Gestational trophoblastic neoplasia pathophysiology: Difference between revisions

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__NOTOC__
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{{Choriocarcinoma}}
{{Gestational trophoblastic neoplasia}}
{{CMG}}{{AE}}{{SM}}{{MD}}
{{CMG}}{{AE}}{{Sab}}
 
==Overview==
[[Pregnancy]] occurs when an [[Ovum|egg]], which is released from the [[ovary]] during [[ovulation]], is fertilized by a [[sperm]]. Human [[pregnancy]] takes approximately 40 weeks. Gestational trophoblastic neoplasia arises from the [[trophoblast]]ic tissue, which provides nutrients to the [[embryo]] and develops into a large part of the [[placenta]]. Invasive mole is basically a [[benign]] [[tumor]] which arises from the invasion of the [[myometrium]] of a [[hydatidiform mole]]. Choriocarcinoma is a [[malignant]] [[tumor]] of the [[Trophoblast|trophoblastic]] [[epithelium]]. Placental-site trophoblastic tumor (PSTT), a rare [[tumor]], arises from the [[implantation]] site of [[placenta]]. Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT) which arises from the [[malignant]] transformation of [[Chorion|chorionic]]-type intermediate [[Trophoblast|trophoblastic]] [[Cell (biology)|cells]]. Invasive mole is usually [[Ploidy|diploid]] but can also be [[Aneuploidy|aneuploid]] in [[karyotype|karyotype.]] Choriocarcinoma has an [[Aneuploidy|aneuploid]] [[karyotype]] and majority of the cases have a [[Y chromosome]].
==Pathophysiology==
==Pathophysiology==
A [[hydatidiform mole]] is characterized by a [[conceptus]] of [[hyperplasia|hyperplastic]] [[trophoblast]]ic tissue attached to the [[placenta]]. The conceptus does not contain the [[inner cell mass]] (the mass of cells inside the primordial embryo that will eventually give rise to the fetus).
===Physiology===
The hydatidiform mole can be of two types: a ''complete mole'', in which the abnormal embryonic tissue is derived from the father only; and a ''partial mole'', in which the abnormal tissue is derived from both parents.  
The normal physiology of [[pregnancy]] can be understood as follows:
* '''Complete moles''' usually occur when an empty ovum is fertilized by a sperm that then duplicates its own DNA (a process called ''androgenesis''). A 46, XY genotype may occur when 2 sperm (one 23, X and the other 23, Y) fertilize an empty egg.<ref>{{cite journal |author=Woo J, Hsu C, Fung L, Ma H |title=Partial hydatidiform mole: ultrasonographic features |journal=Aust N Z J Obstet Gynaecol |volume=23 |issue=2 |pages=103-7 |year=1983 |pmid=6578773}}</ref>). Their DNA is purely paternal in origin (since all chromosomes are derived from the sperm), and is diploid. Ninety percent are 46,XX, and 10% are 46,XY. In a complete mole, the fetus fails to develop.
* [[Pregnancy]] occurs when an [[Ovum|egg]], which is released from the [[ovary]] during [[ovulation]], is fertilized by a [[sperm]].
* '''Partial moles''' can occur if a normal [[haploid]] ovum is fertilized by two sperm, or, if fertilized by one sperm, if the paternal chromosomes become duplicated. Thus their DNA is both maternal and paternal in origin. They can be triploid (e.g. 69 XXX, 69 XXY) or even tetraploid.  
* After [[ejaculation]], the released [[sperm]] must spend some time in the female reproductive tract and undergo [[capacitation]], which is basically the acquisition of [[fertilization]] capability.<ref name="pmid14882325">{{cite journal |vauthors=CHANG MC |title=Fertilizing capacity of spermatozoa deposited into the fallopian tubes |journal=Nature |volume=168 |issue=4277 |pages=697–8 |date=October 1951 |pmid=14882325 |doi= |url=}}</ref><ref name="pmid14895481">{{cite journal |vauthors=AUSTIN CR |title=Observations on the penetration of the sperm in the mammalian egg |journal=Aust J Sci Res B |volume=4 |issue=4 |pages=581–96 |date=November 1951 |pmid=14895481 |doi= |url=}}</ref><ref name="pmid12993150">{{cite journal |vauthors=AUSTIN CR |title=The capacitation of the mammalian sperm |journal=Nature |volume=170 |issue=4321 |pages=326 |date=August 1952 |pmid=12993150 |doi= |url=}}</ref>
Choriocarcinoma of the [[placenta]] during pregnancy is preceded by:
*The [[sperm]] then penetrates the [[Ovum|egg]] after the acrosomal reaction and initiates the process of [[fertilization]] in the [[fallopian tube]].<ref>{{cite book | last = Moore | first = Keith | title = Essentials of human embryology | publisher = B.C. Decker C.V. Mosby Co. distributor | location = Toronto Philadelphia Saint Louis, Mo | year = 1988 | isbn = 9780941158978 }}</ref>
* [[Hydatidiform mole]] (50% of cases)
*The [[sperm]] breaks through the [[Oocyte|oocyte's]] [[Cell membrane|plasma membrane]] and releases its [[Ploidy|haploid]] [[Cell nucleus|nucleus]] into the [[oocyte]].<ref>{{cite book | last = Moore | first = Keith | title = Essentials of human embryology | publisher = B.C. Decker C.V. Mosby Co. distributor | location = Toronto Philadelphia Saint Louis, Mo | year = 1988 | isbn = 9780941158978 }}</ref>
* [[Spontaneous abortion]] (20% of cases)
* Cortical reaction (changes in the [[oocyte]] [[Cell membrane|membrane]]) prevents any further penetration by another [[sperm]].
* [[Ectopic pregnancy]] (2% of cases)
* Unification of the two [[Ploidy|haploid]] [[Cell nucleus|nuclei]] (one each from the [[sperm]] and [[Ovum|egg]]) marks the completion of [[Fertilization\|fertilization]], resulting in the formation of a [[Ploidy|diploid]] [[zygote]].
* Normal term pregnancy (20-30% of cases)
* The [[zygote]] undergoes multiple divisions called [[Cleavage (embryo)|cleavage]] before its migration to the [[uterus]].<ref name="pmid28698706">{{cite journal |vauthors=Miklavcic JJ, Flaman P |title=Personhood status of the human zygote, embryo, fetus |journal=Linacre Q |volume=84 |issue=2 |pages=130–144 |date=May 2017 |pmid=28698706 |pmc=5499222 |doi=10.1080/00243639.2017.1299896 |url=}}</ref>
* Human [[pregnancy]] takes approximately 40 weeks.
 
 


'''Placental Trophoblast and Pregnancy'''
*[[Trophoblast]] (outer layer of the [[blastocyst]]) is composed of [[cytotrophoblast]], [[syncytiotrophoblast]], and intermediate [[trophoblast]].<ref>{{cite book | last = Moore | first = Keith | title = The developing human : clinically oriented embryology | publisher = Elsevier | location = Philadelphia, PA | year = 2016 | isbn = 9780323313384 }}</ref>
*[[Syncytiotrophoblast]] invades the [[Endometrium|endometrial]] stroma and produces [[Human chorionic gonadotropin|human chorionic gonadotropin (hCG)]].<ref>{{cite book | last = Moore | first = Keith | title = The developing human : clinically oriented embryology | publisher = Elsevier | location = Philadelphia, PA | year = 2016 | isbn = 9780323313384 }}</ref>
*[[Cytotrophoblast]] supplies the syncitium with [[Cell (biology)|cells]] and also forms the outpouchings that later become the [[chorionic villi]].<ref>{{cite book | last = Moore | first = Keith | title = The developing human : clinically oriented embryology | publisher = Elsevier | location = Philadelphia, PA | year = 2016 | isbn = 9780323313384 }}</ref>
*Intermediate [[trophoblast]] is situated in the [[Chorionic villi|chroionic villi]], the [[implantation]] site, and the [[Chorion|chorionic sac]].<ref>{{cite book | last = Moore | first = Keith | title = The developing human : clinically oriented embryology | publisher = Elsevier | location = Philadelphia, PA | year = 2016 | isbn = 9780323313384 }}</ref>


For more information on [[fertilization]], click [[Fertilization|here]].<br>For more information on [[pregnancy]], click [[Pregnancy|here]].


===Pathogenesis===
[[Pathogenesis]] of each sub-type of gestational trophoblastic neoplasia is explained as follows:
====Invasive Mole====
*Invasive mole is basically a [[benign]] [[tumor]] which arises from the invasion of the [[myometrium]] of a [[hydatidiform mole]].<ref name="Lurain2010">{{cite journal|last1=Lurain|first1=John R.|title=Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole|journal=American Journal of Obstetrics and Gynecology|volume=203|issue=6|year=2010|pages=531–539|issn=00029378|doi=10.1016/j.ajog.2010.06.073}}</ref>
*It may be preceded by a [[Hydatidiform mole|complete]] or [[Hydatidiform mole|partial molar pregnancy]] and it rarely [[Metastasis|metastasizes]].<ref>https://www.cancer.gov</ref><ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref>
*Invasive moles are more aggressive than [[Hydatidiform mole|complete]] or [[Hydatidiform mole|partial hydatidiform moles]].<ref>https://www.cancer.gov</ref>
*Although rarely [[Metastasis|metastatic]], it can spread through the [[Blood|hematogenous]] route to the following organs:
** [[Lung|Lungs]] (80% of the time)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref><ref name="pmid23999759">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C |title=Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Ann. Oncol. |volume=24 Suppl 6 |issue= |pages=vi39–50 |date=October 2013 |pmid=23999759 |doi=10.1093/annonc/mdt345 |url=}}</ref>
** [[Vagina]] (30%)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref><ref name="pmid23999759">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C |title=Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Ann. Oncol. |volume=24 Suppl 6 |issue= |pages=vi39–50 |date=October 2013 |pmid=23999759 |doi=10.1093/annonc/mdt345 |url=}}</ref>
** [[Pelvis]] (20%)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref><ref name="pmid23999759">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C |title=Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Ann. Oncol. |volume=24 Suppl 6 |issue= |pages=vi39–50 |date=October 2013 |pmid=23999759 |doi=10.1093/annonc/mdt345 |url=}}</ref>
** [[Liver]] (10%)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref>
** [[Brain]] (10%)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref><ref name="pmid27743739">{{cite journal |vauthors=Brown J, Naumann RW, Seckl MJ, Schink J |title=15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage |journal=Gynecol. Oncol. |volume=144 |issue=1 |pages=200–207 |date=January 2017 |pmid=27743739 |doi=10.1016/j.ygyno.2016.08.330 |url=}}</ref>
** Other sites (< 5%)<ref name="pmid20673583">{{cite journal |vauthors=Seckl MJ, Sebire NJ, Berkowitz RS |title=Gestational trophoblastic disease |journal=Lancet |volume=376 |issue=9742 |pages=717–29 |date=August 2010 |pmid=20673583 |doi=10.1016/S0140-6736(10)60280-2 |url=}}</ref>
====Choriocarcinoma====
*[[Choriocarcinoma]] is a [[malignant]] [[tumor]] of the [[Trophoblast|trophoblastic]] [[epithelium]].<ref>https://www.cancer.gov</ref>
*[[Cytotrophoblast|Cytotrophoblastic]] [[Cell (biology)|cells]], functioning as [[Stem cell|stem cells]], can undergo [[malignant]] transformation.<ref name="pmid30571055">{{cite journal |vauthors=Bishop BN, Edemekong PF |title= |journal= |volume= |issue= |pages= |date= |pmid=30571055 |doi= |url=}}</ref>
*After the [[malignant]] transformation, the [[Cell (biology)|cells]] can differentiate into intermediate [[trophoblast]] and [[syncytiotrophoblast]].<ref name="pmid18059230">{{cite journal |vauthors=Mao TL, Kurman RJ, Huang CC, Lin MC, Shih IeM |title=Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis |journal=Am. J. Surg. Pathol. |volume=31 |issue=11 |pages=1726–32 |date=November 2007 |pmid=18059230 |doi=10.1097/PAS.0b013e318058a529 |url=}}</ref>
*This mixture of [[Cell (biology)|cells]] can mimic normal development of a previllous [[blastocyst]].<ref name="pmid17613426">{{cite journal |vauthors=Shih IeM |title=Gestational trophoblastic neoplasia--pathogenesis and potential therapeutic targets |journal=Lancet Oncol. |volume=8 |issue=7 |pages=642–50 |date=July 2007 |pmid=17613426 |doi=10.1016/S1470-2045(07)70204-8 |url=}}</ref>
*[[Choriocarcinoma]] can invade the [[Uterus|uterine]] [[Tissue (biology)|tissue]] and [[Circulatory system|vasculature]] and spread to distant sites such as [[Lung|lungs]], [[brain]], [[liver]], [[pelvis]], [[vagina]], [[spleen]], [[Intestine|intestines]], and [[kidney]].<ref>https://www.cancer.gov</ref>
*[[Choriocarcinoma]] most commonly follows a [[Hydatidiform mole|molar pregnancy]], [[Miscarriage|spontaneous abortion]], or [[ectopic pregnancy]].
*Less commonly, choriocarcinoma can also follow a full-term [[pregnancy]].
====Placental-site Trophoblastic Tumor (PSTT)====
*Placental-site trophoblastic tumor (PSTT), a rare [[tumor]], arises from the [[implantation]] site of [[placenta]].
*It can resemble an amplified form of [[Syncytium|syncytial]] [[endometritis]].<ref>https://www.cancer.gov</ref>
*The [[tumor]] represents [[malignant]] transformation of intermediate [[Trophoblast|trophoblastic]] [[Cell (biology)|cells]].<ref name="pmid12063871">{{cite journal |vauthors=Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS |title=Advances in the understanding of placental site trophoblastic tumor |journal=J Reprod Med |volume=47 |issue=5 |pages=337–41 |date=May 2002 |pmid=12063871 |doi= |url=}}</ref>
*It is associated with less [[vascular]] invasion, [[Bleeding|hemorrhage]], and [[necrosis]] compared to choriocarcinoma.
*Placental-site trophoblastic tumor (PSTT) has a tendency for [[Lymphatic system|lymphatic]] [[metastasis]].<ref>https://www.cancer.gov</ref>
*Because of the lower growth rate, the presentation of placental-site trophoblastic tumor (PSTT) can be delayed by months or even years.<ref>https://www.cancer.gov</ref>
*Majority of the cases of placental-site trophoblastic tumor (PSTT) follow [[Pregnancy|non-molar pregnancies]].<ref name="pmid19552948">{{cite journal |vauthors=Schmid P, Nagai Y, Agarwal R, Hancock B, Savage PM, Sebire NJ, Lindsay I, Wells M, Fisher RA, Short D, Newlands ES, Wischnewsky MB, Seckl MJ |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 |date=July 2009 |pmid=19552948 |doi=10.1016/S0140-6736(09)60618-8 |url=}}</ref>
*35% of placental-site trophoblastic tumors (PSTT) have distant [[Metastasis|metastases]] at the time of [[diagnosis]].<ref name="pmid12063871">{{cite journal |vauthors=Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS |title=Advances in the understanding of placental site trophoblastic tumor |journal=J Reprod Med |volume=47 |issue=5 |pages=337–41 |date=May 2002 |pmid=12063871 |doi= |url=}}</ref><ref name="pmid19552948">{{cite journal |vauthors=Schmid P, Nagai Y, Agarwal R, Hancock B, Savage PM, Sebire NJ, Lindsay I, Wells M, Fisher RA, Short D, Newlands ES, Wischnewsky MB, Seckl MJ |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 |date=July 2009 |pmid=19552948 |doi=10.1016/S0140-6736(09)60618-8 |url=}}</ref>
*Common sites of [[metastasis]] include the [[Lung|lungs]], [[pelvis]], and [[Lymph node|lymph nodes]].
====Epithelioid Trophoblastic Tumor (ETT)====
*Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT).
*It arises from the [[malignant]] transformation of [[Chorion|chorionic]]-type intermediate [[Trophoblast|trophoblastic]] [[Cell (biology)|cells]].<ref name="pmid9808132">{{cite journal |vauthors=Shih IM, Kurman RJ |title=Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma |journal=Am. J. Surg. Pathol. |volume=22 |issue=11 |pages=1393–403 |date=November 1998 |pmid=9808132 |doi= |url=}}</ref>
*Epithelioid trophoblastic tumor (ETT) can clinically present as [[benign]] or [[malignant]].<ref>https://www.cancer.gov</ref>
*Majority of the cases of epithelioid trophoblastic tumors (ETT) present years after full-term [[Gestation|gestations]].<ref name="pmid9808132">{{cite journal |vauthors=Shih IM, Kurman RJ |title=Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma |journal=Am. J. Surg. Pathol. |volume=22 |issue=11 |pages=1393–403 |date=November 1998 |pmid=9808132 |doi= |url=}}</ref><ref name="pmid17149967">{{cite journal |vauthors=Allison KH, Love JE, Garcia RL |title=Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-type intermediate trophoblast |journal=Arch. Pathol. Lab. Med. |volume=130 |issue=12 |pages=1875–7 |date=December 2006 |pmid=17149967 |doi=10.1043/1543-2165(2006)130[1875:ETTROA]2.0.CO;2 |url=}}</ref>


==Genetics==
*Invasive mole is usually [[Ploidy|diploid]] but can also be [[Aneuploidy|aneuploid]] in [[karyotype|karyotype.]]<ref>http://www.cancer.gov</ref>
*[[Choriocarcinoma]] has an [[Aneuploidy|aneuploid]] [[karyotype]] and majority of the cases have a [[Y chromosome]].<ref>http://www.cancer.gov</ref>
*[[Mutation]] in the following [[Gene|genes]] has been associated with recurrent [[hydatidiform mole]], a precursor of and a [[risk factor]] for gestational trophoblastic neoplasia:
** [[NLRP7|NLR family, pyrin domain-containing 7 (NLRP7)]]<ref name="pmid16462743">{{cite journal |vauthors=Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R |title=Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans |journal=Nat. Genet. |volume=38 |issue=3 |pages=300–2 |date=March 2006 |pmid=16462743 |doi=10.1038/ng1740 |url=}}</ref><ref name="pmid21885028">{{cite journal |vauthors=Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H, Diggle C, Carr I, Rittore C, Touitou I, Philibert L, Fisher RA, Fallahian M, Huntriss JD, Picton HM, Malik S, Taylor GR, Johnson CA, Bonthron DT, Sheridan EG |title=Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte |journal=Am. J. Hum. Genet. |volume=89 |issue=3 |pages=451–8 |date=September 2011 |pmid=21885028 |pmc=3169823 |doi=10.1016/j.ajhg.2011.08.002 |url=}}</ref>
** KHDC3-like protein, subcortical maternal complex member (KHDC3L)<ref name="pmid16462743">{{cite journal |vauthors=Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R |title=Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans |journal=Nat. Genet. |volume=38 |issue=3 |pages=300–2 |date=March 2006 |pmid=16462743 |doi=10.1038/ng1740 |url=}}</ref><ref name="pmid21885028">{{cite journal |vauthors=Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H, Diggle C, Carr I, Rittore C, Touitou I, Philibert L, Fisher RA, Fallahian M, Huntriss JD, Picton HM, Malik S, Taylor GR, Johnson CA, Bonthron DT, Sheridan EG |title=Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte |journal=Am. J. Hum. Genet. |volume=89 |issue=3 |pages=451–8 |date=September 2011 |pmid=21885028 |pmc=3169823 |doi=10.1016/j.ajhg.2011.08.002 |url=}}</ref>


== Associated Conditions ==
Conditions associated with gestational trophoblastic neoplasia include:
*[[Hyperthyroidism]]<ref name="pmid26050078">{{cite journal |vauthors=von Welser SF, Grube M, Ortmann O |title=Invasive mole in a perimenopausal woman: a case report and systematic review |journal=Arch. Gynecol. Obstet. |volume=292 |issue=6 |pages=1193–9 |date=December 2015 |pmid=26050078 |doi=10.1007/s00404-015-3777-z |url=}}</ref>
*[[Hypertension]]<ref name="pmid26050078">{{cite journal |vauthors=von Welser SF, Grube M, Ortmann O |title=Invasive mole in a perimenopausal woman: a case report and systematic review |journal=Arch. Gynecol. Obstet. |volume=292 |issue=6 |pages=1193–9 |date=December 2015 |pmid=26050078 |doi=10.1007/s00404-015-3777-z |url=}}</ref>
*[[Mature cystic teratoma]]<ref name="pmid30116304">{{cite journal |vauthors=Simes BC, Mbanaso AA, Zapata CA, Okoroji CM |title=Hyperthyroidism in a complete molar pregnancy with a mature cystic ovarian teratoma |journal=Thyroid Res |volume=11 |issue= |pages=12 |date=2018 |pmid=30116304 |pmc=6086074 |doi=10.1186/s13044-018-0056-7 |url=}}</ref>
*Normal [[pregnancy]]<ref name="pmid28800576">{{cite journal |vauthors=Lu D, Tang JJ, Zakashansky K, Berkowitz RS, Kalir T, Liu Y |title=Heterotopic Pregnancy Including Intrauterine Normal Gestation and Tubal Complete Hydatidiform Mole: A Case Report and Review of the Literature |journal=Int. J. Gynecol. Pathol. |volume=36 |issue=5 |pages=428–432 |date=September 2017 |pmid=28800576 |doi=10.1097/PGP.0000000000000347 |url=}}</ref>


==Gross Pathology==
[[Gross pathology|Gross pathological]] findings of the sub-types of gestational trophoblastic neoplasia are as follows:
====Invasive mole====
*It appears as an erosive [[hemorrhagic]] [[lesion]]
*Hydropic [[Villus|villi]] sticking out from the [[endometrium]] into the [[myometrium]] can also be visible
====Choriocarcinoma====
*Bulky, destructive mass with [[Bleeding|hemorrhage]] and [[necrosis]]<ref name="OberEdgcomb1971">{{cite journal|last1=Ober|first1=William B.|last2=Edgcomb|first2=John H.|last3=Price|first3=Edward B.|title=THE PATHOLOGY OF CHORIOCARCINOMA|journal=Annals of the New York Academy of Sciences|volume=172|issue=10 Physiology a|year=1971|pages=299–426|issn=0077-8923|doi=10.1111/j.1749-6632.1971.tb34943.x}}</ref><ref name="SmithKohorn2005">{{cite journal|last1=Smith|first1=Harriet O.|last2=Kohorn|first2=Ernest|last3=Cole|first3=Laurence A.|title=Choriocarcinoma and Gestational Trophoblastic Disease|journal=Obstetrics and Gynecology Clinics of North America|volume=32|issue=4|year=2005|pages=661–684|issn=08898545|doi=10.1016/j.ogc.2005.08.001}}</ref>
*Can be associated with deep [[Myometrium|myometrial]] invasion
====Epithelioid Trophoblastic Tumor (ETT)====
*[[Cyst|Cystic]] or [[Nodule (medicine)|nodular]] [[hemorrhagic]] masses that can compress and infiltrate the structures around it<ref name="pmid9808132">{{cite journal |vauthors=Shih IM, Kurman RJ |title=Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma |journal=Am. J. Surg. Pathol. |volume=22 |issue=11 |pages=1393–403 |date=November 1998 |pmid=9808132 |doi= |url=}}</ref><ref name="pmid16258513">{{cite journal |vauthors=Fadare O, Parkash V, Carcangiu ML, Hui P |title=Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement |journal=Mod. Pathol. |volume=19 |issue=1 |pages=75–82 |date=January 2006 |pmid=16258513 |doi=10.1038/modpathol.3800485 |url=}}</ref><ref name="MeydanliKucukali2002">{{cite journal|last1=Meydanli|first1=Mutlu M.|last2=Kucukali|first2=Turkan|last3=Usubutun|first3=Alp|last4=Ataoglu|first4=Omur|last5=Kafkasli|first5=Ayse|title=Epithelioid Trophoblastic Tumor of the Endocervix: A Case Report|journal=Gynecologic Oncology|volume=87|issue=2|year=2002|pages=219–224|issn=00908258|doi=10.1006/gyno.2002.6820}}</ref>
*Size of the [[tumor]] ranges from 0.5 - 5 cm.<ref name="pmid9808132">{{cite journal |vauthors=Shih IM, Kurman RJ |title=Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma |journal=Am. J. Surg. Pathol. |volume=22 |issue=11 |pages=1393–403 |date=November 1998 |pmid=9808132 |doi= |url=}}</ref><ref name="pmid17149967">{{cite journal |vauthors=Allison KH, Love JE, Garcia RL |title=Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-type intermediate trophoblast |journal=Arch. Pathol. Lab. Med. |volume=130 |issue=12 |pages=1875–7 |date=December 2006 |pmid=17149967 |doi=10.1043/1543-2165(2006)130[1875:ETTROA]2.0.CO;2 |url=}}</ref>
*Cut surface can have a tan or white appearance with [[Bleeding|hemorrhage]] and [[necrosis]]
*[[Ulcer|Ulceration]] can be present
*[[Fistula]] formation is common
====Placental-site Trophoblastic Tumor (PSTT)====
*It can appear as a [[Nodule (medicine)|nodular]], round, solid mass or varying size
*[[Necrosis]] and [[Bleeding|hemorrhage]] is commonly seen<ref name="pmid6200262">{{cite journal |vauthors=Young RH, Scully RE |title=Placental-site trophoblastic tumor: current status |journal=Clin Obstet Gynecol |volume=27 |issue=1 |pages=248–58 |date=March 1984 |pmid=6200262 |doi= |url=}}</ref><ref name="BaergenRutgers2006">{{cite journal|last1=Baergen|first1=Rebecca N.|last2=Rutgers|first2=Joanne L.|last3=Young|first3=Robert H.|last4=Osann|first4=Kathryn|last5=Scully|first5=Robert E.|title=Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance|journal=Gynecologic Oncology|volume=100|issue=3|year=2006|pages=511–520|issn=00908258|doi=10.1016/j.ygyno.2005.08.058}}</ref>
*Can result in [[perforation]] and extend into the [[Broad ligament of the uterus|broad ligament]] and [[adnexa]]<ref name="pmid14501817">{{cite journal |vauthors=Baergen RN, Rutgers J, Young RH |title=Extrauterine lesions of intermediate trophoblast |journal=Int. J. Gynecol. Pathol. |volume=22 |issue=4 |pages=362–7 |date=October 2003 |pmid=14501817 |doi=10.1097/01.pgp.0000092132.88121.d1 |url=}}</ref>


==Microscopic Pathology==
On [[microscopic]] [[Histopathology|histopathological]] analysis, the characteristic features of each sub-type of gestational trophoblastic neoplasia are explained in the table below:<ref name="abc">Cellular Classification of Gestational Trophoblastic Disease. National Cancer Institute. http://www.cancer.gov/types/gestational-trophoblastic/hp/gtd-treatment-pdq/#section/_5 Accessed on October 8, 2015</ref><ref name="pmid62002622">{{cite journal |vauthors=Young RH, Scully RE |title=Placental-site trophoblastic tumor: current status |journal=Clin Obstet Gynecol |volume=27 |issue=1 |pages=248–58 |date=March 1984 |pmid=6200262 |doi= |url=}}</ref><ref name="pmid171499672">{{cite journal |vauthors=Allison KH, Love JE, Garcia RL |title=Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-type intermediate trophoblast |journal=Arch. Pathol. Lab. Med. |volume=130 |issue=12 |pages=1875–7 |date=December 2006 |pmid=17149967 |doi=10.1043/1543-2165(2006)130[1875:ETTROA]2.0.CO;2 |url=}}</ref>


{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align="center"
| valign="top" |
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Types of Gestational Trophoblastic Neoplasia}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Histopathological features}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
Invasive mole
| style="padding: 5px 5px; background: #F5F5F5;" |
* [[Hyperplasia]] of [[Cytotrophoblast|cytotrophoblastic]] and [[Syncytiotrophoblast|syncytial]] elements and persistence of villous structures
* [[Trophoblast|Trophoblastic]] invasion of the [[myometrium]] with identifiable villous structures
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Choriocarcinoma
| style="padding: 5px 5px; background: #F5F5F5;" |
* Columns and sheets of [[Trophoblast|trophoblastic]] [[Tissue (biology)|tissue]] invading [[Uterus|uterine]] [[muscle]] and [[Blood vessel|blood vessels]]
* [[Syncytiotrophoblast|Syncytiotrophoblasts]] (large [[eosinophilic]] smudgy [[Multinucleate|multinucleated]] [[Cell (biology)|cells]] with large [[Hyperchromicity|hyperchromatic]] [[Cell nucleus|nuclei]]) are intermixed with [[Cytotrophoblast|cytotrophoblasts]] (polygonal [[Cell (biology)|cells]] with distinct borders, and single irregular [[Cell nucleus|nuclei]])
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Placental-site trophoblastic tumor
| style="padding: 5px 5px; background: #F5F5F5;" |
* Infiltrative growth of large, polyhedral to round, mononuclear intermediate [[Trophoblast|trophoblasts]]
* [[Tumor]] [[Cell (biology)|cells]] have plentiful amphophilic, [[eosinophilic]], or clear [[cytoplasm]]
* [[Cell nucleus|Nuclear]] [[pleomorphism]]
* Large, convoluted [[Cell nucleus|nuclei]] with marked [[Hyperchromicity|hyperchromasia]], [[Cell nucleus|nuclear]] grooves, and [[Cell nucleus|nuclear]] pseudoinclusions
* [[Mitosis|Mitotic]] count ranges from 2 - 4 per 10 high-power fields in most cases
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Epithelioid trophoblastic tumor
| style="padding: 5px 5px; background: #F5F5F5;" |
* The [[tumor]] has a monomorphic [[Cell (biology)|cellular]] pattern of [[epithelioid]] [[Cell (biology)|cells]] and may resemble [[Squamous cell carcinoma|squamous cell cancer]] of the [[cervix]] when arising in the [[cervical]] canal
* [[Nodule (medicine)|Nodular]], expansile growth of uniform, medium-sized [[Cell (biology)|cells]] arranged in cords, nests, or sheets
* Characteristic well-circumscribed [[tumor]] border
|}


 
[[File:Intermediate trophoblast 3 - low mag.jpg|center|thumbnail|Courtesy Wikipedia]]
 
 
 
 
 
Gestational Trophoblastic Neoplasias<ref> Cellular Classification of Gestational Trophoblastic Disease. National Cancer Institute. http://www.cancer.gov/types/gestational-trophoblastic/hp/gtd-treatment-pdq/#section/_5 Accessed on October 8, 2015</ref>
===Invasive mole===
Invasive moles (chorioadenoma destruens) are locally invasive, rarely metastatic lesions characterized microscopically by trophoblastic invasion of the myometrium with identifiable villous structures. These may be preceded by either complete or partial molar pregnancy. They are usually diploid in karyotype, but may be aneuploid.
Microscopically, these lesions are characterized by hyperplasia of cytotrophoblastic and syncytial elements and persistence of villous structures. They may resemble choriocarcinoma in histologic appearance. Invasive moles have more aggressive behavior than either complete or partial HMs, and they are treated similarly to choriocarcinoma (i.e., with chemotherapy). However, unlike choriocarcinoma, they may regress spontaneously.
 
===Choriocarcinoma===
 
Choriocarcinoma is a malignant tumor of the trophoblastic epithelium. Uterine muscle and blood vessels are invaded with areas of hemorrhage and necrosis. Columns and sheets of trophoblastic tissue invade normal tissues and spread to distant sites, the most common of which are lungs, brain, liver, pelvis, vagina, spleen, intestines, and kidney. Most choriocarcinomas have an aneuploid karyotype, and about three-quarters of them contain a Y chromosome. Most follow an HM pregnancy, spontaneous abortion, or ectopic pregnancy; but, about one-quarter of them are preceded by a full-term pregnancy. Nearly all GTDs that are preceded by nonmolar pregnancies are choriocarcinomas; the rare exceptions generally are PSTTs.
 
===PSTT===
 
PSTT disease is the result of a very rare tumor arising from the placental implantation site and resembles an exaggerated form of syncytial endometritis. Trophoblastic cells infiltrate the myometrium, and there is vascular invasion. Human placental lactogen is present in the tumor cells, whereas immunoperoxidase staining for human chorionic gonadotropin (hCG) is positive in only scattered cells, and elevations in serum hCG are relatively low compared with the marked elevations seen in choriocarcinoma. hCG is not a reliable marker of tumor volume. PSTTs have much lower growth rates than choriocarcinoma, and presentation after a full-term pregnancy is often delayed by months or years. They are generally resistant to chemotherapy. Therefore, hysterectomy is the standard primary treatment if the tumor is confined to the uterus. However, about 35% of PSTTs have distant metastases at diagnosis. Common sites of metastasis include the lungs, pelvis, and lymph nodes. Central nervous system, renal, and liver metastases have also been observed.
 
===ETT===
 
ETT is an extremely rare gestational trophoblastic tumor. Although originally termed atypical choriocarcinoma, it appears to be less aggressive than choriocarcinoma and is now regarded as a distinct entity. Pathologically, it has a monomorphic cellular pattern of epithelioid cells and may resemble squamous cell cancer of the cervix when arising in the cervical canal. Its clinical behavior appears to be closer to that of PSTT than to choriocarcinoma. It has a spectrum of clinical behavior from benign to malignant. About one-third of patients present with metastases, usually in the lungs.
 
===Microscopic Pathology===
On [[light microscopy]], there is malignant [[trophoblast]]ic proliferation without hydropic villi.Characteristic feature is the identification of intimately related [[syncytiotrophoblast]]s and [[cytotrophoblast]]s without formation of definite placental type villi.Syncytiotrophoblasts are large multi-nucleated cells with [[eosinophilic]] [[cytoplasm]]. They often surround the cytotrophoblasts, reminiscent of their normal anatomical relationship in [[chorionic villi]].  Cytotrophoblasts are polyhedral, mononuclear cells with hyperchromatic nuclei and a clear or pale cytoplasm.  Extensive [[hemorrhage]] is a common finding.
Shown below is an image of choriocarcinoma.
 
[[Image:800px-Choriocarcinoma_-2-_very_high_mag.jpg‎|200px]]
 
The image shows a micrograph of choriocarcinoma showing both of the components necessary for the diagnosis - cytotrophoblasts and syncytiotrophoblasts. The syncytiotrophoblasts are multinucleated and have a dark staining cytoplasm. The cytotrophoblasts are mononuclear and have a pale staining cytoplasm.
 
Choriocarcinomas consist of two cell populations:
# Cytotrophoblasts
#*Pale/clear cytoplasm
# Syncytiotrophoblasts
#* Hyperchromatic cytoplasm
#* Typically multinucleated.
 
Traditionally, the syncytiotrophoblasts are said to produce the beta-hCG;<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>however, it has been determined that cytotrophoblast also produce some.<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>The syncytiotrophoblasts are often arranged around the outside of cytotrophoblast cell clusters, reminicent of the arrangement in the placenta.  On placental Chorionic_villi, the syncytiotrophoblasts are superficial to and, early in pregnancy, cover the cytotrophoblast.Choriocarcinoma is classified as a germ cell tumour.  It can arise in the testis or ovary and from a hydatidiform mole.  It may be part of a mixed germ cell tumour.
 
===Video===
 
 
{{#ev:youtube|X6PZ0nRM554}}
 


==References==
==References==
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Latest revision as of 00:04, 3 April 2019

Gestational trophoblastic neoplasia Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Overview

Pregnancy occurs when an egg, which is released from the ovary during ovulation, is fertilized by a sperm. Human pregnancy takes approximately 40 weeks. Gestational trophoblastic neoplasia arises from the trophoblastic tissue, which provides nutrients to the embryo and develops into a large part of the placenta. Invasive mole is basically a benign tumor which arises from the invasion of the myometrium of a hydatidiform mole. Choriocarcinoma is a malignant tumor of the trophoblastic epithelium. Placental-site trophoblastic tumor (PSTT), a rare tumor, arises from the implantation site of placenta. Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT) which arises from the malignant transformation of chorionic-type intermediate trophoblastic cells. Invasive mole is usually diploid but can also be aneuploid in karyotype. Choriocarcinoma has an aneuploid karyotype and majority of the cases have a Y chromosome.

Pathophysiology

Physiology

The normal physiology of pregnancy can be understood as follows:

Placental Trophoblast and Pregnancy

For more information on fertilization, click here.
For more information on pregnancy, click here.

Pathogenesis

Pathogenesis of each sub-type of gestational trophoblastic neoplasia is explained as follows:

Invasive Mole

Choriocarcinoma

Placental-site Trophoblastic Tumor (PSTT)

Epithelioid Trophoblastic Tumor (ETT)

  • Epithelioid trophoblastic tumor (ETT) is basically a rare variant of placental-site trophoblastic tumor (PSTT).
  • It arises from the malignant transformation of chorionic-type intermediate trophoblastic cells.[27]
  • Epithelioid trophoblastic tumor (ETT) can clinically present as benign or malignant.[28]
  • Majority of the cases of epithelioid trophoblastic tumors (ETT) present years after full-term gestations.[27][29]

Genetics

Associated Conditions

Conditions associated with gestational trophoblastic neoplasia include:

Gross Pathology

Gross pathological findings of the sub-types of gestational trophoblastic neoplasia are as follows:

Invasive mole

Choriocarcinoma

Epithelioid Trophoblastic Tumor (ETT)

Placental-site Trophoblastic Tumor (PSTT)

Microscopic Pathology

On microscopic histopathological analysis, the characteristic features of each sub-type of gestational trophoblastic neoplasia are explained in the table below:[44][45][46]

Types of Gestational Trophoblastic Neoplasia Histopathological features

Invasive mole

Choriocarcinoma

Placental-site trophoblastic tumor

Epithelioid trophoblastic tumor

Courtesy Wikipedia

References

  1. ↑ CHANG MC (October 1951). "Fertilizing capacity of spermatozoa deposited into the fallopian tubes". Nature. 168 (4277): 697–8. PMID 14882325.
  2. ↑ AUSTIN CR (November 1951). "Observations on the penetration of the sperm in the mammalian egg". Aust J Sci Res B. 4 (4): 581–96. PMID 14895481.
  3. ↑ AUSTIN CR (August 1952). "The capacitation of the mammalian sperm". Nature. 170 (4321): 326. PMID 12993150.
  4. ↑ Moore, Keith (1988). Essentials of human embryology. Toronto Philadelphia Saint Louis, Mo: B.C. Decker C.V. Mosby Co. distributor. ISBN 9780941158978.
  5. ↑ Moore, Keith (1988). Essentials of human embryology. Toronto Philadelphia Saint Louis, Mo: B.C. Decker C.V. Mosby Co. distributor. ISBN 9780941158978.
  6. ↑ Miklavcic JJ, Flaman P (May 2017). "Personhood status of the human zygote, embryo, fetus". Linacre Q. 84 (2): 130–144. doi:10.1080/00243639.2017.1299896. PMC 5499222. PMID 28698706.
  7. ↑ Moore, Keith (2016). The developing human : clinically oriented embryology. Philadelphia, PA: Elsevier. ISBN 9780323313384.
  8. ↑ Moore, Keith (2016). The developing human : clinically oriented embryology. Philadelphia, PA: Elsevier. ISBN 9780323313384.
  9. ↑ Moore, Keith (2016). The developing human : clinically oriented embryology. Philadelphia, PA: Elsevier. ISBN 9780323313384.
  10. ↑ Moore, Keith (2016). The developing human : clinically oriented embryology. Philadelphia, PA: Elsevier. ISBN 9780323313384.
  11. ↑ Lurain, John R. (2010). "Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole". American Journal of Obstetrics and Gynecology. 203 (6): 531–539. doi:10.1016/j.ajog.2010.06.073. ISSN 0002-9378.
  12. ↑ https://www.cancer.gov
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Seckl MJ, Sebire NJ, Berkowitz RS (August 2010). "Gestational trophoblastic disease". Lancet. 376 (9742): 717–29. doi:10.1016/S0140-6736(10)60280-2. PMID 20673583.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Brown J, Naumann RW, Seckl MJ, Schink J (January 2017). "15years of progress in gestational trophoblastic disease: Scoring, standardization, and salvage". Gynecol. Oncol. 144 (1): 200–207. doi:10.1016/j.ygyno.2016.08.330. PMID 27743739.
  15. ↑ https://www.cancer.gov
  16. ↑ 16.0 16.1 16.2 Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C (October 2013). "Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Ann. Oncol. 24 Suppl 6: vi39–50. doi:10.1093/annonc/mdt345. PMID 23999759.
  17. ↑ https://www.cancer.gov
  18. ↑ Bishop BN, Edemekong PF. PMID 30571055. Missing or empty |title= (help)
  19. ↑ Mao TL, Kurman RJ, Huang CC, Lin MC, Shih I (November 2007). "Immunohistochemistry of choriocarcinoma: an aid in differential diagnosis and in elucidating pathogenesis". Am. J. Surg. Pathol. 31 (11): 1726–32. doi:10.1097/PAS.0b013e318058a529. PMID 18059230. Vancouver style error: initials (help)
  20. ↑ Shih I (July 2007). "Gestational trophoblastic neoplasia--pathogenesis and potential therapeutic targets". Lancet Oncol. 8 (7): 642–50. doi:10.1016/S1470-2045(07)70204-8. PMID 17613426. Vancouver style error: initials (help)
  21. ↑ https://www.cancer.gov
  22. ↑ https://www.cancer.gov
  23. ↑ 23.0 23.1 Feltmate CM, Genest DR, Goldstein DP, Berkowitz RS (May 2002). "Advances in the understanding of placental site trophoblastic tumor". J Reprod Med. 47 (5): 337–41. PMID 12063871.
  24. ↑ https://www.cancer.gov
  25. ↑ https://www.cancer.gov
  26. ↑ 26.0 26.1 Schmid P, Nagai Y, Agarwal R, Hancock B, Savage PM, Sebire NJ, Lindsay I, Wells M, Fisher RA, Short D, Newlands ES, Wischnewsky MB, Seckl MJ (July 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.
  27. ↑ 27.0 27.1 27.2 27.3 Shih IM, Kurman RJ (November 1998). "Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma". Am. J. Surg. Pathol. 22 (11): 1393–403. PMID 9808132.
  28. ↑ https://www.cancer.gov
  29. ↑ 29.0 29.1 Allison KH, Love JE, Garcia RL (December 2006). "Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-type intermediate trophoblast". Arch. Pathol. Lab. Med. 130 (12): 1875–7. doi:10.1043/1543-2165(2006)130[1875:ETTROA]2.0.CO;2. PMID 17149967.
  30. ↑ http://www.cancer.gov
  31. ↑ http://www.cancer.gov
  32. ↑ 32.0 32.1 Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R (March 2006). "Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans". Nat. Genet. 38 (3): 300–2. doi:10.1038/ng1740. PMID 16462743.
  33. ↑ 33.0 33.1 Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H, Diggle C, Carr I, Rittore C, Touitou I, Philibert L, Fisher RA, Fallahian M, Huntriss JD, Picton HM, Malik S, Taylor GR, Johnson CA, Bonthron DT, Sheridan EG (September 2011). "Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte". Am. J. Hum. Genet. 89 (3): 451–8. doi:10.1016/j.ajhg.2011.08.002. PMC 3169823. PMID 21885028.
  34. ↑ 34.0 34.1 von Welser SF, Grube M, Ortmann O (December 2015). "Invasive mole in a perimenopausal woman: a case report and systematic review". Arch. Gynecol. Obstet. 292 (6): 1193–9. doi:10.1007/s00404-015-3777-z. PMID 26050078.
  35. ↑ Simes BC, Mbanaso AA, Zapata CA, Okoroji CM (2018). "Hyperthyroidism in a complete molar pregnancy with a mature cystic ovarian teratoma". Thyroid Res. 11: 12. doi:10.1186/s13044-018-0056-7. PMC 6086074. PMID 30116304.
  36. ↑ Lu D, Tang JJ, Zakashansky K, Berkowitz RS, Kalir T, Liu Y (September 2017). "Heterotopic Pregnancy Including Intrauterine Normal Gestation and Tubal Complete Hydatidiform Mole: A Case Report and Review of the Literature". Int. J. Gynecol. Pathol. 36 (5): 428–432. doi:10.1097/PGP.0000000000000347. PMID 28800576.
  37. ↑ Ober, William B.; Edgcomb, John H.; Price, Edward B. (1971). "THE PATHOLOGY OF CHORIOCARCINOMA". Annals of the New York Academy of Sciences. 172 (10 Physiology a): 299–426. doi:10.1111/j.1749-6632.1971.tb34943.x. ISSN 0077-8923.
  38. ↑ Smith, Harriet O.; Kohorn, Ernest; Cole, Laurence A. (2005). "Choriocarcinoma and Gestational Trophoblastic Disease". Obstetrics and Gynecology Clinics of North America. 32 (4): 661–684. doi:10.1016/j.ogc.2005.08.001. ISSN 0889-8545.
  39. ↑ Fadare O, Parkash V, Carcangiu ML, Hui P (January 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.
  40. ↑ Meydanli, Mutlu M.; Kucukali, Turkan; Usubutun, Alp; Ataoglu, Omur; Kafkasli, Ayse (2002). "Epithelioid Trophoblastic Tumor of the Endocervix: A Case Report". Gynecologic Oncology. 87 (2): 219–224. doi:10.1006/gyno.2002.6820. ISSN 0090-8258.
  41. ↑ Young RH, Scully RE (March 1984). "Placental-site trophoblastic tumor: current status". Clin Obstet Gynecol. 27 (1): 248–58. PMID 6200262.
  42. ↑ Baergen, Rebecca N.; Rutgers, Joanne L.; Young, Robert H.; Osann, Kathryn; Scully, Robert E. (2006). "Placental site trophoblastic tumor: A study of 55 cases and review of the literature emphasizing factors of prognostic significance". Gynecologic Oncology. 100 (3): 511–520. doi:10.1016/j.ygyno.2005.08.058. ISSN 0090-8258.
  43. ↑ Baergen RN, Rutgers J, Young RH (October 2003). "Extrauterine lesions of intermediate trophoblast". Int. J. Gynecol. Pathol. 22 (4): 362–7. doi:10.1097/01.pgp.0000092132.88121.d1. PMID 14501817.
  44. ↑ Cellular Classification of Gestational Trophoblastic Disease. National Cancer Institute. http://www.cancer.gov/types/gestational-trophoblastic/hp/gtd-treatment-pdq/#section/_5 Accessed on October 8, 2015
  45. ↑ Young RH, Scully RE (March 1984). "Placental-site trophoblastic tumor: current status". Clin Obstet Gynecol. 27 (1): 248–58. PMID 6200262.
  46. ↑ Allison KH, Love JE, Garcia RL (December 2006). "Epithelioid trophoblastic tumor: review of a rare neoplasm of the chorionic-type intermediate trophoblast". Arch. Pathol. Lab. Med. 130 (12): 1875–7. doi:10.1043/1543-2165(2006)130[1875:ETTROA]2.0.CO;2. PMID 17149967.

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