Hepatoblastoma

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This is an interactive discussion between Todd Ponsky, MD and Max Langham, MD on the management of hepatoblastomas.  

Dr. Max Langham is a Professor of Surgery and Pediatrics and the Vice Chairman of the Department of Surgery at the University of Tennessee Health Science Center. 

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I. How do you approach a patient with a newly diagnosed liver mass?
  • You first need a good history and physical.
    • Premature infants have a higher risk of hepatoblastoma.
    • Hepatoblastoma usually occurs in the first couple years of life.
  • Next step is obtain an AFP and this should be automatic.
    • Obtain this even in newborns.The AFP is elevated newborns, but not in the hundred thousands. So it is still helpful. 
  • Obtain a CT Abdomen to further evaluate the mass.
    • This will help determine if the mass is resectable. 
    • You will need a good CT scan with opacification of the portal venous system and hepatic venous system so you can see the boundaries of the tumor.
  • If it is not resectable, then obtain a needle biopsy.
  • The ultimate goal is to get the child to a safe resection.


II. What is the differential diagnosis of a liver mass?

  • Hepatoblastoma
    • This is the most common diagnosis in young children.
    • Hepatoblastoma in children older than 8 years is considered high risk.
  • Rhabdoid tumor
    • This is a small blue round cell tumor that is very aggressive. 
    • Chemotherapy is not very affective in treating this, and they need to be resected. 
  • Congenital hemangioma
    • This is most common in newborns.
    • It is benign and rapidly involuting.
  • Mesenchymal hamartoma
    • This is a benign multicystic mass.
    • They can grow to enormous sizes and require resection. 
  • Hepatocellular cancers 
    • These are associated with inborn error of metabolism, like tyrosinemia. Most are seen later in life. 
    • These patients need to be transplanted in the first couple of years.
  • Mixed tumor: These are hepatoblastoma and HCC. These occur in children over 6 years of age
  • Metastatic tumors, such as metastatic neuroblastoma and Wilm's tumor.


III. How should you perform a biopsy?

  • According to the Children’s Oncology group (https://www.childrensoncologygroup.org), you need a minimum of 10 core biopsies with histology for diagnosis. 
  • A needle biopsy of the liver is favored over surgical biopsy, given the lower complication rate.  This needs to be performed under image guidance.
    • If a needle biopsy is unable to be performed and the surgeon is not comfortable with laparoscopic biopsy, then an open biopsy may be performed. The surgeon will need to obtain a 1 cm sample. 
    • Most common complication after a biopsy is bleeding.
      • These should never be performed as an outpatient.
  • It is critical for the surgeon to go through the liver that will be resected, because hepatoblastoma will seed. 
    • So if it is a right-sided tumor, cross through the right.
  • A multidisciplinary team (surgeon, oncologist, interventional radiologist) need to be onboard to discuss the plan with the pathologist, so the pathologist will be ready to process the specimen.
  • There is no role for frozen sections for hepatoblastomas.


IV. What is the Pretext Staging System (see figure)?

  • The CT scan should be used to understand the anatomy of the tumor.
    • Refer to Strasberg  "Nomenclature of hepatic anatomy and resection: A review of the Brisbane 2000 system”  for a refresher [1].
    • Couinaud originally classified the the liver anatomy based on the districts (arrondissements) of Paris.
  • The Pretext (Pretreatment Extent of disease) staging system is a radiographic imaging based system that was developed in Europe in SIOPEL [2]. 
    • Pretext is a roadmap to determining resectability, and is classified as 1 to 4.
    • Pretext 1 lesions have 3 contiguous sectors of the liver free.
      • This occurs when the lesion is in the left lateral sector or the right posterior sector.
    • Pretext 2 lesions have 2 contiguous sectors free.
      • This can happen three ways: 
        • A right sided lesion with the left hemiliver free.
        • A left sided lesion with the right hemiliver free.
        • A right posterior lesion and left lateral sector lesion with the right anterior and left free. 
  • Pretext 3 lesions have only one sector free.
  • Pretext 4 lesions involve all of the sectors of the liver.


V. What factors make Hepatoblastoma high risk?

  • Age greater than 8 years
  • Presence of metastases
  • Any annotation factors (see below).
  • Low AFP (AFP<100)


VI. When should upfront resection (prior to chemotherapy) be performed? 

  • Based on Children’s Oncology Group study AHEP0731 (https://childrensoncologygroup.org/index.php/ahep0731) and the Pediatric Hepatic International Tumor Trial (PHITT, https://clinicaltrials.gov/ct2/show/NCT03017326), it is ok to perform an upfront resection if it will be:
    • Conventional hepatectomy or less
    • Clearly has 1 cm of normal liver between the middle hepatic vein and the tumor
    • No annotation factors (see below)
    • No involvement of the vena cava or portal vein
  • An upfront resection is better choice than a biopsy.
  • An upfront resection can limit the toxicity of therapy overall by decreasing the chemotherapy needed for possible low risk lesions.
  • Prior to considering an upfront resection, you need to rule out pulmonary metastases.


VII. What are the annotation factors (see table)?

  • These are classified as macrovacular invasion (V, P), multifocality (F), rupture (R), or contiguous extension into neighboring structure (E).
  • A summary of the macrovascular invasion classification is:
    • V0: A lesion that is less than 1 cm from the vena cava or confluence of the hepaticveins
    • V1: Abutting the vena cava or hepatic veins
    • V2: Tumor is big enough to push the veins away
    • V3: Evidence of tumor thrombus
      • Hepatoblastoma can have direct extension of tumor thrombus out of the hepatic veins, into the IVC and even up to the heart.


VIII. What are the different Hepatoblastoma histology types?

  • The following histology types are those with epithelial components [4].
  • Pure fetal histology
    • If an upfront resection can be performed, then chemotherapy is not required.  
    • This is only histology type that can be cured with surgery alone. 
    • Texas Children’s Hospital published how to make the distinction (Lopez-Terrada et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors [3]).
  • Embryonal, and mix fetal/embryonal 
    • These are uncommon and require chemotherapy.
  • Macrotrabecular
  • Small Cell Undifferentiated
    • This is a primitive and high risk tumor.
    • It has a small blue cell morphology with a high nuclear cytoplasmic ratio.
  • Crowded fetal components
  • Pleomorphic


IX. What chemotherapy regimen is used for Hepatoblastoma? 

  • According to AHEP0731 trial, the patients need a total of 6 rounds of a cisplatin based chemotherapy.
    • For patients who are not resectable upfront, they will need chemotherapy upfront. 
      • After two treatments, the surgeon will need to decide if the tumor is resectable or not. If it is resectable, then the surgeon can perform the resection then or after the patient receives an additional two chemotherapy treatments.
    • After resection, patients will need 2 consolidation rounds of chemotherapy.
  • In those that undergo upfront resection, all require chemotherapy except for pure fetal pathology without any metastases.


X. How do you approach pulmonary metastases? 

  • Many will disappear with chemotherapy.
  • If they do not disappear, a biopsy is needed to confirm the lesions are metastatic disease. 
    • Also consider biopsy if there is any question about this being a real metastasis.
  • Once the diagnosis is confirmed, then the patient will require a pulmonary metastectomy.
    • This can be performed either open or thoracoscopically. 
    • Some surgeons will perform the pulmonary metastectomy at the same time as the liver resection, but this would be a very long surgery, so it is recommended to stage the operations. 


XI. When should a patient be referred for a liver transplant? 

  • If the tumor is still found to be unresectable on repeat imaging after the initial 2 courses of chemotherapy, then consider referral to a transplant. 
  • Also refer multifocal tumors for transplant.


XII. What maneuvers can improve safety and success of a liver resection? 

  • Intraoperative ultrasound 
    • This is a great modality to allow you to see the edges of the tumor and also see the vasculature. 
    • It also provides great navigational assistance.
  • Always gain vascular control over the liver prior to starting the dissection.
    • Isolate the suprahepatic vena cava:
      • Dissect up from the falciform ligament to the suprahepatic vena cava, free up the suprahepatic vena cava from the diaphragmatic attachments, and put a loop around the cava above the liver.
    • Also isolate the suprarenal vena cava, and put a loop around it.
    • You can also use the Pringle maneuver instead with a soft clamp, as long as there is not anything anatomic that will prevent you from doing it.
    • Disasters that occur during liver resection are bleeding and air embolism.
      • The vena cava is a low pressure system and a lot of air can go through it and lead to cardiac arrest.
  • Multidisciplinary care should extend to anesthesiology. 
    • It is important to communicate with your anesthesiologist to discuss the fluid management of the patient during the case.
    • Several studies discuss using a hypovolemic type of anesthesia and preserving transfusions until later in the case.
    • It is important to keep a low central venous pressure (CVP), because with a higher CVP, the liver will swell, especially in a baby, making the veins harder to dissect.
  • Take inflow before outflow.
    • Do not interrupt the hepatic veins before you control the inflow, because the liver will swell on you.
  • Perform an anatomic resection.  
    • There are occasions when non-atomic resections are ok, like if there are lesions hanging off a segment.
  • Device choice to dissect through the parenchyma is the surgeon’s choice.
    • Dr. Langham using a hand held Harmonic.
    • Staplers are an option in older children and adults, but in babies, the width of the stapler is usually wider than the margin, and can crush the margin when you put the stapler down, which can give you a false positive margin or cause you to take more than you want. 
    • Vascular staplers are a good option. 
      • Always make sure to perform a test clamp first to confirm you are taking what you want.


XIII. When should you consider vascular reconstruction/extreme resection over a transplant? 

  • A liver transplant has a great 3-5 year disease free survival, but it does come at the expense of requiring life long immunosuppressants, risk of rejection, and secondary malignancy (i.e. post transplant lymphoproliferative disorders).
  • Extreme resection is classified as performing vascular reconstruction, such as the vena cava to get a margin. These may provide equivalent oncologic results to transplant without immunosuppressants.
    • In a recent SIOPEL study, nearly half were resected using conventional resection and did not need a liver transplant [5].
      • In the USA, about 90% of patients with pretext 4 are transplanted.
    • These have a risk of portal hypertension, vascular thrombosis, and possibly leaving residual liver remnants.
  • At this time, it is not known which is best, but the decision should be made the a surgeon that can do both.


XIV. How do you manage positive margins? 

  • Leaving gross disease is not acceptable. 
    • This usually happens when the patient has an emergent resection (i.e. abdominal trauma that causes rupture of the liver tumor).
  • Once the child is stabilized, they will need to be resected to achieve negative margins. 


XV. How do you manage recurrent disease? 

  • Children either relapse locally or in the lungs.
  • If they recur locally in the liver, then they need to be referred for a transplant. Salvage transplantation is not optimal, but may be better than resection.
  • Recurrent pulmonary metastases will need to be re-excised.


XVI. What is the next step after resection? 

  • After resection, the patient will need two rounds of consolidation chemotherapy. 
  • Patients need long term follow up for at least 5 years. 
  • Most recurrences happen within the first 3 years of therapy.


XVII. Is there any role for radiation in Hepatoblastoma treatment?

  • There is no known data for radiation therapy for hepatoblastoma or metastatic pulmonary lesions.


XVIII. Key Points:

  • Hepatoblastoma most commonly occurs in children ages 1-3 years. 
  • Hepatoblastoma in children older than 8 years of age, has a higher risk.
  • Initial workup includes getting an AFP and a CT Abdomen. A CT chest should be performed also to look for pulmonary metastases.
  • If a child has pulmonary metastases, they require upfront chemotherapy. It is up to the surgeon if they would like to obtain a pulmonary mass biopsy to confirm the diagnosis prior to chemotherapy.
  • If the patient has no pulmonary metastases and has a pretext 1 lesion, then an upfront resection is recommended.
  • If pathology returns as pure fetal, then the patient does not require chemotherapy.
  • If cannot perform upfront resection, then they will need an initial 2-4 rounds of chemotherapy. Re-imaging should be performed after the first 2 rounds of chemotherapy. If it is still unresectable, the child will need referral to a transplant center.
  • Risk factors for poor prognosis are subtype other than fetal, age greater than 8 years, and vascular involvement.
  • Key step in the operation is to stop the inflow before the outflow.
  • Method for dissecting the liver parenchyma is up to the surgeon’s preference.
  • Extreme resection with vascular reconstruction is an alternative to transplant, and avoids immunosuppression. The decision though should be made by someone who is able to do both in order to make a good decision. 


RESOURCES

Children’s Oncology Group in the US: https://childrensoncologygroup.org

APSA Handbook for Children with Liver Tumors: http://www.eapsa.org/apsa/media/Documents/Handbooks%20on%20Cancer%20Surgery/Handbook_Liver_Tumors_Spring2015.pdf 

Childhood Liver Tumor Study Group of the International Society of Pediatric Oncology (SIOPEL) in Europe: http://www.siopel.org

Japanese Study Group for Pediatric Liver Tumor: http://home.hiroshima-u.ac.jp/eiso/english/pedlivtumor.html

Max Langham, MD: mlangham@uthsc.edu


REFERENCES

[1]         Strasberg SM. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J Hepatobiliary Pancreat Surg. 2005;12(5):351-355. doi:10.1007/s00534-005-0999-7.

[2]         Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer Oxf Engl 1990. 2000;36(11):1418-1425.

[3]         López-Terrada DH. Hepatoblastoma. Diagn Histopathol. 2014;20(2):67-75. doi:10.1016/j.mpdhp.2014.01.002.

[4]         López-Terrada D, Gunaratne PH, Adesina AM, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. 2009;40(6):783-794. doi:10.1016/j.humpath.2008.07.022.

[5]         Zsiros J, Brugieres L, Brock P, et al. Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol. 2013;14(9):834-842. doi:10.1016/S1470-2045(13)70272-9.

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