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Last updated: May 29, 2018
Years published: 2018
NORD gratefully acknowledges Kevin M. Sullivan, MD, FCF/CRI Research Fellow, University of Washington Schilling Research Fellow, University of Washington General Surgery Resident, and the Fibrolamellar Cancer Foundation, for the preparation of this report.
Fibrolamellar carcinoma is a rare form of cancer that affects the liver. Unlike most cancers of the liver, it occurs with greater frequency in adolescents and young adults who are otherwise healthy. There are often no symptoms or signs of the disorder for a long time. Symptoms that can develop include abdominal pain, unintended weight loss, and a general feeling of poor health (malaise). Treatment is usually through surgical removal (resection) of the tumor. When surgery is not possible or is unsuccessful, then other therapies may be considered. Recurrence following successful surgical removal of a tumor can occur, meaning that sometimes the tumor can come back after it was removed. The exact, underlying cause of this disorder is unknown.
The term fibrolamellar comes from the fibrous bands of tissue that occur in a unique โlamellarโ pattern when tissue from a tumor is viewed under a microscope. Fibrolamellar carcinoma was first reported in the medical literature in 1956 and described as a different type of liver cancer from the more common kind of liver cancer, hepatocellular carcinoma (HCC). Most people with HCC have an underlying liver disease called cirrhosis, which is scarring of the liver that can occur as a result of long term liver damage due to hepatitis or alcohol use. Most people with fibrolamellar carcinoma do not have an underlying liver disease and do not have cirrhosis. Many physicians now consider fibrolamellar carcinoma a separate form of cancer distinct from HCC.
The signs and symptoms usually arise with advanced disease. For many years, affected individuals may not have any noticeable signs or symptoms (asymptomatic) because they are otherwise healthy. Initial symptoms are nonspecific, which means they can be seen in a variety of different medical conditions. Every person is unique and how this disorder affects one person can be different from how it affects another person. Fibrolamellar carcinoma may not cause problems for many, many years or it can be aggressive, quickly spreading locally or spreading to other parts of the body (metastasizing).
When symptoms do develop, they can include abdominal pain or discomfort, unintended weight loss, and a general feeling of poor health (malaise). Abdominal pain is the most common symptom, although it can vary in both duration and intensity. Additional symptoms can include shoulder or back pain, fever, nausea or vomiting, loss of appetite, night sweats, the accumulation of fluid in the abdominal cavity causing swelling of the abdomen (ascites), enlargement or swelling (distention) of the abdomen, a feeling of fullness in the stomach, and enlargement of the liver (hepatomegaly). Sometimes, there is a mass in the liver that can be felt by touch (palpable). Yellowing of the skin and whites of the eyes (jaundice) can also occur and is usually caused by blockage (obstruction) of the biliary tract, which includes the liver, gallbladder, and biliary ducts. These organs and structures help to regulate and release bile, which is made by the liver to help with digestion.
A rare finding that has been reported is gynecomastia, a condition characterized by an increase in breast tissues in males. Other uncommon findings are low blood sugar levels (hypoglycemia) because the tumor uses up glucose in the body, or changes in mental status such as confusion due to the buildup of ammonia in the body.
As with many forms of cancer, the exact, underlying cause of fibrolamellar carcinoma is unknown. Researchers speculate that multiple factors including genetic and environmental ones play a role in the disorderโs development. Current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the bodyโs genetic code, are the underlying basis that causes cells to become malignant.
Researchers have determined that many people with fibrolamellar carcinoma have the same underlying genetic abnormality called a DNAJB1-PRKACA fusion gene. This genetic abnormality is highly specific to fibrolamellar carcinoma, meaning it is not found in normal liver tissue or elsewhere in other organs. Genes normally produce (encode) proteins that have several functions within the body. The abnormality found in fibrolamellar carcinoma is caused when there is a loss of genetic material (deletion) on chromosome 19, which leads to the abnormal combination of two genes, the DNAJB1 and the PRKACA genes (see figure below). The fusion of these two areas on the DNA creates a new gene called a โchimericโ gene, which in turn produces an abnormal protein product. Similar to the fusion of the two genes, the fusion protein is an abnormal combination of the two normal proteins (see figure below). Researchers believe that the abnormal protein created by this chimeric gene may contribute to or influence the development of fibrolamellar carcinoma, or be the main factor driving tumor formation and growth. The exact reason why the loss of genetic material and fusion of these two genes happens is not fully understood. The exact way that the fusion protein causes the cells to grow excessively as a cancer is also not fully understood.
Figure: FLC fusion gene and protein
Other types of liver cancer are usually associated with underlying disease (e.g. hepatitis) or damage (e.g. scarring [cirrhosis]) to the liver. Generally, individuals with fibrolamellar carcinoma do not have any identified or proven risk factors other than the presence of the DNAJB1-PRKACA chimeric gene. Researchers are studying the disorder to try and determine where there are specific environmental risk factors, or any additional genetic risk factors.
Fibrolamellar carcinoma is an ultra rare form of cancer. It affects both men and women and affects approximately 1 in 5,000,000 people in the general population. Fibrolamellar carcinoma occurs with greater frequency among young adults with a median age of diagnosis of 25. It is found all over the world and the rate of occurrence can vary geographically. The disorder accounts for about 1% of all people with primary liver cancer in the United States, but accounts for about 5.8 percent of all people with primary liver cancer in Mexico.
A diagnosis of fibrolamellar carcinoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis of fibrolamellar carcinoma can be difficult because symptoms may be nonspecific and can be caused by many different types of disorders. Because the disorder occurs in young adults, a diagnosis of cancer is usually not suspected initially until many other more common conditions are ruled out.
Clinical Testing and Workup
Doctors may recommend advanced imaging techniques such as computed tomography (CT) scan, magnetic resonance imaging (MRI), or ultrasound to try and confirm a diagnosis. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of specific organs and bodily tissues. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures such as the liver.
A doctor may need to perform a biopsy to confirm a diagnosis. During a biopsy, a doctor will use CT or ultrasound imaging to obtain a sample area in the liver with a needle in order to examine the tissue under the microscope. Rarely, a small part of tumor has to be surgically removed to obtain the sample to study. A biopsy may be necessary to distinguish fibrolamellar carcinoma from benign tumors such as FNH or other cancers such as HCC.
The tissue sample then oftentimes undergoes immunostaining to aid in a diagnosis. During immunostaining, antibodies are applied to a sample of the tumor from a biopsy or from surgical removal. The antibodies are used to test for certain proteins (markers), for example CK7 and CD68, which are highly expressed in individuals with fibrolamellar carcinoma. Detection of these markers does not confirm a diagnosis of fibrolamellar carcinoma but is another finding indicative of the disorder.
Some physicians have advocated a test known as fluorescent in situ hybridization (FISH). During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific gene allowing researchers to better view that specific region of the chromosome. This allows physician to detect the DNAJB1-PRKACA chimeric gene on chromosome 19.
There is no known blood test that can make a diagnosis of fibrolamellar carcinoma. In other forms of liver cancer such as hepatocellular carcinoma, there are elevated levels of alpha fetoprotein in the blood. Physicians may run a blood test to see whether this protein is present. This helps to distinguish fibrolamellar carcinoma from hepatocellular carcinoma.
Treatment
The treatment of fibrolamellar carcinoma is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists: physicians with expertise in the diagnosis and treatment of liver disorders (hepatologists), physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), physicians who use imaging to perform various interventions (interventional radiologists), surgeons who perform an operation to remove the cancer, and other healthcare professionals. Psychosocial support for the entire family is essential as well.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; presence of cancer in lymph nodes or other areas of the body; tumor size and exact location within the liver; the presence or absence of certain symptoms; an individualโs age and general health; and/or other elements. All of these factors are taken into consideration when deciding if surgery can be performed. Similarly, decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
The main treatment option for fibrolamellar carcinoma is surgical removal (resection) of the tumor. Generally, liver resection has proven the most effective method in treating individuals with fibrolamellar carcinoma. The surrounding lymph nodes are also removed because of the risk of the cancer spreading. When the entire tumor can be removed surgically (complete resection) the prognosis is generally considered to be much improved. Fibrolamellar carcinoma can come back (recur) in individuals who have been successfully treated by surgery. Recurrence is usually treated with additional surgery.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Instead, various treatments including chemotherapy have been reported in the medical literature as part of smaller studies. Additional treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with fibrolamellar carcinoma.
Some individuals with fibrolamellar carcinoma may be treated with a liver transplant. This is not considered a standard treatment option and is generally reserved for when a tumor cannot be removed by resection of only the tumor, individuals have failed to respond to other therapies, or have underlying damage to the liver such as cirrhosis. Liver transplantation is only done if the cancer has not spread from the liver to another part of the body. During a liver transplant, the affected liver is removed and replaced by a healthy liver from a donor. This is a major surgical procedure that carries significant risk. After the surgery, affected individuals require lifelong supplemental medications to suppress the immune system (immunosuppressive medications). This is done to minimize the risk of the body rejecting the donated liver as foreign and attacking it through the immune system.
The identification of the DNAJB1-PRKACA chimeric gene has enabled investigators to research therapies targeted toward this specific gene or the associated protein. Some physicians believe the abnormal protein created by this chimeric gene drive the growth of cancer in affected individuals. Medications are being studied that block or inhibit this protein. More research is necessary to determine the long-term safety and effectiveness of these treatments for individuals with fibrolamellar carcinoma.
Many other types of cancer are treated with a new therapy called immunotherapy. This type of treatment aims to enhance the bodyโs innate ability to fight cancer cells using the immune system. For example, the most common form of immunotherapy called PD-1 or PD-L1 blockade releases the โbrakesโ on the immune system that some cancers use to try to evade the immune cells. Researchers are currently studying whether immunotherapy could potentially be used in fibrolamellar carcinoma.
Some individuals have been treated with hepatic artery chemoembolization. Chemoembolization is a way of decreasing blood supply to the tumor site within the liver in an attempt to control the disease. During this procedure a catheter is placed into the main artery that supplies blood the liver (hepatic artery). Chemotherapeutic drugs and drug that block (occlude) the blood vessels are delivered right near the tumor to block the blood supply to the tumor. This can slow or stop tumor growth and sometimes shrink the size of a tumor.
Because fibrolamellar carcinoma is rare, there is no standard regimen of chemotherapy for the disease in patients who cannot undergo surgery. Therefore, clinical trials are important to gain more information on the safety and effectiveness of new treatments or drugs.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
The Fibrolamellar Cancer Foundation (FCF) is the leading research funder and patient advocacy organization in the world. FCFโs mission is to a) support research to find a cure b) improve awareness and education amongst patients and the healthcare/research community c) create and support a patient community for those fibrolamellar carcinoma. FCF believes in creating a collaborative research community amongst multiple academic, private sector and government agencies to share learnings and work together to find a cure. For more information, visit: https://fibrofoundation.org/
Fibroregistry.org is a website run by caregivers and patients with fibrolamellar carcinoma. This website is a registry. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, visit: https://www.fibroregistry.org/
JOURNAL ARTICLES
Graham RP, Yeh WM, Lam-Himlin D, et al. Molecular testing for the clinical diagnosis of fibrolamellar carcinoma. Mod Pathol. 2018;31:141-149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758901/
Tomasini MD, Wang Y, Karamafrooz A, et al. Conformational landscape of the PRKACA-DNAJB1 chimeric kinase, the driver for fibrolamellar hepatocellular carcinoma. Sci Rep. 2018;8:720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768683/
Dinh TA, Vitucci EC, Wauthier E, et al. Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma. Sci Rep. 2017;7:44653. https://www.ncbi.nlm.nih.gov/pubmed/28304380
Wahab MA, El Hanafy E, El Nakeeb A, Ali MA. Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma (experience with 22 patients over a 15-year period. World J Gastrointest Surg. 2017;9:61-67. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329705/
Riggle KM, Turnham R, Scott JD, Yeung RS, Riehle KJ. Fibrolamellar hepatocellular carcinoma: mechanistic distinction from adult hepatocellular carcinoma. Pediatr Blood Cancer. 2016;63:1163-1167. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877189/
Kassahun WT. Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments. World J Surg Oncol. 2016;14:151. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877801/
Graham RP, Jin L, Knutson DL, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015;28:822-829. https://www.ncbi.nlm.nih.gov/pubmed/25698061
Lim II, Farber BA, LaQuaglia MP. Advances in fibrolamellar hepatocellular carcinoma: a review. Eur J Pediatr Surg. 2014;24:461-466. https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0034-1396420
Kaseb AO, Shama M, Sahin IH, et al. Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma. Oncology. 2013;85:197-203. https://www.ncbi.nlm.nih.gov/pubmed/24051705
Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer. 2006;106:1331-1338. https://www.ncbi.nlm.nih.gov/pubmed/16475212
INTERNET
Kalman RS, Abou-Alfa GK. Epidemiology, clinical manifestations, diagnosis and treatment of fibrolamellar carcinoma. UpToDate, Inc. 2017 Oct 10. Available at: https://www.uptodate.com/contents/epidemiology-clinical-manifestations-diagnosis-and-treatment-of-fibrolamellar-carcinoma Accessed February 20, 2018.
Choti MA, Nathan H. Fibrolamellar carcinoma. Emedicine Journal, September 17, 2015. Available at: https://emedicine.medscape.com/article/278354-overview Accessed February 21, 2018.
Genetic and Rare Diseases (GARD) Information Center. Fibrolamellar Carcinoma. April 23, 2015. Available at: https://rarediseases.info.nih.gov/diseases/9396/fibrolamellar-carcinoma Accessed February 21, 2018.
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