Childhood Liver Cancers Liver tumors comprise less than 5 percent of all childhood cancers. The most common forms of liver cancers in children are hepatoblastoma and hepatocellular carcinoma. The liver The liver is the body's largest internal organ and one of the most complex. Located beneath the rib cage in the upper right quadrant of the abdomen, this wedge-shaped organ is divided into two main lobes--right and left--and two smaller lobes. The liver is like a chemical refinery that operates 24 hours a day. It receives blood from both the hepatic artery and the portal vein and modifies substances contained in the blood that passes through it. This includes everything that is swallowed and absorbed into the bloodstream. For example, after food is digested by the stomach and small intestine, the liver metabolizes, or chemically changes, it into forms that are easier for the rest of the body to use. Another major function of the liver is to filter blood. Harmful material from food, drugs, or bacteria are removed by this unique filtration system. The liver changes these toxic substances into forms which can be easily eliminated from the body. The liver produces bile, a greenish-brown fluid essential for proper digestion. Bile is stored in the gallbladder. When food is ingested, the gallbladder contracts and releases bile into the intestine. Bile is also used to rid the body of unwanted compounds, such as bilirubin, which is a by-product of red blood cell turnover. The liver produces, stores, and provides glucose to keep the body active. It also produces, stores, and exports fat to help regulate the supply of body fuel. The liver regulates the balance of many important hormones including adrenal, thyroid, and sex hormones. It regulates the supply of essential minerals and vitamins, such as copper and iron. The liver produces, excretes, and converts cholesterol into other important substances. It manufactures key proteins, such as those used to transport other substances in the blood, and those providing resistance to infection. Other proteins made by the liver aid in the clotting of blood. These are but a few examples of the hundreds of complex functions of the liver. Who gets liver cancer? Approximately one child in every million will be diagnosed with a liver tumor each year in North America. Boys are affected by these malignancies more frequently than girls. Since there are different risk factors for hepatoblastoma and hepatocellular carcinoma, they are discussed separately. Hepatoblastoma Hepatoblastoma is a rare form of liver cancer most often diagnosed in children under the age of three. Premature infants have a higher risk of developing hepatoblastoma than children who were not born prematurely. Children with Beckwith-Wiedemann syndrome, familial adenomatous polyposis, and Aicardi syndrome also have a higher risk of developing hepatoblastoma than the general population. However, most children with these syndromes do not develop hepatoblastoma, and most children with hepatoblastoma do not have one of these syndromes. Hepatocellular carcinoma Hepatocellular carcinoma is seen most often in children under the age of four and those between twelve and fifteen years of age. This form of liver cancer has been associated with several other conditions, including some rare metabolic diseases. The strongest association has been with hepatitis B and C, and other conditions that lead to cirrhosis of the liver. Hepatitis B is an infectious disease of the liver caused by the hepatitis B virus (HBV) that results in acute or chronic hepatitis. Hepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV) that results in chronic hepatitis. Many children who develop hepatocellular carcinoma have been previously infected with hepatitis B or sometimes hepatitis C. Biliary atresia is a disease diagnosed in infants in which there is inflammation and obstruction of the ducts carrying bile from the liver. The disease causes cirrhosis, which places the child at an increased risk of hepatocellular carcinoma. Other causes of cirrhosis that may in time lead to hepatocellular carcinoma include alpha-1-antitrypsin deficiency, von Gierke disease, and ataxia telangiectasia. Signs and symptoms Hepatoblastomas are usually found when a parent notices a painless, upper right quadrant or midline abdominal mass. The abdomen may appear distended and 15 to 20 percent of children have abdominal pain. A small number of children have jaundice, a yellowing of the skin and the whites of the eyes. The child may have a poor appetite (anorexia) and recent weight loss. Nausea and vomiting, in addition to weakness, may also be present. A urinary symptom brought this child to medical attention: In December 1994, I noticed something unusual when changing her diaper before bedtime. It looked as if someone had taken an orange crayon and colored the inside of her diaper. I called her pediatrician who suggested we bring her in the next day, along with the diaper, just to check her over before the holidays. I wasn't too worried, because I thought that maybe it was just food coloring from something that she ate coming out in her urine. When we saw the doctor the next day, he immediately found a lump, and asked if she had received any blows or falls injuring the stomach area recently. We were sent to the hospital and she was given some blood tests and a CT scan, which showed the tumor. The signs and symptoms of hepatocellular carcinoma are very similar to those of hepatoblastoma. A parent may find a lump or mass in the upper right or middle of the abdomen, with or without distension of the abdomen. The child may complain of abdominal pain and general weakness. Fifteen to twenty percent of children have jaundice or fever. Poor appetite and weight loss are frequently present. Bleeding into the abdominal cavity (hemoperitoneum) may occur because of tumor rupture. Diagnosis Several tests and procedures are necessary to diagnose liver cancer. Most of these procedures are the same for both hepatoblastoma and hepatocellular carcinoma. In addition to completing a history and physical examination of the child, the doctor will order a complete blood count (CBC). The doctor also orders bloodwork to evaluate liver enzymes, alfa fetoprotein (AFP), and bilirubin levels. AFP is elevated in 90 to 95 percent of all children with hepatoblastoma. Though not to the same degree, it may also be elevated in children with hepatocellular carcinoma. AFP provides a convenient way of monitoring tumor response to treatment and is regularly checked. Liver function tests, such as AST, ALT, LDH, and alkaline phosphatase, are also usually ordered. Ultrasonography (US) and computed tomography (CT) of the liver and abdomen are performed. The doctor may also order a magnetic resonance imaging (MRI) of the liver. A need for imaging may not be recognized at the outset of illness, however, as this parent describes: Logan had been sick for three months prior to the diagnosis with severe vomiting, weight loss, a hard abdomen, and irritability. He cried day and night and was very clingy. He had a lot of trouble sleeping. Four different doctors saw Logan and said it was just a stomach bug. When his testicle became enlarged and purple, he was diagnosed as having hydrocele (accumulation of fluid in the testicle). He was taken to surgery and the hydrocele was repaired. He continued to have all the same symptoms after that, but only worse. I took Logan to the emergency room three weeks later because I had enough. Scans were performed and we were told that Logan had a mass in his liver and they were 99.9 percent sure it was cancer. The definitive test is a liver biopsy, which is a diagnostic procedure used to obtain a small amount of cancerous liver tissue. This may be done during an open surgical biopsy or by a fine needle biopsy guided by CT or US. Staging Once liver cancer has been diagnosed, the oncologist will order more tests and scans to determine the extent (stage) of the disease. An imaging study, such as a CT, MRI, or bone scan, may be performed to check for metastases. Staging is very important because it has a direct impact on prognosis and choosing the most appropriate therapy. The following staging system is based on the extent of tumor involvement and its ability to be removed surgically: Stage I. The tumor is able to be completely removed. Stage II. The tumor is removed surgically, but there are microscopic traces of disease still present. Stage III. The tumor is not able to be removed surgically at diagnosis or is partially removed. Lymph nodes are positive for disease or there is tumor spill during surgery. Stage IV. The disease has spread to distant areas in the body, regardless of the extent of liver involvement. Ten percent of patients with hepatoblastoma have metastatic disease in the lungs at diagnosis. Rare areas of spread can include the central nervous system and the abdomen. Common areas of metastases in children with hepatocellular carcinoma include the lungs, bone marrow, and lymph nodes. This little boy's tumor had spread beyond his liver before he was determined to have cancer: Logan was nineteen months old when he was diagnosed with hepatoblastoma. At diagnosis, the tumor was the size of a grapefruit and had spread to his lymph nodes and also the right atrium of his heart. Prognostic indicators Treatments for childhood liver cancers have improved in the last two decades. The appropriate treatment for liver cancer is determined by analysis of many clinical and biologic features. To choose the best treatment for children with hepatoblastoma, doctors consider the child's age, health, stage of disease, type of cancer cells, and the level of alpha fetoprotein in the blood. Long-term survival for hepatoblastoma is approximately 60 to 70 percent with a survival rate of 90 percent in early stage disease. The prognosis for children with hepatocellular carcinoma is much worse than for those with hepatoblastoma because hepatocellular carcinoma cancer cells are very aggressive. These tumors often involve all lobes of the liver, making surgery difficult. Doctors, therefore, carefully consider the child's age, stage of disease, and the cellular characteristics of the tumor to choose the treatment that provides the best chance for cure. Treatment At diagnosis, many parents are confused about how to find the best doctors and treatments for their child. State-of-the-art care is available from physicians who participate in the Children's Cancer Group (CCG) and/or the Pediatric Oncology Group (POG). These study groups, composed of pediatric surgeons and oncologists, urologists, radiation oncologists, researchers and nurses, establish the standard of care for patients worldwide, conduct new studies to discover better therapies, and establish follow-up for survivors. They are in the process of merging into one entity called the Children's Oncology Group (COG). If the treatment center you are referred to is a member of one of these groups, you can rest assured that your child will have access to the best thinking on the treatment of pediatric cancers. All children with liver tumors have all or part of their tumor removed surgically, and many children require chemotherapy. Liver transplantation is also necessary in some cases. The aggressiveness of treatment is based on the type of liver cancer and its histology (how it looks under a microscope), the extent of tumor involvement and stage of disease, as well as the child's age and overall health. The AFP levels of children with liver cancer are followed throughout treatment to evaluate the effectiveness of therapy and later to screen for recurrence. Surgery Surgery is the cornerstone therapy for both hepatoblastoma and hepatocellular carcinoma. Complete removal of the tumor provides the best chance for a cure. Large portions of liver can be removed, because the liver regenerates itself rapidly. Generally, surgery occurs very soon after diagnosis. However, some oncologists feel that preoperative chemotherapy is the best approach because it can minimize the amount of healthy liver that will need to be removed along with the tumor. Sometimes it isn't possible to completely remove the tumor at diagnosis due to extensive tumor involvement of the liver or because the disease has spread to other organs. In some cases, the CT or MRI suggests that more than one lobe of the liver is involved, making surgery not possible. In these instances, preoperative chemotherapy can shrink the tumor to a size that will allow resection. Surgery is also used to remove tumors that have metastasized to the lungs. The types of surgery for childhood liver tumors are: Wedge resection. Removal of part of one lobe of the liver. Lobectomy. Removal of a whole lobe of the liver. Trisegmentectomy. Removal of an entire lobe and part of the other. Thoracotomy. Removal of tumors from the lungs. These parents of children having surgery for liver cancer describe the experience: Coley's surgery was very scary, I think more for us than for her. She has been my role model for bravery throughout the entire process. The surgery took a few hours and has left her with a large scar that goes from one side of her stomach to the other in an upside down U. I was very scared to see her in intensive care, because I was afraid that I would break down when I saw her with all those tubes. But after waiting all those hours, when we were finally able to see her, she looked so beautiful. She had made it! The doctors told us she would be out for a day or so, but while they were telling us this, she was trying to say "waffle" with the tube still down her throat. The doctors were shocked, and they took the tube out a day earlier than they expected. •  •  •  •  •   Just ten days after his second birthday, Logan had a five-hour operation to remove the entire right lobe of his liver and his gallbladder. During surgery he lost quite a lot of blood and was given five units while in the operating room. He was transferred to ICU and was given another unit of blood and platelets. He remained there for only 36 hours and was transferred to the oncology floor. By the third day, he was walking around. He had very little pain and he never complained. By the fourth day, he was running up and down the hall feeling wonderful. You would never guess that he had just had a major operation. On the fifth day, we were able to take him home. Two weeks after the operation, he went back to have one more round of chemotherapy and then we were done. A child with a previously damaged liver who is diagnosed with hepatocellular carcinoma may not be eligible for surgery. For example, a child with liver damage from hepatitis B or C could not survive if large portions of his liver were surgically removed. Consequently, only small tumors are removed under these circumstances. Chemotherapy Chemotherapy is almost always used to treat both forms of liver cancer. It is considered systemic therapy because the anticancer drugs are injected into the bloodstream to reach all areas of the body. This method of treatment not only attacks the disease located in the liver, but it also destroys cancerous cells that may have spread to other areas. Hepatoblastoma is very sensitive to chemotherapy. Effective chemotherapy agents include cisplatin, vincristine, fluorouracil, and doxorubicin. Other drugs, such as ifosfamide, dactinomycin, and etoposide may be used for more advanced stages of disease. This parent describes side effects, but the treatment was effective: The doctor went over the protocol and told us that Logan's chance of survival was 70 percent. The chemotherapy was hung and dripping within two hours of the pathology report. Logan received cisplatin, vincristine, and 5-FU. He had chemotherapy every three weeks that usually took an average of two days. Logan had many reactions to chemotherapy--vomiting, diarrhea, nickel-sized blisters on his bottom, thrush, rashes, hair loss, loss of appetite, blotchy skin color, severe high frequency hearing loss, seizures (he was put on phenobarbitol), leg and hand/arm pain. After Logan received the first round, there was a small decrease in the tumor. After the second, there was a little more. Since his tumor was responding, we decided to stay on the protocol. After the fifth course, Logan was admitted for surgery to have the tumor removed. Hepatocellular carcinoma is not as sensitive to chemotherapy as hepatoblastoma. Initial treatment for hepatocellular carcinoma usually includes the drugs cisplatin and doxorubicin. For more advanced disease, vincristine and fluorouracil may be used. Radiation Radiation therapy is not commonly used to treat tumors of the liver because normal, healthy liver tissue is extremely sensitive to the damaging effects of radiation. However, radiation may be used to treat tumors that have spread to other areas in the body. Liver transplantation Liver transplantation is used to treat children with hepatoblastoma and hepatocellular carcinoma whose tumors are unresectable because of involvement in both lobes of the liver or who have relapsed. Advances made in transplantation include transferring portions of a liver from a child's parent to the child, where it regenerates and becomes fully functional. Removing the entire liver, called hepatectomy, and then transplanting a new, healthy organ from a donor is considered by some to be experimental. However, long-term survival rates following this procedure are improving. Other treatments Researchers are constantly working to find new methods for treating liver cancer to increase survival rates. Currently, there are some phase I and phase II clinical trials taking place across North America which try to improve the quality of life for children with liver cancer, as well as strive for the ultimate goal of a cure. Some of these experimental treatments follow: Cryosurgery is a technique that involves freezing cancerous cells to kill tumors. Ethanol ablation involves injecting concentrated alcohol directly into the tumor via the hepatic artery. High-dose chemotherapy followed by stem cell transplantation is being used by some institutions in an attempt to improve long-term survival in children with a poor prognosis. Hepatic arterial chemoembolization is being researched, using new drugs such as floxuridine. Chemotherapy drugs, such as tamoxifen, are being used in phase II studies along with a combination of other anticancer agents. A new form of therapy, called antiangiogenesis, which attempts to destroy tumors by starving them of their blood supply, is also being tested in phase I studies. Newest treatment options To learn of the newest treatments available, call (800) 4-CANCER and ask for the PDQ (physicians data query) for hepatoblastoma or hepatocellular carcinoma. You can also access the PDQ on the Internet at http://cancernet.nci.nih.gov/. These free statements explain the disease, state-of-the-art treatments, and ongoing clinical trials. There are two versions available: one for patients, which uses simple language and contains no statistics, and one for professionals, which is technical, thorough, and includes citations to scientific literature. This child's cancer treatment included a liver transplant: Matthew was diagnosed with hepatoblastoma in June of 1993. His only symptom was an enlarged belly. He seemed to be a normal, active eighteen-month-old. His medical team estimated that his tumor was initially the size of a grapefruit. Four months of chemotherapy shrank the tumor to about the size of an egg, making surgery safer and more likely to be successful. Two additional months of chemotherapy were used as follow-up after his surgery. His alpha feto protein level returned to normal following the surgery in September of 1993 and remained normal until spring of 1996, when it started to slowly climb. After ruling out all other possible causes, we knew it would only be a matter of time before our fears were confirmed. A CT scan found the liver mass. Surgery was scheduled right away to attempt to resect the tumor. We tried several different chemotherapy protocols in the next five months, but Matthew was not improving. We met with the liver transplant team and Matthew was placed on the list. As the clock continued to tick and his AFP continued to climb, he continued on chemotherapy. In April of 1997, Matthew had his liver transplant. It was thrilling for us to see him recover from major surgery so quickly! Matthew has only had two episodes of rejection, and both responded well to treatment with high doses of steroids. At almost two years following his transplant, his AFP has remained normal and our hospital visits are not so frequent. Matthew played ball this past summer, completed his kindergarten year with very few absences and is now a first grader learning to read! This fact sheet was adapted from Childhood Cancer: A Parent's Guide to Solid Tumor Cancers, by Nancy Keene, © 2001 by Patient-Centered Guides. For more information, call (800) 998-9938 or see www.patientcenters.com.