Fibrolamellar hepatocellular carcinoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

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

Disease	Clinical manifestations													Diagnosis		Comments
	Symptoms									Signs
	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging
Hepatocellular carcinoma/Metastasis	RUQ	+	−	+	+	+	+	+	+	+	−	+	Normal Hyperactive if obstruction present	High levels of AFP in serum Abnormal liver function tests Thrombocytopenia	US CT MRI Liver biopsy	Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis
Cholangiocarcinoma	RUQ	+	−	+	+	−	−	+	−	−	−	+	Normal	Elevated CA 19-9 Increased amylase / lipase Increased stool fat content	Contrast-enhanced ultrasound CT scan Calcification Pseudocyst Dilation of main pancreatic duct MRI	Predisposes to pancreatic cancer
Pancreatic carcinoma	MidEpigastric	−	−	+	+	+	−	+	−	−	−	+	Normal	↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9	MDCT with PET/CT MRI EUS	Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau's syndrome) Pancreatic panniculitis
Focal nodular hyperplasia	Diffuse	±	−	−	±	−	−	+	+	−	−	−	Normal	Normal Liver function tests Normal AFP Minor elevations of Aspartate Alanine aminotransferase Alkaline phosphatase Gamma glutamyl transpeptidase	Us Multiphasic helical CT scan	Open biopsy if diagnosis can not be established
Disease	Abdominal Pain	Fever	Rigors and chills	Nausea or vomiting	Jaundice	Constipation	Diarrhea	Weight loss	GI bleeding	Hypo- tension	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Gallbladder cancer	Midepigastric	−	−	+	+	−	+	+	−	−	−	−	Normal	↑ Alkaline phosphatase ↑ CA 19-9	US CT MRI
Liver hemangioma	Intermittent RUQ	−	−	+	+	−	−	−	−	−	−	−	Normal	Abnormal LFTs	US Single-photon emission computerized tomography(SPECT) MRI	US will reveal hypoechoic lesions
Liver abscess	RUQ	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Abnormal liver function tests	US CT
Cirrhosis	RUQ+Bloating	+	−	+	+	−	−	+	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular, shrunken liver Ascites	Stigmata of liver disease Cruveilhier- Baumgarten murmur
Inflammatory lesions	RUQ	±	−	+	+	−	−	−	−	−	−	−	Normal	Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia	US Nodular,shrunken or coarse liver	Stigmata of liver disease

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 [3,4], 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

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 β (PDGFR-β), and vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3.
• Sorafenib targets both tumor growth (Raf-MEK-ERK pathway) and neoangiogenesis (VEGFRs, PDGFR-β), 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.
• 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.

Procedure	Description
Hepatic resection	Cirrhosis often limits the feasibility of liver resection in patients with typical hepatocellular carcinoma (HCC) because cirrhotic patients have increased perioperative risk and require a larger future liver remnant to be left behind to allow adequate liver function. In contrast, fibrolamellar carcinoma (FLC) is rarely associated with cirrhosis, and patients are often young and otherwise healthy (For this reason, aggressive liver resections can be more readily undertaken in patients with FLC than in those with typical HCC.) Several factors are associated with a better prognosis following surgery, including younger age at diagnosis, earlier tumor stage at diagnosis, and absence of large vessel invasion or thrombosis. The ability to perform complete resection has been reported to be one of the most important and well-described prognostic factors for FLC. Factors associated with a particularly poor prognosis include lymph node metastasis, multiple tumors, metastatic disease at presentation, and vascular invasion. Patients with resected FLC generally have a prognosis similar to that for noncirrhotic patients with resected typical HCC. Aggressive surgical approaches, even for recurrent disease, can be undertaken with good results.
Orthotopic liver transplantation	Total hepatectomy followed by orthotopic liver transplantation (OLT) should be considered in patients with unresectable FLC that is confined to the liver.  Even among patients who develop tumor recurrence, the time to recurrence is significantly longer in patients with FLC than in those with typical HCC. This may be a result of more indolent behavior by FLC versus typical HCC. Alternatively, it may result from the fact that accompanying cirrhosis in typical HCC increases the risk of recurrence (including development of a second primary tumor) via a field effect. Orthotopic liver transplantation can result in long-term survival but is a resource-intensive treatment approach. In typical HCC, orthotopic liver transplantation confers the advantage of removing the at-risk cirrhotic liver in addition to the tumor itself. In FLC, this theoretical advantage is likely not present because no such field effect is present (due to the lack of cirrhosis in most cases). As such, it is not clear that the use of donor organs in patients with FLC is an appropriate use of this scarce resource. Newer innovative approaches (eg, adult living-related donations, split-liver techniques, and potential use of marginal donor organs) may allow for a future increase in the use of orthotopic liver transplantation for FLC.

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.

References