Liver neoplasms

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

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:[1]

  • "Large cell dysplasia" (AKA large cell change) - not considered a precursor for HCC, not considered a dysplasia.[2]
  • 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)[3]
  • Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC).

Tabular comparison

Features of HCC & its precursors - generated from DCHH[4] and STC:

Features SCD 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

Notes:

  • SCD = small cell dysplasia.

Small cell dysplasia

  • Considered a precurser to HCC.

Microscopy

Features:[5]

  • 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 grade dysplasia

Microscopy

  • Uniform cells - "noticeably different from normal".[6]
    • 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]".[7]

DDx:

High grade dysplasia

  • "Bader" version of low grade dyplasia.

Features - in addition to those of low grade dysplasia:[9]

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

Micrograph:

Hepatic neoplasms

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

Hepatic adenoma

  • AKA hepatocellular adenoma.
  • Grow under the influence of sex hormones.
    • Associated with OCP use - may regress with discontinuation.
    • May rupture in pregnancy.
  • Usually diagnosed by radiology.

Gross

Features:[10]

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

Microscopy

Features:

  • Sheets or cords of cells with mild variation of cell and nuclear size.[11]
  • Cords of cells upto 3 cells thick.[12]
  • 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.

Images:

DDx:

  • Well-differentiated HCC.[13]
    • Hepatic adenoma is differentiated from well-differentiated HCC by its architecture; adenomas have cords of cells upto 3 cells thick & have preserved reticulin architecture.

Hepatoblastoma

  • Most common liver cancer in children.[14][15]
  • Surgical biopsy; core needle biopsy not done as as lesion is vascular.

Clinical

Histology

  • Six histologic subtypes - that are subdivided into two groups (epithelial, mixed epithelial and mesenchymal).[17]


Hepatocellular carcinoma

  • Commonly abbreviated HCC.

Clinical

  • Serum AFP elevated - in approx. 50% of patients.[18]
  • Treatments: RFA (radiofrequency ablation), ethanol ablation, liver resection, liver transplant.[19]
  • Mean survival at time of diagnosis ~6 months.[19]

Epidemiology

  • Highest where prevalence of hepatitis B virus (HBV) is high.[20]
  • HCC generally arises in the setting of cirrhosis.
    • HBV commonly leads to HCC without cirrhosis[21] - may be without cirrhosis as it is regressed.

Risk factors:[22][23]

  • Chronic alcoholism.
  • Hepatitis C virus (HCV) - chronic infection.
  • HBV - chronic infection.
  • Aflatoxins (food contaminant - mould).[19]
  • Hereditary tyrosinemia.
  • Hereditary hemochromatosis.

Gross

Features:[24]

  • Unifocal, multifocal or diffusely infiltrative.
    • Tumours are multifocal in approx. 50% of cases;[25][26] some authors have suggested it is upto 75% of cases.[19]
  • Pale in relation to surrounding liver or green (due to bile secretion).

Microscopic

Requirements:[27]

  • 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).

Additional findings:[28]

  • 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:[29]

  • 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.[30]

ASIDE:

  • Trabecula = little beam.

Images:

Fibrolamellar HCC

Features:[31]

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

Grading

Edmondson-Steiner grading system:[32][33]

  • Well-differentiated.
    • Cannot be diagnosed on biopsy,[34] 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.

My thoughts (based on MacSween[33]):

  • Well-differentiated = looks like 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.
  • CK18 +ve.[35]

Cholangiocarcioma

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.[36]
  • More common among asians.

Risks:

  • Infection - liver flukes (endemic to Southeast Asia):
    • Opisthorchis sinensis.[37]
    • Opisthorchis viverrini.[38]
  • Caroli disease - rare congenital disease.[39]
  • Primary sclerosing cholangitis - may be assoc. with inflammatory bowel disease (IBD), esp. ulcerative colitis (UC).

Gross

  • Classically one large mass, may have satellite nodules.

Micro

Features:[40]

  • 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,[41] these can be confused for malignancy. One must always check whether a biliary stent was in situ at time of biopsy.[42]

IHC

Classic IHC pattern:[43]

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

ICC vs. HCC:[44]

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

HCC vs. ICC:[45]

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

Metastases

  • 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.[46]
  • 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.

ASIDE - may be of use: PMID 17478344.

Gross pathology/radiology

  • Multifocal or solitary.

Microscopic

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

Image: Liver metastasis - adenocarcinoma (WC).

IHC

  • Metastases are typically negative for HepPar-1.
    • HepPar-1 (hepatocytes paraffin antibody 1) - labels hepatocellular mitochondria.[47]

See also

References

  1. ↑ STC. S.30-37, 19 Jan 2009.
  2. ↑ Park, YN.; Roncalli, M. (Nov 2006). "Large liver cell dysplasia: a controversial entity.". J Hepatol 45 (5): 734-43. doi:10.1016/j.jhep.2006.08.002. PMID 16982109.
  3. ↑ Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. Shirakawa H, Kuronuma T, Nishimura Y, Hasebe T, Nakano M, Gotohda N, Takahashi S, Nakagohri T, Konishi M, Kobayashi N, Kinoshita T, Nakatsura T. Int J Oncol. 2009 Mar;34(3):649-56. PMID 19212669.
  4. ↑ DCHH PP.170-1.
  5. ↑ STC S.32, 19 Jan 2009.
  6. ↑ STC - 19 Jan 2009. (???)
  7. ↑ DCHH PP.170-1.
  8. ↑ DCHH PP.170-1.
  9. ↑ DCHH PP.170-1.
  10. ↑ STC S.20, 19 Jan 2009.
  11. ↑ PBoD P.923.
  12. ↑ STC S.19, 19 Jan 2009.
  13. ↑ SN. 29 May 2009.
  14. ↑ PBoD P.923.
  15. ↑ URL: http://emedicine.medscape.com/article/986802-overview. Accessed on: 29 November 2009.
  16. ↑ http://emedicine.medscape.com/article/986802-diagnosis
  17. ↑ http://emedicine.medscape.com/article/986802-diagnosis
  18. ↑ GLP P.588.
  19. ↑ 19.0 19.1 19.2 19.3 http://emedicine.medscape.com/article/282814-overview
  20. ↑ PBoD P.924.
  21. ↑ PBoD P.924.
  22. ↑ PBoD P.924.
  23. ↑ Leong TY, Leong AS (2005). "Epidemiology and carcinogenesis of hepatocellular carcinoma". HPB (Oxford) 7 (1): 5–15. doi:10.1080/13651820410024021. PMC 2023917. PMID 18333156. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2023917/.
  24. ↑ PBoD P.925.
  25. ↑ PMID 17696722
  26. ↑ PMID 11676064
  27. ↑ Adapted from STC (19 Jan 2009).
  28. ↑ Adapted from STC (19 Jan 2009).
  29. ↑ GLP P.590-1.
  30. ↑ GLP P.591.
  31. ↑ GLP PP.595-6.
  32. ↑ Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. EDMONDSON HA, STEINER PE. Cancer. 1954 May;7(3):462-503. PMID 13160935.
  33. ↑ 33.0 33.1 MacSween 5th Ed. P.783.
  34. ↑ AP. 28 May 2009.
  35. ↑ AP. 28 May 2009.
  36. ↑ GLP P.608.
  37. ↑ PBoD P.926.
  38. ↑ de Martel C, Plummer M, Franceschi S (March 2010). "Cholangiocarcinoma: Descriptive epidemiology and risk factors". Gastroenterol Clin Biol. doi:10.1016/j.gcb.2010.01.008. PMID 20202771.
  39. ↑ Ananthakrishnan AN, Saeian K (April 2007). "Caroli's disease: identification and treatment strategy". Curr Gastroenterol Rep 9 (2): 151–5. PMID 17418061.
  40. ↑ GLP P.609.
  41. ↑ Carrasco, CH; Wallace, S; Charnsangavej, C; Richli, W; Wright, KC; Fanning, T; Gianturco, C (Dec 1985). "Expandable biliary endoprosthesis: an experimental study.". AJR Am J Roentgenol 145 (6): 1279-81. PMID 3877438.
  42. ↑ STC. 2 October 2009.
  43. ↑ GLP P.609.
  44. ↑ [Evaluation of immunohistochemical markers for differential diagnosis of hepatocellular carcinoma from intrahepatic cholangiocarcinoma] Dong H, Cong WL, Zhu ZZ, Wang B, Xian ZH, Yu H. Zhonghua Zhong Liu Za Zhi. 2008 Sep;30(9):702-5. Chinese. PMID 19173916.
  45. ↑ Lei JY, Bourne PA, diSant'Agnese PA, Huang J (April 2006). "Cytoplasmic staining of TTF-1 in the differential diagnosis of hepatocellular carcinoma vs cholangiocarcinoma and metastatic carcinoma of the liver". Am. J. Clin. Pathol. 125 (4): 519–25. doi:10.1309/59TN-EFAL-UL5W-J94M. PMID 16627262.
  46. ↑ OA. 29 November 2009.
  47. ↑ The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review. Lamps LW, Folpe AL. Adv Anat Pathol. 2003 Jan;10(1):39-43. Review. PMID 12502967.
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