How is Hepatoblastoma Treated, Know the Survival Rate, Stages, Risk Factors, Causes, Symptoms, Pathophysiology of Hepatoblastoma

Hepatoblastoma is a childhood liver cancer which is normally traced in infants and children all around the world. As per statistics, though the occurrence of this form of liver cancer is not very common, the disease has been surging up since 1975-76. Fortunately, due to radical improvements in medicines, surgeries and pathological testing processes over the past few decades, the mortality rate in Hepatoblastoma has decreased drastically. Relentless efforts by medical researchers and medical practitioners have enabled to reduce the mortality rate of Hepatoblastoma by 50% during the period 1975-2014. Surgery has remained as the principal means of healing hepatoblastoma, but the importance of chemotherapy has turned out to be increasingly important over the past few decades in both the adjuvant, as also neo-adjuvant cases in Hepatoblastoma.

Hepatoblastoma is a rarely occurring liver cancer, which affects mostly infants and to some extent children too. Physiologically these cancerous tissues appear as an abdominal mass or tumors formed with tissues just resembling fetal liver cells, bile duct cells or mature liver cells.

Tissues of Hepatoblastoma are known to originate from immature liver cells. Tumor so formed are found to be unifocal in most of the cases and affect the right lobe of the liver at the first instance than left lobe of the liver, while in advance stages of hepatoblastoma it has metastasized. As many as 70% patients have also possessed the symptoms of beta-catenine mutations. In recent studies, it’s detected that “Wnt signaling pathway” ( a signal transduction pathway constituted with proteins that help to pass signals from outside of the cell to inside of it) also have very positive link in formation of cancer cells inside a liver.

Due to rarity of hepatoblastoma, the exact causes of Hepatoblastoma are yet to be found out precisely. However, several research studies have linked several genetic conditions behind Hepatoblastoma. Such genetic conditions and disorders include:

• Wilson disease
• Beckwith- Wiedemann Syndrome
• Porphyria Cutanea Tarda
• Familial Adenomatous Polyposis
• Tyrosinemia
• Hemihypertrophy or Hemihyperplasia, and
• Metabolism problems like tyrosinemia, Alphaalpha-1 -antitrypsin deficiency, Glycogen storage disease type I etc.

There are multiple risk factors associated with Hepatoblastoma. The known risk factors for hepatoblastoma are described as follows:

• Beckwith-Wiedemann Syndrome. The risk increases from 1000 to 10000 folds for infants having this genetic disorder.
• Hemihyperplasia. It’s a condition that results in asymmetrical body growth along with increased abnormal growth rate and increases the risk for hepatoblastoma.
• Familial Adenomatous Polyposis (FAP). There is a close association between Hepatoblastoma and FAP. Children having this genetic disease are at 800 times more risk to get liver cancer or hepatoblastoma.
• Lower Body Weight. Infants having abnormal body weights are more susceptible to hepatoblastoma than infants with normal body weight.
• Lifestyle Before Or During Pregnancy. Studies have found link between regular smoking and tobacco consumption before or during pregnancy, and it increases the risk of hepatoblastoma.

Symptoms of Hepatoblastoma differ from one patient to another. Hepatoblastoma symptoms solely depend on the size and location of the tumor and metastasis condition. Here are some common signs and symptoms of Hepatoblastoma:

• Large abdominal mass or swollen abdomen is the most common sign of Hepatoblastoma. It’s accompanied by pain in entire abdomen.
• Jaundice is a common symptom of Hepatoblastoma.
• The patient constantly loses weight in hepatoblastoma.
• Children affected by hepatoblastoma feel loss of appetite or complete lack of appetite.
• Some specific symptoms of early puberty appear in boys with this liver cancer or hepatoblastoma.
• Nausea and vomiting along with fever can occur frequently in a Hepatoblastoma patient.
• Fever, itching of skin, decreased urination and back pain are other symptoms of Hepatoblastoma.

The signs and symptoms as stated above may resemble other medical conditions as well, hence only a proper diagnosis can fix the existence of hepatoblastoma accurately.

Staging of Hepatoblastoma depends on the extent of liver affected and to what extent the cancer has spread to other parts of the body. At an advanced stage in Hepatoblastoma, it’s found to affect abdominal lymph nodes and lungs severely.

Oncologists follow two systems for staging of Hepatoblastoma:

PRETEXT. PRETEXT or the PRE-Treatment EXTent of disease is a common system of staging hepatoblastoma that is based on imaging of the complete liver before a surgery is done on it. Human liver has four distinctive lobes, through PRETEXT stage medical experts can point out the number of lobes affected with tumor. Thus stage-I of hepatoblastoma depicts that only one liver lobe has a tumor and mapping goes so forth.

COG Staging in Hepatoblastoma. There is another staging system called COG staging in hepatoblastoma. COG is the abbreviation of Children’s Oncology Group. In this form of hepatoblastoma staging, in addition to the staging done in PRETEXT, imaging of other parts of the body and results of surgery undertaken during primary diagnosis are also mapped.

Taking these two systems into account, the four stages of Hepatoblastoma can be interpreted as follows:

Hepatoblastoma Stage-I. At this stage of hepatoblastoma the tumor doesn’t spread outside the liver. It’s removed surgically right at the time of diagnosis. Cancer cells are not detectable on the margins of the removed tissue.

Hepatoblastoma Stage-II. At this hepatoblastoma stage, the tumor doesn’t spread outside the liver and is removed surgically right at the time of diagnosis, but cancer cells are detectable on the edges of the removed tissues.

Hepatoblastoma Stage-III. Due to large size of the tumor, it cannot be removed surgically during diagnosis. As the tumor is too big, it puts pressure on vital tissues in the liver. In many patients, the hepatoblastoma cancer even spreads into the lymph nodes of the liver. At this stage of hepatoblastoma, the spread of tumor is not detectable in the vital parts or organs.

Hepatoblastoma Stage-IV. This is an advanced stage of hepatoblastoma when the cancer cells spread to the other parts of the body through circulatory system. In majority of cases, lungs get affected before other vital organs.

Occurrence of Hepatoblastoma or childhood liver cancer is comparatively very low with respect to other types of cancers. The world wide incidence of this form of childhood cancer, which is hepatoblastoma, has been surging up in all countries. In USA, within last 30 years, hepatoblastoma has increased from 0.8% to 1.6%. In Japan on the other hand, researchers have found occurrence of hepatoblastoma is more in infants and children having below normal body weight. Hepatoblastoma is also found in higher ratios in those infants and children whose mothers are regular smokers and also have a habit of tobacco consumption on regular basis.

The first diagnostic symptom of the hepatoblastoma is based on the bulkiness of abdomen. Once the presence of large mass is detected in the belly region, initial diagnosis is made through radiological imaging and blood tests. Tumor of Hepatoblastoma secretes a protein into the blood called alpha-fetoprotein (AFP). Hence, detection of higher level of AFP helps in early diagnosis of hepatoblastoma. Such blood tests are followed by imaging tests like ultrasound, MRI and CT scan of the abdomen.

Biopsy of the hepatoblastoma tumor is considered the most authentic form of diagnosis of hepatoblastoma except in the following situations:

• In case of infantile epithelioid hemangioendothelioma of the liver, which is a very rare form of tumor, the only way to trace its stage and existence is through imaging.
• In case of infantile hepatic choriocarcinoma also, the only ways of detection are imaging and markedly elevated beta-human chorionic gonadotropin.

Various treatment options are available for Hepatoblastoma, which depend upon several factors as stated below:

• The histology of the hepatoblastoma tumor.
• Response to chemotherapy.
• Resectability of the hepatoblastoma tumor during diagnosis.
• If the hepatoblastoma tumor has already metastasized or not.

Depending on the above mentioned factors, the best treatment options for hepatoblastoma available are:

Complete surgical resection followed by chemotherapy if needed is the mode of treatment in this case of hepatoblastoma.

Gross surgical resection with or without microscopic margins and followed by chemotherapy. In some cases preoperative chemotherapy is also applied depending upon the severity of the situation.

Hepatoblastoma tumor ruptured during the diagnosis may result in major hemorrhage that is controlled by transcatheter arterial embolization or partial resection to improve the patient condition. In some situations, favorable outcome in hepatoblastoma is possible when partial resection is followed by chemotherapy and definitive surgery.

The treatment process in this case of hepatoblastoma is as follows:

• Application of Chemotherapy as per requirement is followed by reassessment for resectability. If reassessment gives positive result then surgical resection is done for treating hepatoblastoma.
• Application of Chemotherapy followed by orthotopic liver transplantation for treating hepatoblastoma.
• TACE or Transarterial Chemoembolization is sometimes used to improve the chances of resectability in hepatoblastoma before definitive surgical decisions.

Application of Chemotherapy followed by re-evaluation of resectability.

• On examination if it is found that there is a good chance of successful resectability of the primary tumor and extrahepatic tumors after the completion of chemotherapy course, surgical resection is done and is followed by another course of chemotherapy for treating hepatoblastoma.
• In some situations the primary tumor of hepatoblastoma remains unresectable, even if the extrahepatic disease is completely reduced after chemotherapy followed by surgery. In such situation, orthotopic liver transplantation becomes a must for treatment of hepatoblastoma.
• If extrahepatic disease is not resectable or the patient is not in orthotopic liver transplantation stage, chemotherapy, radiation therapy or TACE may be applied further depending upon the condition.

Surgical resection. Patient who has undergone complete resection at the time of initial diagnosis, treating hepatoblastoma consists of aggressive surgical applications, i.e. thoracotomy against the isolated pulmonary metastases that sometimes develop in the course of the hepatoblastoma may make the disease controllable. If needed the isolated metastases is resected completely in patients whose primary tumor is controlled. Clinical trial is a better way to treat the patients in case of recurrent hepatoblastoma symptoms, which cannot be surgically controlled.

Chemotherapy. Patients treated with cisplatin, vincristine or fluorouracil could be salvaged with doxorubicin-containing regimens. However, patients treated with doxorubicin or cisplatin could not be salvaged with vincristine or fluorouracil. Combination of vincristine or irinotecan and single-agent irinotecan has been proved to be successful in some cases of hepatoblastoma.

Transplantation of Liver. This treatment option of hepatoblastoma is the last option, which is considered for patients with non-metastatic Hepatoblastoma recurrence in the liver that is not resectable.

Hepatoblastoma affects only 2 to 3 infants and a child in a million, i.e., its occurrence is very rare. However, survival rate in hepatoblastoma has increased quite effectively over the past three decades. Several studies have been conducted to understand the prognosis and survival rate in Hepatoblastoma.

A study conducted by International Society of Pediatric Oncology on a 5-year overall survival (OS) of Hepatoblastoma with PRETEXT group staging system, where the study protocol recommended treatment of children with preoperative Doxorubicin and Cisplatin chemotherapy and also included children with metastasis, was as follows:

• About 100% survival rate for PRETEXT I.
• About 91% survival rate for PRETEXT II.
• About 68% survival rate for PRETEXT III.
• About 57% survival rate for PRETEXT IV.
• About 25% survival rate for patients with metastasis.

In another study by the same organization in a 3-year overall survival (OS) study on Hepatoblastoma patients without extra-hepatic disease by PRETEXT group goes as follows:

• About 100% survival rate for PRETEXT I.
• About 95% survival rate for PRETEXT II.
• About 84% survival rate for PRETEXT III.
• About 61% survival rate for PRETEXT IV.

It’s also interpreted that there is almost 58% survival rate in case of intra-abdominal extrahepatic situation without metastasis and 44% survival rate with distant metastasis.

In all these above mentioned studies, patients with orthotopic liver transplantation was also included for getting the prognosis and survival rate more accurately.

Though the perfect reasons behind occurrence of Hepatoblastoma is not found till to-date, researchers have observed some links between Hepatoblastoma and the genetic disorders in infants and children. Hence, there is no precise preventive method for hepatoblastoma that is advised by researchers and doctors. In some cases, the oncologists and other medical practitioners advise for certain lifestyle changes to the married couples and pregnant mothers, since a few extensive medical research have observed a direct relation between certain habits like smoking during pregnancy with the occurrence of hepatoblastoma.

Although some treatments are available for treating Hepatoblastoma, researches are still trying to find out newer and best possible techniques that could cure this childhood liver cancer. They are also looking for the best possible combination of chemotherapy drugs so that the furthering of the hepatoblastoma could be stopped and also cured to the best known extent.