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 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:[1]

  • "Large cell dysplasia" (AKA large cell change) - not considered a precursor for HCC, not considered a dysplasia.[2]
  • Small liver cell dysplasia (AKA small cell dysplasia).
  • Low grade dysplasia.
  • High grade dysplasia.

Neoplastic lesions

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).

Lesions that arise in a non-cirrhotic liver

Hepatocellular:

Other:

Tabular comparison

Precursors

Features of HCC & its precursors - generated from DCHH[4] 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.[6]

Microscopic

Features:[7]

  • 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

Microscopic

  • Uniform cells - "noticeably different from normal".[8]
    • 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]".[4]

DDx:

High-grade hepatocellular dysplasia

  • Generally referred to as high-grade dysplasia as the context is usually clear.

General

Microscopic

Features - in addition to those of low grade dysplasia:[4]

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

Image:

DDx:

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:

Image:

Hepatic adenoma

  • AKA hepatocellular adenoma, abbreviated HCA.

General

Gross

Features:[11]

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

Microscopic

Features:

  • Sheets or cords of cells with mild variation of cell and nuclear size.[12]
  • Cords of cells upto 3 cells thick.[13]
  • 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:

Images

  • Hepatic adenoma. (WC/Nephron)

  • Hepatic adenoma - reticulin. (WC/Nephron)

www:

Subclassification

Based on molecular changes:[15][16]

  1. Inflammatory hepatic adenoma.
  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.[18]

Microscopic

Features:

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

Note:

Malignant hepatic neoplasms

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

Hepatoblastoma

General

  • Most common liver cancer in children.[12][19]
    • 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:

Clinical:

  • Usually present with hepatomegaly.
  • High AFP.[21]

Microscopic

Features:

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

DDx:

Images

  • Hepatoblastoma - very high mag. (WC/Nephron)

  • Hepatoblastoma - high mag. (WC/Nephron)

Subtypes

  • Six histologic subtypes - that are subdivided into two groups:[22]
    • Epithelial type:
      1. Fetal pattern.
      2. Embryonal and fetal pattern.
      3. Macrotrabecular pattern.
      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.[24]
  • Beta-catenin +ve (cytoplasmic and nuclear).[24]

Hepatocellular carcinoma

  • Abbreviated HCC.
Main article: Hepatocellular carcinoma

Cholangiocarcinoma

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.[26]
  • More common among asians.

Risks:

Gross

  • Classically one large mass - outline described as cauliflower-like.[31]
    • May have satellite nodules.

Image

  • Cholangiocarcinoma. (WC)

Microscopic

Features:[32]

  • 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,[33] these can be confused for malignancy. One must always check whether a biliary stent was in situ at time of biopsy.[34]
  • Usually abundant desmoplasia, ergo hard to get good, i.e. diagnositic, endoluminal brushing specimens.[35]
  • May have hyaline inclusions.[36]

DDx:

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:

IHC

Classic IHC pattern:[37]

  • CK7 +ve.
  • CK20 +ve/-ve.
  • HepPar-1 -ve.
  • AFP -ve.[38]

ICC vs. HCC:[39]

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

HCC vs. ICC:[40]

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

Sign out

MASS, PANCREAS, CORE BIOPSY:
- ADENOCARCINOMA, MODERATELY DIFFERENTIATED.

Note:

Micro

The sections show an atypical gland-forming lesion (adenocarcinoma) in a fibrous background. This lesion is separate from the benign pancreatic glands that are present. The atypical glands are unequally spaced. Moderate-to-marked cytologic atypia is present. Mitotic activity is not readily apparent.

Hepatic angiosarcoma

Main article: Angiosarcoma
  • AKA angiosarcoma of the liver.

General

  • Liver angiosarcomas are associated with vinyl chloride exposure.[41]

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.[42]
  • 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:

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.

DDx:

Image

  • Liver metastasis - adenocarcinoma. (WC/Nephron)

IHC

  • Metastases are typically negative for HepPar-1.
    • HepPar-1 (hepatocytes paraffin antibody 1) - labels hepatocellular mitochondria.[44]

Note:

  • If a primary is already established by pathology and the clinical impression is a metastasis, it isn't necessary to do IHC if the morphology of the lesion in the liver is compatible with the established primary.

Sign out

LIVER, PORTION OF SEGMENTS 2 AND 3, RESECTION:
- METASTATIC ADENOCARCINOMA.
-- 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

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. ↑ Shirakawa, H.; Kuronuma, T.; Nishimura, Y.; Hasebe, T.; Nakano, M.; Gotohda, N.; Takahashi, S.; Nakagohri, T. et al. (Mar 2009). "Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer.". Int J Oncol 34 (3): 649-56. PMID 19212669. http://www.spandidos-publications.com/serveFile/ijo_34_3_649_PDF.pdf?type=article&article_id=ijo_34_3_649&item=PDF.
  4. ↑ 4.0 4.1 4.2 4.3 Tadrous, Paul.J. Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum (1st ed.). Wiley. pp. 170-1. ISBN 978-0470519035.
  5. ↑ URL: http://www.mda-sy.com/vb/showthread.php?p=5083&langid=1. Accessed on: 16 February 2012.
  6. ↑ Szczepański, W. (1997). "Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma.". Pol J Pathol 48 (3): 147-57. PMID 9401407.
  7. ↑ STC S.32, 19 Jan 2009.
  8. ↑ STC - 19 Jan 2009. (???)
  9. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 221. ISBN 978-0781765275.
  10. ↑ Rooks, JB.; Ory, HW.; Ishak, KG.; Strauss, LT.; Greenspan, JR.; Hill, AP.; Tyler, CW. (Aug 1979). "Epidemiology of hepatocellular adenoma. The role of oral contraceptive use.". JAMA 242 (7): 644-8. PMID 221698.
  11. ↑ STC S.20, 19 Jan 2009.
  12. ↑ 12.0 12.1 Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 923. ISBN 0-7216-0187-1.
  13. ↑ STC S.19, 19 Jan 2009.
  14. ↑ SN. 29 May 2009.
  15. ↑ Katabathina, VS.; Menias, CO.; Shanbhogue, AK.; Jagirdar, J.; Paspulati, RM.; Prasad, SR. (Oct 2011). "Genetics and imaging of hepatocellular adenomas: 2011 update.". Radiographics 31 (6): 1529-43. doi:10.1148/rg.316115527. PMID 21997980.
  16. ↑ Sasaki, M.; Yoneda, N.; Kitamura, S.; Sato, Y.; Nakanuma, Y. (Oct 2011). "Characterization of hepatocellular adenoma based on the phenotypic classification: The Kanazawa experience.". Hepatol Res 41 (10): 982-8. doi:10.1111/j.1872-034X.2011.00851.x. PMID 21883740.
  17. ↑ Maylee, H.; Harada, K.; Igarashi, S.; Tohda, G.; Yamamoto, M.; Ren, XS.; Osawa, T.; Hasegawa, Y. et al. (Jun 2012). "Case of telangiectatic/inflammatory hepatocellular adenoma arising in a patient with primary sclerosing cholangitis.". Hepatol Res 42 (6): 611-8. doi:10.1111/j.1872-034X.2011.00962.x. PMID 22568458.
  18. ↑ Yu, J.; Wang, Y.; Yu, X.; Liang, P.. "Hepatobiliary mucinous cystadenoma and cystadenocarcinoma: report of six cases and review of the literature.". Hepatogastroenterology 57 (99-100): 451-5. PMID 20698207.
  19. ↑ URL: http://emedicine.medscape.com/article/986802-overview. Accessed on: 29 November 2009.
  20. ↑ DeBaun MR, Tucker MA (March 1998). "Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry". J. Pediatr. 132 (3 Pt 1): 398–400. PMID 9544889.
  21. ↑ URL: http://emedicine.medscape.com/article/986802-diagnosis. Accessed on: 11 February 2011.
  22. ↑ URL: http://emedicine.medscape.com/article/986802-diagnosis. Accessed on: 11 February 2011.
  23. ↑ URL: http://www.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt{actionForm.contentReference}=cap_foundation%2FcaseOfMonth%2FMar10%2Fmar_2010_cotm_diagnosis.html&_state=maximized&_pageLabel=cntvwr#null. Accessed on: 11 February 2011.
  24. ↑ 24.0 24.1 Halász, J.; Holczbauer, A.; Páska, C.; Kovács, M.; Benyó, G.; Verebély, T.; Schaff, Z.; Kiss, A. (May 2006). "Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma.". Hum Pathol 37 (5): 555-61. doi:10.1016/j.humpath.2005.12.015. PMID 16647953.
  25. ↑ URL: http://www.cancer.org/cancer/bileductcancer/detailedguide/bile-duct-cancer-what-is-bile-duct-cancer. Access on: 23 May 2013.
  26. ↑ Iacobuzio-Donahue, Christine A.; Montgomery, Elizabeth A. (2005). Gastrointestinal and Liver Pathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 608. ISBN 978-0443066573.
  27. ↑ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. pp. 926. ISBN 0-7216-0187-1.
  28. ↑ Park, do H.; Son, HY. (Apr 2008). "Images in clinical medicine. Clonorchis sinensis.". N Engl J Med 358 (16): e18. doi:10.1056/NEJMicm054461. PMID 18420495.
  29. ↑ 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.
  30. ↑ Ananthakrishnan AN, Saeian K (April 2007). "Caroli's disease: identification and treatment strategy". Curr Gastroenterol Rep 9 (2): 151–5. PMID 17418061.
  31. ↑ Nakanishi, Y.; Zen, Y.; Kawakami, H.; Kubota, K.; Itoh, T.; Hirano, S.; Tanaka, E.; Nakanuma, Y. et al. (Jul 2008). "Extrahepatic bile duct carcinoma with extensive intraepithelial spread: a clinicopathological study of 21 cases.". Mod Pathol 21 (7): 807-16. doi:10.1038/modpathol.2008.65. PMID 18425077.
  32. ↑ Iacobuzio-Donahue, Christine A.; Montgomery, Elizabeth A. (2005). Gastrointestinal and Liver Pathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 609. ISBN 978-0443066573.
  33. ↑ 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.
  34. ↑ STC. 2 October 2009.
  35. ↑ STC. 6 December 2010.
  36. ↑ Aishima, S.; Fujita, N.; Mano, Y.; Iguchi, T.; Taketomi, A.; Maehara, Y.; Oda, Y.; Tsuneyoshi, M. (Sep 2010). "p62+ Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease.". Am J Clin Pathol 134 (3): 457-65. doi:10.1309/AJCP53YVVJCNDZIR. PMID 20716803.
  37. ↑ Iacobuzio-Donahue, Christine A.; Montgomery, Elizabeth A. (2005). Gastrointestinal and Liver Pathology: A Volume in the Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 609. ISBN 978-0443066573.
  38. ↑ STC. 6 December 2010.
  39. ↑ [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.
  40. ↑ 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.
  41. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 212. ISBN 978-1416054542.
  42. ↑ OA. 29 November 2009.
  43. ↑ Kondo, Y.; Nakajima, T. (Sep 1987). "Pseudoglandular hepatocellular carcinoma. A morphogenetic study.". Cancer 60 (5): 1032-7. PMID 2440554.
  44. ↑ 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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