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Hepatocellular carcinoma
Hepatocellular carcinoma overview

Irene Y. Chen, M.D.
Diana Agostini-Vulaj, D.O.

Minor changes: 18 February 2021

Copyright: 2003-2021, PathologyOutlines.com, Inc.

PubMed Search: pathology[TIAB] hepatocellular carcinoma[TIAB] general "full text"[SB] review[PT]

Irene Y. Chen, M.D.
Diana Agostini-Vulaj, D.O.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Chen IY, Agostini-Vulaj D. Hepatocellular carcinoma overview. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorhcc.html. Accessed March 4th, 2021.
Definition / general
  • Primary malignancy of liver with hepatocellular differentiation
Essential features
  • Most common (> 80%) primary liver malignancy worldwide
  • ~ 80% of hepatocellular carcinoma cases arise in cirrhosis
  • Specific subtypes have associated molecular / cytogenetic abnormalities:
    • Scirrhous subtype: TSC1 / TSC2 mutations
    • Steatohepatitic subtype: frequent IL6 / JAK / STAT activation
    • Macrotrabecular massive subtype: TP53 mutation and FGF19 amplification
    • Fibrolamellar subtype: DNAJB1-PRKACA fusion gene
Terminology
  • "Hepatoma" is old term for hepatocellular carcinoma
ICD coding
  • ICD-O: 8170/3 - hepatocellular carcinoma, NOS
  • ICD-10: C22.0 - liver cell carcinoma
  • ICD-11: XH4W48 - hepatocellular carcinoma, NOS
Epidemiology
Sites
  • Primary location: liver
  • Most common metastatic sites (in decreasing order of frequency): lung, portal vein, portal lymph node, intra-abdominal lymph node, bone (Case Rep Oncol Med 2020;2020:7526042)
Pathophysiology
  • Stepwise process (low grade dysplastic nodule → high grade dysplastic nodule → early hepatocellular carcinoma → progressed hepatocellular carcinoma) accompanied by accumulation of molecular alterations (Hepatology 2014;60:1983)
  • Molecular alterations include: telomere shortening, TERT activation, cell cycle checkpoint inhibitor inactivation (Nat Genet 2015;47:505)
  • TERT promoter mutation is a salient event to hepatocellular carcinoma progression (Hepatology 2014;60:1983)
Etiology
  • Cirrhosis
    • ~ 80% of hepatocellular carcinoma cases arise in cirrhosis (Hepatology 2018;68:723)
    • Patients with cirrhosis from any etiology are at risk for developing hepatocellular carcinoma
  • Infectious
    • Hepatitis B virus (HBV)
      • Direct oncogenic effect by integration of the HBV DNA into the host genome, which subsequently induces genomic instability and mutagenesis of cancer related genes, including p53 and WNT / β catenin pathway; can cause hepatocellular carcinoma without antecedent cirrhosis (J Hepatol 2016;64:S84, N Engl J Med 2019;380:1450)
      • HBV vaccination reduces the incidence of hepatocellular carcinoma
    • Hepatitis C virus (HCV)
  • Metabolic
    • Nonalcoholic fatty liver disease (NAFLD)
      • Increased prevalence due to metabolic syndrome, obesity and type 2 diabetes; insulin resistance leads to increased insulin-like growth factor 1 (IGF1), which eventually activates PI3K and MAPK pathways, leading to cell proliferation and inhibition of apoptosis (Medicina (Kaunas) 2019;55:526, PLoS One 2014;9:e97136)
      • Limited treatment options available
    • Others: hemochromatosis, alpha-1 antitrypsin deficiency, hypercitrullinemia, fructosemia
  • Environmental exposures
    • Aflatoxins:
      • Mycotoxins produced by Aspergillus flavus (aflatoxin B1) and Aspergillus parasiticus
      • Contaminates grain, corns and peanuts in tropical and subtropical regions, particularly in Asia and Africa
      • Aflatoxin B1 reacts with DNA to form mutagenic adducts, leading to codon 249 mutation of TP53 (Liver Cancer International 2020;1:41)
    • Alcohol: major risk factor in the Western countries (J Hepatol 2018;69:1274)
    • Others: anabolic steroids, Thorotrast, oral contraceptives, tobacco
  • Developmental / congenital
    • Abernethy malformation: congenital vascular malformation, which causes splanchnic venous blood to bypass the liver and drain directly into the systemic circulation; also known as congenital extrahepatic portosystemic shunt (CEPS) (Hepatology 2020;71:658)
    • Alagille syndrome: autosomal dominant disorder caused by loss of function in JAG1 (85%) or NOTCH2 (15%), resulting in bile duct paucity (World J Gastroenterol 2018;24:3980)
    • Ataxia telangiectasia: autosomal recessive disorder caused by defect in the ATM gene, resulting in increased oxidative stress (World J Gastroenterol 2018;24:3980, Front Pediatr 2019;7:458)
    • Bile salt export protein deficiency: mutation in ABCB11 causes poor excretion of bile salt, resulting in chronic inflammation and carcinogenesis (World J Gastroenterol 2018;24:3980, Hepatology 2006;44:478)
    • Tyrosinemia type I: mutation in FAH (15q23-q25) leads to deficiency of fumaryl acetoacetate hydrolase in the tyrosine degradation pathway, resulting in accumulation of toxic metabolites including maleylacetoacetate and fumarylacetoacetate (World J Gastroenterol 2018;24:3980)
  • Progression of benign entity
Diagrams / tables

Images hosted on other servers:

Diagnostic
algorithm of liver
nodule workup in
cirrhotic patients

Barcelona Clinic Liver
Cancer algorithm
for patient
management

Clinical features
  • Signs and symptoms: abdominal pain, weight loss, hepatomegaly and splenomegaly, jaundice, ascites
Diagnosis
  • Imaging: ultrasound, contrast enhanced CT / MRI with or without diagnostic tissue biopsy (see also figure 1 under diagrams)
  • Tissue confirmation not always necessary to establish diagnosis (unlike for most malignancies)
  • See radiology description for more details
Laboratory
  • Laboratory tests: α fetoprotein is elevated in 70 - 90% of cases and has sensitivity of 60% and specificity of 90% in hepatocellular carcinoma detection; elevated liver function tests (LFTs) Gastroenterology 2009;137:110
Radiology description
  • Liver nodule in cirrhosis (N Engl J Med 2019;380:1450) (see also figure 1 under diagrams)
    • If < 1cm: ultrasound surveillance every 3 - 4 months
    • If > 1cm: contrast enhanced CT / MRI
      • Diagnostic features for hepatocellular carcinoma include hyperenhancement during arterial phase and washout in the venous or delayed phase (due to alteration in blood supply during malignant transformation, as benign hepatocytes receive blood supply from portal vein, whereas malignant hepatocyte receive blood supply from hepatic artery)
      • If diagnostic features are not identified, evaluate radiologic features from other imaging techniques and consider liver biopsy for histologic diagnosis
  • Liver Imaging Reporting and Data System (LI-RADS) contains 5 diagnostic categories:
    • LR-1: definitely benign
    • LR-2: probably benign
    • LR-3: intermediate probability of malignancy
    • LR-4: probably hepatocellular carcinoma
    • LR-5: definitely hepatocellular carcinoma
Radiology images

Contributed by Irene Y. Chen, M.D.
Abdominal CT   Abdominal CT

Abdominal CT

MR abdomen (T1) without contrast

MR abdomen (T1) without contrast

MR abdomen (T1) with contrast

MR abdomen (T1) with contrast

Prognostic factors
Case reports
Treatment
  • Surgical intervention
    • Tumor resection for patients with solitary tumor and patients with preserved liver function
    • Liver transplant for patients meeting Milan criteria of solitary tumor < 5 cm or up to 3 tumors < 3 cm (Liver Transpl 2004;10:S115)
  • Ablation therapy
  • Systemic therapy
  • Barcelona Clinic Liver Cancer (BCLC) algorithm is the most widely applied hepatocellular carcinoma management system, which classifies patients into five stages (see also figure 2 under diagrams) (Liver Transpl 2004;10:S115)
Gross description
  • Well circumscribed mass that appears tan-yellow to green (color variation depends on proportion of fat and bile content)
  • Areas of hemorrhage and necrosis are common
  • Solitary or dominant nodule with multiple satellite nodules or multiple discrete nodules or multiple distinct nodules
  • Background liver is usually cirrhotic
  • Rarely, hepatocellular carcinoma can have exophytic growth, also known as pedunculated hepatocellular carcinoma (World J Surg 2002;26:1133)
Gross images

Contributed by Irene Y. Chen, M.D.
Right hepatic lobectomy

Right hepatic lobectomy

Hepatectomy for transplant

Hepatectomy for transplant

Partial hepatectomy

Partial hepatectomy for transplant

Microscopic (histologic) description
  • Architectural patterns:
    • 4 principal growth patterns, including trabecular, pseudoglandular, solid and macrotrabecular (in decreasing order of frequency)
    • 50% of cases have mixed patterns; macrotrabecular pattern is associated with worse prognosis
    • Other features include lack of portal triad in the tumor, reduction of normal reticulin framework, expansion of the hepatocyte plates and increased arterialization with unpaired arteries or arterioles
  • Cytologic features:
    • Polygonal cells with nuclear atypia, including high N/C ratio, irregular nuclear membrane, multinucleation and prominent nuclei
    • Cytoplasm varies from clear to eosinophilic, depending on the fat and glycogen content
    • Cytoplasmic alterations include Mallory-Denk bodies, hyaline bodies, pale bodies
    • Bile production (usually extracellular) may be seen
  • Histologic grading (3 tiered system):
    • WHO grading system (3 tiered system)
      • Well differentiated: tumor cells resemble mature hepatocytes; minimal to mild nuclear atypia
      • Moderately differentiated: tumor cells appear malignant on H&E and morphology suggests hepatocellular differentiation; moderate nuclear atypia
      • Poorly differentiated: tumor cells appear malignant on H&E and often cannot be distinguished from other poorly differentiated neoplasms; marked nuclear atypia
    • Modified Edmondson-Steiner grading system (4 tiered system) (Cancer 1954;7:462)
      • Grade I: tumor cells are difficult to differentiated from hyperplastic liver cells
      • Grade II: tumor cells resemble mature hepatocytes with slightly larger and more hyperchromatic nuclei; sharp and clear cut cell borders; frequent acini formation
      • Grade III: tumor cells are larger and have more hyperchromatic nuclei with less acidophilic cytoplasms; trabecular distortion; numerous tumor giant cells
      • Grade IV: tumor cells are intensely hyperchromatic, with scant and less granular cytoplasm; tumor cells appear less cohesive and can appear giant, spindled or short and plump; medullary growth pattern with loss of trabeculation; less acini
Microscopic (histologic) images

Contributed by Irene Y. Chen, M.D.
Trabecular pattern   Trabecular pattern

Trabecular pattern

Pseudoacinar pattern

Pseudoacinar pattern

Hyaline eosinophilic inclusions

Hyaline eosinophilic inclusions

Arginase-1

Arginase-1
(ARG1)

Hepatocyte Paraffin 1 (HepPar1)

Hepatocyte Paraffin 1 (HepPar1)

Cytology description
Cytology images

Images hosted on other servers:

Clusters of malignant cells at low power

Peripheral
endothelial wrapping
and thickened
trabeculae

Positive stains
  • Arginase1: cytoplasmic or nuclear; useful in confirming hepatocellular differentiation; highly sensitive and specific, thus more useful than HepPar1 for poorly differentiated hepatocellular carcinoma (Am J Surg Pathol 2010;34:1147)
  • HepPar1: cytoplasmic and granular; overall highly sensitive but 50% of poorly differentiated hepatocellular carcinoma lose expression (Am J Surg Pathol 2002;26:978)
  • Glypican 3: cytoplasmic; high sensitivity in poorly differentiated and scirrhous hepatocellular carcinoma but low sensitivity in well differentiated hepatocellular carcinoma (nonneoplastic liver is negative)
  • AFP: cytoplasmic; highly specific but low sensitivity; frequently negative in well differentiated hepatocellular carcinoma
  • Polyclonal CEA, villin and CD10 reveal canalicular pattern; limited sensitivity in poorly differentiated hepatocellular carcinoma
  • Albumin ISH: high sensitivity and specificity for primary liver carcinoma (Am J Surg Pathol 2015;39:25)
  • PanCK and CAM5.2 (CK8 / CK18) are positive
  • Reticulin: highlights the thickened hepatocyte plates (> 3 cell thick); see also negative stains below
Negative stains
Molecular / cytogenetics description
  • Diagnosis of hepatocellular carcinoma often does not require molecular or cytogenetic testing but these ancillary studies can aid in diagnosing difficult cases and identifying a specific subtype of hepatocellular carcinoma (J Hepatol 2017;67:727):
    • Scirrhous subtype: TSC1 / TSC2 mutations
    • Steatohepatitic subtype: frequent IL6 / JAK / STAT activation
    • Macrotrabecular massive subtype: TP53 mutation and FGF19 amplification
    • Fibrolamellar subtype: DNAJB1-PRKACA fusion gene
Sample pathology report
  • Liver and gallbladder, native, hepatectomy for transplantation:
    • Hepatocellular carcinoma, multiple (see comment)
    • Comment: Tumor 1 is located in the right lobe and 3 cm in size with no necrosis. Tumor 2 is located in the right lobe and 2.5 cm in size with incomplete necrosis (viable tumor present). Percentage of tumor necrosis for tumor 2 is 75%. Tumor 3 is located in the left lobe and 1.5 cm in size with no necrosis. Tumor 4 is located in the right lobe and 2.5 cm in size with incomplete necrosis (viable tumor present). Percentage of tumor necrosis for tumor 4 is 10%. Tumor 5 is located in the left lobe and 1.5 cm in size with no necrosis. Histologic type is hepatocellular carcinoma with grade G2 - G3: moderately to poorly differentiated. The tumor is confined to the liver and biliary and vascular margins are free of tumor. Vascular invasion present. No lymph nodes submitted or found. AJCC 8th edition pathologic stage is ypT2NX (combined stage II) and UNOS stage is T4a. The background liver shows cirrhosis.
Differential diagnosis
Board review style question #1

Which of the following is true about this liver neoplasm?

  1. Diffuse CK7 immunohistochemical expression would be expected in this neoplasm
  2. Hepatitis B is not a risk factor to develop this neoplasm
  3. Molecular analyses are required to define this neoplasm
  4. This neoplasm commonly arises in the setting of cirrhosis
Board review style answer #1
D. This neoplasm commonly arises in the setting of cirrhosis. The image demonstrates a hepatocellular carcinoma.

Comment Here

Reference: Hepatocellular carcinoma overview
Board review style question #2
Which of the following subtypes of hepatocellular carcinoma is associated with a worse prognosis compared with conventional hepatocellular carcinoma?

  1. Chromophobe hepatocellular carcinoma
  2. Clear cell hepatocellular carcinoma
  3. Lymphocyte rich hepatocellular carcinoma
  4. Sarcomatoid hepatocellular carcinoma
Board review style answer #2
D. Sarcomatoid hepatocellular carcinoma. All of the other answer choices are associated with a similar or better prognosis than conventional hepatocellular carcinoma.

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Reference: Hepatocellular carcinoma overview
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