Liver and intrahepatic bile ducts - tumor
Hepatocellular carcinoma
Fibrolamellar variant

Author: Rondell P. Graham, MBBS
Editor: Raul S. Gonzalez, M.D.
Deputy Editor Review: Debra Zynger, M.D.

Revised: 28 August 2018, last major update April 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Fibrolamellar hepatocellular carcinoma[TI] "loattrfree full text"[sb]

Cite this page: Graham, R. Fibrolamellar variant of hepatocellular carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/livertumorfibrolamellar.html. Accessed November 12th, 2018.
Definition / general
  • Uncommon yet distinctive primary hepatocellular malignancy
  • Typically affects young individuals from teens - 40 years
  • Large oncocytic neoplastic cells forming tumor tongues separated by collagen bundles
  • Characteristically no underlying chronic liver disease
  • > 95% of cases harbor the oncogenic DNAJB1-PRKACA fusion gene formed by intrachromosomal deletion on chromosome 19 (Mod Pathol 2018;31:141)
  • Rare cases related to biallelic PRKAR1A loss (Hepatology 2017 Dec 9 [Epub ahead of print])
  • Likely a distinct entity due to unique distinctive clinical, histologic and molecular biologic features
Essential features
  • Primary hepatocellular neoplasm
  • Eosinophilic tumor cells characterized by ample granular cytoplasm
  • Intratumoral fibrosis
  • Recurrent protein kinase A oncogenic driver abnormalities
Terminology
  • Fibrolamellar carcinoma
ICD-10 coding
  • C22.0: liver cell carcinoma
Epidemiology
  • Predilection for teenage to 40 years old
  • ~99% of cases diagnosed under the age of 50 years at presentation (Mod Pathol 2018;31:141)
  • Propensity for late recurrence
Sites
  • Liver
Etiology
Clinical features
  • Rare over 50 years old
  • No gender preference
  • Symptoms related to hepatic mass (Semin Diagn Pathol 2017;34:146)
  • Rarely associated with gynecomastia or other paraneoplastic phenomena (Lancet 1984;1:538)
  • Not associated with viral hepatitis, inborn errors of metabolism or cirrhosis
  • Metastasizes to abdominal lymph nodes and peritoneum with greater propensity than conventional hepatocellular carcinoma (Eur J Pediatr Surg 2014;24:461)
Diagnosis
  • Combination of
    • Compatible histomorphology
    • Appropriate immunophenotype (CK7, CD68 positive) or detection of key genomic events (DNAJB1-PRKACA, PRKACA rearrangement, PRKACA amplification, PRKAR1A loss)
Laboratory
  • Serum alpha fetoprotein is classically not elevated
  • No other routinely used serum or plasma markers
  • Circulating tumor DNA assay has yet to be made commercially available
Radiology description
  • CT scan and MRI: nonspecific findings; central scar (similar to focal nodular hyperplasia) may be identified; often calcified
Prognostic factors
Case reports
Treatment
Gross description
  • Single (75%), large (frequently > 10 cm), hard, well circumscribed, bulging, tan tumor with fibrous bands
  • Central stellate scar is noted in approximately 70%
  • Variable bile staining, hemorrhage and necrosis
Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description
  • Trabecula, sheets or cords of neoplastic cells with abundant oncocytic cytoplasm cells in background of dense collagen bundles frequently arranged in parallel lamellae
  • Cells are large and polygonal with well defined cell borders
  • Abundant granular and eosinophilic cytoplasm due to abundant mitochondria
  • Pale or pink bodies are frequently noted but not necessary for diagnosis
  • Typical nuclear features include open chromatin and prominent macronucleoli (Adv Anat Pathol 2007;14:217)
  • Vascular invasion may be seen
  • Histologically, fibrous bands coalesce into central scar
  • Nonneoplastic liver is within normal histologic limits
  • Radiologic calcification corresponds to stromal calcification
  • Calcified individual cells may be identified as well
  • Variable: focal nuclear anisonucleosis, sheet like growth without intervening fibrous bands, pseudoglandular or pelioid patterns
Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Rondell P. Graham, MBBS

Fibrolamellar low power

Fibrolamellar



Case of the Week #161

Pale bodies

Trichrome

CK7

Hep Par

Ki67



Images hosted on other servers:

Various images

Cytology description
  • Individual cells with ample cytoplasm, open nuclear chromatin and prominent nucleoli; may contain bile
Cytology images

Images hosted on PathOut server:

Contributed by Rondell P. Graham, MBBS

Fibrolamellar 40x



Images hosted on other servers:

Various images

Negative stains
  • Liver fatty acid binding protein (LFABP)
  • In rare cases PRKAR1A; often individuals with the Carney complex
Electron microscopy description
  • Numerous mitochondria
  • Abundant endoplasmic reticulum membranes with concentric whorls
  • Internalized canaliculi lined by microvilli (Mod Pathol 2017;30:892)
Molecular / cytogenetics description
Differential diagnosis
  • Cholangiocarcinoma: truly glandular, often conspicuous pleomorphism
  • Focal nodular hyperplasia: ductular reaction around central scar, lesional cells are not characteristically oncocytic, does not have the nuclear features of fibrolamellar carcinoma
  • Hepatocellular carcinoma, sclerosing variant: no oncocytes, smaller tumor cells, pseudoglandular pattern common
  • Metastatic carcinoma with sclerotic stroma: conspicuous pleomorphism
  • Neuroendocrine tumors: only oncocytic examples; the nuclear features are often not typical of fibrolamellar carcinoma; positive for neuroendocrine markers
  • Paraganglioma: may have abundant oncocytic cytoplasm; round nuclei without the typical features of fibrolamellar carcinoma, vascular stroma without dense fibrosis; positive for neuroendocrine markers and negative for cytokeratins (Am J Surg Pathol 2002;26:945)
Board review question #1
What is the characteristic status of the nonneoplastic liver in patients with fibrolamellar carcinoma?

  1. Chronic viral hepatitis C without advanced fibrosis
  2. Cirrhosis due to chronic viral hepatitis B
  3. Glycogen storage disease
  4. Normal
  5. Steatohepatitis
Board review answer #1
D. Normal