance imaging (MRI) are the imaging modalities used to define the extent of tumor involvement of the liver and aid in pre-surgical planning. A chest CT can help detect lung metastasis as up to 20% of cases present with metastases; the lung is the most common location of metastases.[7] After imaging, a biopsy, alpha-fetoprotein level, liver function tests, and a hepatitis panel are performed as needed.

Treatment / Management

Surgical resection is the mainstay of treatment with resectability of the tumor determining the need for neo-adjuvant or adjuvant chemotherapy. At presentation, approximately 60% of tumors are unresectable.[10] If unresectable and chemotherapy fails to shrink the tumor to a resectable size, a liver transplant can be done and has a good long-term survival rate.[11] The benefit of radiation therapy is unclear, with some unresectable cases responding well. Alpha-fetoprotein levels are useful for tracking surgical success and whether the tumor has metastasized.[9] An increased risk of post-transplant lymphoproliferative disorder after immunosuppression for liver transplant has been suggested in some publications.[6]

Differential Diagnosis

The differential diagnosis includes hepatocellular carcinoma (HCC), focal nodular hyperplasia, hepatic adenoma, lymphoma, and metastases. HCC can appear similar to the macrotrabecular subtype of hepatoblastoma, however, usually affects an adult patient population with risk factors such as metabolic disorders, liver cirrhosis, or childhood hepatitis B infection. Focal nodular hyperplasia usually affects older children and adults. Hepatic adenoma can resemble pure fetal hepatoblastomas; however, these rarely occur in persons under 5 years of age unless they have an underlying metabolic disorder.

Staging

The Children’s Hepatic Tumors International Collaboration (CHIC) constructed a staging and risk stratification system intended to standardize the assessment of this tumor across the globe. This new staging system is called the Children’s Hepatic Tumors International Collaboration – Hepatoblastoma Stratification and incorporates confirmed prognostic factors from prior risk stratification systems with new additional factors to stratify patients into 4 risk groups.

Found to be most predictive are AFP levels, patient age, Pretreatment Extent of Disease (PRETEXT) group (I, II, III, or IV), the presence of metastases, and PRETEXT annotation factor. PRETEXT group is based on the extent of the tumor in the liver. PRETEXT annotation factor is determined to be positive if at least 1 of the following 5 factors are present: involvement of the vena cava or all 3 hepatic veins, or both (V); involvement of portal bifurcation or both right and left portal veins, or both (P); extrahepatic contiguous tumor extension (E); multifocal liver tumor (F); tumor rupture at diagnosis (R). Gender, low birth weight, prematurity, and Beckwith-Wiedemann syndrome were not found to be significant. Of note, the histologic type was not included in this risk stratification system but may be incorporated at a future date. Validation of these risk groups is in progress.[2][12]

Prognosis

Prognosis is based on numerous factors including age of diagnosis, PRETEXT group, metastases, alfa fetal protein (AFP) levels, histologic subtype, completeness of resection, and clinical stage of the disease.  With certainty, the well-differentiated fetal subtype is associated with a better prognosis compared with small cell undifferentiated and macrotrabecular, which are linked to unfavorable prognosis.[12] Alfa-fetoprotein is typically high upon diagnosis, but a significant drop after neo-adjuvant chemotherapy portends a better response to treatment. Younger age of diagnosis has historically been a poor prognostic factor; however, recent studies have called this into question, providing evidence that these younger patients do just as well as older children.[13]  Specifically, children younger than 1 year of age have a better prognosis and children greater than 6 years of age have a worse prognosis.[2] Tumor presence at the resection margin, multifocality, and metastases have been shown to be poor prognostic factors. Beta-catenin expression has been shown to be associated with a lower period of event-free survival, while EpCAM expression has been associated with higher tumor viability and a poorer response to neo-adjuvant chemotherapy.[14][15]

Complications

  • Intraperitoneal tumor rupture
  • Complications related to chemotherapy
  • Post-transplant complications
  • Psychosocial effects of treatment and painful procedures

Enhancing Healthcare Team Outcomes

Improved clinical outcomes are achieved when hepatoblastomas are managed by an interprofessional team consisting of a pediatrician, oncologist, radiologist, pediatric surgeon, and a transplant specialist.[16] After surgical resection, these children are monitored by intensive care unit (ICU) nurses, therapists, dietitians, and an intensivist.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Cancer, Hepatoblastoma - Questions

Take a quiz of the questions on this article.

Take Quiz
One-third of hepatoblastomas are associated with Beckwith-Wiedemann syndrome, familial adenomatous polyposis, Edward syndrome (trisomy 18), nephroblastoma, and which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
The histological subtype of hepatoblastoma associated with the best prognosis is which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 2-year-old boy presents with right-sided abdominal swelling that his mother first noticed in the bathtub 2 months ago. It has been increasing in size, and the boy now has a decreased appetite and mild pain in the area. Ultrasound and magnetic resonance imaging were performed and demonstrated a solitary liver mass. To stage this tumor, what is the best next step?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What entity typically is not in the differential diagnosis of hepatoblastoma in a child?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 3-year-old boy is diagnosed with a hepatoblastoma. Which of the following is most likely true regarding this boy's tumor?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Cancer, Hepatoblastoma - References

References

Shanmugam N,Scott JX,Kumar V,Vij M,Ramachandran P,Narasimhan G,Reddy MS,Kota V,Munirathnam D,Kelgeri C,Sundaram K,Rela M, Multidisciplinary management of hepatoblastoma in children: Experience from a developing country. Pediatric blood     [PubMed]
Czauderna P,Lopez-Terrada D,Hiyama E,Häberle B,Malogolowkin MH,Meyers RL, Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Current opinion in pediatrics. 2014 Feb     [PubMed]
Finegold MJ,Lopez-Terrada DH,Bowen J,Washington MK,Qualman SJ, Protocol for the examination of specimens from pediatric patients with hepatoblastoma. Archives of pathology     [PubMed]
Heck JE,Meyers TJ,Lombardi C,Park AS,Cockburn M,Reynolds P,Ritz B, Case-control study of birth characteristics and the risk of hepatoblastoma. Cancer epidemiology. 2013 Aug     [PubMed]
Curia MC,Zuckermann M,De Lellis L,Catalano T,Lattanzio R,Aceto G,Veschi S,Cama A,Otte JB,Piantelli M,Mariani-Costantini R,Cetta F,Battista P, Sporadic childhood hepatoblastomas show activation of beta-catenin, mismatch repair defects and p53 mutations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2008 Jan     [PubMed]
Ng K,Rana A,Masand P,Patel K,Heczey A,Goss J,Himes R, Fatal Central Nervous System Post-Transplant Lymphoproliferative Disease in a Patient Who Underwent Liver Transplantation for Hepatoblastoma. Journal of pediatric gastroenterology and nutrition. 2018 Jan     [PubMed]
Zhong S,Zhao Y,Fan C, Hepatoblastoma with pure fetal epithelial differentiation in a 10-year-old boy: A rare case report and review of the literature. Medicine. 2018 Jan     [PubMed]
Pateva IB,Egler RA,Stearns DS, Hepatoblastoma in an 11-year-old: Case report and a review of the literature. Medicine. 2017 Jan     [PubMed]
Hiyama E, Pediatric hepatoblastoma: diagnosis and treatment. Translational pediatrics. 2014 Oct     [PubMed]
Meyers RL,Tiao G,de Ville de Goyet J,Superina R,Aronson DC, Hepatoblastoma state of the art: pre-treatment extent of disease, surgical resection guidelines and the role of liver transplantation. Current opinion in pediatrics. 2014 Feb     [PubMed]
Uchida H,Sakamoto S,Sasaki K,Takeda M,Hirata Y,Fukuda A,Hishiki T,Irie R,Nakazawa A,Miyazaki O,Nosaka S,Kasahara M, Surgical treatment strategy for advanced hepatoblastoma: Resection versus transplantation. Pediatric blood     [PubMed]
Meyers RL,Maibach R,Hiyama E,Häberle B,Krailo M,Rangaswami A,Aronson DC,Malogolowkin MH,Perilongo G,von Schweinitz D,Ansari M,Lopez-Terrada D,Tanaka Y,Alaggio R,Leuschner I,Hishiki T,Schmid I,Watanabe K,Yoshimura K,Feng Y,Rinaldi E,Saraceno D,Derosa M,Czauderna P, Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. The Lancet. Oncology. 2017 Jan     [PubMed]
Dall'Igna P,Brugieres L,Christin AS,Maibach R,Casanova M,Alaggio R,de Goyet JV,Zsiros J,Morland B,Czauderna P,Childs M,Aronson DC,Branchereau S,Brock P,Perilongo G, Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group. Pediatric blood     [PubMed]
Kiruthiga KG,Ramakrishna B,Saha S,Sen S, Histological and immunohistochemical study of hepatoblastoma: correlation with tumour behaviour and survival. Journal of gastrointestinal oncology. 2018 Apr     [PubMed]
Wu JF,Chang HH,Lu MY,Jou ST,Chang KC,Ni YH,Chang MH, Prognostic roles of pathology markers immunoexpression and clinical parameters in Hepatoblastoma. Journal of biomedical science. 2017 Aug 29     [PubMed]
Sharma D,Subbarao G,Saxena R, Hepatoblastoma. Seminars in diagnostic pathology. 2017 Mar     [PubMed]
L�pez-Terrada D,Alaggio R,de D�vila MT,Czauderna P,Hiyama E,Katzenstein H,Leuschner I,Malogolowkin M,Meyers R,Ranganathan S,Tanaka Y,Tomlinson G,Fabr� M,Zimmermann A,Finegold MJ, Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2014 Mar;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Urologic. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Urologic, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Urologic, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Urologic. When it is time for the Surgery-Urologic board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Urologic.