Liver neoplasms

This article examines liver neoplasms and pre-malignant lesions of the liver. In North America, most malignant liver lesions are metastases.

This article focuses on primary malignancies of the liver, neoplastic liver lesions, and biliary malignancies. It only briefly discusses metastatic lesions. An introduction to liver pathology is in the liver article. Medical liver disease is dealt with in the medical liver disease article.

Overview

Dysplasic lesions of the liver

Types:

• "Large cell dysplasia" (AKA large cell change) - not considered a precursor for HCC, not considered a dysplasia.
• Small liver cell dysplasia (AKA small cell dysplasia).
• Low grade dysplasia.
• High grade dysplasia.

Neoplastic lesions

• Hepatic adenoma.

Malignant lesions of the liver

• Hepatocellular carcinoma (HCC) - most common malignant liver primary in adults.
• Hepatoblastoma - malignant liver primary in children.
• Intrahepatic cholangiocarcinoma (ICC).
• Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC).

Lesions that arise in a non-cirrhotic liver

Hepatocellular:

• Hepatic adenoma.
• Fibrolamellar hepatocellular carcinoma.
• Focal nodular hyperplasia.

Other:

• Metastasis.
• Cholangiocarcinoma.
• Hemangioma.

Tabular comparison

Precursors

Features of HCC & its precursors - generated from DCHH and STC:

Features	SLCD	Low-grade dysplasia	High-grade dysplasia	HCC
Plate thickness	<3 cells	<=2 cells	<=3 cells, usu. >2 cells	>3 cells
Reticulin (stain)	intact chicken wire	intact chicken wire	intact chicken wire	damaged chicken wire
Nuclear changes	nuc. enlargement, hyperchromasia	+/- atypia (???)	marked atypia	+/- incr. NCR, +/-irreg. nuc. contour
Cytoplasmic change	hyperchromasia, decr. as cell size preserved	none (???)	+/- basophilia	variable (lighter vs. hyperchromasia)
Portal tracts	?	loss of portal tracts	loss of portal tracts	loss of portal tracts
Management	follow ???	follow	ablate	ablate/surgery

Abbreviations:

• SLCD = small liver cell dysplasia.

Notes:

• Large cell dysplasia:
  • Cell size ~ 2x normal, NC ratio ~ normal.
• SLCD:
  • Cell size ~ 1/2x normal, NC ratio - increased.

Hepatic tumours

Benign:

Entity	Gross	Microscopic	IHC/stains	Other	Images
Hepatic hemangioma	similar to normal liver parenchyma, red (hemorrhagic), well-circumscribed	spaces lined by benign endothelial cells	CD31+ (???)	-	gross (rsna.org)
Focal nodular hyperplasia	central scar, large vessels, usu. well-circumscribed	large arteries, unpaired arteries, bile duct proliferation		usu. diagnosed by imaging	gross (rsna.org)
Hepatocellular adenoma	subcapsular, well-circumscribed	loss of portal tracts, nuclear glycogenation	reticulin - liver plate thickness <= 3	background not cirrhotic, assoc. OCP	gross (mda-sy.com)[5]

Malignant:

Entity	Gross	Microscopic	IHC/stains	Other	Images
Liver metastasis	multiple, white lesions	variable, usu. tubular (glandular) with pseudostratified hyperchromatic nuclei	CK7-, CK20-, HepPar-1-, CK19-	colorectal carcinoma most common	Metastases. (WC)
Hepatocellular carcinoma	poorly circumscribed, +/-necrosis, +/-hemorrhage	loss of portal tracts, unpaired arteries, +/-nuclear atypia	reticulin - liver plate thickness > 3	background often cirrhotic	HCC. (WC/Uthman)
Cholangiocarcinoma	cauliflower-like outline, white, classically solitary, no cirrhosis	tubular architecture and mild nuclear atypia (adenocarcinoma), desmoplastic stroma	CK7+, CK19+	background usu. not cirrhotic	Cholangiocarcinoma. (WC)

Dysplasia of the liver

Small liver cell dysplasia

• Abbreviated SLCD.
• AKA small cell dysplasia.

General

• Considered a precursor to HCC.
  • Frequently found in livers with HCC - when compared to livers without HCC.

Microscopic

Features:

• Cells similar in size to normal hepatocytes.
  • Name derived from the fact that there is also an entity that was called large cell dysplasia (AKA large cell change).
• Increased NC ratio - "more blue".
• Mild nuclear and cytoplasmic hyperchromatism.

Notes:

• Normal hepatic architecture (main differentiator from HCC).
• Remember "... blue is bad".

Micrograph:

• Low resolution micrograph of SCD (medscape.com).

Low grade dysplasia

Microscopic

• Uniform cells - "noticeably different from normal".
  • Changes in nuclear size, irregular nuclear contour and/or changes in cytoplasm staining.
• Loss of portal tracts.
• Irregular margin.

Notes:

• DCHH describes LGD as: "normal hepatocytes in plates [of normal thickness]".

DDx:

• Nodular regenerative hyperplasia - lacks: compressed rim of cells, central portal tract.

High grade dysplasia

General

• "Bader" version of low grade dyplasia.

Microscopic

Features - in addition to those of low grade dysplasia:

• Liver plate >2 cells thick.
• Significant nuclear atypia.
• Basophilic cytoplasm.

Image:

• Series of liver micrographs including high grade dysplasia (radiographics.rsna.org).

Benign hepatic neoplasms

Bile duct adenoma

Should not be confused with bile duct hamartoma.

General

• Benign.
• Important as it can be misdiagnosed as cancer.

Microscopic

Features:

• Disordered bile ducts within in a fibrotic stroma.
  • No (yellow) bile within, as these lesions do not have a connection to the biliary tree.
  • +/-Lymphocytic cuff.

Negatives:

• No mitotic activity.
• No necrosis.

DDx:

• Cholangiocarcinoma.
• Metastatic adenocarcinoma.
• Bile duct hamartoma (von Meyenburg complex).

Image:

• Bile duct adenoma (ganfyd.org).

Hepatic adenoma

• AKA hepatocellular adenoma, abbreviated HCA.

General

• Grow under the influence of sex hormones.
  • Associated with oral contraceptive pill (OCP) use - may regress with discontinuation.
  • May rupture in pregnancy.
• Usually diagnosed by radiology.

Gross

Features:

• Often subcapsular location.
• Well circumscribed, but not encapsulated.

Microscopic

Features:

• Sheets or cords of cells with mild variation of cell and nuclear size.
• Cords of cells upto 3 cells thick.
• Cells may have cytoplasmic clearing due to glycogen or be pale - obvious if seen.
• Vascular - large arteries, dilated thin-walled veins.

Negatives:

• No bile ducts.
• No portal tracts.
• No cirrhosis! If cirrhosis is present it isn't a hepatic adenoma - important.

DDx:

• Well-differentiated hepatocellular carcinoma.
  • Hepatic adenoma is differentiated from well-differentiated HCC by its architecture; adenomas have cords of cells upto 3 cells thick & have preserved reticulin architecture.
• Focal nodular hyperplasia.

Images

• 

  Hepatic adenoma. (WC/Nephron)

• 

  Hepatic adenoma - reticulin. (WC/Nephron)

www:

• Hepatic adenoma (ajronline.org).
• Series of liver micrographs including hepatic adenoma (radiographics.rsna.org).

Subclassification

Based on molecular changes:

1. Inflammatory hepatic adenoma.
   • AKA telangiectatic adenoma.
   • Associated with obesity.^{[citation needed]}
2. Hepatocyte nuclear factor 1 alpha-mutated hepatic adenoma.
   • Inactivating mutation.
3. Beta-catenin-mutated hepatic adenoma
   • Activating mutation.
4. Unclassified hepatic adenoma.

Note:

• Beta-catenin is considered an oncogene.

IHC

• AFP -ve. (???)
• HNF1alpha +ve/-ve.
• Beta-catenin +ve/-ve.

Hepatobiliary mucinous cystadenoma

• AKA biliary cystadenoma.

General

• Benign neoplasm.
  • May transform into a malignancy.

Microscopic

Features:

• Cystic spaces lined by a mucinous epithelium (simple columnar epithelium with a clear cytoplasm).

Note:

• Similar to pancreatic mucinous cystadenoma.

Malignant hepatic neoplasms

In North America, the most common malignant liver tumour is metastases.

Hepatoblastoma

General

• Most common liver cancer in children.
  • Rare in adolescents and adults.
  • Age of diagnosis usu. ~1 year old; most less than 3 years old.
• Surgical biopsy; core needle biopsy not done as as lesion is vascular.

Associations:

• Beckwith-Wiedemann syndrome.
• Familial adenomatous polyposis.

Clinical:

• Usually present with hepatomegaly.
• High AFP.

Microscopic

Features:

• Small round cell tumour.
• Fetal hepatocytes ~ 1:3 NC ratio, eosinophilic cytoplasm.
• +/-Mesenchymal component
  • Immature fibrous tissue, osteoid or cartilage.

DDx:

• Small round cell tumours.
  • Neuroblastoma.
• Teratoma.
• Hepatocellular carcinoma - separated based on histomorphology alone.

Images

• 

  Hepatoblastoma - very high mag. (WC/Nephron)

• 

  Hepatoblastoma - high mag. (WC/Nephron)

Subtypes

• Six histologic subtypes - that are subdivided into two groups:
  • Epithelial type:
    1. Fetal pattern.
    2. Embryonal and fetal pattern.
    3. Macrotrabecular pattern.
       • May mimic hepatocellular carcinoma histologically.
    4. Small cell undifferentiated pattern.
       • Poor prognosis.
  • Mixed epithelial and mesenchymal type:
    1. With teratoid features.
    2. Without teratoid features.

IHC

• Alpha-fetoprotein +ve.
• Hepatocyte specific antigen +ve esp. in fetal component.
• Beta-catenin +ve (cytoplasmic and nuclear).

Hepatocellular carcinoma

• Commonly abbreviated HCC.

General

Clinical:

• Serum AFP elevated - in approx. 50% of patients.
• Treatments: RFA (radiofrequency ablation), ethanol ablation, liver resection, liver transplant.
• Mean survival at time of diagnosis ~6 months.

Epidemiology:

• Highest where prevalence of hepatitis B virus (HBV) is high.
• HCC generally arises in the setting of cirrhosis.
  • Cirrhosis may be regressed and therefore not appreciated.

HCCs without cirrhosis:

• Hepatitis B virus.
• Hemochromatosis.
• Fibrolamellar HCC.

Risk factors:

• Chronic alcoholism.
• Hepatitis C virus (HCV) - chronic infection.
• Hepatitis B virus (HBV) - chronic infection.
• Aflatoxins (food contaminant - mould).
• Hereditary tyrosinemia.
• Hereditary hemochromatosis.

Gross

Features:

• Unifocal, multifocal or diffusely infiltrative.
  • Tumours are multifocal in approx. 50% of cases; some authors have suggested it is upto 75% of cases.
• Pale in relation to surrounding liver or green (due to bile secretion).

Microscopic

Requirements:

• Architectural changes.
  • Liver plate more than 3 cells thick - key feature.
  • Loss of reticulin scaffold - incomplete loss is considered significant.
  • CD34+ staining cells, suggesting loss of epithelial cells that form the sinusoids.
  • Loss of structures seen in a normal liver lobule (bile ductules, portal triad).
  • Invasion of the portal tract - useful in well-diff. lesions.

Additional findings:

• Nuclear changes.
  • Increased NC ratio - key feature if present.
  • Nuclear hyperchromasia.
  • Abnormal nuclear contour.
  • Mitoses.
• Cytoplasmic changes.
  • Cytoplasmic hyperchromasia, clearing or lighter staining.

Varied architecture - may be:

• Pseudoglandular - can be confused with adenocarcinoma.
• Trabecular.
• Fibrolamellar.
• Solid.

Notes:

• HCC with trabecular morphology has some resemblance to normal liver - but has extra cells.
• Fibrolamellar - better prognosis, classically in young adults.
• Stroma is usually scant.

ASIDE:

• Trabecula = little beam.

DDx:

• Cholangiocarcinoma.
• Combined HCC-CC.

Images

• 

  HCC - low mag. (WC)

• 

  HCC - intermed mag. (WC)

Fibrolamellar hepatocellular carcinoma

• Abbreviated fibrolamellar HCC, FL-HCC, and FHCC.

General

• Rare variant.
• Classically afflicts younger patients.
  • Mean age at onset ~27 years in one study.
• Individuals usually do not have the classic risk factors for HCC, i.e. no cirrhosis, no hepatitis.

Clinical:

• AFP usu. not elevated.

Microscopic

Features:

• Large polygonal tumours cells with:
  • Graunular eosinophilic cytoplasm.
  • Low NC ratio.
• Layered dense collagen bundles.

DDx:

• Amyloidosis of the liver.

Note:

• If conventional HCC is seen focally within the tumour, it is conventional HCC.

Images

• 

  FHCC - intermed. mag. (WC)

• 

  FHCC - very high mag. (WC)

Sclerosing HCC

Features:

• Fibrosis. (???)

Notes:

• Seen in non-cirrhotic livers.

Grading

Edmondson-Steiner grading system:

• Well-differentiated.
  • Some say "it cannot be diagnosed on biopsy," as it cannot be reliably differentiated from a regenerative nodule.
• Moderately differentiated.
  • Round, regular nuclei, some hyperchromatism, nucleoli present, increase NC ratio.
• Poor differentiated.
  • Very prominent nucleoli, pronounced nuclear irregularity.
• Undifferentiated.
  • Anaplastic giant cells.

Simplified description - based on MacSween:

• Well-differentiated = cytologically near normal.
• Moderate = looks like a cancer, small nucleoli.
• Poor = bad cancer, raisin-like (irregular) nuclear membrane, large nucleoli (~1/3 of nucleus).
• Undifferentiated = death on a slide, huge cells (3-4x the size of other cells).

IHC

• CD34 +ve sinusoids; sinusoids in normal liver are CD34 -ve.
• HepPar-1 +ve; may be neg. in high grade tumours.
• AFP +ve; may be neg. even if the serum AFP is elevated.
• CK8/18 +ve.
• Glypican-3 +ve (cytoplasmic, granular cytoplasmic or membranous).

Bile canaliculi:

• CD10 +ve.
• pCEA +ve.

Image:

• HCC - HepPar-1 (nature.com).

Sign out

Negative core biopsy

LIVER CORE, BIOPSY:
- CIRRHOSIS.
- HEPATOCYTE CYTOLOGY WITHIN NORMAL LIMITS.

Cholangiocarcinoma

• AKA bile duct carcinoma.

General

• Malignancy of the biliary tree.
• May be intrahepatic, i.e. intrahepatic cholangiocarcinoma (abbreviated ICC), or extrahepatic.

Epidemiology

• Rare - approximately 1/5 the incidence of HCC.
• More common among asians.

Risks:

• Infection - liver flukes (endemic to Southeast Asia):
  • Clonorchis sinensis (AKA Opisthorchis sinensis).
  • Opisthorchis viverrini.
• Caroli disease - rare congenital disease.
• Primary sclerosing cholangitis - may be assoc. with inflammatory bowel disease (IBD), esp. ulcerative colitis (UC).

Gross

• Classically one large mass - outline described as cauliflower-like.
  • May have satellite nodules.

Image

• 

  Cholangiocarcinoma. (WC)

Microscopic

Features:

• Usually an adenocarcinoma, i.e. gland forming with:
  • Cuboidal or columnar mucin producing cells, and
  • A dense fibrous (desmoplastic) stroma.

Notes:

• Biliary stents lead to reactive changes, these can be confused for malignancy. One must always check whether a biliary stent was in situ at time of biopsy.
• Usually abundant desmoplasia, ergo hard to get good, i.e. diagnositic, endoluminal brushing specimens.
• May have hyaline inclusions.

DDx:

• Metastatic adenocarcinoma.
  • Pancreatic adenocarcinoma.
• Fulminant hepatic necrosis.
  • Bile ducts usu. left behind... look like well-differentiated adenocarcinoma.
• Bile duct adenoma.
  • No necrosis, no mitotic activity, no significant nuclear pleomorphism.

Images

• 

  Cholangiocarcinoma - low mag. Shows the typical desmoplastic stroma. (WC/Nephron)

• 

  Cholangiocarcinoma - high mag. Shows a normal portal triad adjacent to atypical glandular cells within the interlobular septum and obvious tumour. (WC/Nephron)

www:

• Cholangiocarcinoma & liver flukes - several images (upmc.edu).
• Cholangiocarcinoma - several images (upmc.edu).

IHC

Classic IHC pattern:

• CK7 +ve.
• CK20 +ve/-ve.
• HepPar-1 -ve.
• AFP -ve.

ICC vs. HCC:

• ICC: CK19 (92.5%), MUC-1 (73.8%) +ve.
• HCC: HepPar-1 (85.6%), CD34 (87.8%) +ve.

HCC vs. ICC:

• TTF-1: ~90-100% +ve (cytoplasmic) in HCC vs. ~10% in cholangiocarcinoma.

Hepatic angiosarcoma

Main article: Angiosarcoma

• AKA angiosarcoma of the liver.

General

• Liver angiosarcomas are associated with vinyl chloride exposure.

Microscopic

Features:

• Atypical endothelial cells - may be subtle.

Hepatic metastasis

• AKA liver metastases.

General

• Metastases are very common - often from the gastrointestinal tract, e.g. colorectal cancer.
  • Most liver masses in are not biopsied... as a primary lesion is evident.
• Dependent on the extent of disease, CRC metastatic to the liver may be curable with a liver resection.
• It is important to consider germ cell tumours in the DDx as these may be curable with chemotherapy.
• Clear cell variant of HCC may be misdiagnosed as metastatic clear cell carcinoma.
• Interhepatic cholangiocarcinoma is an adenocarcinoma - it may look like a metastatic lesion.

Further reading:

• Anders, RA.; Kamel, IR. (May 2007). "Biopsy considerations in the diagnosis of hepatic masses.". Clin Gastroenterol Hepatol 5 (5): 541-4. doi:10.1016/j.cgh.2007.02.028. PMID 17478344.

Gross pathology/radiology

• Multifocal or solitary.

Microscopic

Features:

• Histologic features are dependent on primary and degree of differentiation.

The classic liver metastasis (colorectal carcinoma):

• Gland forming columnar shaped cells with pseudostratified hyperchromatic cigar-shaped nuclei.

Image

• 

  Liver metastasis - adenocarcinoma. (WC/Nephron)

IHC

• Metastases are typically negative for HepPar-1.
  • HepPar-1 (hepatocytes paraffin antibody 1) - labels hepatocellular mitochondria.

Sign out

LIVER, PORTION OF SEGMENTS 2 AND 3, RESECTION:
- METATSTATIC ADENOACARCINOMA.
-- RESECTION MARGIN CLEARANCE 2 MM.
- LIVER STEATOSIS, MILD.

Micro

The section show liver parenchyma with an invasive adenocarcinoma. The adenocarcinoma has well formed glands with dirty necrosis. The nuclei are appear crowded and have an ellipsoid shape. Focally, zones of necrosis are present. See background liver.

BACKGROUND LIVER (BASED ON H&E ONLY) Fibrosis: not identified.
Fibrous septa: absent.
Septa with curved contours: absent.
Large droplet steatosis (% of hepatocytes): mild (20%).
Ballooning of hepatocytes: not identified.
Mallory-Denk bodies: not identified.
Portal inflammation: present, mild.
Interface activity: not identified.
Lobular necroinflammation: not identified.
Ducts: present in normal numbers.
Duct injury: not identified.
Ductular reaction: not identified.
Cholestasis: present peritumoural, otherwise absent.
Terminal hepatic venules: present.
Ground glass cells with routine stains: not identified.

See also

• Pancreas.
• Gastrointestinal pathology.
• Liver pathology.