Fibrolamellar Hepatocellular Carcinoma: Still Rare but Deadly

John R. Craig, MD PhD, Retired pathologist and formerly Medical Director, St. Jude Cancer Center, Fullerton, CA; Member, Board of Directors, FibroFoundation

Q: You were the lead author in a 1980 paper in Cancer that clearly delineated an unusual form of Hepatocellular Carcinoma that you termed “Fibrolamellar Carcinoma”. Now, 37 years later, what insights of importance can you share about this unique malignancy?

A: CRISPR/Cas 9 technology, fruit flies, mice and zebrafish are among the tools being used in numerous academic laboratories, encouraged by the Fibrolamellar Foundation, to determine whether the 400kb deletion found on Chromosome 19 in 90% of patients with Fibrolamellar Hepatocellular Carcinoma (S. Simon PhD, Rockefeller University) is a driver mutation.
In 1980, with renowned liver pathologist co-authors Hugh Edmondson and Robert Peters, I compiled and published the first large series of Fibrolamellar Hepatocellular Carcinoma (FL-HCC) cases in the journal Cancer.
This rare cancer has an annual detection rate of approximately 100-200 patients in the USA and occurs primarily in young adults 15-30 years of age.
After our publication, we received many consultations by pathologists who were eager to share patient information and observation. Over the next 25 years, additional publications introduced unusual findings such as increased serum vitamin B12 binding globulin and other tumor markers, such as des-carboxy prothrombin, and plasma neurotensin. Unfortunately, none of these observations advanced either the detection of the tumor or improved treatment.
Some patients are cared for at academic medical centers, but neither chemotherapy nor radiation treatment has been found to be useful. Complete surgical resection offers the best hope but is usually performed late in the course of the disease since the young patients are often thought to be in good health and have few symptoms.
In recent years, these young patients often connect by social media and have developed Facebook pages. They communicate about their disease, their suffering, treatment options, and acceptance of their disease. There is an annual fall meeting of patients and families to share their experiences.
The family of one young patient (Tucker Davis) answered the plea of their son, and in his honor, in 2008, established the Fibrolamellar Foundation with the goal of finding a cure.
The mutation described above is the result of a fusion of the first exon of DNAJB1 with exons 2-10 of PRKACA. This mutation results in a functional chimeric protein, DNAJ-PKAc, which is highly expressed in almost all FL-HCCs. Little is understood about how the mutant PKA kinase may drive cancer formation.
Numerous academic laboratories are developing models to study this genetic deletion and attempt to learn how it changes the hepatocyte and promotes metastasis. There is hope that treatment may be discovered by interrupting this mutation effect within the malignant cells.
Protein kinases are involved in complex intracellular signaling involving cell proliferation, motility, angiogenesis, anti-tumor immune reactions and other functions. There are more than 518 kinases known within the human genome but the functions of most are not understood. However, small molecule kinase inhibitors are already active in current cancer treatment for chronic myelogenous leukemia, acute lymphoblastic leukemia, and several other cancers of lung and breast. However, no kinase inhibitors are known for this mutant kinase in FL-HCC.
In our initial article, we suggested a possible etiology due to modern industrial life with pesticides or chemicals. But a recent search of old records in a large reference academic center identified some patients with this cancer long before 1940. Thus, our modern industrial contamination may not be a reason for tumorigenesis.
Similar to many other organizations representing rare diseases, the Fibrolamellar Foundation is a philanthropy that has encouraged collaboration by major academic centers and scientific research meetings bringing together diverse scientists to discuss the models and consider investigations. Ultimately, collaborative clinical trials will be necessitated since this malignancy is rare.
We believe that collaborative research with multiple experts in diverse fields who share data and concepts will be necessary in order to apply the knowledge and develop the understanding of how to connect this chimeric protein mutation and ultimately produce an effective treatment.
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