Difference between revisions of "Gestational trophoblastic disease"

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'''Gestational trophoblastic disease''' (GTD) includes [[choriocarcinoma]] and hydatidiform moles.
'''Gestational trophoblastic disease''' (abbreviated '''GTD'''), also '''gestational trophoblastic neoplasia''' (abbreviated '''GTN'''), includes [[choriocarcinoma]] and hydatidiform moles.


=Overview=
=Overview=
===Most common===
===Most common===
Overview of gestational trophoblastic disease:
Overview of gestational trophoblastic disease:
{| class="wikitable"
{| class="wikitable sortable"
|
! Type of mole
| '''Gross'''
! Gross
| '''Nuclear atypia'''
! [[Nuclear atypia]]
| '''Villi'''
! [[Chorionic villi]]
| '''[[IHC]]'''
! [[IHC]]
| '''DNA content'''
! DNA content
| '''Images'''
! Micrographs
|-
|-
| Complete mole
| Complete mole
| "snowstorm"
| "snowstorm"
| +/- ?
| +/- ?
| yes, all abnormal <ref>[http://pathologyoutlines.com/placenta.html#completemole http://pathologyoutlines.com/placenta.html#completemole]</ref>
| yes, all abnormal  
| p57(KIP2) -ve
| p57(KIP2) -ve
| Paternal, diploid
| Paternal, diploid
Line 35: Line 35:
| beta-hCG +ve
| beta-hCG +ve
| ?
| ?
| [http://www.webpathology.com/image.asp?case=36&n=1 choriocarcinoma (webpathology.com)]
| [[Image:Choriocarcinoma_-2-_very_high_mag.jpg|thumb|center|120px|Choriocarcinoma. (WC)]]
|-
|-
|}
|}
Line 56: Line 56:
==Choriocarcinoma==
==Choriocarcinoma==
{{Main|Choriocarcinoma}}
{{Main|Choriocarcinoma}}
===General===
*Classified as a [[germ cell tumour]].
*May be preceded by a [[complete hydatidiform mole]].<ref name=Ref_PBoD1110-1>{{Ref PBoD|1110-1111}}</ref>
===Microscopic===
Features:
*Two cell populations:
#'''C'''ytotrophoblasts - '''key feature'''.
#*'''C'''lear cytoplasm.
#*Polygonal shaped cells in cords/masses.
#*Distinct cell borders.
#*Single uniform nucleus.
#Syncytiotrophoblasts - may be absent.<ref>URL: [http://www.webpathology.com/image.asp?n=4&Case=36 http://www.webpathology.com/image.asp?n=4&Case=36]. Accessed on: 8 February 2011.</ref>
#*Large + many irreg. or lobular hyperchromatic nuclei.
#*Eosinophilic vacuolated cytoplasm (contains hCG).
*+/-Hemorrhage.
*+/-Necrosis.
Notes:
*No ''[[chorionic villi]]'' should be present.
**If chorionic villi are present... it is likely a type of [[hydatidiform mole]].
*The dual cell population may not be evident at first.
**Hemorrhage and marked nuclear pleomorphism are suggestive of the diagnosis.
Images:
*www:
**[http://www.webpathology.com/image.asp?n=5&Case=36 Choriocarcinoma - low mag. (webpathology.com)].
**[http://www.webpathology.com/image.asp?case=36&n=1 Choriocarcinoma (webpathology.com)].
**[http://www.webpathology.com/image.asp?n=4&Case=36 Choriocarcinoma (webpathology.com)].
**[http://chestjournal.chestpubs.org/content/138/1/220.full Choriocarcinoma (chestjournal.chestpubs.org)].<ref>{{Cite journal  | last1 = Venkatram | first1 = S. | last2 = Muppuri | first2 = S. | last3 = Niazi | first3 = M. | last4 = Fuentes | first4 = GD. | title = A 24-year-old pregnant patient with diffuse alveolar hemorrhage. | journal = Chest | volume = 138 | issue = 1 | pages = 220-3 | month = Jul | year = 2010 | doi = 10.1378/chest.09-2688 | PMID = 20605823 }}</ref>
**[http://oac.med.jhmi.edu/Pathology/Repro/Placenta/279B_Full.html Choriocarcinoma - uterus (med.jhmi.edu)].
*[[WC]]:
**[http://commons.wikimedia.org/wiki/File:Choriocarcinoma_-2-_high_mag.jpg Choriocarcinoma - high mag. (WC)].
**[http://commons.wikimedia.org/wiki/File:Choriocarcinoma_-2-_very_high_mag.jpg Choriocarcinoma - very high mag. (WC)].
===IHC===
*beta-hCG +ve.<ref name=pmid19145204>{{cite journal |author=Kalhor N, Ramirez PT, Deavers MT, Malpica A, Silva EG |title=Immunohistochemical studies of trophoblastic tumors |journal=Am. J. Surg. Pathol. |volume=33 |issue=4 |pages=633–8 |year=2009 |month=April |pmid=19145204 |doi=10.1097/PAS.0b013e318191f2eb |url=}}</ref>
**Classically said to be produced by syncytiotrophoblasts.<ref name=pmid20735820>{{Cite journal  | last1 = Cole | first1 = LA. | title = Biological functions of hCG and hCG-related molecules. | journal = Reprod Biol Endocrinol | volume = 8 | issue =  | pages = 102 | month =  | year = 2010 | doi = 10.1186/1477-7827-8-102 | PMID = 20735820 | PMC = 2936313 | URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936313/ }}
</ref>
***Cytotrophoblasts also produce some.<ref name=pmid20735820/><ref name=pmid12242037>{{Cite journal  | last1 = Kovalevskaya | first1 = G. | last2 = Genbacev | first2 = O. | last3 = Fisher | first3 = SJ. | last4 = Caceres | first4 = E. | last5 = O'Connor | first5 = JF. | title = Trophoblast origin of hCG isoforms: cytotrophoblasts are the primary source of choriocarcinoma-like hCG. | journal = Mol Cell Endocrinol | volume = 194 | issue = 1-2 | pages = 147-55 | month = Aug | year = 2002 | doi =  | PMID = 12242037 }}</ref>


==Hydatidiform moles==
==Hydatidiform moles==
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#Partial mole - see [[partial mole]].
#Partial mole - see [[partial mole]].
#Complete mole - see [[complete mole]].
#Complete mole - see [[complete mole]].
#Invasive mole.
 
#*Within uterine muscle +/- vessels.
Extent:
*Invasive mole - '''not''' a subtype.
**Within uterine muscle +/- vessels.


===Microscopic===
===Microscopic===
Hydropic changes:
Hydropic changes:
{| class="wikitable"
{| class="wikitable sortable"
| '''Entity'''
! Entity
| '''Villi (outline)'''
! [[Chorionic villi]] (outline)
| '''Cisterns'''
! Cisterns
| '''Blood vessels'''
! [[Blood vessel]]s
| '''Nucleated RBCs'''
! Nucleated RBCs
| '''p57 / Ki-67<ref>URL: [http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf]. Accessed on: 28 May 2011.</ref> staining'''
! p57 / Ki-67<ref>URL: [http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf]. Accessed on: 28 May 2011.</ref> staining ‡
| '''Ploidy'''
! Ploidy
| '''Image'''
! Micrograph
|-
|-
| Complete mole
| Complete mole
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| [http://www.ipath-network.com/ipath/object/view/181344]
| [http://www.ipath-network.com/ipath/object/view/181344]
|}
|}
Note:
* ‡ The amount of [[Ki-67]] staining varies considerably based on what one reads. Chen ''at al.''<ref>{{Cite journal  | last1 = Chen | first1 = Y. | last2 = Shen | first2 = D. | last3 = Gu | first3 = Y. | last4 = Zhong | first4 = P. | last5 = Xie | first5 = J. | last6 = Song | first6 = Q. | title = The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion. | journal = Wien Klin Wochenschr | volume = 124 | issue = 5-6 | pages = 184-7 | month = Mar | year = 2012 | doi = 10.1007/s00508-011-0119-4 | PMID = 22218717 }}</ref> suggest 25% versus 5% for partial mole versus hydropic abortus.


====Mole vs. normal====
====Mole versus normal====
*Moles have large [[chorionic villi]] with edema and abnormal blood vessels.<ref>URL: [http://pathologyoutlines.com/placenta.html#hydatgeneral http://pathologyoutlines.com/placenta.html#hydatgeneral].</ref>
*Moles have large [[chorionic villi]] with edema and abnormal blood vessels.<ref>URL: [http://pathologyoutlines.com/placenta.html#hydatgeneral http://pathologyoutlines.com/placenta.html#hydatgeneral].</ref>


====Non-molar vs. partial vs. complete - short version====
====Non-molar versus partial versus complete - short version====
Features:<ref>{{Cite journal  | last1 = Howat | first1 = AJ. | last2 = Beck | first2 = S. | last3 = Fox | first3 = H. | last4 = Harris | first4 = SC. | last5 = Hill | first5 = AS. | last6 = Nicholson | first6 = CM. | last7 = Williams | first7 = RA. | title = Can histopathologists reliably diagnose molar pregnancy? | journal = J Clin Pathol | volume = 46 | issue = 7 | pages = 599-602 | month = Jul | year = 1993 | doi =  | PMID = 8157742 }}</ref>
Features:<ref name=pmid8157742>{{Cite journal  | last1 = Howat | first1 = AJ. | last2 = Beck | first2 = S. | last3 = Fox | first3 = H. | last4 = Harris | first4 = SC. | last5 = Hill | first5 = AS. | last6 = Nicholson | first6 = CM. | last7 = Williams | first7 = RA. | title = Can histopathologists reliably diagnose molar pregnancy? | journal = J Clin Pathol | volume = 46 | issue = 7 | pages = 599-602 | month = Jul | year = 1993 | doi =  | PMID = 8157742 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501384/?page=3 }}</ref>
*Non-molar pregnancy: polar proliferation of trophoblastic tissue.
*Non-molar pregnancy: polar proliferation of trophoblastic tissue.
*Partial mole: Norwegian fjord periphery, circumferential or multifocal trophoblastic proliferation, fetal parts.
*Partial mole: Norwegian fjord periphery, circumferential or multifocal trophoblastic proliferation, fetal parts.
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===IHC===
===IHC===
*p57(KIP2) - the gene is strongly paternally imprinted and the paternal copy is inactived; its expression is from the maternal gene.
*p57(KIP2) - the gene is strongly paternally imprinted and the paternal copy is inactived; its expression is from the maternal gene.
**Complete moles lacks the maternal genome; thus, p57(KIP2) immunostaining is absent.<ref name=pmid15754295>{{cite journal |author=Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE |title=p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses |journal=Hum. Pathol. |volume=36 |issue=2 |pages=180–6 |year=2005 |month=February |pmid=15754295 |doi=10.1016/j.humpath.2004.12.007 |url=}}</ref>
**Complete moles lack the maternal genome; thus, p57(KIP2) immunostaining (in the cytotrophoblasts and villous stromal cells) is absent.<ref name=pmid15754295>{{cite journal |author=Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE |title=p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses |journal=Hum. Pathol. |volume=36 |issue=2 |pages=180–6 |year=2005 |month=February |pmid=15754295 |doi=10.1016/j.humpath.2004.12.007 |url=}}</ref><ref name=pmid12514787>{{Cite journal  | last1 = Fukunaga | first1 = M. | title = Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles. | journal = Hum Pathol | volume = 33 | issue = 12 | pages = 1188-92 | month = Dec | year = 2002 | doi = 10.1053/hupa.2002.129421 | PMID = 12514787 }}</ref>
***Intermediate trophoblasts and maternal tissue are positive controls.<ref name=pmid12514787/>  
**Memory device:  
**Memory device:  
***'''''p'''57 is '''p'''ositive in '''p'''artial moles''.
***'''''p'''57 is '''p'''ositive in '''p'''artial moles''.
Line 169: Line 134:
===Molecular===
===Molecular===
*The type of mole can be determined by [[cytogenetics]].<ref>[http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf]</ref>
*The type of mole can be determined by [[cytogenetics]].<ref>[http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf]</ref>
==Hydropic abortus==
===General===
*May be seen in the context of a previously detected fetal heart beat.
===Microsopic===
Features:
*Enlarged chorionic villi with some cisterns.
DDx:<ref>{{cite journal |authors=Rios-Doria E, Pennington KP, Reiter DJ, Parker EU |title=Diagnostic challenges in differentiating between hydropic abortus, and complete and partial hydatidiform molar pregnancies in early gestation |journal=Int J Gynecol Cancer |volume=33 |issue=9 |pages=1482–1484 |date=September 2023 |pmid=37268312 |doi=10.1136/ijgc-2022-004104 |url=}}</ref>
*Molar pregnancy.
===Sign out===
<pre>
Submitted as "Retained Products of Conception":
- Small and large chorionic villi with cisterns, suggestive of hydropic abortus, see comment.
- Benign decidual tissue present.
- Negative for evidence of fetal tissue in sampled tissue, see comment.
 
Comment:
Imaging previously described a gestational sac and a fetal heart beat. 
</pre>


==Partial hydatidiform mole==
==Partial hydatidiform mole==
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===General===
===General===
Genetics:
Genetics:
*Polypoid - usually triploid (e.g. 69XXY).
*Usually triploid (e.g. 69XXY).
Images: [http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=12&cat2=86&cat3=795&cat4=3&stype=n]


===Microscopic===
===Microscopic===
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***Contain fluid in the centre, i.e. are "hydropic".
***Contain fluid in the centre, i.e. are "hydropic".
**Villi with cytotrophoblastic inclusions.
**Villi with cytotrophoblastic inclusions.
***Cytotrophoblast in the core of a villus (normally it is only at the surface of the villus).
***[[Cytotrophoblast]] in the core of a villus (normally it is only at the surface of the villus).
*May have fetal parts, such as nucleated RBCs.
*May have fetal parts, such as nucleated RBCs.
*Trophoblastic proliferation.
*Trophoblastic proliferation.
Line 191: Line 177:
*"Norwegian fjord periphery"<ref name=pmid8157742>{{Cite journal  | last1 = Howat | first1 = AJ. | last2 = Beck | first2 = S. | last3 = Fox | first3 = H. | last4 = Harris | first4 = SC. | last5 = Hill | first5 = AS. | last6 = Nicholson | first6 = CM. | last7 = Williams | first7 = RA. | title = Can histopathologists reliably diagnose molar pregnancy? | journal = J Clin Pathol | volume = 46 | issue = 7 | pages = 599-602 | month = Jul | year = 1993 | doi =  | PMID = 8157742 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501384/?page=3 }}</ref> - jagged border / irregular sawtooth-like periphery.
*"Norwegian fjord periphery"<ref name=pmid8157742>{{Cite journal  | last1 = Howat | first1 = AJ. | last2 = Beck | first2 = S. | last3 = Fox | first3 = H. | last4 = Harris | first4 = SC. | last5 = Hill | first5 = AS. | last6 = Nicholson | first6 = CM. | last7 = Williams | first7 = RA. | title = Can histopathologists reliably diagnose molar pregnancy? | journal = J Clin Pathol | volume = 46 | issue = 7 | pages = 599-602 | month = Jul | year = 1993 | doi =  | PMID = 8157742 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501384/?page=3 }}</ref> - jagged border / irregular sawtooth-like periphery.
**Complete moles tend to have a smooth border
**Complete moles tend to have a smooth border
DDx:
*[[Complete hydatidiform mole]].
*[[Placental mesenchymal dysplasia]].
*Hydropic abortus - see [[products of conception]] and [[chorionic villi]].


Images:  
Images:  
*[http://www-medlib.med.utah.edu/WebPath/PLACHTML/PLAC067.html Partial mole (med.utah.edu)].
*[http://www-medlib.med.utah.edu/WebPath/PLACHTML/PLAC067.html Partial mole (med.utah.edu)].
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=12&cat2=86&cat3=795&cat4=3&stype=n Partial mole - several images (gfmer.ch)].
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=12&cat2=86&cat3=795&cat4=3&stype=n Partial mole - several images (gfmer.ch)].
===IHC===
Features:<ref name=pmid22218717>{{Cite journal  | last1 = Chen | first1 = Y. | last2 = Shen | first2 = D. | last3 = Gu | first3 = Y. | last4 = Zhong | first4 = P. | last5 = Xie | first5 = J. | last6 = Song | first6 = Q. | title = The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion. | journal = Wien Klin Wochenschr | volume = 124 | issue = 5-6 | pages = 184-7 | month = Mar | year = 2012 | doi = 10.1007/s00508-011-0119-4 | PMID = 22218717 }}</ref>
*Ki-67 ~ 25+/-5% of cytotrophoblasts and intermediate trophoblasts.
**Hydropic abortus ~ 5+/-1%.
*p53 ~ 22+/-12% of cytotrophoblasts and intermediate trophoblasts.
**Hydropic abortus ~ 5+/-3%.


==Complete hydatidiform mole==
==Complete hydatidiform mole==
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*Male derived, i.e. arise from DNA in sperm; empty egg fertilized.  
*Male derived, i.e. arise from DNA in sperm; empty egg fertilized.  


===Radiology===
===Gross/Radiology===
*"Snowstorm" appearance on ultrasound.<ref>URL:[http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589 http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589]. Accessed on: 27 July 2010.</ref>
*"Snowstorm" appearance on ultrasound.<ref>URL:[http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589 http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589]. Accessed on: 27 July 2010.</ref>
*May be described as "grape-like" on gross exam.<ref name=pmid18162339>{{Cite journal  | last1 = Abike | first1 = F. | last2 = Temizkan | first2 = O. | last3 = Payasli | first3 = A. | last4 = Avsar | first4 = F. | last5 = Karahan | first5 = N. | last6 = Baspinar | first6 = S. | title = Postmenopausal complete hydatidiform mole: a case report. | journal = Maturitas | volume = 59 | issue = 1 | pages = 95-8 | month = Jan | year = 2008 | doi = 10.1016/j.maturitas.2007.10.005 | PMID = 18162339 }}</ref>
Image:
*[http://library.med.utah.edu/WebPath/PLACHTML/PLAC063.html Complete mole (utah.edu)].


===Microscopic===
===Microscopic===
Line 216: Line 218:
**Very rarely nucleated [[RBC]]s.
**Very rarely nucleated [[RBC]]s.


Images:
====Images====
*[http://commons.wikimedia.org/wiki/File:Intermediate_trophoblast_3_-_low_mag.jpg Complete mole and intermediate trophoblast - intermed. mag. (WC)].
<gallery>
*[http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%281%29_complete_type.jpg Complete mole - low mag. (WC)].
Image:Intermediate_trophoblast_3_-_low_mag.jpg | Complete mole and intermediate trophoblast - intermed. mag. (WC)
*[http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%282%29_complete_type.jpg Complete mole - high mag. (WC)].
Image:Hydatidiform_mole_%281%29_complete_type.jpg | Complete mole - low mag. (WC)
Image:Hydatidiform_mole_%282%29_complete_type.jpg | Complete mole - high mag. (WC)
</gallery>


==Invasive hydatidiform mole==
==Invasive hydatidiform mole==
*[[AKA]] ''invasive mole''.
*[[AKA]] ''chorioadenoma destruens''.<ref name=pmid6300738>{{Cite journal  | last1 = McDonald | first1 = TW. | last2 = Ruffolo | first2 = EH. | title = Modern management of gestational trophoblastic disease. | journal = Obstet Gynecol Surv | volume = 38 | issue = 2 | pages = 67-83 | month = Feb | year = 1983 | doi =  | PMID = 6300738 }}</ref>
===General===
===General===
*This is not a distinct diagnosis - see ''[[hydatidiform mole]]''.
*This is not a distinct subtype - see ''[[hydatidiform mole]]''.


===Microscopic===
===Microscopic===
Line 231: Line 237:


DDx:
DDx:
*[[Choriocarcinoma]].
*[[Choriocarcinoma]] - lack [[chorionic villi]], usu. hemorrhagic.
 
====Images====
<gallery>
Image:Invasive hydatidiform mole - very low mag.jpg | Invasive mole - very low mag. (WC)
Image:Invasive_hydatidiform_mole_-_low_mag.jpg | Invasive mole - low mag. (WC)
Image:Invasive_hydatidiform_mole_-_intermed_mag.jpg | Invasive mole - intermed. mag. (WC)
Image:Invasive_hydatidiform_mole_-_high_mag.jpg | Invasive mole - high mag. (WC)
Image:Invasive hydatidiform mole - very high mag.jpg | Invasive mole - very high mag. (WC)
</gallery>


=Entities - intermediate trophoblast=
=Entities - intermediate trophoblast=
Line 246: Line 261:
| paucicellular, hyaline material
| paucicellular, hyaline material
| no mitotic activity
| no mitotic activity
| IHC?
| p16 -ve, MIB1 low
| [[EPS]] ???
| [[EPS]], [[squamous carcinoma]]
| post-partum
| post-partum
| [http://www.ijpmonline.org/viewimage.asp?img=IndianJPatholMicrobiol_2009_52_2_240_48931_u4.jpg (ijpmonline.org)]
| [[Image:Placental_site_nodule_-_intermed_mag.jpg |thumb| center| 80px|PSN. (WC)]] [http://www.ijpmonline.org/viewimage.asp?img=IndianJPatholMicrobiol_2009_52_2_240_48931_u4.jpg (ijpmonline.org)]
|-
|-
| [[Exaggerated placental site]] (EPS)
| [[Exaggerated placental site]] (EPS)
Line 260: Line 275:
|-
|-
| [[Placental site trophoblastic tumour]] (PSTT)
| [[Placental site trophoblastic tumour]] (PSTT)
| abundant cytoplasm - not clear
| abundant cytoplasm - not clear, dyscohesive
| +/-multinucleation
| +/-multinucleation
| MIB1 high
| MIB1 high, p63 -ve, CD146 +ve
| [[EPS]]
| [[EPS]], [[choriocarcinoma]]
| Other?
| Other?
| [http://www.webpathology.com/case.asp?case=588 (webpathology.com)]
| [http://www.webpathology.com/case.asp?case=588 (webpathology.com)]
Line 270: Line 285:
| nests of cells in hyaline stroma
| nests of cells in hyaline stroma
| eosinophilic cytoplasm, central nucleus
| eosinophilic cytoplasm, central nucleus
| MIB1 low
| MIB1 low, p63 +ve, CD146 -ve
| [[squamous carcinoma]]
| [[squamous carcinoma]]
| Other?
| Other?
Line 276: Line 291:
|-
|-
| [[Choriocarcinoma]]
| [[Choriocarcinoma]]
| polygonal cells with clear cytoplasm (cytotrophoblasts)
| polygonal cells with clear cytoplasm ([[cytotrophoblast]]s)
| multinucleated cells with smudged nuclei (syncytiotrophoblasts), usu. '''no''' [[chorionic villi]]
| multinucleated cells with smudged nuclei ([[syncytiotrophoblast]]s), '''no''' [[chorionic villi]]
| beta-hCG
| beta-hCG +ve, p63 +ve
| DDx?
| [[invasive hydatidiform mole]], [[PSTT]]
| elevated beta-hCG (serum); '''not''' intermediate trophoblast derived.
| elevated beta-hCG (serum); '''not''' intermediate trophoblast derived.
| [http://www.webpathology.com/image.asp?case=36&n=1 (webpathology.com)]
| [[Image:Choriocarcinoma_-2-_very_high_mag.jpg|thumb|center|120px|Choriocarcinoma. (WC)]] [http://www.webpathology.com/image.asp?case=36&n=1 (webpathology.com)]
|- <!--
|- <!--
| Entity?
| Entity?
Line 294: Line 309:
==Placental site nodule==
==Placental site nodule==
*Abbreviated ''PSN''.
*Abbreviated ''PSN''.
 
{{Main|Placental site nodule}}
===General===
*Benign.
*Intermediate trophoblast remnants from a previous gestation.<ref name=pmid19332926>{{Cite journal  | last1 = Jacob | first1 = S. | last2 = Mohapatra | first2 = D. | title = Placental site nodule: a tumor-like trophoblastic lesion. | journal = Indian J Pathol Microbiol | volume = 52 | issue = 2 | pages = 240-1 | month =  | year =  | doi =  | PMID = 19332926 | url = http://www.ijpmonline.org/text.asp?2009/52/2/240/48931 }}</ref>
 
===Microscopic===
Features:<ref name=pmid19332926/>
*Paucicellular with hyaline material scattered cells.
*Variable cell population:
**Small-large cells.
**Clear to eosinophilic cytoplasm.
**+/-Multinucleation.
 
Notes:
*No mitotic activity.
 
Images:
*[http://www.ijpmonline.org/viewimage.asp?img=IndianJPatholMicrobiol_2009_52_2_240_48931_u4.jpg PSN (ijpmonline.org)].<ref name=pmid19332926/>
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=12&cat3=1256&stype=d PSN (gfmer.ch)] - includes images from ''Jacob and Mohapatra''.<ref name=pmid19332926/>
 
DDx:
*Invasive (cervical) [[squamous cell carcinoma]].
**Can be sorted-out with IHC (SCC will typically be: p16 +ve, MIB1 +ve).
*[[Exaggerated placental site]].
**Different histomorphology than PSN; EPS:<ref name=pmid19332926/> syncytiotrophoblastic tissue, in cords/nests, no hyaline nodules.


==Exaggerated placental site==
==Exaggerated placental site==
*Abbreviated ''EPS''.
*Abbreviated ''EPS''.
 
*Previously known as ''syncytial endometritis''.<ref>URL: [http://www.webpathology.com/image.asp?case=565&n=7 http://www.webpathology.com/image.asp?case=565&n=7]. Accessed on: 22 May 2014.</ref>
===General===
{{Main|Exaggerated placental site}}
*Benign.
 
Definition:
*"Increased number" of implantation-site [[Intermediate trophoblast|intermediate trophoblastic cells]].
 
Note:
*Used to go by a terrible old term: ''syncytial endometritis'':<ref name=ouhsc_kfung>URL: [http://moon.ouhsc.edu/kfung/IACP-OLP/TC-Text/TC-01-Supp.pdf http://moon.ouhsc.edu/kfung/IACP-OLP/TC-Text/TC-01-Supp.pdf]. Accessed on: 15 August 2011.</ref>
**Not syncytial -- mostly.
**Not inflammatory.
===Microscopic===
Features:<ref name=ouhsc_kfung/>
*Intermediate trophoblast:
**Abundant (eosinophilic) cytoplasm.
*Usu. adjacent to:
**[[Chorionic villi]].
**Decidua - endometrial stromal cells with a nucleus central, eosinphilic cytoplasm, well-defined cell borders.
*No mitotic activity.
 
DDx:
*[[PSTT]].
 
===IHC===
*MIB1 ~0%.
**Used to differentiate from [[PSTT]].


==Placental site trophoblastic tumour==
==Placental site trophoblastic tumour==
Line 355: Line 322:
*Derived from ''intermediate trophoblast''.
*Derived from ''intermediate trophoblast''.
*Follows pregnancy.
*Follows pregnancy.
*May be associated with [[nephrotic syndrome]]<ref name=pmid15457847>{{Cite journal  | last1 = Bonazzi | first1 = C. | last2 = Urso | first2 = M. | last3 = Dell'Anna | first3 = T. | last4 = Sacco | first4 = S. | last5 = Buda | first5 = A. | last6 = Cantú | first6 = MG. | title = Placental site trophoblastic tumor: an overview. | journal = J Reprod Med | volume = 49 | issue = 8 | pages = 585-8 | month = Aug | year = 2004 | doi =  | PMID = 15457847 }}</ref> with granular IgM staining.<ref>{{Cite journal  | last1 = Komatsuda | first1 = A. | last2 = Nakamoto | first2 = Y. | last3 = Asakura | first3 = K. | last4 = Yasuda | first4 = T. | last5 = Imai | first5 = H. | last6 = Miura | first6 = AB. | title = Case report: nephrotic syndrome associated with a total hydatidiform mole. | journal = Am J Med Sci | volume = 303 | issue = 5 | pages = 309-12 | month = May | year = 1992 | doi =  | PMID = 1580319 }}</ref>


Clinical:
Clinical:
Line 365: Line 333:
===Microscopic===
===Microscopic===
Features:
Features:
*Large cells.
*Large cells:
*Nuclear pleomorphism.
**Nuclear pleomorphism.
*Cytoplasm:
**Cytoplasm:
**Abundant.  
***Abundant.  
**Solid, i.e. not vesicular.
***Solid, i.e. not vesicular.
**Light basophilic, not clear - '''key feature'''.
***Light basophilic, not clear - '''key feature'''.
*[[NC ratio]] ~ normal.
**[[NC ratio]] ~ normal.
*+/-Multinucleated cells.
*+/-Multinucleated cells.
*Ectatic blood vessels.
Note:
*'''No''' chorionic villi.
**If villi are present... it is probably a [[hydatidiform mole]].


DDx:
DDx:
*[[Exaggerated placental site]].
*[[Exaggerated placental site]] - EPS has near zero Ki-67.
**EPS vs. PSTT: EPS has a low MIB1 (Ki-67).
*[[Choriocarcinoma]] - choriocarcinoma biphasic.<ref>URL: [http://www.webpathology.com/image.asp?n=3&Case=588 http://www.webpathology.com/image.asp?n=3&Case=588]. Accessed on: 1 January 2012.</ref>
*[[Choriocarcinoma]].
**PSTT vs. choriocarcinoma: choriocarcinoma biphasic.<ref>URL: [http://www.webpathology.com/image.asp?n=3&Case=588 http://www.webpathology.com/image.asp?n=3&Case=588]. Accessed on: 1 January 2012.</ref>


Images:
Images:
*[http://www.webpathology.com/case.asp?case=588 Collection of PSTT images (webpathology.com)].
*[http://www.webpathology.com/case.asp?case=588 Collection of PSTT images (webpathology.com)].
===IHC===
Features:<ref>{{Cite journal  | last1 = Shih | first1 = IM. | last2 = Kurman | first2 = RJ. | title = Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies. | journal = Hum Pathol | volume = 29 | issue = 1 | pages = 27-33 | month = Jan | year = 1998 | doi =  | PMID = 9445130 }}</ref>
*CD146 +ve.
*p63 -ve.
*Ki-67 ~14+/-7%.
**Choriocarcinoma ~69+/-20%.


==Epithelioid trophoblastic tumour==
==Epithelioid trophoblastic tumour==
Line 392: Line 370:
*Vaginal bleeding.  
*Vaginal bleeding.  
*Elevated beta-hCG.
*Elevated beta-hCG.
===Gross===
Features:<ref name=pmid16258513>{{Cite journal  | last1 = Fadare | first1 = O. | last2 = Parkash | first2 = V. | last3 = Carcangiu | first3 = ML. | last4 = Hui | first4 = P. | title = Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement. | journal = Mod Pathol | volume = 19 | issue = 1 | pages = 75-82 | month = Jan | year = 2006 | doi = 10.1038/modpathol.3800485 | PMID = 16258513 }}</ref>
*Solid mass.
*Flesh-like appearance.
Image:


===Microscopic===
===Microscopic===
Line 403: Line 388:
Images:
Images:
*[http://www.webpathology.com/image.asp?case=589&n=2 ETT (webpathology.com)].<ref name=webp_ett/>
*[http://www.webpathology.com/image.asp?case=589&n=2 ETT (webpathology.com)].<ref name=webp_ett/>
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=12&cat3=861&stype=d ETT - several images (gfmer.ch)].


===IHC===
===IHC===
Line 410: Line 394:
*p16 -ve.  
*p16 -ve.  
**+ve (nuclear) in squamous cell carcinoma of the cervix.
**+ve (nuclear) in squamous cell carcinoma of the cervix.
Others:
*HMCK -ve.
**SCC +ve.
Note:
*p63 not useful... +ve in both SCC and ETT.


=See also=
=See also=
Line 422: Line 413:


[[Category:Gynecologic pathology]]
[[Category:Gynecologic pathology]]
[[Category:Gestational trophoblastic disease]]

Latest revision as of 22:07, 7 December 2023

Gestational trophoblastic disease (abbreviated GTD), also gestational trophoblastic neoplasia (abbreviated GTN), includes choriocarcinoma and hydatidiform moles.

Overview

Most common

Overview of gestational trophoblastic disease:

Type of mole Gross Nuclear atypia Chorionic villi IHC DNA content Micrographs
Complete mole "snowstorm" +/- ? yes, all abnormal p57(KIP2) -ve Paternal, diploid complete mole + intermed. trophoblast (WC), complete mole (WC)
Partial mole grape-like
clusters 		+/- large villi, villi with cisterns,
villi with cytotrophoblastic inclusions 		p57(KIP2) +ve Maternal & paternal, tripoid partial mole (utah.edu)
Choriocarcinoma haemorrahagic, necrotic marked none beta-hCG +ve ?
Choriocarcinoma. (WC)

More comprehensive overview

Benign abnormal looking placenta:

Abnormal fertilization:

Tumours:

Entities

Choriocarcinoma

Main article: Choriocarcinoma

Hydatidiform moles

General

  • Significance: increased risk for choriocarcinoma (in complete moles).
  • Non-neoplastic proliferation.

Etymology:

  • Hydatid is literally watery vesicle.[1]

Types

  1. Partial mole - see partial mole.
  2. Complete mole - see complete mole.

Extent:

  • Invasive mole - not a subtype.
    • Within uterine muscle +/- vessels.

Microscopic

Hydropic changes:

Entity Chorionic villi (outline) Cisterns Blood vessels Nucleated RBCs p57 / Ki-67[2] staining ‡ Ploidy Micrograph
Complete mole bizarre; often not ovoid; fissures/slit-like gaps well-developed canalicular (thin walled) / few (???) rare -ve / ~70% diploid / tetraploid [1], [2], [3], [4]
Partial mole jagged, still quasi ovoid poorly developed / small present common +ve / ~70% triploid [5], [6]
Hydropic abortus smooth poorly developed / small common common +ve / ~20% diploid [7]

Note:

  • ‡ The amount of Ki-67 staining varies considerably based on what one reads. Chen at al.[3] suggest 25% versus 5% for partial mole versus hydropic abortus.

Mole versus normal

Non-molar versus partial versus complete - short version

Features:[5]

  • Non-molar pregnancy: polar proliferation of trophoblastic tissue.
  • Partial mole: Norwegian fjord periphery, circumferential or multifocal trophoblastic proliferation, fetal parts.
  • Complete mole: grapes grossly, large villi with round borders.

IHC

  • p57(KIP2) - the gene is strongly paternally imprinted and the paternal copy is inactived; its expression is from the maternal gene.
    • Complete moles lack the maternal genome; thus, p57(KIP2) immunostaining (in the cytotrophoblasts and villous stromal cells) is absent.[6][7]
      • Intermediate trophoblasts and maternal tissue are positive controls.[7]
    • Memory device:
      • p57 is positive in partial moles.
      • 3 Ps - partial moles are triploid.

Molecular

Hydropic abortus

General

  • May be seen in the context of a previously detected fetal heart beat.

Microsopic

Features:

  • Enlarged chorionic villi with some cisterns.

DDx:[9]

  • Molar pregnancy.

Sign out

Submitted as "Retained Products of Conception":
- Small and large chorionic villi with cisterns, suggestive of hydropic abortus, see comment.
- Benign decidual tissue present.
- Negative for evidence of fetal tissue in sampled tissue, see comment.
 
Comment:
Imaging previously described a gestational sac and a fetal heart beat.

Partial hydatidiform mole

  • AKA partial mole.

General

Genetics:

  • Usually triploid (e.g. 69XXY).

Microscopic

Features:

  • Abnormal chorionic villi.
    • Villi too large (>0.1 mm ?).
    • Villi with cisterns.
      • Contain fluid in the centre, i.e. are "hydropic".
    • Villi with cytotrophoblastic inclusions.
      • Cytotrophoblast in the core of a villus (normally it is only at the surface of the villus).
  • May have fetal parts, such as nucleated RBCs.
  • Trophoblastic proliferation.
  • "Norwegian fjord periphery"[5] - jagged border / irregular sawtooth-like periphery.
    • Complete moles tend to have a smooth border

DDx:

Images:

IHC

Features:[11]

  • Ki-67 ~ 25+/-5% of cytotrophoblasts and intermediate trophoblasts.
    • Hydropic abortus ~ 5+/-1%.
  • p53 ~ 22+/-12% of cytotrophoblasts and intermediate trophoblasts.
    • Hydropic abortus ~ 5+/-3%.

Complete hydatidiform mole

  • AKA complete mole, AKA classic mole.

General

Epidemiology:

Genetics:

  • Diploid - most are 46XX.
  • Male derived, i.e. arise from DNA in sperm; empty egg fertilized.

Gross/Radiology

  • "Snowstorm" appearance on ultrasound.[13]
  • May be described as "grape-like" on gross exam.[14]

Image:

Microscopic

Features:

  • No normal villi.
  • No fetal parts seen.
    • Very rarely nucleated RBCs.

Images

  • Complete mole and intermediate trophoblast - intermed. mag. (WC)

  • Complete mole - low mag. (WC)

  • Complete mole - high mag. (WC)

Invasive hydatidiform mole

  • AKA invasive mole.
  • AKA chorioadenoma destruens.[15]

General

Microscopic

Features:

  • Chorionic villi - abnormal +/- normal.
  • Trophoblastic cells within uterine muscle +/- vessels - key feature.

DDx:

Images

  • Invasive mole - very low mag. (WC)

  • Invasive mole - low mag. (WC)

  • Invasive mole - intermed. mag. (WC)

  • Invasive mole - high mag. (WC)

  • Invasive mole - very high mag. (WC)

Entities - intermediate trophoblast

Entity Key feature Other histologic features IHC DDx Other Image
Placental site nodule (PSN) paucicellular, hyaline material no mitotic activity p16 -ve, MIB1 low EPS, squamous carcinoma post-partum
PSN. (WC)
(ijpmonline.org)
Exaggerated placental site (EPS) abundant intermediate trophoblasts - between muscle no mitotic activity MIB1 ~0% PSTT, PSN post-partum Image?
Placental site trophoblastic tumour (PSTT) abundant cytoplasm - not clear, dyscohesive +/-multinucleation MIB1 high, p63 -ve, CD146 +ve EPS, choriocarcinoma Other? (webpathology.com)
Epithelioid trophoblastic tumour (ETT) nests of cells in hyaline stroma eosinophilic cytoplasm, central nucleus MIB1 low, p63 +ve, CD146 -ve squamous carcinoma Other? (webpathology.com)
Choriocarcinoma polygonal cells with clear cytoplasm (cytotrophoblasts) multinucleated cells with smudged nuclei (syncytiotrophoblasts), no chorionic villi beta-hCG +ve, p63 +ve invasive hydatidiform mole, PSTT elevated beta-hCG (serum); not intermediate trophoblast derived.
Choriocarcinoma. (WC)
(webpathology.com)

Placental site nodule

  • Abbreviated PSN.
Main article: Placental site nodule

Exaggerated placental site

  • Abbreviated EPS.
  • Previously known as syncytial endometritis.[16]
Main article: Exaggerated placental site

Placental site trophoblastic tumour

  • Abbreviated PSTT.
  • Malignant counterpart of exaggerated placental site (abbreviated EPS).

General

  • Derived from intermediate trophoblast.
  • Follows pregnancy.
  • May be associated with nephrotic syndrome[17] with granular IgM staining.[18]

Clinical:

  • Raised (serum) beta-hCG - but usually not has high as in choriocarcinoma.
    • In ~70% < 1000 IU/L.[19]
    • In a series of 55 cases the average beta-hCG was ~700 IU/L.[20]
  • Prognosis dependent on time of diagnosis from last pregnancy.
    • <48 months = good prognosis.[19]

Microscopic

Features:

  • Large cells:
    • Nuclear pleomorphism.
    • Cytoplasm:
      • Abundant.
      • Solid, i.e. not vesicular.
      • Light basophilic, not clear - key feature.
    • NC ratio ~ normal.
  • +/-Multinucleated cells.
  • Ectatic blood vessels.

Note:

DDx:

Images:

IHC

Features:[22]

  • CD146 +ve.
  • p63 -ve.
  • Ki-67 ~14+/-7%.
    • Choriocarcinoma ~69+/-20%.

Epithelioid trophoblastic tumour

  • Abbreviated ETT.

General

  • Often in endocervix.
  • Malignant counterpart of placental site nodule or PSN.

Clinical:

  • Vaginal bleeding.
  • Elevated beta-hCG.

Gross

Features:[23]

  • Solid mass.
  • Flesh-like appearance.

Image:

Microscopic

Features:[24]

  • Architecture: nests in hyaline matrix.
  • Cytoplasm: abundant, eosinophilic.

DDx:

Images:

IHC

Features:[25]

  • Cyclin E +ve (nuclear).
  • p16 -ve.
    • +ve (nuclear) in squamous cell carcinoma of the cervix.

Others:

  • HMCK -ve.
    • SCC +ve.

Note:

  • p63 not useful... +ve in both SCC and ETT.

See also

References

  1. ↑ URL: http://dictionary.reference.com/browse/hydatid.
  2. ↑ URL: http://www.ihcworld.com/_newsletter/2003/focus_mar_2003.pdf. Accessed on: 28 May 2011.
  3. ↑ Chen, Y.; Shen, D.; Gu, Y.; Zhong, P.; Xie, J.; Song, Q. (Mar 2012). "The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion.". Wien Klin Wochenschr 124 (5-6): 184-7. doi:10.1007/s00508-011-0119-4. PMID 22218717.
  4. ↑ URL: http://pathologyoutlines.com/placenta.html#hydatgeneral.
  5. ↑ 5.0 5.1 Howat, AJ.; Beck, S.; Fox, H.; Harris, SC.; Hill, AS.; Nicholson, CM.; Williams, RA. (Jul 1993). "Can histopathologists reliably diagnose molar pregnancy?". J Clin Pathol 46 (7): 599-602. PMID 8157742. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501384/?page=3.
  6. ↑ Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE (February 2005). "p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses". Hum. Pathol. 36 (2): 180–6. doi:10.1016/j.humpath.2004.12.007. PMID 15754295.
  7. ↑ 7.0 7.1 Fukunaga, M. (Dec 2002). "Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles.". Hum Pathol 33 (12): 1188-92. doi:10.1053/hupa.2002.129421. PMID 12514787.
  8. ↑ http://jcp.bmjjournals.com/cgi/reprint/51/6/438.pdf
  9. ↑ Rios-Doria E, Pennington KP, Reiter DJ, Parker EU (September 2023). "Diagnostic challenges in differentiating between hydropic abortus, and complete and partial hydatidiform molar pregnancies in early gestation". Int J Gynecol Cancer 33 (9): 1482–1484. doi:10.1136/ijgc-2022-004104. PMID 37268312.
  10. ↑ URL: http://pathologyoutlines.com/placenta.html#incompletemole. Accessed on: 9 August 2011.
  11. ↑ Chen, Y.; Shen, D.; Gu, Y.; Zhong, P.; Xie, J.; Song, Q. (Mar 2012). "The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion.". Wien Klin Wochenschr 124 (5-6): 184-7. doi:10.1007/s00508-011-0119-4. PMID 22218717.
  12. ↑ 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. 1111. ISBN 0-7216-0187-1.
  13. ↑ URL:http://www.jultrasoundmed.org/cgi/content/abstract/18/9/589. Accessed on: 27 July 2010.
  14. ↑ Abike, F.; Temizkan, O.; Payasli, A.; Avsar, F.; Karahan, N.; Baspinar, S. (Jan 2008). "Postmenopausal complete hydatidiform mole: a case report.". Maturitas 59 (1): 95-8. doi:10.1016/j.maturitas.2007.10.005. PMID 18162339.
  15. ↑ McDonald, TW.; Ruffolo, EH. (Feb 1983). "Modern management of gestational trophoblastic disease.". Obstet Gynecol Surv 38 (2): 67-83. PMID 6300738.
  16. ↑ URL: http://www.webpathology.com/image.asp?case=565&n=7. Accessed on: 22 May 2014.
  17. ↑ Bonazzi, C.; Urso, M.; Dell'Anna, T.; Sacco, S.; Buda, A.; Cantú, MG. (Aug 2004). "Placental site trophoblastic tumor: an overview.". J Reprod Med 49 (8): 585-8. PMID 15457847.
  18. ↑ Komatsuda, A.; Nakamoto, Y.; Asakura, K.; Yasuda, T.; Imai, H.; Miura, AB. (May 1992). "Case report: nephrotic syndrome associated with a total hydatidiform mole.". Am J Med Sci 303 (5): 309-12. PMID 1580319.
  19. ↑ 19.0 19.1 Schmid, P.; Nagai, Y.; Agarwal, R.; Hancock, B.; Savage, PM.; Sebire, NJ.; Lindsay, I.; Wells, M. et al. (Jul 2009). "Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study.". Lancet 374 (9683): 48-55. doi:10.1016/S0140-6736(09)60618-8. PMID 19552948.
  20. ↑ Baergen, RN.; Rutgers, JL.; Young, RH.; Osann, K.; Scully, RE. (Mar 2006). "Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance.". Gynecol Oncol 100 (3): 511-20. doi:10.1016/j.ygyno.2005.08.058. PMID 16246400.
  21. ↑ URL: http://www.webpathology.com/image.asp?n=3&Case=588. Accessed on: 1 January 2012.
  22. ↑ Shih, IM.; Kurman, RJ. (Jan 1998). "Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies.". Hum Pathol 29 (1): 27-33. PMID 9445130.
  23. ↑ Fadare, O.; Parkash, V.; Carcangiu, ML.; Hui, P. (Jan 2006). "Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement.". Mod Pathol 19 (1): 75-82. doi:10.1038/modpathol.3800485. PMID 16258513.
  24. ↑ 24.0 24.1 URL: http://www.webpathology.com/image.asp?case=589&n=2. Accessed on: 15 August 2011.
  25. ↑ Mao, TL.; Seidman, JD.; Kurman, RJ.; Shih, IeM. (Sep 2006). "Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor--an aid in differential diagnosis.". Am J Surg Pathol 30 (9): 1105-10. doi:10.1097/01.pas.0000209854.28282.87. PMID 16931955.
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