Pathology of Pathology of Gestational Gestational Trophoblastic Disease Trophoblastic Disease Modified WHO classification of GTD Modified WHO classification of GTD Molar lesions Molar lesions Hydatidiform mole Hydatidiform mole CHM CHM PHM PHM Invasive mole Invasive mole Non molar lesions Non molar lesions Choriocarcinoma Choriocarcinoma Placental site trophoblastic tumor (PSTT) Placental site trophoblastic tumor (PSTT) Epithelioid trophoblastic tumor (ETT) Epithelioid trophoblastic tumor (ETT) Miscellaneous Miscellaneous trophoblastic trophoblastic lesions lesions Exaggerated placental site Exaggerated placental site Placental site nodule Placental site nodule Normal Normal pregnancy pregnancy PHM PHM CHM CHM 10% 10% 90% 90% Ploidy Ploidy 2N 2N 3N 3N 2N 2N 2N 2N Chromosome Chromosome 46XX 46XX 46XY 46XY 69XXY 69XXY (70%) (70%) 69XXX 69XXX (27%) (27%) 69XYY 69XYY (3%) (3%) 46XX 46XX (89 (89-97%) 97%) 46XY 46XY (7 (7-13%) 13%) No 46 YY No 46 YY Parentality Parentality Biparental Biparental Biparental Biparental Diandric Diandric Paternal Paternal Diandric Diandric Molar pregnancy Pathology of CHM Pathology of CHM Macro : Vesicles, maximal diameter 2 cm. Macro : Vesicles, maximal diameter 2 cm. Pathology of CHM Pathology of CHM Micro Micro Enlarged villi, cavitation (necrosis) Enlarged villi, cavitation (necrosis) Trophoblastic proliferation around villi Trophoblastic proliferation around villi with minimal atypia with minimal atypia Absence or paucity of fetal stromal BVs Absence or paucity of fetal stromal BVs Atypia of ITs at Atypia of ITs at decidual implantation decidual implantation site. site.
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Pathology of Pathology of
Gestational Gestational
Trophoblastic DiseaseTrophoblastic Disease
Modified WHO classification of GTDModified WHO classification of GTD
�� Focal to diffuse trophoblastic atypiaFocal to diffuse trophoblastic atypia�� Villous stromaVillous stroma
�� HypercellularHypercellular (stellate mesenchymal cells in blue (stellate mesenchymal cells in blue myxoid matrix) = fibroadenoma likemyxoid matrix) = fibroadenoma like
�� Prominent karyorrhexis in villous mesnchymal Prominent karyorrhexis in villous mesnchymal cells, cells, stromal nuclear debrisstromal nuclear debris
�� Numerous vessels Numerous vessels with nucleated RBCswith nucleated RBCs
Early CHMEarly CHM
Typical features in early CHMTypical features in early CHM�� Abnormally shaped villi Abnormally shaped villi (bullous or (bullous or polypoid)polypoid)
�� Stromal mucinStromal mucin�� Stromal nuclear debrisStromal nuclear debris (resulted (resulted of increased stromal proloferation of increased stromal proloferation and apoptosisand apoptosis
Ploidy analysisPloidy analysis�� Triploid Triploid PHM VS non PHMPHM VS non PHM
Interphase cytogeneticsInterphase cytogenetics�� Identify chromosome aberrations by in situ Identify chromosome aberrations by in situ
hybridization (ISH) using chromosome hybridization (ISH) using chromosome specific probes (chromosome 1, X, Y)specific probes (chromosome 1, X, Y)
P57P57kip2 kip2 oror IPL/PHLDA2IPL/PHLDA2
�� Located at Located at chromosome 11p15.5chromosome 11p15.5�� Strongly Strongly paternally imprintedpaternally imprinted, being , being expressed predominantlyexpressed predominantly from maternal allele from maternal allele
�� Potent cell cycle inhibitor and tumor Potent cell cycle inhibitor and tumor suppressorsuppressor
�� lack of lts activity can lead to loss of cell cycle lack of lts activity can lead to loss of cell cycle control and hyperproliferationcontrol and hyperproliferation
�� Normal pregnancy and PHM : positive at nuclei Normal pregnancy and PHM : positive at nuclei of villous stroma, villous CT, decidual and of villous stroma, villous CT, decidual and extravillous trophoblastextravillous trophoblast
�� CHM : negative at nuclei of villous stroma, CHM : negative at nuclei of villous stroma, villous CTvillous CT
BVs BVs or even the or even the extrauterine extrauterine sitessites
�� Dependent on extent of invasionDependent on extent of invasion
Invasive mole
GTDGTD
�� GTDs are distinct from other tumors in the GTDs are distinct from other tumors in the human body in that they are genetically or human body in that they are genetically or allograft in the motherallograft in the mother’’s bodys body..
�� They are They are fetal tumorsfetal tumors that are arising in that are arising in the motherthe mother’’s body.s body.
�� The The remarkable curabilityremarkable curability of GTDs with of GTDs with chemoRx might reflect the underlying chemoRx might reflect the underlying immune response of the mother to paternal immune response of the mother to paternal antigens expressed on the surface of antigens expressed on the surface of trophoblastic cells.trophoblastic cells.
Int J Gynecol Cancer 2006;16:1500Int J Gynecol Cancer 2006;16:1500--1515
�� BiBi--laminar patternlaminar pattern (recapitulates (recapitulates trophoblast of early implanting trophoblast of early implanting blastocyst)blastocyst)
�� Extensive myometrial invasion Extensive myometrial invasion without destruction or necrosis of without destruction or necrosis of myometriummyometrium
�� Tumor in dilated vascular sinusesTumor in dilated vascular sinuses
Choriocarcinoma
Biphasic trophoblasts
Choriocarcinoma
Marked trophoblastic atypia
Hemorrhagic necrosis
Special studySpecial study of choriocarcinomaof choriocarcinoma
�� In myometrium with or without In myometrium with or without
projection into endometrial cavityprojection into endometrial cavity
�� No striking hemorrhage or necrosisNo striking hemorrhage or necrosis
MicroMicro�� Recapitulate appearance seen at placental bedRecapitulate appearance seen at placental bed
�� Diffuse infiltration of mononuclear and multinuclear IT Diffuse infiltration of mononuclear and multinuclear IT arranged in cords, islands, sheets between arranged in cords, islands, sheets between myometrial bundlesmyometrial bundles
�� Vascular invasion recapitulates normal implantation Vascular invasion recapitulates normal implantation site : cell migrate through and replace vessel walls , site : cell migrate through and replace vessel walls , maintaining overall vascular architecturemaintaining overall vascular architecture
�� Less intravascular proliferationLess intravascular proliferation
�� Vary mitotic activityVary mitotic activity
�� Abundant extracellular eosinophilic fibrinoid materialAbundant extracellular eosinophilic fibrinoid material
Pathology of PSTTPathology of PSTT
PSTT
Sheets of atypical IT ITs dissecting through muscle fibers
PSTT
extracellular eosinophilic fibrinoid material
mononuclear and multinclear IT
Pathology of ETTPathology of ETTProposed by Mazur in 1989Proposed by Mazur in 1989
��50% of cases arise in lower 50% of cases arise in lower uterine segment or uterine segment or endocervixendocervix
Pathology of ETTPathology of ETT
MicroMicro�� Mixture of mononuclear cells with eosinophilic Mixture of mononuclear cells with eosinophilic or clear cytoplasm forming nests or cordsor clear cytoplasm forming nests or cords
�� Areas of hyalinization or eosinophilic debris Areas of hyalinization or eosinophilic debris simulating tumor cell necrosis at center of simulating tumor cell necrosis at center of tumor nests (resembling keratin material in tumor nests (resembling keratin material in SCC)SCC)
Hemorrhage Focal or haphazard Usually present Massive and cent ral
Cellular necrosis Usually Absent Extensive Extensive
Calcification Absent Usually present Absent
Vascular invasion
From periphery to lumen
Absent From lumen to periphery
Fibrinoid change Present Present Absent
Mitosis Variable ;0-6/10HPF
Variable ;1-10/10HPF
High ;2-22/10 HPF
Clinical features of PSTT , ETT and choriocarcinoma
Feature PSTT ETT Choriocarcinoma
Clinical Presentation
Missed Abortion Abnormal vaginal bleeding
Persistent GTD after HM
Last Pregnancy or GTD
Variable , can be remote
Variable , can be remote
months
History of mole 5-8% 14% 50%
Serum hCG Low (< 100-2,000IU/L)
Low (50 – 500IU/mL )
High (>10,000IU/mL )
Behavior Variable Variable Aggressive if untreated
Response to chemotherapy
Variable Variable Good
Treatment Surgery (hysterectomy )
Surgery (hysterectomy )
Chemotherapy
Markers for trophoblastsMarkers for trophoblasts
�� hCGhCG�� hPLhPL�� Inhibin Inhibin αα
�� Shih & Kurman showed that Shih & Kurman showed that Inhibin Inhibin αα was expressed was expressed by all population of trophoblasts except CTby all population of trophoblasts except CT
�� Melanoma cell adhesion molecule (MelMelanoma cell adhesion molecule (Mel--CAM) = MUC18CAM) = MUC18�� Kurman found that MelKurman found that Mel--CAM is specific and sensitive CAM is specific and sensitive
marker for IT in normal placenta implantation site and marker for IT in normal placenta implantation site and GTD lesionGTD lesion
�� HLAHLA--GG (non classical major histocompatibility (non classical major histocompatibility class I)class I)�� Singer et al showed positivity in all GTD lesions, but Singer et al showed positivity in all GTD lesions, but
negative in non trophoblastic uterine neoplasmsnegative in non trophoblastic uterine neoplasms
Biomarkers for diagnosis GTDsBiomarkers for diagnosis GTDs
PSTTPSTT ETTETT ChorioCAChorioCA
hCGhCG focalfocal focalfocal diffusediffuse
hPLhPL diffusediffuse focalfocal Few cellsFew cells
PLAPPLAP Occasional Occasional
cellscellsfocalfocal rarerare
P63P63 -- ++ +/+/--
Ki67Ki67 >10%>10% >10%>10% >10%>10%
MelMel--CAMCAM ++ ++ focalfocal
Inhibin Inhibin αα ++ ++ focalfocal
CKCK ++ ++ ++
HLAHLA--GG ++ ++ ++
P63P63
�� Nuclear transcription factor belonging to P53 Nuclear transcription factor belonging to P53 familyfamily
�� Two major isoformsTwo major isoforms
�� CT expresses N isoformCT expresses N isoform
�� Chorionic type ITChorionic type IT expresses TA isoformexpresses TA isoform
�� Different P63 isoforms may be important in Different P63 isoforms may be important in control of trophoblastic differentiation and control of trophoblastic differentiation and placental developmentplacental development
Am J Sur Pathol 2004;28:1177Am J Sur Pathol 2004;28:1177--8383
P63 in normal villous and ETTP63 in normal villous and ETT
Normal villous ETT
HLAHLA--GG
�� Presence on all types of non villous trophoblast, Presence on all types of non villous trophoblast, but is not detected in villous CT and STbut is not detected in villous CT and ST
�� All trophoblastic tumors and tumor like All trophoblastic tumors and tumor like lesions express HLAlesions express HLA--G strongly and G strongly and diffusely diffusely
�� Vast majority of nonVast majority of non--trophoblastic tumors do not trophoblastic tumors do not express HLAexpress HLA--GG
�� Melanoma, renal cell , breast, ovarian and large Melanoma, renal cell , breast, ovarian and large cell carcinoma of lung may show focal cell carcinoma of lung may show focal expressionexpression
Practical immunohistochemistry approach to Practical immunohistochemistry approach to
diagnosis of lesions of nondiagnosis of lesions of non--villous trophoblast in villous trophoblast in
biopsy specimensbiopsy specimens
1.1. To confirm trophoblastic nature of To confirm trophoblastic nature of cellscells
4.4. In practical terms, distinction In practical terms, distinction between PSTT and ETT is not really an between PSTT and ETT is not really an important oneimportant one
Practical immunohistochemistry approach to Practical immunohistochemistry approach to
diagnosis of lesions of nondiagnosis of lesions of non--villous trophoblast in villous trophoblast in