eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Fibrolamellar Carcinoma

Author: Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Coauthor(s): Hari Nathan, MD, House Staff, Department of Surgery, The Johns Hopkins Hospital; Postdoctoral Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Contributor Information and Disclosures

Updated: Mar 9, 2009

Introduction

Background

Although fibrolamellar carcinoma (FLC) has conventionally been considered to be a histologic variant of hepatocellular carcinoma (HCC), it has more recently been recognized as a distinct clinical entity with respect to its epidemiology, etiology, and prognosis.

Fibrolamellar carcinoma is a rare primary hepatic malignancy that was first described as a pathological variant of hepatocellular carcinoma by Edmondson in 1956.1 In his review of liver tumors and tumorlike liver lesions, Edmondson included a report of a 14-year-old girl with an unusually long survival following hepatic resection for liver cancer. Fibrolamellar carcinoma was more widely recognized as a distinct clinical entity from conventional hepatocellular carcinoma after 2 simultaneous reports in 1980 by Craig et al2 and Berman et al,3 both of which again highlighted the young age of onset and the relatively good prognosis that continue to distinguish fibrolamellar carcinoma from conventional hepatocellular carcinoma.

Due to the histological characteristics of fibrolamellar carcinoma, it has been referred to in the literature by several names: eosinophilic hepatocellular carcinoma with lamellar fibrosis,4 polygonal cell hepatocellular carcinoma with fibrous stroma,3 hepatocellular carcinoma with increased stromal fibrosis,5 eosinophilic glassy cell hepatoma,4 and fibrolamellar oncocytic hepatoma.4

Pathophysiology

The more typical form of hepatocellular carcinoma is often associated with active hepatic inflammation, hepatitis B or C viral infection, alcohol-related liver disease, nonalcoholic fatty liver disease (NAFLD), cirrhosis from any other cause, or dietary aflatoxin B1. In contrast, the etiology of fibrolamellar carcinoma remains unclear. It typically occurs in the absence of underlying liver inflammation or fibrosis,6 and no histological precursor lesion to fibrolamellar carcinoma has been identified.7

Little is known about the molecular pathogenesis of fibrolamellar carcinoma. Fibrolamellar carcinoma exhibits fewer chromosomal alterations than typical hepatocellular carcinoma, but frequent gains of chromosome 1q have been noted (as in typical hepatocellular carcinoma).8 Overexpression of genes in the RAS, MAPK, PIK3, and xenobiotic degradation pathways has been reported in fibrolamellar carcinoma.8 In contrast to viral-associated hepatocellular carcinoma, epigenetic instability is rare in fibrolamellar carcinoma.9

Fibrolamellar carcinoma has been reported to occur in association with focal nodular hyperplasia (FNH),10,11,12,13 a type of benign liver lesion, and both diseases tend to present in younger patients and in the setting of normal liver parenchyma. Additionally, fibrolamellar carcinoma and focal nodular hyperplasia share several features, such as a stellate central scar on imaging studies and copper accumulation on histological examination, that have prompted some to suggest that focal nodular hyperplasia may be a benign precursor lesion to fibrolamellar carcinoma.13,14 However, an etiological relationship has yet to be demonstrated and is not widely accepted.7

CT scan showing fibrolamellar carcinoma with a la...

CT scan showing fibrolamellar carcinoma with a large stellate central scar.

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CT scan showing fibrolamellar carcinoma with a la...

CT scan showing fibrolamellar carcinoma with a large stellate central scar.


Frequency

United States

Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI), the age-adjusted incidence rate of fibrolamellar carcinoma in the United States is 0.02 per 100,000 per year, which is 100-fold lower than the incidence rate of typical hepatocellular carcinoma (1.99 per 100,000 per year).15

International

Fibrolamellar carcinoma has been reported all over the world,16 but worldwide incidence data are not available.

Mortality/Morbidity

The population-based relative survival of patients with fibrolamellar carcinoma in the United States is 73% at 1 year and 32% at 5 years.15 In contrast, hepatocellular carcinoma relative survival is 26% at 1 year and 7% at 5 years.15 However, these figures include death from all causes. For example, because hepatocellular carcinoma patients tend to be older than those with fibrolamellar carcinoma, they may be at higher risk of death related to medical comorbidities (eg, heart disease or stroke). Nevertheless, even when only patients younger than 40 years are analyzed, fibrolamellar carcinoma still appears to have a better prognosis than typical hepatocellular carcinoma.15

More importantly, fibrolamellar carcinoma usually occurs in the setting of a normal liver parenchyma, while typical hepatocellular carcinoma occurs in the setting of a cirrhotic liver 80% of the time. Because cirrhosis is an independent risk factor for mortality, the observed difference in survival between fibrolamellar carcinoma and typical hepatocellular carcinoma may not in fact reflect differences in tumor biology or cancer-specific mortality.7 Two studies have found that fibrolamellar carcinoma and hepatocellular carcinoma in children have similar prognoses and responses to therapy.17,18 Two studies in adults have found that fibrolamellar carcinoma and typical hepatocellular carcinoma in noncirrhotics have similar prognoses after resection,19,20 supporting the viewpoint that the survival differences seen in older groups may be confounded by competing causes of death.


Fibrolamellar carcinoma: Note the large tumor siz...

Fibrolamellar carcinoma: Note the large tumor size in the background of a noncirrhotic liver.

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Fibrolamellar carcinoma: Note the large tumor siz...

Fibrolamellar carcinoma: Note the large tumor size in the background of a noncirrhotic liver.


Race

In the United States, patients with fibrolamellar carcinoma are overwhelmingly (>85%) non-Hispanic white people, with smaller numbers seen among Chinese-Americans (6%), blacks (4%), and white Hispanic persons (4%).15 In contrast, typical hepatocellular carcinoma occurs in non-Hispanic white patients 57% of the time, with significant numbers of cases diagnosed in blacks (13%), Chinese-Americans (8%), white Hispanics (7%), and other ethnic groups.15

Sex

While typical hepatocellular carcinoma demonstrates a 3:1 male-to-female ratio. Fibrolamellar carcinoma demonstrates no such sex disparity.15 It affects males and females equally.

Age

The median age of diagnosis is 33 years for fibrolamellar carcinoma, with 63% of cases diagnosed in patients younger than 40 years.15  In contrast, the median age of diagnosis is 66 years for typical hepatocellular carcinoma, with only 4% of cases diagnosed in patients younger than 40 years.15 It is important to remember, however, that despite the younger age of onset of fibrolamellar carcinoma, the most common form of primary liver cancer (60-80%) in children and young adults is nevertheless typical hepatocellular carcinoma.7

Clinical

History

Fibrolamellar carcinoma (FLC) typically presents with nonspecific symptoms or no symptoms at all. When symptoms develop, they are most commonly the following:2,3,21,22,23

  • Abdominal pain
  • Weight loss
  • Malaise

Uncommonly, presenting signs and symptoms may include the following:

  • Migratory thrombophlebitis (Trousseau syndrome) or venous thrombosis as a result of direct invasion of the hepatic veins and inferior vena cava (IVC) or mass effect on the IVC24
  • Pain and fever simulating a hepatic abscess25
  • Obstructive jaundice due to biliary compression26,27
  • Gynecomastia, due to aromatase production by fibrolamellar carcinoma cells and resultant conversion of circulating androgens to estrogens21,28,29

Other unusual presentations of fibrolamellar carcinoma have been summarized by Torbenson.7

Physical

  • The most common physical finding is an abdominal mass or fullness due to hepatomegaly.21
  • Unlike patients with typical hepatocellular carcinoma, the stigmata of chronic liver disease and portal hypertension are usually absent in patients with fibrolamellar carcinoma.

Causes

  • Specific risk factors for fibrolamellar carcinoma remain unidentified.
  • Unlike typical hepatocellular carcinoma (HCC), fibrolamellar carcinoma is not associated with hepatotoxins, cirrhosis, α1-antitrypsin deficiency, or hemochromatosis.
  • Less than 10-20% of cases of fibrolamellar carcinoma are associated with hepatitis B viral infection, but this may just be related to the high worldwide prevalence of hepatitis B infection.7
  • Fibrolamellar carcinoma is rarely associated with hepatitis C viral infection.

More on Fibrolamellar Carcinoma

Overview: Fibrolamellar Carcinoma
Differential Diagnoses & Workup: Fibrolamellar Carcinoma
Treatment & Medication: Fibrolamellar Carcinoma
Follow-up: Fibrolamellar Carcinoma
Multimedia: Fibrolamellar Carcinoma
References
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Further Reading

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Keywords

fibrolamellar carcinoma review article, fibrolamellar cancer review article, fibrolamellar cancer treatment, fibrolamellar cancer diagnosis, fibrolamellar cancer pictures, fibrolamellar cancer image, fibrolamellar carcinoma treatment, fibrolamellar carcinoma diagnosis, fibrolamellar carcinoma pictures, fibrolamellar carcinoma images, liver tumor, liver cancer, hepatic cancer, fibrolamellar hepatoma, hepatocellular carcinoma with lamellar fibrosis, FLC, hepatocellular cancer, HCC, eosinophilic hepatocellular carcinoma with lamellar fibrosis, polygonal cell with fibrous stroma, eosinophilic glassy cell hepatoma, fibrolamellar oncocytic hepatoma, fibrolamellar carcinoma

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Contributor Information and Disclosures

Author

Michael A Choti, MD, MBA, Jacob C Handelsman Professor of Surgery, Professor of Oncology and Engineering, Johns Hopkins University School of Medicine
Michael A Choti, MD, MBA is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Surgeons, American Hepato-Pancreato-Biliary Association, American Society of Clinical Oncology, American Surgical Association, Association for Academic Surgery, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, Society of Surgical Oncology, and Society of University Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Hari Nathan, MD, House Staff, Department of Surgery, The Johns Hopkins Hospital; Postdoctoral Fellow, Department of Surgery, The Johns Hopkins University School of Medicine
Hari Nathan, MD is a member of the following medical societies: American College of Surgeons, American Hepato-Pancreato-Biliary Association, Association for Academic Surgery, and Society for Surgery of the Alimentary Tract
Disclosure: Nothing to disclose.

Medical Editor

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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