Friday, January 21, 2022

This week we focus on another rare malignancy, hepatoblastoma. As its name suggests, this is a tumor of the liver, similar to its much more common cousin, hepatocellular carcinoma, but in contrast to HCC, hepatoblastoma is a malignancy of children. It is most common during the first three years of life but can occur up to age 10. Luckily, like most childhood cancers, it is frequently curable, with cure rates greater than 50%.

I noted above that it was a rare cancer. Its incidence rate is 0.05-0.15/100,000/year in those under 15 years of age, or roughly one per million annually.

So what makes hepatoblastoma interesting to us as opposed to other rare cancers? There has been a striking and fairly rapid increase in its incidence rate over the past 30 to 40 years; in fact, it is hard to find a cancer that has had a more dramatic increase.

The National Cancer Institute’s Surveillance, Epidemiology and End-Results (SEER) program records and tracks cancers that occur in approximately 25% of the United States, and the data this registry collects basically serves as the U.S. population cancer statistics. Most of what we read about what cancers are common or uncommon, which are going up or down, comes from this source. A study of hepatoblastoma using this data for 1973 to 2009 found a remarkable average annual increase in its incidence rate of 2.18%. A similar study was conducted using the Taiwan Cancer Registry from 1995 to 2012 and found an annual average increase of hepatoblastoma in children of 7.4%.

I think the reader can appreciate that when such dramatic increases over a relatively short period of time are observed, they signal some important lifestyle or environmental factor of significance in society. Clearly, something happened to occasion such a dramatic change in incidence. And even more intriguingly, it was not confined to the U.S.

Generally, an investigation starts by looking at descriptive statistics—gender, race, age, country. We have already answered some of these questions, but I would add that the rise occurred for both genders and did not differ by race.

So where do we go from here? Here we come into the realm of case reports and astute clinical observation by sharp clinicians. While I am committed to the idea that intuition and logic cannot be the be-all and end-all of knowledge and science but must be confirmed by good scientific experimentation, where do our ideas and hypotheses come from? Here is an example of that.

I believe the explanation for hepatoblastoma arises from a small group of Japanese surgeons led by Hitoshi Ikeda at the National Children’s Medical Research Center in Tokyo. They were aware of the rise of hepatoblastoma and sought reasons for the rise—associations with genetic disorders, chromosomal anomalies, maternal exposures—but none of these were proving fruitful.

Then they noted that they treated two patients with hepatoblastoma who weighed 826 gms and 792 gms at birth, respectively, and a eureka moment had arrived. They went back to review patients seen in the Japan Children’s Cancer Registry. For the nine years from 1985 to 1993, there were 38 children with cancer who weighed less than 1,500 gms at birth among the 9,923 children with cancer. Of these 38, nine had hepatoblastoma. Of the 38, there were 12 who weighed less than 1,000 gms at birth (very low birthweight)—seven of them developed hepatoblastoma. The average birthweight in Japan during this same period was approximately 3,150 gms. Thus, it was estimated that the incidence rate of hepatoblastoma in children with a birthweight of 500-999 gms was approximately 1/10,000 versus the 1/1 million we previously estimated for average children.

Later studies in the U.S. and elsewhere have borne out these findings. So why would a very low birthweight increase the risk of this liver tumor? One explanation is that infants born so early end up requiring intensive neonatal ICU care, usually prolonged, in order to survive—and this is accompanied by prolonged exposure to oxygen. It is the oxygen exposure required for these infants that is toxic to the liver and increases the risk of the tumor.

Another possibility is what I would refer to as survivorship bias. Until perhaps 30 to 40 years ago, these infants would never have survived their births. Thank God, the advances in perinatal care and its technology now make miracles occur so that children with low birthweight and very low birthweight can survive. But perhaps there is some innate abnormality, genetic or otherwise, that led both to the premature birth and to the malignancy. In prior eras, we would not have been aware of the risk of hepatoblastoma because the children did not survive long enough to get it, but now we can observe it.

A similar survivorship bias occurs with trisomy 21 (Down’s syndrome)—Children with this chromosomal abnormality are at increased risk for acute leukemia, but the medical community was unaware of it because children with Down’s syndrome did not generally survive out of early childhood. Now that survival into adulthood and middle age is common, it is a well-recognized association.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

By Alfred I. Neugut


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