Fibrolamellar hepatocellular carcinoma
Synonyms and keywords: Fibrolamellar carcinoma; FLC Eosinophilic hepatocellular carcinoma with lamellar fibrosis, Polygonal cell hepatocellular carcinoma with fibrous stroma, Hepatocellular carcinoma with increased stromal fibrosis, Eosinophilic glassy cell hepatoma, and fibrolamellar oncocytic hepatoma.

# Overview
Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of primary liver cancer. Fibrolamellar hepatocellular carcinoma was first described Edmondson in 1956. Fibrolamellar hepatocellular carcinoma is most commonly seen in children and young adults. The pathogenesis of fibrolamellar hepatocellular carcinoma is characterized by the lack of cirrhosis.  Common causes of fibrolamellar hepatocellular carcinoma, include: active hepatic inflammation, hepatitis B or C viral infection, alcohol-related liver disease, nonalcoholic fatty liver disease, and dietary aflatoxin B1. The majority of patients with fibrolamellar hepatocellular carcinoma remain asymptomatic for years. Early clinical features include abdominal pain, weight loss, and malaise.  If left untreated, the majority of patients with fibrolamellar hepatocellular carcinoma  may progress to develop metastasis to abdominal lymph nodes, peritoneum, and lung. Common complications of fibrolamellar hepatocellular carcinoma include: hepatic failure, caval compression syndrome, gynecomastia, and cold agglutinin disease. Surgical resection or transplantation is the standard of care for fibrolamellar carcinoma (FLC) for eligible patients. Trans-arterial chemo-embolization (TACE) may be a useful option in patients who have unresectable disease.

# Historical Perspective
Fibrolamellar hepatocellular carcinoma was first described by Edmondson in 1956.

# Classification
There is no classification for fibrolamellar hepatocellular carcinoma.

# Pathophysiology
- The pathogenesis of fibrolamellar hepatocellular carcinoma is characterized by the lack of cirrhosis.
- The overexpression of DNAJB1-PRKACA gene has been associated with the development of fibrolamellar hepatocellular carcinoma.
- On gross pathology characteristic findings of fibrolamellar hepatocellular carcinoma include:
- Hard, cirrhosis, and well-circumscribed
- Tumor bulging
- White-brown tumor with fibrous bands throughout and central satellite scar
- On microscopic histopathological analysis, characteristic findings of fibrolamellar hepatocellular carcinoma, include:
- Tumor cells growing in sheets
- Trabeculae that are separated by collagen bundles (lamellar pattern)
- Large cells that contain abundant mitochondria
- Coarsely granular cytoplasm
- On immunohistochemistry, characteristic findings of fibrolamellar hepatocellular carcinoma, include:
- Positive staining for hepatocyte paraffin 1 (HepPar1)
- Positive staining for glypican 3 (GPC3)
- Positive staining polyclonal carcinoembryonic antigen (pCEA)
- CD10 positivity

# Causes
- Common causes of fibrolamellar hepatocellular carcinoma, include:
- Active hepatic inflammation
- Hepatitis B or C viral infection
- Alcohol-related liver disease
- Nonalcoholic fatty liver disease
- Dietary aflatoxin B1

# Differentiating Fibrolamellar Hepatocellular Carcinoma from Other Diseases
Fibrolamellar hepatocellular carcinoma must be differentiated from other diseases that cause abdominal pain, weight loss, and malaise such as:
- Hepatocellular carcinoma
- Focal nodular hyperplasia
- Hepatic adenoma
- Hepatic metastasis
Abbreviations:
RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

# Epidemiology and Demographics
- In 2012, the incidence of fibrolamellar hepatocellular carcinoma was estimated to be 0.02 cases per 100,000 individuals in United States.
- FLC is a very rare tumor, although the incidence varies geographically. In the United States and Thailand, less than 1 percent of all primary liver tumors are FLC , while in Mexico, FLC represents 5.8 percent of all primary liver cancers

## Age
- The median age of fibrolamellar hepatocellular carcinoma diagnosis is 33 years.
- Fibrolamellar hepatocellular carcinoma is more commonly observed among patients aged 15 to 40 years old.
- Fibrolamellar hepatocellular carcinoma is more commonly observed among young patients.

## Gender
- Fibrolamellar hepatocellular carcinoma affects men and women equally.

## Race
- There is a racial predilection for Caucasian race.

# Risk Factors
There are no risk factors for the development of fibrolamellar hepatocellular carcinoma.

# Natural History, Complications and Prognosis
- The majority of patients with fibrolamellar hepatocellular carcinoma remain asymptomatic for years.
- Early clinical features include abdominal pain, weight loss, and malaise.
- If left untreated, the majority of patients with fibrolamellar hepatocellular carcinoma  may progress to develop metastasis to abdominal lymph nodes, peritoneum, and lung.
- Common complications of fibrolamellar hepatocellular carcinoma, include:
- Hepatic failure
- Caval compression syndrome
- Gynecomastia
- Cold agglutinin disease
- Prognosis will depend on stage at diagnosis. The average survival of patients with fibrolamellar carcinoma in the United States is 73% at 1 year and 32% at 5 years.

# Diagnosis

## Diagnostic Criteria
- The diagnosis of fibrolamellar hepatocellular carcinoma is made with the following diagnostic criteria:
- Positive imaging findings
- Central scar
- Small calcifications
- Single large tumor
- Clinical criteria:
- Young onset
- No previous history of liver disease

## Symptoms
- Fibrolamellar hepatocellular carcinoma is usually asymptomatic.
- Symptoms of fibrolamellar hepatocellular carcinoma may include the following:
- Fatigue
- Weight loss
- Abdominal distension
- Nausea

## Physical Examination
- Patients with fibrolamellar hepatocellular carcinoma may be well-appearing or cachectic.
- Physical examination of the abdomen may be remarkable for:
Auscultation
- Positive liver scratch test for enlarged liver size.
Percussion
- Dull percussion
Palpation
- Abdominal mass
- Tenderness in right upper quadrant
- Hepatomegaly
- Other physical signs for fibrolamellar hepatocellular carcinoma,  may include:
Pallor
Jaundice
Plantar and palmar erythema
- Pallor
- Jaundice
- Plantar and palmar erythema

## Laboratory Findings
- Laboratory findings consistent with the diagnosis of fibrolamellar hepatocellular carcinoma, include:
- Elevated serum levels of aspartate aminotransferase (AST)
- Elevated serum levels of alanine aminotransferase (ALT)
- Elevated serum levels  of alpha-fetoprotein (unspecific)
- Elevated transcobalamin I level

## Imaging Findings
- CT is the imaging modality of choice for fibrolamellar hepatocellular carcinoma
- On CT,  findings of fibrolamellar hepatocellular carcinoma, include:
- Single large tumors
- Central scar (seen in ~75% of cases)
- Central scar shows persistent enhancement on delayed contrast-enhanced CT.
- On MRI, findings of fibrolamellar hepatocellular carcinoma, include:
- T1: typically iso- to hypointense to the liver
- T2: hypo- to slightly hyperintense
- T1C+: arterial phase: heterogeneous enhancement/portal delayed phase: iso- to hypointense

## Other Diagnostic Studies
- Fibrolamellar hepatocellular carcinoma may also be diagnosed using PET.
- Findings on PET scan, include:
- Technetium-99m sulphur colloid scans (taken up by Kupffer cells) are useful as these tumors will not accumulate the agent, whereas FNH does.

# Treatment
- Surgical resection or transplantation is the standard of care for fibrolamellar carcinoma (FLC) for eligible patients.
- Trans-arterial chemo-embolization (TACE) may be a useful option in patients who have unresectable disease.
- FLC is not typically responsive to chemotherapy.
- In addition to systemic chemotherapy, recent research has focused on taking advantage of the new understanding of the pathogenesis and molecular genetics of FLC.

## Medical Therapy
- Chemotherapy is recommended for metastatic fibrolamellar carcinoma (FLC).
- Single-agent chemotherapy or combinations of chemotherapeutic drugs give responses of no more than 25%, with questionable benefit for overall survival.
Sorafenib
- Sorafenib is an orally delivered small molecule that inhibits several different protein kinases, including Raf-1 and B-Raf, platelet-derived growth factor  (PDGFR-), and vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3.
- Sorafenib targets both tumor growth (Raf-MEK-ERK pathway) and neoangiogenesis (VEGFRs, PDGFR-), both of which are thought to be important in the pathogenesis of typical HCC.

## Surgical Therapy
- Optimal management for most hepatic malignancies, including typical hepatocellular carcinoma and fibrolamellar carcinoma, is complete surgical resection
Wedge Resection
Anatomic liver resection
Total hepatectomy with orthotopic liver transplantation.
- Wedge Resection
- Anatomic liver resection
- Total hepatectomy with orthotopic liver transplantation.
- There may be occasional utility in treating fibrolamellar carcinoma with neoadjuvant chemotherapy or trans-arterial chemo-embolization (TACE) with the goal of downstaging the tumor to allow resection.

## Prevention
- There are no primary preventive measures available for fibrolamellar hepatocellular carcinoma.
- Once diagnosed and successfully treated, patients with fibrolamellar hepatocellular carcinoma are followed-up every 3, 6 or 12 months.
- Follow-up testing include ultrasound, physical exam, and laboratory testing.