View source for Gestational trophoblastic disease

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

=Overview=
===Most common===
Overview of gestational trophoblastic disease:
{| class="wikitable sortable"
! Type of mole			
! Gross
! [[Nuclear atypia]]
! [[Chorionic villi]]
! [[IHC]]
! DNA content
! Micrographs
|-
| Complete mole		
| "snowstorm"		
| +/- ?	
| yes, all abnormal 
| p57(KIP2) -ve
| Paternal, diploid
| [http://commons.wikimedia.org/wiki/File:Intermediate_trophoblast_3_-_low_mag.jpg complete mole + intermed. trophoblast (WC)], [http://en.wikipedia.org/wiki/File:Hydatidiform_mole_%281%29_complete_type.jpg complete mole (WC)] 
|-
| Partial mole		
| grape-like<br>clusters	
| +/- 		
| large villi, villi with cisterns, <br>villi with cytotrophoblastic inclusions 
| p57(KIP2) +ve
| Maternal & paternal, tripoid
| [http://library.med.utah.edu/WebPath/PLACHTML/PLAC064.html partial mole (utah.edu)]
|-
| Choriocarcinoma	
| haemorrahagic, necrotic 
| marked	
| none 
| beta-hCG +ve
| ?
| [[Image:Choriocarcinoma_-2-_very_high_mag.jpg|thumb|center|120px|Choriocarcinoma. (WC)]]
|-
|}

===More comprehensive overview===
Benign abnormal looking placenta:
*[[Placental site nodule]] (PSN).
*[[Exaggerated placental site]] (EPS).

Abnormal fertilization:
*[[Hydatidiform mole]].

Tumours:
*Invasive mole.
*[[Choriocarcinoma]].
*[[Placental site trophoblastic tumour]] (PSTT).
*[[Epithelioid trophoblastic tumour]] (ETT).

=Entities=
==Choriocarcinoma==
{{Main|Choriocarcinoma}}

==Hydatidiform moles==
===General===
*Significance: increased risk for choriocarcinoma (in complete moles).
*Non-neoplastic proliferation.

Etymology:
*''Hydatid'' is literally ''watery vesicle''.<ref>URL: [http://dictionary.reference.com/browse/hydatid http://dictionary.reference.com/browse/hydatid].</ref>

====Types====
#Partial mole - see [[partial mole]].
#Complete mole - see [[complete mole]].

Extent:
*Invasive mole - '''not''' a subtype.
**Within uterine muscle +/- vessels.

===Microscopic===
Hydropic changes:
{| class="wikitable sortable"
! Entity
! [[Chorionic villi]] (outline)
! Cisterns
! [[Blood vessel]]s
! 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 ‡
! Ploidy
! Micrograph
|-
| Complete mole
| bizarre; often not ovoid; fissures/slit-like gaps
| well-developed
| canalicular (thin walled) / few (???)
| rare
| -ve / ~70%
| diploid / tetraploid
| [http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%281%29_complete_type.jpg], [http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%282%29_complete_type.jpg], [http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%283%29_complete_type.jpg], [http://commons.wikimedia.org/wiki/File:Hydatidiform_mole_%284%29_complete_type.jpg]
|-
| Partial mole
| jagged, still quasi ovoid 
| poorly developed / small
| present
| common
| +ve / ~70%
| triploid
| [http://www.flickr.com/photos/78147607@N00/571279403], [http://www.flickr.com/photos/78147607@N00/570796738]
|-
| Hydropic abortus
| smooth 
| poorly developed / small
| common
| common
| +ve / ~20%
| diploid
| [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 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>

====Non-molar versus partial versus complete - short version====
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.
*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.<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: 
***'''''p'''57 is '''p'''ositive in '''p'''artial moles''.
***'''3 Ps''' - partial moles are triploid.

===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>

==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.
**Without atypia.<ref>URL: [http://pathologyoutlines.com/placenta.html#incompletemole http://pathologyoutlines.com/placenta.html#incompletemole]. Accessed on: 9 August 2011.</ref>
*"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

DDx:
*[[Complete hydatidiform mole]].
*[[Placental mesenchymal dysplasia]].
*Hydropic abortus - see [[products of conception]] and [[chorionic villi]].

Images: 
*[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)].

===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==
*[[AKA]] ''complete mole'', [[AKA]] ''classic mole''.

===General===
Epidemiology:
*May precede [[choriocarcinoma]]<ref name=Ref_PBoD1111>{{Ref PBoD|1111}}</ref> ~ 1-2% risk.

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

===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>
*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===
Features:
*No normal villi.
*No fetal parts seen.
**Very rarely nucleated [[RBC]]s.

====Images==== 
<gallery>
Image:Intermediate_trophoblast_3_-_low_mag.jpg | Complete mole and intermediate trophoblast - intermed. 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==
*[[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===
*This is not a distinct subtype - see ''[[hydatidiform mole]]''.

===Microscopic===
Features:
*[[Chorionic villi]] - abnormal +/- normal.
*Trophoblastic cells within uterine muscle +/- vessels - '''key feature'''.

DDx:
*[[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=
{| class="wikitable sortable" style="margin-left:auto;margin-right:auto"
! 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
| [[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)
| abundant [[intermediate trophoblast]]s - 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?
| [http://www.webpathology.com/case.asp?case=588 (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?
| [http://www.webpathology.com/image.asp?case=589&n=2 (webpathology.com)]
|-
| [[Choriocarcinoma]]
| polygonal cells with clear cytoplasm ([[cytotrophoblast]]s)
| multinucleated cells with smudged nuclei ([[syncytiotrophoblast]]s), '''no''' [[chorionic villi]]
| beta-hCG +ve, p63 +ve
| [[invasive hydatidiform mole]], [[PSTT]]
| elevated beta-hCG (serum); '''not''' intermediate trophoblast derived.
| [[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?
| Key feature?
| Other histologic features?
| IHC?
| DDx?
| Other?
| Image? -->
|}

==Placental site nodule==
*Abbreviated ''PSN''.
{{Main|Placental site nodule}}

==Exaggerated placental site==
*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>
{{Main|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]]<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:
*Raised (serum) beta-hCG - but usually not has high as in [[choriocarcinoma]].
**In ~70% < 1000 IU/L.<ref name=pmid19552948>{{Cite journal  | last1 = Schmid | first1 = P. | last2 = Nagai | first2 = Y. | last3 = Agarwal | first3 = R. | last4 = Hancock | first4 = B. | last5 = Savage | first5 = PM. | last6 = Sebire | first6 = NJ. | last7 = Lindsay | first7 = I. | last8 = Wells | first8 = M. | last9 = Fisher | first9 = RA. | title = Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. | journal = Lancet | volume = 374 | issue = 9683 | pages = 48-55 | month = Jul | year = 2009 | doi = 10.1016/S0140-6736(09)60618-8 | PMID = 19552948 }}</ref>
**In a series of 55 cases the average beta-hCG was ~700 IU/L.<ref name=pmid16246400>{{Cite journal  | last1 = Baergen | first1 = RN. | last2 = Rutgers | first2 = JL. | last3 = Young | first3 = RH. | last4 = Osann | first4 = K. | last5 = Scully | first5 = RE. | title = Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance. | journal = Gynecol Oncol | volume = 100 | issue = 3 | pages = 511-20 | month = Mar | year = 2006 | doi = 10.1016/j.ygyno.2005.08.058 | PMID = 16246400 }}</ref>
*Prognosis dependent on time of diagnosis from last pregnancy.
**<48 months = good prognosis.<ref name=pmid19552948/>

===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:
*'''No''' chorionic villi.
**If villi are present... it is probably a [[hydatidiform mole]].

DDx:
*[[Exaggerated placental site]] - EPS has near zero 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>

Images:
*[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==
*Abbreviated ''ETT''.
===General===
*Often in endocervix.
*Malignant counterpart of ''placental site nodule'' or ''PSN''.

Clinical:
*Vaginal bleeding. 
*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===
Features:<ref name=webp_ett>URL: [http://www.webpathology.com/image.asp?case=589&n=2 http://www.webpathology.com/image.asp?case=589&n=2]. Accessed on: 15 August 2011.</ref>
*Architecture: nests in hyaline matrix.
*Cytoplasm: abundant, eosinophilic.

DDx:
*Invasive [[squamous cell carcinoma]].

Images:
*[http://www.webpathology.com/image.asp?case=589&n=2 ETT (webpathology.com)].<ref name=webp_ett/>

===IHC===
Features:<ref name=pmid16931955>{{Cite journal  | last1 = Mao | first1 = TL. | last2 = Seidman | first2 = JD. | last3 = Kurman | first3 = RJ. | last4 = Shih | first4 = IeM. | title = Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor--an aid in differential diagnosis. | journal = Am J Surg Pathol | volume = 30 | issue = 9 | pages = 1105-10 | month = Sep | year = 2006 | doi = 10.1097/01.pas.0000209854.28282.87 | PMID = 16931955 }}</ref>
*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=
*[[Hydatid disease]] - due to Echinoccus spp. such as E. granulosus.
*[[Chorionic villi]].
*[[Ectopic pregnancy]].
*[[Placenta]].
*[[Arias-Stella reaction]] - benign atypical changes of the endometrium associated with trophoblastic tissue.

=References=
{{reflist|2}}

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