Study shows increase in liver transplantation for hepatoblastoma while improving outcomes  



Liver transplantation for hepatoblastoma, the most common liver malignancy in children, is on the rise because more tumors are being detected earlier, improving outcomes for these sick patients, according to a study by Children Hospital of Pittsburgh of UPMC.

Results of the study, “Analysis of national and single-center incidence and survival after liver transplantation for hepatoblastoma: New trends and future opportunities,” led by Rakesh Sinshi, MD, codirector, Pediatric Transplantation at the Hillman Center for Pediatric Transplantation at Children’s Hospital, were published in the February 2013 issue of Surgery.

Dr Sindhi and the group observed outcomes in 35 children with hepatoblastoma who received transplants over three decades at Children’s Hospital, making this the largest published single center experience in the United States. Nearly twice as many patients received liver transplants for the malignancy at Children’s Hospital in the most recent decade compared to the previous two decades. This observation led the group to ask whether the incidence of this malignancy and of liver transplantation for hepatoblastoma has increased in the United States, thereby posing additional challenges in allocating the scarce resource of pediatric livers available for transplantation, and whether increased use of liver transplantation has improved post-transplantation outcomes for children diagnosed with this form of cancer.

To evaluate national trends, the researchers reviewed data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry representing 9.451% of the U.S. population from 1975 to 2007; the United Network for Organ Sharing (UNOS) from 1988 to 2010; and Children’s Hospital from 1987 to 2011.

The group found that estimated hepatoblastoma cases in the United States increased four-fold between 1975 and 2007, liver transplantation for hepatoblastoma during the last two decades increased 20-fold between 1988 and 2010, with 153 liver transplants occurring in the last 5 years, and hepatoblastoma surpassed other inoperable liver malignancies requiring liver transplantation from 2.8% to 7.5%.

“For several years, it has been recognized that many children with hepatoblastoma were born early. Advances in the care of premature babies, and their increased survival as a result, is an important reason for the increased incidence of this tumor,” said Dr Sindhi.

Estimates suggest that more than six in 10 children with hepatoblastoma can be cured with surgical removal of the mass after chemotherapy. Liver transplantation is appropriate if the tumor is confined to the liver, but cannot be removed safely because of its location or involvement of many parts of the liver. Three of four children treated with transplantation can be cured.

Recurrences usually occur within the first two years after transplantation in one-sixth of children undergoing liver transplantation. Recurrences are more common if the liver tumor was accompanied by spread to other organs before transplantation, or if the tumor was less responsive to chemotherapy. Remarkably, if the tumor outside the liver is removed completely with either chemotherapy or surgery before transplantation is undertaken, half of such children can still be cured with liver transplantation. In this regard, hepatoblastoma tumors are very different from the liver cancer that can develop in adult and older age groups. They also found that hepatoblastoma tumors with “anaplastic” or highly aggressive tumor cells were less likely to recur after liver transplantation than what has been reported previously after surgical resection. 

Rakesh Sindhi, MD, is co-director of Pediatric Transplantation and director of Pediatric Transplant Research at Children’s Hospital of Pittsburgh of UPMC. Dr Sindhi received his medical degree from the Armed Forces Medical College in Pune, India and completed general surgery residency at the Tufts-New England Medical Center in Boston, MA. He completed a transplant surgery fellowship at the University of Nebraska in Omaha, NE, and immunology research fellowship at Children’s Hospital of Cincinnati in Ohio. Dr Sindhi joined the transplant surgical faculty at UPMC in 1998 after similar positions at the UC-Davis Medical Center in Sacramento, CA, and the Medical University of South Carolina in Charleston, SC. Since 1999, Dr. Sindhi has performed pediatric liver and intestinal transplantation at Children’s Hospital of Pittsburgh of UPMC. Dr Sindhi’s clinical interests include liver transplantation for cancer, outcomes assessment and prediction, and development of novel immunosuppressive strategies. His research interests include personalized prediction of post-transplant outcomes and identification of novel pathways for congenital organ failure using cellular and genomic discovery methods. Dr Sindhi has authored or co-authored three patents, 101 publications, and has licensed non-invasive blood tests to predict transplant rejection. Email:

Case study: Hemophagocytic Lymphohistiocytosis (HLH)

By Alexandra (Lisa) H. Filipovich, MD, Director of the Immune Deficiency and Histiocytosis Program at Cincinnati Children’s Hospital Medical Center  

This case study describes diagnosis and treatment performed in the HLH Center in the Cancer and Blood Diseases Institute at Cincinnati Children’s Hospital Medical Center. A two-year girl was referred from the United Arab Emirates with history of relapsing HLH, a lifethreatening genetic condition. The only curative therapy is hematopoietic cell transplantation (HCT).

Clinical history

At 18 months of age, the patient fell ill with fevers, skin rashes, irritability and loss of appetite. Soon after admission to the local hospital, she developed respiratory distress and severe swelling requiring mechanical ventilation and hemodialysis. She was found to be in liver failure, with very low blood counts and persistently elevated blood markers of inflammation. A bone marrow biopsy revealed hemophagocytosis (bone marrow cells “eating” normal blood cells), the hallmark of HLH. Treatment was started with steroids and chemotherapy. Although some symptoms improved initially, her condition worsened one month later and a recurrence of active HLH followed soon after. The disease had spread to involve the brain.

Our approach

Soon after, the family came to Cincinnati for additional diagnostic testing and curative treatment with HCT. Although the patient had siblings who appeared to be perfect matches for the transplant, not enough was known about the genetic cause of her disease and the possibility existed that one of the matching siblings could also be at risk to develop HLH. This is where the capabilities of the Diagnostic Immunology Laboratory (DIL) and the Molecular Genetics division at Cincinnati Children’s came into play. These clinical laboratories are the only ones in North America that can test for all known genetic causes of HLH. In short order, the causal gene defect was identified in the sick child and other siblings were found not at risk for the same condition. The patient’s older brother was identified as the bone marrow donor.

In the meantime, the patient required on-going chemotherapy and high dose steroids, as well as chemotherapy delivered directly into the spinal fluid (intrathecal chemotherapy) to better control the HLH in the brain. After months of illness and high dose steroid treatment, she gained a great deal of weight, contributing to poor mobility, bed sores, and heightened risk of infections.

The HCT was performed at two years of age. Due to the patient’s condition, we used a reduced intensity course of pre-transplant chemotherapy (RIC). Studies at Cincinnati Children’s comparing outcomes of RIC versus conventional HCT for HLH had shown that post-transplant survival following RIC was superior to the conventional approaches to pre-transplant chemotherapies (90% vs. 50% long-term disease-free survival). Although the patient still required some intrathecal chemotherapy post HCT, she began to strengthen and achieved a full recovery with normal brain function in a matter of months. She was able to return to the U.A.E. before her third birthday, cured of HLH. At a follow up visit to Cincinnati Children’s one year later, the patient appeared svelte and energetic – a normal, happy child.


While this child was fortunate to have a perfect match for HCT, not all patients with HLH will have suitable HCT donors and other therapeutic approaches are being developed to control the disease. Current research at Cincinnati Children’s is investigating the feasibility of gene therapy for patients without suitably matched HCT donors, and the use of small molecule therapy for cases of HLH in adults that tend to be milder, but recurrent. Molecular studies are underway to unravel the complex immunology of active HLH disease in order to identify targeted biologic agents with fewer side effects.

Once universally lethal, HLH is now curable. 

Case study: Anorectal malformation  

By Shumyle Alam, MD, Director of the Urogenital Center at Cincinnati Children’s Hospital Medical Center

This case study describes work at Cincinnati Children’s Hospital Medical Center that identified a set of urologic concerns including a neurogenic bladder in a child referred primarily for treatment of his anorectal malformation (ARM).

Clinical history

The patient was born with an anorectal malformation and left hydronephrosis. He was born to a G4P5 healthy female. Family history was positive for kidney stones on his father’s side. After birth, he had a colostomy performed and urology consultation obtained for hydronephrosis of the left kidney (Figure 1). He also suffered from multiple urinary tract infections. The urologic opinion was to perform an incision of the stricture of the ureter using an endoscopic technique and place a stent. No mention was made of the urinary tract infections.

The family elected to bring the child to the Colorectal Center at Cincinnati Children’s for care of the ARM and to defer urologic care until after the surgery.

Our approach

A trigger list was constructed by Shumyle Alam, MD, and the Urogenital Center nurses to help the Colorectal Center identify patients at increased risk for urologic problems associated with ARM. The list defined at-risk children who might need urologic intervention, assessing their long term needs and risk for renal damage.

Diagnosing neurogenic bladder

This patient was identified as high risk for urologic problems based on his history of hydronephrosis, urinary tract infection, and known bladder neck fistula. His chart was forwarded to our office and a testing and evaluation plan was determined.

A nuclear medicine glomerular filtrate (GFR) study was performed as well as a voiding cystourethrogram (VCUG) and MRI of the spine. The VCUG demonstrated grade V vesicoureteral reflux (Figure 2). The GFR demonstrated normal overall renal function and the MRI demonstrated a normal spinal cord without evidence of tethering.  

The family was counselled at length regarding the bladder neck fistula. It was previously expected that children with ARM and normal spinal imaging would have good bladder function after ARM repair. Based on our experience at Cincinnati Children’s, we now know that this group of males with ARM represents the most concerning patient population regarding bladder dysfunction.

Plans were made to initiate clean intermittent catheterization after his ARM repair, if necessary.

Surgical course

Dr. Alberto Peña performed repair of the ARM and Dr Alam performed the cystoscopy to delineate the patient’s anatomy in March 2011. The patient recovered without incident, but as predicted, failed his voiding trial and was placed on intermittent catheterization. A team of nurses in the Urogenital Center helped the family learn catheterization and it went without incident. The success of the intervention was directly related to assessing the patient’s needs, preparing the family before surgery, and having a team of individuals to support and teach the parents after surgery.

A video-urodynamics study confirmed a neurogenic bladder. A lasix renal scan demonstrated symmetric renal function but delayed drainage of the left side. Once catheterizations were achieved without difficulty, a left sided extravesical reimplant was performed at the time of the colostomy closure.

The patient recovered without incident; after a few months, he was brought back to the OR for a dismembered pyeloplasty as the hydronephrosis did not resolve. During surgery, he was found to have a crossing vessel causing the hydronephrosis. (Figure 3). This was a very important finding, as it was not a stricture but a vascular anomaly. An incision would have resulted in massive blood loss. The patient recovered without incident and is now dry of urine, with normal renal function bilaterally, and his bowels are managed with enemas.


This case demonstrates the benefit of multidisciplinary evaluation that all patients receive at the Colorectal Center and Urogenital Center at Cincinnati Children’s. All charts are reviewed and the trigger list helps ensure that no urologic conditions are missed.

The patient described had a unique set of conditions that were addressed efficiently in one visit. We have learned that a thorough evaluation and treatment plan before surgery helps to minimize anaesthetics, improves family understanding and expectations, and may result in better outcomes. A collaborative, multidisciplinary model helps achieve these goals. 

The Hospital for Sick Children
Collaborating with partners around the world to advance the health of children

As the largest paediatric academic health sciences centre in Canada and one of the world’s leading centres for child health, The Hospital for Sick Children (SickKids) collaborates with partners around the world to advance the health of children through integrated child health education, research and clinical initiatives.

Through SickKids International, with its international advisory services and International Patient Office, SickKids engages in opportunities to enhance child health and build sustainable system capacity. Undertaking research and providing education and care in the global context is essential to fulfilling SickKids’ vision for Healthier Children. A Better World. SickKids furthers this vision by contributing to paediatric sustainability and self-sufficiency for health systems across the globe.

A large part of SickKids’ international work is focused on offering paediatric education and training to health-care professionals around the world. Education services are customized to specific learning needs and can take place at SickKids in Toronto, Canada, or in the health-care professionals’ home country.

SickKids also provides high-quality advisory services to governments, organizations and institutions that are engaged in healthcare delivery. These collaborations draw on the expertise and experience of Sick- Kids’ team, a diverse network of skilled and knowledgeable professionals spanning the range of children’s health concerns.

“It is rewarding to see our expertise and innovations being culturally adapted and implemented in other parts of the globe and having a significant impact on improving the quality of life of children worldwide,” said Cathy Séguin, Vice-President of International Affairs at SickKids. “Our strategy is to share our knowledge and help other organizations build capacity in their own countries.”

SickKids’ international programs have reached children in more than 75 countries. SickKids is currently providing advisory services to centres in Qatar, India and Ireland, and education and training to more than 110 people from more than 20 countries.

SickKids in Qatar

SickKids recently celebrated the third anniversary of its international partnership project with Hamad Medical Corporation (HMC) in Doha, Qatar. A five-year partnership between SickKids and HMC was signed in February 2010 to provide advisory services for the development and operation of a new 217-bed, 45,000-square foot, state-of-the-art children’s hospital. The facility SickKids is helping to create will be the first hospital in Qatar specializing in paediatric care. Located in Sidra Medical and Research Centre, a large, not-for-profit healthcare complex in the heart of Doha, this project has been designed according to international best practice standards in paediatric care and will have a tremendous impact on health care in Qatar.

The project’s scope encompasses every aspect of paediatric health care in the country, from primary to tertiary paediatric services, with a focus on developing paediatric clinical programs, developing staff through education and training, and developing child health research in Qatar. Working with its partners in Qatar to share international best practices in paediatric care, SickKids staff is providing expertise in the areas of paediatric medicine, surgical services, interprofessional practice and education, family-centred care and research.

To improve the academic standards of paediatricians in Doha, SickKids has provided substantial training in continuing education, faculty development and enhancement of the residency program.

On the national stage, the work Sick- Kids’ staff is doing with their partners in Doha is influencing policies for children’s health in Qatar. SickKids team members from Oncology and Child Psychiatry are providing primary consultancy advice for the Qatar National Strategies in each of these specialties.

Educational events, such as the Nursing Leadership Symposium and Child Health Research Day, two areas where SickKids and HMC are working hard to create a strong foundation for future growth, demonstrate the collaborative relationship between SickKids and HMC.

The nursing symposium explored the many ways nursing leaders can take positive action through evidence-based best practices and research, and the benefits such action can have on patient care. Speakers at the symposium included nursing professionals from both SickKids and HMC. Open to researchers in HMC and across Qatar, the annual Child Health Research Day highlights the importance of research in a world-class paediatric health organization and showcases the child health research done by HMC investigators.

“The Qatar project continues to be an incredible experience for the SickKids staff who are able to share their expertise in paediatric care,” said Séguin. “It’s exciting to see how our work to establish a state-ofthe- art children’s hospital in Qatar has blossomed to include learning experiences such as the nursing symposium and research day, which will further enhance child health services for Qatar.”

 Date of upload: 18th Jul 2013


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