Difference between revisions of "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.
[[Image:Secondary tumor deposits in the liver from a primary cancer of the pancreas.jpg|thumb|right|300px|Liver metastases at [[gross pathology|gross]].]]
This article examines '''liver neoplasms''' and '''pre-malignant lesions of the liver'''.  In North America, most malignant liver lesions are [[liver metastasis|metastases]].


This article focuses on primary malignancies of the liver, neoplastic liver lesions, and biliary malignancies.
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.
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==
=Overview=
===Dysplasic lesions of the liver===
===Dysplasic lesions of the liver===
Types:<ref>STC. S.30-37, 19 Jan 2009.</ref>
Types:<ref>STC. S.30-37, 19 Jan 2009.</ref>
*"Large cell dysplasia" (AKA ''large cell change'') - not considered a precursor for HCC, not considered a dysplasia.<ref name=pmid16982109>{{Cite journal  | last1 = Park | first1 = YN. | last2 = Roncalli | first2 = M. | title = Large liver cell dysplasia: a controversial entity. | journal = J Hepatol | volume = 45 | issue = 5 | pages = 734-43 | month = Nov | year = 2006 | doi = 10.1016/j.jhep.2006.08.002 | PMID = 16982109 }}</ref>
*"Large cell dysplasia" (AKA ''large cell change'') - not considered a precursor for HCC, not considered a dysplasia.<ref name=pmid16982109>{{Cite journal  | last1 = Park | first1 = YN. | last2 = Roncalli | first2 = M. | title = Large liver cell dysplasia: a controversial entity. | journal = J Hepatol | volume = 45 | issue = 5 | pages = 734-43 | month = Nov | year = 2006 | doi = 10.1016/j.jhep.2006.08.002 | PMID = 16982109 }}</ref>
*Small cell dysplasia.
*[[Small liver cell dysplasia]] ([[AKA]] small cell dysplasia).
*Low grade dysplasia.
*Low grade dysplasia.
*High grade dysplasia.
*High grade dysplasia.


===Neoplastic lesions===
===Neoplastic lesions===
*Hepatic adenoma.
*[[Hepatic adenoma]].


===Malignant lesions of the liver===
===Malignant lesions of the liver===
*Hepatocellular carcinoma (HCC) - most common malignant liver primary in adults.
*[[Hepatocellular carcinoma]] (HCC) - most common malignant liver primary in adults.
*Hepatoblastoma - malignant liver primary in children.  
*[[Hepatoblastoma]] - malignant liver primary in children.  
*Intrahepatic cholangiocarcinoma (ICC).<ref name=pmid19212669>{{Cite journal  | last1 = Shirakawa | first1 = H. | last2 = Kuronuma | first2 = T. | last3 = Nishimura | first3 = Y. | last4 = Hasebe | first4 = T. | last5 = Nakano | first5 = M. | last6 = Gotohda | first6 = N. | last7 = Takahashi | first7 = S. | last8 = Nakagohri | first8 = T. | last9 = Konishi | first9 = M. | title = Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. | journal = Int J Oncol | volume = 34 | issue = 3 | pages = 649-56 | month = Mar | year = 2009 | doi =  | PMID = 19212669 | url = http://www.spandidos-publications.com/serveFile/ijo_34_3_649_PDF.pdf?type=article&article_id=ijo_34_3_649&item=PDF}}</ref>
*Intrahepatic [[cholangiocarcinoma]] (ICC).<ref name=pmid19212669>{{Cite journal  | last1 = Shirakawa | first1 = H. | last2 = Kuronuma | first2 = T. | last3 = Nishimura | first3 = Y. | last4 = Hasebe | first4 = T. | last5 = Nakano | first5 = M. | last6 = Gotohda | first6 = N. | last7 = Takahashi | first7 = S. | last8 = Nakagohri | first8 = T. | last9 = Konishi | first9 = M. | title = Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. | journal = Int J Oncol | volume = 34 | issue = 3 | pages = 649-56 | month = Mar | year = 2009 | doi =  | PMID = 19212669 | url = http://www.spandidos-publications.com/serveFile/ijo_34_3_649_PDF.pdf?type=article&article_id=ijo_34_3_649&item=PDF}}</ref>
*Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC).
*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]].
*[[Liver hemangioma]].


===Tabular comparison===
===Tabular comparison===
 
====Precursors====
Features of HCC & its precursors - generated from DCHH<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref> and STC:
Features of HCC & its precursors - generated from DCHH<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref> and STC:
{| class="wikitable"
{| class="wikitable"
| '''Features''' || '''SCD''' || '''Low-grade dysplasia''' || '''High-grade dysplasia''' || '''HCC'''
| '''Features''' || '''SLCD''' || '''Low-grade dysplasia''' || '''High-grade dysplasia''' || '''HCC'''
|-
|-
| Plate thickness || <3 cells || <=2 cells || <=3 cells, usu. >2 cells || '''>3 cells'''
| Plate thickness || <3 cells || <=2 cells || <=3 cells, usu. >2 cells || '''>3 cells'''
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|}
|}
Abbreviations:
Abbreviations:
*SCD = small cell dysplasia.
*SLCD = small liver cell dysplasia.


Notes:
Notes:
*Large cell dysplasia:
*Large cell dysplasia:
**Cell size ~ 2x normal, [[NC ratio]] ~ normal.
**Cell size ~ 2x normal, [[NC ratio]] ~ normal.
*SCD:
*SLCD:
**Cell size ~ 1/2x normal, NC ratio - increased.
**Cell size ~ 1/2x normal, NC ratio - increased.


==Small cell dysplasia==
====Hepatic tumours====
Benign:
{| class="wikitable sortable"
! 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+ (???)
| -
| [http://radiographics.rsna.org/content/24/6/1719/F8.expansion.html gross (rsna.org)]
|-
| [[Focal nodular hyperplasia]]
| central scar, large vessels, usu. well-circumscribed
| large arteries, unpaired arteries, bile duct proliferation
|
| usu. diagnosed by imaging
| [http://radiographics.rsna.org/content/24/1/3/F1.expansion.html gross (rsna.org)]
|-
| [[Hepatocellular adenoma]]
| subcapsular, well-circumscribed
| loss of portal tracts, nuclear glycogenation
| reticulin - liver plate thickness <= 3
| background not cirrhotic, assoc. [[OCP]]
| [http://www.mda-sy.com/up//uploads/images/mda-sy-d768fd265c.jpg gross (mda-sy.com)<ref>URL: [http://www.mda-sy.com/vb/showthread.php?p=5083&langid=1 http://www.mda-sy.com/vb/showthread.php?p=5083&langid=1]. Accessed on: 16 February 2012.</ref>]
|}
 
Malignant:
{| class="wikitable sortable"
! Entity
! Gross
! Microscopic
! IHC/stains
! Other
! Images
|-
| [[Liver metastasis]]
| multiple, white lesions
| variable, usu. tubular (glandular) with pseudostratified hyperchromatic nuclei
| CK7-, [[CK20]]+ (colorectal), HepPar-1-, [[CK19]]-
| [[colorectal carcinoma]] most common
| [[Image:Secondary_tumor_deposits_in_the_liver_from_a_primary_cancer_of_the_pancreas.jpg | thumb| center| 150px| Metastases. (WC)]]
|-
| [[Hepatocellular carcinoma]]
| poorly circumscribed, +/-necrosis, +/-hemorrhage
| loss of portal tracts, unpaired arteries, +/-nuclear atypia
| reticulin - liver plate thickness > 3
| background often cirrhotic
| [[Image:Hepatocellular_carcinoma_1.jpg |thumb|center|150px| 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
| [[Image:Cholangiocarcinoma.png |thumb|center|150px| Cholangiocarcinoma. (WC)]]
|}
 
=Dysplasia of the liver=
==Small liver cell dysplasia==
*Abbreviated ''SLCD''.
*[[AKA]] ''small cell dysplasia''.
===General===
===General===
*Considered a precursor to HCC.
*Considered a precursor to [[HCC]].
**Frequently found in livers with HCC - when compared to livers without HCC.<ref name=pmid9401407>{{Cite journal  | last1 = Szczepański | first1 = W. | title = Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma. | journal = Pol J Pathol | volume = 48 | issue = 3 | pages = 147-57 | month =  | year = 1997 | doi =  | PMID = 9401407 }}</ref>


===Microscopy===
===Microscopic===
Features:<ref>STC S.32, 19 Jan 2009.</ref>
Features:<ref>STC S.32, 19 Jan 2009.</ref>
*Cells similar in size to normal hepatocytes.
*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'').
**Name derived from the fact that there is also an entity that was called ''large cell dysplasia'' (AKA ''large liver cell dysplasia'',<ref name=pmid9401407>{{Cite journal  | last1 = Szczepański | first1 = W. | title = Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma. | journal = Pol J Pathol | volume = 48 | issue = 3 | pages = 147-57 | month =  | year = 1997 | doi =  | PMID = 9401407 }}</ref> and ''large cell change'').
*Increased [[NC ratio]] - "more blue".
*Increased [[NC ratio]] - "more blue".
*Mild nuclear and cytoplasmic hyperchromatism.
*Mild nuclear and cytoplasmic hyperchromatism.
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*[http://www.medscape.com/viewarticle/515219_3 Low resolution micrograph of SCD (medscape.com)].
*[http://www.medscape.com/viewarticle/515219_3 Low resolution micrograph of SCD (medscape.com)].


==Low grade dysplasia==
==Low-grade hepatocellular dysplasia==
===Microscopy===
*Generally referred to as ''low-grade dysplasia'' as the context is usually clear.
===Microscopic===
*Uniform cells - "noticeably different from normal".<ref>STC - 19 Jan 2009. (???)</ref>  
*Uniform cells - "noticeably different from normal".<ref>STC - 19 Jan 2009. (???)</ref>  
**Changes in nuclear size, irregular nuclear contour and/or changes in cytoplasm staining.
**Changes in nuclear size, irregular nuclear contour and/or changes in cytoplasm staining.
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*[[Nodular regenerative hyperplasia]] - lacks: compressed rim of cells, central portal tract.<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref>
*[[Nodular regenerative hyperplasia]] - lacks: compressed rim of cells, central portal tract.<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref>


==High grade dysplasia==
==High-grade hepatocellular dysplasia==
*"Bader" version of low grade dyplasia.
*Generally referred to as ''high-grade dysplasia'' as the context is usually clear.
===General===
*"Bader" version of ''[[Low-grade hepatocellular dysplasia|low-grade dyplasia]]''.


===Microscopic===
Features - in addition to those of low grade dysplasia:<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref>
Features - in addition to those of low grade dysplasia:<ref name=Ref_DCHH170-1>{{Ref DCHH|170-1}}</ref>
*Liver plate >2 cells thick.
*Liver plate >2 cells thick.
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*Basophilic cytoplasm.
*Basophilic cytoplasm.


Micrograph:
DDx:
*[[Low-grade hepatocellular dysplasia]].
*[[Hepatocellular carcinoma]].
 
Image:
*[http://radiographics.rsna.org/content/22/5/1023.figures-only Series of liver micrographs including high grade dysplasia (radiographics.rsna.org)].
*[http://radiographics.rsna.org/content/22/5/1023.figures-only Series of liver micrographs including high grade dysplasia (radiographics.rsna.org)].


==Hepatic neoplasms==
=Benign hepatic neoplasms=
In North America, the most common malignant liver tumour is metastases.
==Bile duct hamartoma==
A. [[File:1 BDH 1 680x512px.tif|Trichrome shows fibrous spaces with dilated ducts (20X).]]
B. [[File:2 BDH 1 680x512px.tif|Bizarre, ramifying tubules with dilatations (100X).]]
<br>
C. [[File:3 BDH 1 680x512px.tif|Bland epithelial linings (400X).]]
D. [[File:4 BDH 1 680x512px.tif|Surrounding tract with tortuous bile ducts & inflammation, likely secondary to hamartomas (200X).]]
 
 
Bile duct hamartomas. A. Trichrome shows fibrous spaces with dilated ducts. B. Bizarre, ramifying tubules with dilatations. C. Bland epithelial linings. D. Surrounding tract with tortuous bile ducts & inflammation, likely secondary to hamartomas.
 
==Bile duct adenoma==
:''Should '''not''' be confused with [[bile duct hamartoma]].''
{{Main|Bile duct adenoma}}


==Hepatic adenoma==
==Hepatic adenoma==
*[[AKA]] ''hepatocellular adenoma'', abbreviated ''HCA''.
*[[AKA]] ''hepatocellular adenoma'', abbreviated ''HCA''.
{{Main|Hepatic adenoma}}
==Hepatobiliary mucinous cystadenoma==
*[[AKA]] ''biliary cystadenoma''.
===General===
===General===
*Grow under the influence of sex hormones.
*Benign neoplasm.
**Associated with OCP use - may regress with discontinuation.
**May transform into a malignancy.<ref name=pmid20698207>{{Cite journal  | last1 = Yu | first1 = J. | last2 = Wang | first2 = Y. | last3 = Yu | first3 = X. | last4 = Liang | first4 = P. | title = Hepatobiliary mucinous cystadenoma and cystadenocarcinoma: report of six cases and review of the literature. | journal = Hepatogastroenterology | volume = 57 | issue = 99-100 | pages = 451-5 | month =  | year =  | doi =  | PMID = 20698207 }}</ref>
**May rupture in pregnancy.
*Usually diagnosed by radiology.
 
===Gross===
Features:<ref>STC S.20, 19 Jan 2009.</ref>
*Often subcapsular location.
*Well circumscribed, but not encapsulated.


===Microscopic===
===Microscopic===
Features:
Features:
*Sheets or cords of cells with mild variation of cell and nuclear size.<ref name=Ref_PBoD923>{{Ref PBoD|923}}</ref>
*Cystic spaces lined by a mucinous epithelium (simple columnar epithelium with a clear cytoplasm).
*Cords of cells upto 3 cells thick.<ref>STC S.19, 19 Jan 2009.</ref>
*Surrounding dense ovarian like stroma.
*Cells may have cytoplasmic clearing due to glycogen or be pale - '''obvious if seen'''.
*Vascular - large arteries, dilated thin-walled veins.


Negatives:
DDX:
*No bile ducts.
[[Biliary Intraductal Papillary Neoplasm]]
*No portal tracts.
*no surrounding ovarian stroma
*No cirrhosis!  If cirrhosis is present it isn't a hepatic adenoma - '''important'''.
*Intraductal - connects with the biliary tree lumen.


Images:
Note:
*[http://commons.wikimedia.org/wiki/File:Hepatic_adenoma_low_mag.jpg Hepatic adenoma (WC)].
*Similar to [[pancreatic mucinous cystadenoma]].
*[http://commons.wikimedia.org/wiki/File:Hepatic_adenoma_low_mag_reticulin.jpg Hepatic adenoma - reticulin (WC)].
*[http://www.ajronline.org/cgi/content-nw/full/182/6/1520/FIG3 Hepatic adenoma (ajronline.org)].
*[http://radiographics.rsna.org/content/22/5/1023.figures-only Series of liver micrographs including hepatic adenoma (radiographics.rsna.org)].


DDx:
==Cavernous hemangioma==
*Well-differentiated HCC.<ref>SN. 29 May 2009.</ref>
 
**Hepatic adenoma is differentiated from ''well-differentiated HCC'' by its architecture; adenomas have cords of cells upto 3 cells thick & have preserved reticulin architecture.
A. [[File:1 CAV 1 680x512px.tif|Fibrous foci with increased spaces, hepatocyte focus with nonspecific fibrotic bridge (40X).]]
B. [[File:2 CAV 1 680x512px.tif|Cavernous hemangioma with flat, non-atypical endothelium (200X).]]
<br>
C. [[File:3 CAV 1 680x512px.tif|Tortuous bile ducts/ductules, not to be considered generalized in presence of mass (200X).]]
D. [[File:4 CAV 1 680x512px.tif|Tortuous bile ductsductules, not to be considered generalized in presence of mass (200X).]]


====Subclassification====
Based on molecular changes:<ref>{{Cite journal  | last1 = Katabathina | first1 = VS. | last2 = Menias | first2 = CO. | last3 = Shanbhogue | first3 = AK. | last4 = Jagirdar | first4 = J. | last5 = Paspulati | first5 = RM. | last6 = Prasad | first6 = SR. | title = Genetics and imaging of hepatocellular adenomas: 2011 update. | journal = Radiographics | volume = 31 | issue = 6 | pages = 1529-43 | month = Oct | year = 2011 | doi = 10.1148/rg.316115527 | PMID = 21997980 }}</ref><ref name=pmid21883740>{{Cite journal  | last1 = Sasaki | first1 = M. | last2 = Yoneda | first2 = N. | last3 = Kitamura | first3 = S. | last4 = Sato | first4 = Y. | last5 = Nakanuma | first5 = Y. | title = Characterization of hepatocellular adenoma based on the phenotypic classification: The Kanazawa experience. | journal = Hepatol Res | volume = 41 | issue = 10 | pages = 982-8 | month = Oct | year = 2011 | doi = 10.1111/j.1872-034X.2011.00851.x | PMID = 21883740 }}</ref>
#Inflammatory hepatic adenoma.
#Hepatocyte nuclear factor 1 alpha-mutated hepatic adenoma.
#*Inactivating mutation.
#Beta-catenin-mutated hepatic adenoma
#*Activating mutation.
#Unclassified hepatic adenoma.


Note:
Cavernous hemangioma. A. Fibrous foci with increased spaces, hepatocyte focus with nonspecific fibrotic bridge. B. Cavernous hemangioma with flat, non-atypical endothelium. C. Tortuous bile ductules, not to be considered generalized in presence of mass. D. Tortuous bile ducts, not to be considered generalized in presence of mass.
*Beta-catenin is considered an oncogene.


===IHC===
=Malignant hepatic neoplasms=
*AFP -ve. (???)
In North America, the most common malignant liver tumour is [[liver metastasis|metastases]].
*HNF1alpha +ve/-ve.
*Beta-catenin +ve/-ve.


==Hepatoblastoma==
==Hepatoblastoma==
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Associations:
Associations:
*Beckwith-Wiedemann syndrome.<ref name=pmid9544889>{{cite journal |author=DeBaun MR, Tucker MA |title=Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry |journal=J. Pediatr. |volume=132 |issue=3 Pt 1 |pages=398–400 |year=1998 |month=March |pmid=9544889 |doi= |url=}}</ref>
*[[Beckwith-Wiedemann syndrome]].<ref name=pmid9544889>{{cite journal |author=DeBaun MR, Tucker MA |title=Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry |journal=J. Pediatr. |volume=132 |issue=3 Pt 1 |pages=398–400 |year=1998 |month=March |pmid=9544889 |doi= |url=}}</ref>
*[[Familial adenomatous polyposis]].
*[[Familial adenomatous polyposis]].


Clinical:
Clinical:
*Usually present with hepatomegaly.
*High AFP.<ref>URL: [http://emedicine.medscape.com/article/986802-diagnosis http://emedicine.medscape.com/article/986802-diagnosis]. Accessed on: 11 February 2011.</ref>
*High AFP.<ref>URL: [http://emedicine.medscape.com/article/986802-diagnosis http://emedicine.medscape.com/article/986802-diagnosis]. Accessed on: 11 February 2011.</ref>


Line 167: Line 252:
**Immature fibrous tissue, osteoid or cartilage.
**Immature fibrous tissue, osteoid or cartilage.


Images:
DDx:
*[http://commons.wikimedia.org/wiki/File:Hepatoblastoma_-_2_-_very_high_mag.jpg Hepatoblastoma - very high mag. (WC)].
*[[Small round cell tumours]].
*[http://commons.wikimedia.org/wiki/File:Hepatoblastoma_-_high_mag.jpg Hepatoblastoma - high mag. (WC)].
**[[Neuroblastoma]].
*[[Teratoma]].
*[[Hepatocellular carcinoma]] - separated based on histomorphology alone.
 
====Images====
<gallery>
Image:Hepatoblastoma_-_2_-_very_high_mag.jpg | Hepatoblastoma - very high mag. (WC/Nephron)
Image:Hepatoblastoma_-_high_mag.jpg | Hepatoblastoma - high mag. (WC/Nephron)
</gallery>


====Subtypes====
====Subtypes====
Line 178: Line 271:
**# Macrotrabecular pattern.
**# Macrotrabecular pattern.
**#* May mimic [[hepatocellular carcinoma]] histologically.<ref>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 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.</ref>
**#* May mimic [[hepatocellular carcinoma]] histologically.<ref>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 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.</ref>
**# Small cell undifferentiated pattern
**# Small cell undifferentiated pattern.
**#* Poor prognosis.
** Mixed epithelial and mesenchymal type:
** Mixed epithelial and mesenchymal type:
**# With teratoid features.
**# With teratoid features.
**# Without teratoid features.
**# Without teratoid features.
===IHC===
*Alpha-fetoprotein +ve.
*Hepatocyte specific antigen +ve esp. in fetal component.<ref name=pmid16647953>{{Cite journal  | last1 = Halász | first1 = J. | last2 = Holczbauer | first2 = A. | last3 = Páska | first3 = C. | last4 = Kovács | first4 = M. | last5 = Benyó | first5 = G. | last6 = Verebély | first6 = T. | last7 = Schaff | first7 = Z. | last8 = Kiss | first8 = A. | title = Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma. | journal = Hum Pathol | volume = 37 | issue = 5 | pages = 555-61 | month = May | year = 2006 | doi = 10.1016/j.humpath.2005.12.015 | PMID = 16647953 }}</ref>
*Beta-catenin +ve (cytoplasmic and nuclear).<ref name=pmid16647953/>


==Hepatocellular carcinoma==
==Hepatocellular carcinoma==
*Abbreviated ''HCC''.
{{Main|Hepatocellular carcinoma}}
==Biliary Intraductal Papillary Neoplasm<ref>{{Cite journal  | Masayuki Ohtsuka, Hiroaki Shimizu, Atsushi Kato, et al., “Intraductal Papillary Neoplasms of the Bile Duct,” International Journal of Hepatology, vol. 2014, Article ID 459091, 10 pages, 2014. doi:10.1155/2014/459091}}</ref>==
===General===
===General===
*Commonly abbreviated ''HCC''.
*Rare
*Highest incidence in Far Eastern countries
*Association with hepatolithiasis and clonorchiasis
*Between 50 and 70 years of age
*Slight male predominance
*Intermittent abdominal pain
*Acute cholangitis
*Jaundice


====Clinical====
*Biliary counterpart of [[pancreatic intraductal papillary mucinous neoplasm]]
*Serum AFP elevated - in approx. 50% of patients.<ref>{{Ref GLP|588}}</ref>
*Biliary counterpart of [[intracholecystic papillary neoplasm]] (gall bladder)
*Treatments: RFA (radiofrequency ablation), ethanol ablation, liver resection, liver transplant.<ref name=emed_hcc>[http://emedicine.medscape.com/article/282814-overview http://emedicine.medscape.com/article/282814-overview]</ref>
*Construct consumes some cases of biliary cystadenoma/cystadenocarcinoma, biliary papilloma/papillomatosis, intraductal growth type of cholangiocarcinoma and papillary carcinoma of the extrahepatic bile duct.
*Mean survival at time of diagnosis ~6 months.<ref name=emed_hcc/>


====Epidemiology====
===Radiology===
*Highest where prevalence of hepatitis B virus (HBV) is high.<ref name=Ref_PBoD924>{{Ref PBoD|924}}</ref>
*Bile duct dilatation
*HCC generally arises in the setting of [[cirrhosis]].
*Intraductal masses
**HBV commonly leads to HCC without [[cirrhosis]]<ref name=Ref_PBoD924>{{Ref PBoD|924}}</ref> - may be ''without'' cirrhosis as it is regressed.
 
Risk factors:<ref name=Ref_PBoD924>{{Ref PBoD|924}}</ref><ref name=pmid18333156>{{cite journal |author=Leong TY, Leong AS |title=Epidemiology and carcinogenesis of hepatocellular carcinoma |journal=HPB (Oxford) |volume=7 |issue=1 |pages=5–15 |year=2005 |pmid=18333156 |pmc=2023917 |doi=10.1080/13651820410024021 |url=}}</ref>
*Chronic alcoholism.
*Hepatitis C virus (HCV) - chronic infection.
*HBV - chronic infection.
*Aflatoxins (food contaminant - mould).<ref name=emed_hcc/>
*Hereditary tyrosinemia.
*Hereditary hemochromatosis.


===Gross===
===Gross===
Features:<ref name=Ref_PBoD925>{{Ref PBoD|925}}</ref>
*Singular, or occasionally multiple, polypoid masses extending into the lumen of a dilated bile duct
*Unifocal, multifocal or diffusely infiltrative.
*Or multilocular well-defined cystic mass containing mucinous fluid
**Tumours are multifocal in approx. 50% of cases;<ref name=pmid17696722>{{cite journal |author=Yusuf MA, Badar F, Meerza F, ''et al.'' |title=Survival from hepatocellular carcinoma at a cancer hospital in Pakistan |journal=Asian Pac. J. Cancer Prev. |volume=8 |issue=2 |pages=272–4 |year=2007 |pmid=17696722 |doi= |url=}}</ref><ref name=pmid11676064>{{cite journal |author=Sharieff S, Burney KA, Ahmad N, Salam A, Siddiqui T |title=Radiological features of hepatocellular carcinoma in Southern Pakistan |journal=Trop Doct |volume=31 |issue=4 |pages=224–5 |year=2001 |month=October |pmid=11676064 |doi= |url=}}</ref> some authors have suggested it is upto 75% of cases.<ref name=emed_hcc/>
*Granular or papillary mucosa
*Pale in relation to surrounding liver or green (due to bile secretion).
*Communication with bile duct may be difficult to confirm


===Microscopic===
===Microscopic===
Requirements:<ref>Adapted from STC (19 Jan 2009).</ref>
*Papillary or villous growth within the lumen of an intra or extrahepatic bile duct
*Architectural changes.
*Papillary fronds with fine vascular cores
**Liver plate more than 3 cells thick - '''key feature'''.
*Epithelium types
**Loss of reticulin scaffold - incomplete loss is considered significant.
**Pancreatobiliary
**CD34+ staining cells, suggesting loss of epithelial cells that form the sinusoids.
**Intestinal - marked mucin secretion
**Loss of structures seen in a normal liver lobule (bile ductules, portal triad).
**Gastric
**Invasion of the portal tract - useful in well-diff. lesions.<ref name=pmid19177576>{{Cite journal  | last1 = Kojiro | first1 = M. | last2 = Wanless | first2 = IR. | last3 = Alves | first3 = V. | last4 = Badve | first4 = S. | last5 = Balabaud | first5 = C. | last6 = Bedossa | first6 = P. | last7 = Bhathal | first7 = P. | last8 = Bioulac-Sage | first8 = P. | last9 = Brunt | first9 = EM. | title = Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. | journal = Hepatology | volume = 49 | issue = 2 | pages = 658-64 | month = Feb | year = 2009 | doi = 10.1002/hep.22709 | PMID = 19177576 | url = http://onlinelibrary.wiley.com/doi/10.1002/hep.22709/pdf }}</ref>
**Oncocytic types
*Dysplasia
**High or low grade
**Marked variation in histologic grade between different regions of individual tumors


Additional findings:<ref>Adapted from STC (19 Jan 2009).</ref>
*Common association with invasive cholangiocarcinoma
*Nuclear changes.
**Tubular adenocarcinoma
**Increased NC ratio - '''key feature''' if present.
**Mucinous (colloid) carcinoma (often in association with the intestinal type).
**Nuclear hyperchromasia.
**Abnormal nuclear contour.
**Mitoses.
*Cytoplasmic changes.
**Cytoplasmic hyperchromasia, clearing or lighter staining.


Varied architecture - may be:<ref>{{Ref GLP|590-1}}</ref>
====DDX====
*Pseudoglandular - can be confused with adenocarcinoma.
*[[Biliary Mucinous Cystic Neoplasm]]
*[[Trabecular]].
***Epithelium is surrounded by a distinct ovarian-like stroma.
*Fibrolamellar.
*Solid.


Notes:
====Photos====
*HCC with trabecular morphology has some resemblance to normal liver - but has extra cells.
<gallery>
*Fibrolamellar - better prognosis, classically in young adults.
Image:BileDuct IntraductalPapillaryNeoplasm LP CTR.jpg|Bile Ducts - Intraductal Papillary Neoplasm - Low power (SKB)
*Stroma is usually scant.<ref>{{Ref GLP|591}}</ref>
Image:BileDuct IntraductalPapillaryNeoplasm MP CTR.jpg|Bile Ducts - Intraductal Papillary Neoplasm - Medium power (SKB)
Image:BileDuct IntraductalPapillaryNeoplasm HP CTR.jpg|Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)
Image:BileDucts IntraductalPapillaryNeoplasm NonMucinousType LP PA.jpg|Bile Ducts - Intraductal Papillary Neoplasm - Low power (SKB)
Image:BileDucts IntraductalPapillaryNeoplasm OncocyticType HP PA.jpg|Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)
Image:BileDucts IntraductalPapillaryNeoplasm NonMucinousType HP2 PA.jpg|Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)
</gallery>


ASIDE:
A. [[File:1 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
*''[[Trabecula]]'' = ''little beam''.
B. [[File:2 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
 
<br>
Images:
C. [[File:3 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
*[http://commons.wikimedia.org/wiki/File:Hepatocellular_carcinoma_low_mag.jpg HCC - low mag. (WC)].
D. [[File:4 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
*[http://commons.wikimedia.org/wiki/File:Hepatocellular_carcinoma_intermed_mag.jpg HCC - intermed mag. (WC)].
<br>
 
E. [[File:5 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
====Fibrolamellar hepatocellular carcinoma====
F. [[File:6 papillary cbd aca 1 680x512px.tif| Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.]]
*Abbreviated ''fibrolamellar HCC'', ''FL-HCC'', and ''FHCC''.
=====General=====
*Rare variant.
*Classically afflicts younger patients.
**Mean age at onset ~27 years in one study.<ref name=pmid16475212>{{Cite journal  | last1 = Stipa | first1 = F. | last2 = Yoon | first2 = SS. | last3 = Liau | first3 = KH. | last4 = Fong | first4 = Y. | last5 = Jarnagin | first5 = WR. | last6 = D'Angelica | first6 = M. | last7 = Abou-Alfa | first7 = G. | last8 = Blumgart | first8 = LH. | last9 = DeMatteo | first9 = RP. | title = Outcome of patients with fibrolamellar hepatocellular carcinoma. | journal = Cancer | volume = 106 | issue = 6 | pages = 1331-8 | month = Mar | year = 2006 | doi = 10.1002/cncr.21703 | PMID = 16475212 }}</ref>
*Individuals usually do '''not''' have the classic risk factors for HCC, i.e. no [[cirrhosis]], no hepatitis.<ref name=pmid16475212/>


Clinical:
Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma. A. The papillary tumor comprises mostly variably dilated acini. B. Tumor also shows areas of micropapillae. C. Some areas within the non-invasive tumor showed necrosis, with the black pyknotic nuclei amid red debris. D. Definite invasion was established low power by glands headed in perpendicular directions. E. Embedded in fibroblastic response are non-acinar walls and isolated epithelial groups. F. Also embedded in fibroblastic response are flat glands with nuclei showing loss of polarity (lack of respect for lateral intercellular borders shown by variable orientation to base of gland).
*AFP usu. not elevated.<ref name=pmid16475212/>


=====Microscopic=====
Notes -  
Features:<ref>{{Ref GLP|595-6}}</ref>
*Reflect on the known marked variation in histologic grade between different regions of individual tumors when rendering an opinion on a small biopsy specimen.
*Large polygonal tumours cells with:
*Consider the possibility of an invasive component and submit tissue generously.
**Graunular eosinophilic cytoplasm.
**Low NC ratio.<ref>STC. 6 December 2010.</ref>
*Layered dense collagen bundles.


Images:
See also:
*[[WC]]:
PubCan [http://www.pubcan.org/printicdotopo.php?id=5755]
**[http://commons.wikimedia.org/wiki/File:Fibrolamellar_hepatocellular_carcinoma_-2-_intermed_mag.jpg FHCC - intermed. mag. (WC)].
**[http://commons.wikimedia.org/wiki/File:Fibrolamellar_hepatocellular_carcinoma_-2-_very_high_mag.jpg FHCC - very high mag. (WC)].
 
====Sclerosing HCC====
Features:
*Fibrosis. (???)
 
Notes:
*Seen in non-cirrhotic livers.
 
===Grading===
Edmondson-Steiner grading system:<ref name=pmid13160935>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.</ref><ref name=macsween5th>{{Ref MacSween|783}}</ref>
*Well-differentiated.
**Some say "it cannot be diagnosed on biopsy,"<ref>AP. 28 May 2009.</ref> 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:<ref name=macsween5th/>
*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.
*CK18 +ve.<ref>AP. 28 May 2009.</ref>
*Glypican-3 +ve (cytoplasmic, granular cytoplasmic or membranous).<ref name=pmid19212669>{{Cite journal  | last1 = Shirakawa | first1 = H. | last2 = Kuronuma | first2 = T. | last3 = Nishimura | first3 = Y. | last4 = Hasebe | first4 = T. | last5 = Nakano | first5 = M. | last6 = Gotohda | first6 = N. | last7 = Takahashi | first7 = S. | last8 = Nakagohri | first8 = T. | last9 = Konishi | first9 = M. | title = Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. | journal = Int J Oncol | volume = 34 | issue = 3 | pages = 649-56 | month = Mar | year = 2009 | doi =  | PMID = 19212669 | url = http://www.spandidos-publications.com/serveFile/ijo_34_3_649_PDF.pdf?type=article&article_id=ijo_34_3_649&item=PDF}}</ref>
 
Image:
*[http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800682f12.html#figure-title HCC - HepPar-1 (nature.com)].<ref name=pmid17486052>{{Cite journal  | last1 = Goodman | first1 = ZD. | title = Neoplasms of the liver. | journal = Mod Pathol | volume = 20 Suppl 1 | issue =  | pages = S49-60 | month = Feb | year = 2007 | doi = 10.1038/modpathol.3800682 | PMID = 17486052 }}</ref>


==Cholangiocarcinoma==
==Cholangiocarcinoma==
===General===
*[[AKA]] ''bile duct carcinoma''.<ref>URL: [http://www.cancer.org/cancer/bileductcancer/detailedguide/bile-duct-cancer-what-is-bile-duct-cancer http://www.cancer.org/cancer/bileductcancer/detailedguide/bile-duct-cancer-what-is-bile-duct-cancer]. Access on: 23 May 2013.</ref>
*Malignancy of the biliary tree.
{{Main|Cholangiocarcinoma}}
*May be intrahepatic, i.e. ''intrahepatic cholangiocarcinoma'' (abbreviated ''ICC''), or extrahepatic.
 
====Epidemiology====
*Rare - approximately 1/5 the incidence of HCC.<ref>{{Ref GLP|608}}</ref>
*More common among asians.
 
Risks:
*Infection - liver flukes (endemic to Southeast Asia):
**''Clonorchis sinensis'' ([[AKA]] ''Opisthorchis sinensis''<ref name=Ref_PBoD926>{{Ref PBoD|926}}</ref>).<ref name=pmid18420495>{{Cite journal  | last1 = Park | first1 = do H. | last2 = Son | first2 = HY. | title = Images in clinical medicine. Clonorchis sinensis. | journal = N Engl J Med | volume = 358 | issue = 16 | pages = e18 | month = Apr | year = 2008 | doi = 10.1056/NEJMicm054461 | PMID = 18420495 |URL = http://www.nejm.org/doi/full/10.1056/NEJMicm054461 }}</ref>
**''Opisthorchis viverrini''.<ref name=pmid20202771>{{cite journal |author=de Martel C, Plummer M, Franceschi S |title=Cholangiocarcinoma: Descriptive epidemiology and risk factors |journal=Gastroenterol Clin Biol |volume= |issue= |pages= |year=2010 |month=March |pmid=20202771 |doi=10.1016/j.gcb.2010.01.008 |url=}}</ref>
*[[Caroli disease]] - rare congenital disease.<ref name=pmid17418061>{{cite journal |author=Ananthakrishnan AN, Saeian K |title=Caroli's disease: identification and treatment strategy |journal=Curr Gastroenterol Rep |volume=9 |issue=2 |pages=151–5 |year=2007 |month=April |pmid=17418061 |doi= |url=}}</ref>
*[[Primary sclerosing cholangitis]] - may be assoc. with inflammatory bowel disease (IBD), esp. [[ulcerative colitis]] (UC).
 
===Gross===
*Classically one large mass, may have satellite nodules.
 
===Microscopic===
Features:<ref>{{Ref GLP|609}}</ref>
*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,<ref name=pmid3877438>{{Cite journal  | last1 = Carrasco | first1 = CH | last2 = Wallace | first2 = S | last3 = Charnsangavej | first3 = C | last4 = Richli | first4 = W | last5 = Wright | first5 = KC | last6 = Fanning | first6 = T | last7 = Gianturco | first7 = C | title = Expandable biliary endoprosthesis: an experimental study. | journal = AJR Am J Roentgenol | volume = 145 | issue = 6 | pages = 1279-81 | month = Dec | year = 1985 | doi =  | PMID = 3877438 }}</ref> these can be confused for malignancy.  One must always check whether a biliary stent was in situ at time of biopsy.<ref>STC. 2 October 2009.</ref>
*Usually abundant desmoplasia, ergo hard to get good, i.e. diagnositic, endoluminal brushing specimens.<ref>STC. 6 December 2010.</ref>
 
DDx:
*Metastatic adenocarinoma.
**[[Pancreatic adenocarcinoma]].


Images:
==Hepatic angiosarcoma==
*[[WC]]:
**[http://commons.wikimedia.org/wiki/File:Cholangiocarcinoma_-_low_mag.jpg Cholangiocarcinoma - low mag. (WC)] - the image shows the typical demosplastic stroma.
**[http://commons.wikimedia.org/wiki/File:Cholangiocarcinoma_-_high_mag.jpg Cholangiocarcinoma - high mag. (WC)] - the image shows a normal portal triad adjacent to atypical glandular cells within the interlobular septum and obvious tumour.
*www:
**[http://path.upmc.edu/cases/case296.html Cholangiocarcinoma & liver flukes - several images (upmc.edu)].
**[http://path.upmc.edu/cases/case420.html Cholangiocarcinoma - several images (upmc.edu)].
===IHC===
Classic IHC pattern:<ref>{{Ref GLP|609}}</ref>
*CK7 +ve.
*CK20 +ve/-ve.
*HepPar-1 -ve.
*AFP -ve.<ref>STC. 6 December 2010.</ref>
 
ICC vs. HCC:<ref name=pmid19173916>[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.</ref>
*ICC: CK19 (92.5%), MUC-1 (73.8%) +ve.
*HCC: HepPar-1 (85.6%), CD34 (87.8%) +ve.
 
HCC vs. ICC:<ref name=pmid16627262>{{cite journal |author=Lei JY, Bourne PA, diSant'Agnese PA, Huang J |title=Cytoplasmic staining of TTF-1 in the differential diagnosis of hepatocellular carcinoma vs cholangiocarcinoma and metastatic carcinoma of the liver |journal=Am. J. Clin. Pathol. |volume=125 |issue=4 |pages=519–25 |year=2006 |month=April |pmid=16627262 |doi=10.1309/59TN-EFAL-UL5W-J94M |url=}}</ref>
*TTF-1: ~90-100% +ve (cytoplasmic) in HCC vs. ~10% in cholangiocarcinoma.
 
==Angiosarcoma==
{{Main|Angiosarcoma}}
{{Main|Angiosarcoma}}
 
*[[AKA]] ''angiosarcoma of the liver''.
===General===
===General===
*Liver angiosarcomas are associated with vinyl chloride exposure.<ref name=Ref_PCPBoD8_212>{{Ref PCPBoD8|212}}</ref>
*Liver angiosarcomas are associated with vinyl chloride exposure.<ref name=Ref_PCPBoD8_212>{{Ref PCPBoD8|212}}</ref>
Line 368: Line 374:
*Atypical endothelial cells - may be subtle.
*Atypical endothelial cells - may be subtle.


==Metastases==
==Hepatic metastasis==
*Metastases are very common - often from the gastrointestinal tract, e.g. [[colorectal cancer]]. 
{{Main|Liver metastasis}}
**Most liver masses in are not biopsied... as a primary lesion is evident.<ref>OA. 29 November 2009.</ref>
*[[AKA]] ''liver metastases''.
*Dependent on the extent of disease, CRC metastatic to the liver may be curable with a liver resection.
*[[AKA]] ''metastatic liver disease''.
*It is important to consider [[germ cell tumour]]s in the DDx as these may be curable with chemotherapy.
==Hematopoietic tumors==
*Clear cell variant of HCC may be misdiagnosed as metastatic clear cell carcinoma.
A [[File:1 MM 1 Covenant 680x512px.tif|One liver core was normal (Row 1 Left 40X).]]
*Interhepatic cholangiocarcinoma is an adenocarcinoma - it may look like a metastatic lesion.
<br>
<br>
Further reading:
B [[File:2 MM 1 Covenant 680x512px.tif|A triad with a proliferated bile ductule, otherwise normal (Row 1 Right 400X).]]
*{{Cite journal  | last1 = Anders | first1 = RA. | last2 = Kamel | first2 = IR. | title = Biopsy considerations in the diagnosis of hepatic masses. | journal = Clin Gastroenterol Hepatol | volume = 5 | issue = 5 | pages = 541-4 | month = May | year = 2007 | doi = 10.1016/j.cgh.2007.02.028 | PMID = 17478344 }}
<br>
C [[File:3 MM 1 Covenant 680x512px.tif|The other core showed a mass of tumor mashed against normal liver (Row 2 Left 40X).]]
<br>
D [[File:4 MM 1 Covenant 680x512px.tif|Tumor cells showed round to ovoid nuclei without pattern and with grey cytoplasm that proved to be CD138 positive (Row 2 Right 400X).]]
<br>
Plasmacytoma appearing as a tumor mass. A. One liver core was normal. B. A triad with a proliferated bile ductule, otherwise normal. C. The other core showed a mass of tumor mashed against normal liver. D. Tumor cells showed round to ovoid nuclei without pattern and with grey cytoplasm that proved to be CD138 positive.


===Gross pathology/radiology===
A. [[File:1 B cell lym liver 1 680x512px.tif|Apparent inflamed fibrous tract with lobular inflammatory collections in adjacent liver (Row 1 Left 40X).]]
*Multifocal or solitary.
<br>
 
B. [[File:2 B cell lym liver 1 680x512px.tif|Apparent inflamed fibrous band between two relatively hepatocyte regions (Row 1 Right 40X).]]
===Microscopic===
<br>
*Histologic features are dependent on primary and degree of differentiation.
C. [[File:3 B cell lym liver 1 680x512px.tif|Apparent piecemeal necrosis with bile ductular proliferation (Row 2 Left 200X).]]
The classic liver metastasis ([[colorectal carcinoma]]):
<br>
*Gland forming columnar shaped cells with pseudostratified hyperchromatic cigar-shaped nuclei.
D. [[File:4 B cell lym liver 1 680x512px.tif|Apparent portal inflammation with unaffected interlobular bile duct (Row 2 Right 200X).]]
<br>
E. [[File:5 B cell lym liver 1 680x512px.tif|Apparent lobular infiltrate with small masse.]]
<br>
F. [[File:6 B cell lym liver 1 680x512px.tif|Proof is at high power. All cells are similar to macrophages but are too closely crowded to be macrophages. The monomorphism (one type of cell) should inspire immunohistochemical stains, which showed the patient had a B cell lymphoma.]]
<br>
B cell lymphoma mimicking hepatitis with fibrosis. A. Apparent inflamed fibrous tract with lobular inflammatory collections in adjacent liver. B. Apparent inflamed fibrous band between two relatively hepatocyte regions. C. Apparent piecemeal necrosis with bile ductular proliferation. D. Apparent portal inflammation with unaffected interlobular bile duct. E. Apparent lobular inflammation with collections a bit too large for usual lobular inflammation.  F. Proof is at high power. All cells are similar to macrophages but are too closely crowded to be macrophages. The monomorphism (one type of cell) should inspire immunohistochemical stains, which showed the patient had a B cell lymphoma.


[[File:5 02965636298621 sl 1.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
[[File:5 02965636298621 sl 2.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
[[File:5 02965636298621 sl 3.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
[[File:5 02965636298621 sl 4.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
[[File:5 02965636298621 sl 31.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
[[File:5 02965636298621 sl 6.png|Malignant B cell lymphoma, NOS, in a 63 year old man’s liver]]
<br>
<br>
Image:
Malignant B cell lymphoma, NOS, in a 63 year old man’s liver. No other specimens were available for further classification. A. Tumor expands a triad and occupies parenchymal regions. B. Bounding a bile duct, modestly sized round to reniform lymphoid cells, many without nucleoli, accompany small round lymphocytes. Some of the larger cells have clefts (arrows). C. CD3 stain shows many of the lymphoid cells are intercalated reactive T cells. D. Ki67 shows less than half the tumor cells, mostly the larger ones, are in proliferative phase, arguing against the notion of a high grade B cell lymphoma. E. CD79A establishes B cell phenotype (CD20 was also positive). F. That the tumor cells are BCL2 positive evinces B cell neoplasia. The cells were CD10, BCL6, and cyclin D1 negative, militating against mantle cell lymphoma and CLL, with no follicular origin identified.
*[http://commons.wikimedia.org/wiki/File:Adenocarcinoma_liver_metastasis.jpg Liver metastasis - adenocarcinoma, not obviously CRC (WC)].


===IHC===
[[File:4 89735893919405 sl 1.png| High grade B cell lymphoma involving liver]]
*Metastases are typically negative for ''HepPar-1''.
[[File:4 89735893919405 sl 2.png| High grade B cell lymphoma involving liver]]
**HepPar-1 (hepatocytes paraffin antibody 1) - labels hepatocellular mitochondria.<ref name=pmid12502967>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.</ref>
[[File:4 89735893919405 sl 3.png| High grade B cell lymphoma involving liver]]
[[File:4 89735893919405 sl 4.png| High grade B cell lymphoma involving liver]]
[[File:4 89735893919405 sl 5.png| High grade B cell lymphoma involving liver]]<br>
High grade B cell lymphoma involving liver in a 77 year old woman. A. A band of cancer abuts fibrotic liver with steatosis. B. Cancer cells show primitive, round to ovoid, variably sized, dark nucleoli and an aberrant mitoses. Cytoplasm is scant. C. Cancer cells are CD79a positive. D. Most cancer cell nuclei were positive for Ki-67, overall about 80%. E. A minority of cancer cells are CD10 positive.


==See also==
=See also=
*[[Pancreas]].
*[[Pancreas]].
*[[Gastrointestinal pathology]].
*[[Gastrointestinal pathology]].
*[[Liver pathology]].
*[[Liver pathology]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


[[Category:Gastrointestinal pathology]]
[[Category:Gastrointestinal pathology]]
[[Category:Liver pathology]]
[[Category:Liver pathology]]

Latest revision as of 23:15, 31 January 2017

Liver metastases at gross.

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

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+ (colorectal), 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 liver cell dysplasia,[6] and 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 hepatocellular dysplasia

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

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.

DDx:

Image:

Benign hepatic neoplasms

Bile duct hamartoma

A. Trichrome shows fibrous spaces with dilated ducts (20X). B. Bizarre, ramifying tubules with dilatations (100X).
C. Bland epithelial linings (400X). D. Surrounding tract with tortuous bile ducts & inflammation, likely secondary to hamartomas (200X).


Bile duct hamartomas. A. Trichrome shows fibrous spaces with dilated ducts. B. Bizarre, ramifying tubules with dilatations. C. Bland epithelial linings. D. Surrounding tract with tortuous bile ducts & inflammation, likely secondary to hamartomas.

Bile duct adenoma

Should not be confused with bile duct hamartoma.
Main article: Bile duct adenoma

Hepatic adenoma

  • AKA hepatocellular adenoma, abbreviated HCA.
Main article: Hepatic adenoma

Hepatobiliary mucinous cystadenoma

  • AKA biliary cystadenoma.

General

  • Benign neoplasm.
    • May transform into a malignancy.[9]

Microscopic

Features:

  • Cystic spaces lined by a mucinous epithelium (simple columnar epithelium with a clear cytoplasm).
  • Surrounding dense ovarian like stroma.

DDX: Biliary Intraductal Papillary Neoplasm

  • no surrounding ovarian stroma
  • Intraductal - connects with the biliary tree lumen.

Note:

Cavernous hemangioma

A. Fibrous foci with increased spaces, hepatocyte focus with nonspecific fibrotic bridge (40X). B. Cavernous hemangioma with flat, non-atypical endothelium (200X).
C. Tortuous bile ducts/ductules, not to be considered generalized in presence of mass (200X). D. Tortuous bile ductsductules, not to be considered generalized in presence of mass (200X).


Cavernous hemangioma. A. Fibrous foci with increased spaces, hepatocyte focus with nonspecific fibrotic bridge. B. Cavernous hemangioma with flat, non-atypical endothelium. C. Tortuous bile ductules, not to be considered generalized in presence of mass. D. Tortuous bile ducts, not to be considered generalized in presence of mass.

Malignant hepatic neoplasms

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

Hepatoblastoma

General

  • Most common liver cancer in children.[10][11]
    • 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.[13]

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:[14]
    • 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.[16]
  • Beta-catenin +ve (cytoplasmic and nuclear).[16]

Hepatocellular carcinoma

  • Abbreviated HCC.
Main article: Hepatocellular carcinoma

Biliary Intraductal Papillary Neoplasm[17]

General

  • Rare
  • Highest incidence in Far Eastern countries
  • Association with hepatolithiasis and clonorchiasis
  • Between 50 and 70 years of age
  • Slight male predominance
  • Intermittent abdominal pain
  • Acute cholangitis
  • Jaundice

Radiology

  • Bile duct dilatation
  • Intraductal masses

Gross

  • Singular, or occasionally multiple, polypoid masses extending into the lumen of a dilated bile duct
  • Or multilocular well-defined cystic mass containing mucinous fluid
  • Granular or papillary mucosa
  • Communication with bile duct may be difficult to confirm

Microscopic

  • Papillary or villous growth within the lumen of an intra or extrahepatic bile duct
  • Papillary fronds with fine vascular cores
  • Epithelium types
    • Pancreatobiliary
    • Intestinal - marked mucin secretion
    • Gastric
    • Oncocytic types
  • Dysplasia
    • High or low grade
    • Marked variation in histologic grade between different regions of individual tumors
  • Common association with invasive cholangiocarcinoma
    • Tubular adenocarcinoma
    • Mucinous (colloid) carcinoma (often in association with the intestinal type).

DDX

Photos

  • Bile Ducts - Intraductal Papillary Neoplasm - Low power (SKB)

  • Bile Ducts - Intraductal Papillary Neoplasm - Medium power (SKB)

  • Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)

  • Bile Ducts - Intraductal Papillary Neoplasm - Low power (SKB)

  • Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)

  • Bile Ducts - Intraductal Papillary Neoplasm - High power (SKB)

A. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma. B. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.
C. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma. D. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.
E. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma. F. Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma.

Intraductal papillary neoplasm of common bile duct with associated invasive carcinoma. A. The papillary tumor comprises mostly variably dilated acini. B. Tumor also shows areas of micropapillae. C. Some areas within the non-invasive tumor showed necrosis, with the black pyknotic nuclei amid red debris. D. Definite invasion was established low power by glands headed in perpendicular directions. E. Embedded in fibroblastic response are non-acinar walls and isolated epithelial groups. F. Also embedded in fibroblastic response are flat glands with nuclei showing loss of polarity (lack of respect for lateral intercellular borders shown by variable orientation to base of gland).

Notes -

  • Reflect on the known marked variation in histologic grade between different regions of individual tumors when rendering an opinion on a small biopsy specimen.
  • Consider the possibility of an invasive component and submit tissue generously.

See also: PubCan [1]

Cholangiocarcinoma

Main article: Cholangiocarcinoma

Hepatic angiosarcoma

Main article: Angiosarcoma
  • AKA angiosarcoma of the liver.

General

  • Liver angiosarcomas are associated with vinyl chloride exposure.[19]

Microscopic

Features:

  • Atypical endothelial cells - may be subtle.

Hepatic metastasis

Main article: Liver metastasis
  • AKA liver metastases.
  • AKA metastatic liver disease.

Hematopoietic tumors

A One liver core was normal (Row 1 Left 40X).
B A triad with a proliferated bile ductule, otherwise normal (Row 1 Right 400X).
C The other core showed a mass of tumor mashed against normal liver (Row 2 Left 40X).
D Tumor cells showed round to ovoid nuclei without pattern and with grey cytoplasm that proved to be CD138 positive (Row 2 Right 400X).
Plasmacytoma appearing as a tumor mass. A. One liver core was normal. B. A triad with a proliferated bile ductule, otherwise normal. C. The other core showed a mass of tumor mashed against normal liver. D. Tumor cells showed round to ovoid nuclei without pattern and with grey cytoplasm that proved to be CD138 positive.

A. Apparent inflamed fibrous tract with lobular inflammatory collections in adjacent liver (Row 1 Left 40X).
B. Apparent inflamed fibrous band between two relatively hepatocyte regions (Row 1 Right 40X).
C. Apparent piecemeal necrosis with bile ductular proliferation (Row 2 Left 200X).
D. Apparent portal inflammation with unaffected interlobular bile duct (Row 2 Right 200X).
E. Apparent lobular infiltrate with small masse.
F. Proof is at high power. All cells are similar to macrophages but are too closely crowded to be macrophages. The monomorphism (one type of cell) should inspire immunohistochemical stains, which showed the patient had a B cell lymphoma.
B cell lymphoma mimicking hepatitis with fibrosis. A. Apparent inflamed fibrous tract with lobular inflammatory collections in adjacent liver. B. Apparent inflamed fibrous band between two relatively hepatocyte regions. C. Apparent piecemeal necrosis with bile ductular proliferation. D. Apparent portal inflammation with unaffected interlobular bile duct. E. Apparent lobular inflammation with collections a bit too large for usual lobular inflammation. F. Proof is at high power. All cells are similar to macrophages but are too closely crowded to be macrophages. The monomorphism (one type of cell) should inspire immunohistochemical stains, which showed the patient had a B cell lymphoma.

Malignant B cell lymphoma, NOS, in a 63 year old man’s liver Malignant B cell lymphoma, NOS, in a 63 year old man’s liver Malignant B cell lymphoma, NOS, in a 63 year old man’s liver Malignant B cell lymphoma, NOS, in a 63 year old man’s liver Malignant B cell lymphoma, NOS, in a 63 year old man’s liver Malignant B cell lymphoma, NOS, in a 63 year old man’s liver
Malignant B cell lymphoma, NOS, in a 63 year old man’s liver. No other specimens were available for further classification. A. Tumor expands a triad and occupies parenchymal regions. B. Bounding a bile duct, modestly sized round to reniform lymphoid cells, many without nucleoli, accompany small round lymphocytes. Some of the larger cells have clefts (arrows). C. CD3 stain shows many of the lymphoid cells are intercalated reactive T cells. D. Ki67 shows less than half the tumor cells, mostly the larger ones, are in proliferative phase, arguing against the notion of a high grade B cell lymphoma. E. CD79A establishes B cell phenotype (CD20 was also positive). F. That the tumor cells are BCL2 positive evinces B cell neoplasia. The cells were CD10, BCL6, and cyclin D1 negative, militating against mantle cell lymphoma and CLL, with no follicular origin identified.

High grade B cell lymphoma involving liver High grade B cell lymphoma involving liver High grade B cell lymphoma involving liver High grade B cell lymphoma involving liver High grade B cell lymphoma involving liver
High grade B cell lymphoma involving liver in a 77 year old woman. A. A band of cancer abuts fibrotic liver with steatosis. B. Cancer cells show primitive, round to ovoid, variably sized, dark nucleoli and an aberrant mitoses. Cytoplasm is scant. C. Cancer cells are CD79a positive. D. Most cancer cell nuclei were positive for Ki-67, overall about 80%. E. A minority of cancer cells are CD10 positive.

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. ↑ 6.0 6.1 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. ↑ 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.
  10. ↑ 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.
  11. ↑ URL: http://emedicine.medscape.com/article/986802-overview. Accessed on: 29 November 2009.
  12. ↑ 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.
  13. ↑ URL: http://emedicine.medscape.com/article/986802-diagnosis. Accessed on: 11 February 2011.
  14. ↑ URL: http://emedicine.medscape.com/article/986802-diagnosis. Accessed on: 11 February 2011.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ .
  18. ↑ URL: http://www.cancer.org/cancer/bileductcancer/detailedguide/bile-duct-cancer-what-is-bile-duct-cancer. Access on: 23 May 2013.
  19. ↑ 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.
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