1. Chapter 22 Gestational Trophoblastic Disease Women ’ s Hospital, School of Medicine Zhejiang University Xiaodong Cheng

2. Gestational trophoblastic disease A group of diseases A group of diseases originated from placental trophoblastic cells originated from placental trophoblastic cells Gestational trophoblasitc disease (GTD) Gestational trophoblasitc disease (GTD) Hydatidiform mole (complete and partial) Hydatidiform mole (complete and partial) Invasive mole Invasive mole Choriocarcinoma Choriocarcinoma Placental-site trophoblastic tumor (PSTT) Placental-site trophoblastic tumor (PSTT) Gestational trophoblastic neoplasia (GTN) Gestational trophoblastic neoplasia (GTN) Non-gestational trophoblastic tumor Non-gestational trophoblastic tumor Uncommon, derived from germ cells in ovarian or testicular Uncommon, derived from germ cells in ovarian or testicular histologically clinically

3. Development and differentiation of gestational trophoblastic cells gestational trophoblastic cells evolved from extra-embryonic cells gestational trophoblastic cells evolved from extra-embryonic cells At the time of implantation At the time of implantation cytotrophoblast outermost layer of the blastocyst cytotrophoblast outermost layer of the blastocyst 7-8 days after implantation 7-8 days after implantation syncytiotrophoblast implantation site syncytiotrophoblast implantation site Before villi formation previllous trophoblast Before villi formation previllous trophoblast 2 weeks after pregnancy, primary villi formation 2 weeks after pregnancy, primary villi formation Villous surface villous trophoblast Villous surface villous trophoblast Other parts extravillous trophoblast Other parts extravillous trophoblast

5. Development and Differentiation of gestational trophoblastic cells Cytotrophoblast Cytotrophoblast trophoblast stem cells trophoblast stem cells proliferability and differentiability proliferability and differentiability Syncytiotrophoblast Syncytiotrophoblast differentiated mature cells differentiated mature cells synthesize pregnancy-related hormones synthesize pregnancy-related hormones material exchange between the fetus and the mother material exchange between the fetus and the mother Two differentiated forms of Cytotrophoblast Two differentiated forms of Cytotrophoblast villous surface area Syncytiotrophoblast villous surface area Syncytiotrophoblast extravillous Intermediate trophoblast extravillous Intermediate trophoblast

6. Hydatidiform mole

7. Complete moles Complete moles Hydropic degeneration of all villi Hydropic degeneration of all villi Villous edema, trophoblastic hyperplasia, fetal-derived Villous edema, trophoblastic hyperplasia, fetal-derived blood vessels disappear in stroma blood vessels disappear in stroma Partial moles Partial moles combine embryo or fetus combine embryo or fetus Villous edema partially, trophoblastic proliferation Villous edema partially, trophoblastic proliferation lighterly, fetal-derived blood vessels present stroma lighterly, fetal-derived blood vessels present stroma

8. Complete moles Partial moles

9. Hydatidiform mole Related Factors Complete moles Complete moles Area common in Latin America, Asia Area common in Latin America, Asia uncommon in North America and Europe uncommon in North America and Europe Race differences of the same race in different regions Race differences of the same race in different regions Nutrition and Economy lack of Vit A Nutrition and Economy lack of Vit A Age 35 years Age 35 years The fertilization of an empty egg The fertilization of an empty egg the fertilization of an empty egg by a haploid sperm the fertilization of an empty egg by a haploid sperm Diploid genome 90% of the time (usually 46,XX) Diploid genome 90% of the time (usually 46,XX) Genomic imprinting disorder Genomic imprinting disorder

10. Hydatidiform mole Partial moles Partial moles high-risk factors are still unknown high-risk factors are still unknown "Haploid egg" fertilization "Haploid egg" fertilization usually two sperm fertilize a normal egg usually two sperm fertilize a normal egg a triploid karyotype (69 chromosomes ), with the extra haploid set of chromosomes derived from father a triploid karyotype (69 chromosomes ), with the extra haploid set of chromosomes derived from father

11. CompletePartial Karyotype 46, XX(90%) 46, XY(10%) Triploid (69XXY, 69XXX) EmbryoAbsentPresent VilliHydropic Few hydropic Few hydropic Trophoblasts Diffuse hyperplasia Diffuse hyperplasia Mild focal hyperplasia Mild focal hyperplasia Villus outline regularirregular Blood vessel absencepresence Comparison of complete and partial hydatidiform moles

12. Hydatidiform mole Clinical Presentation Complete moles Complete moles Abnormal vaginal bleeding during early pregnancy( 8-12week) Abnormal vaginal bleeding during early pregnancy( 8-12week) most common symptom most common symptom Uterine enlargement exceeding normal pregnant uterus Uterine enlargement exceeding normal pregnant uterus Others Others Abdominal pain Abdominal pain Pregnancy-induced hypertension Pregnancy-induced hypertension Theca lutein ovarian cyst Theca lutein ovarian cyst Hyperthyroidism (CHM) Hyperthyroidism (CHM) Partial moles Partial moles Mild symptoms, Confused with abortion easily Mild symptoms, Confused with abortion easily

13. Hydatidiform mole hCG regression pattern after hydatidiform Mean time of the hCG regressed to normal Mean time of the hCG regressed to normal — 9 weeks no more than 14 weeks — 9 weeks no more than 14 weeks Abnormal hCG regression pattern after hydatidiform Abnormal hCG regression pattern after hydatidiform signifies the presence of GTN signifies the presence of GTN Complete mole Complete mole 15% local invasion and 4% distant metastasis 15% local invasion and 4% distant metastasis High – risk : High – risk : ① HCG>100,000U/L ② Enlargement of Uterine ③ Theca lutein ovarian cyst >6cm Partial mole Partial mole 4%local invasion and almost no distant metastasis 4%local invasion and almost no distant metastasis High – risk :unclear High – risk :unclear

14. Hydatidiform mole Diagnosis Diagnosis  Abnormal bleeding after amenorrhea  Inappropriately enlarged uterus  Absence of fetal heart sounds not palpate fetus between 16-20 th week not palpate fetus between 16-20 th week  Vaginal discharge hydatidiform-like tissue Hydatidiform mole should be considered

15. Hydatidiform mole Diagnosis Diagnosis Ultrasound Ultrasound Complete moles produce a characteristic vesicular sonographic pattern, usually referred to as a “ snowstorm ” pattern Complete moles produce a characteristic vesicular sonographic pattern, usually referred to as a “ snowstorm ” pattern HCG HCG  Elevated above expected for gestational age  Dynamic observation for 8-10 weeks, continued to rise  HCG-related molecules Hyperglycosylated HCG Hyperglycosylated HCG free β-HCG subunit free β-HCG subunit DNA karyotype DNA karyotype Complete moles — usually diploid Complete moles — usually diploid Partial moles — usually triploid Partial moles — usually triploid

16. a “snowstorm” pattern

17. Hydatidiform mole Treatment Treatment Suction curettage  Molar pregnancy should be terminated as soon as possible when diagnosis has been confirmed  Suction curettage is a first choice, must be fully done in operating room  tissue from curettage should be submitted to pathology be submitted to pathology

18. Hydatidiform mole Treatment Theca lutein cysts of the ovary Theca lutein cysts of the ovary do not need special treatment do not need special treatment Prophylactic chemotherapy: Prophylactic chemotherapy: A controversial topic A controversial topic only be offered to patients with high-risk factor or only be offered to patients with high-risk factor or impossible follow-up impossible follow-up Hysterectomy Hysterectomy Only remove local invasion, but not distant metastasis Only remove local invasion, but not distant metastasis Only for old women without childbearing desire Only for old women without childbearing desire

19. Hydatidiform mole Follow-up necessary for diagnosis of early GTN necessary for diagnosis of early GTN Methods: Methods: HCG HCG Symptom: Abnormal uterine bleeding Symptom: Abnormal uterine bleeding Pelvic examination Pelvic examination Ultrasound, chest X-ray and CT Ultrasound, chest X-ray and CT Contraception: Contraception: Condom and oral contraceptives, not IUD Condom and oral contraceptives, not IUD Duration for contraceptiom — 1 year Duration for contraceptiom — 1 year

20. Gestational Trophoblastic Neoplasia

21. General Consideration Antecedent gestation Antecedent gestation 60% hydatidiform mole 60% hydatidiform mole 30% follow abortion 30% follow abortion 10% term pregnancy or ectopic pregnancy 10% term pregnancy or ectopic pregnancy from mole from mole — invasive mole — invasive mole or choriocarcinoma from Non-mole or choriocarcinoma from Non-mole — choriocarcinoma — choriocarcinoma

22. Gestational Trophoblastic Neoplasia Pathogenesis Invasive mole Invasive mole Invasive mole is a hydatidiform mole that invades the myometrium and may produce distant metastases. Invasive mole is a hydatidiform mole that invades the myometrium and may produce distant metastases. Microscopic finding are the same as in hydatidiform mole Microscopic finding are the same as in hydatidiform mole Choriocarcinoma Choriocarcinoma Gloss ： invades the myometrium, penetrate the serosa Gloss ： invades the myometrium, penetrate the serosa and may produce distant metastases and may produce distant metastases Microscopy ： no villi, but instead sheets or foci of trophoblasts on a background of hemorrhage and necrosis Microscopy ： no villi, but instead sheets or foci of trophoblasts on a background of hemorrhage and necrosis

23. Invasive mole Choriocarcinoma Choriocarcinoma Choriocarcinoma

24. invades the myometrium Lung metastases Brain metastases cervical metastases

25. Gestational Trophoblastic Neoplasia Clinical Manifestation Nonmetastatic GTN the antecedent gestational event is usually HM the antecedent gestational event is usually HM Abnormal vaginal bleeding after mole Abnormal vaginal bleeding after mole Others: Others:  Enlarged uterus  Theca lutein cysts of the ovary  Abdominal pain  Fake pregnancy symptoms

26. Gestational Trophoblastic Neoplasia Metastatic GTN Usually chroriocarcinoma Primary symptoms Primary symptoms Metastatic symptoms Metastatic symptoms Lung metastases are frequently common Lung metastases are frequently common vaginal metastases are the second common vaginal metastases are the second common liver and brain metastases usually death cause liver and brain metastases usually death cause other metastastic sites other metastastic sites spleen, kidney, bladder, gastrointestinal system, and bone spleen, kidney, bladder, gastrointestinal system, and bone Simultateously occur or not

27. Gestational Trophoblastic Neoplasia Diagnosis Symptoms and signs: Symptoms and signs: ◆ Abnormal vaginal bleeding after post-evacuation, abortion, term pregnancy or ectopic pregnancy, after post-evacuation, abortion, term pregnancy or ectopic pregnancy, ◆ Metastatic symptoms GTT should be considered

28. Gestational Trophoblastic Neoplasia HCG assay HCG assay Most important and sometimes only diagnostic evidence Most important and sometimes only diagnostic evidence Diagnostic criteria for post- HM GTN (FIGO2000) Diagnostic criteria for post- HM GTN (FIGO2000) hCG plateau for >4 values （ ±10 ％）， over 3 weeks hCG plateau for >4 values （ ±10 ％）， over 3 weeks hCG increase of ≥10% over 2 weeks hCG increase of ≥10% over 2 weeks hCG persistence after evacuation of mole for 6 months hCG persistence after evacuation of mole for 6 months Diagnostic criteria for non post-HM GTN HCG elevated at 4w after abortion, term or ectopic pregnancy Re-rising HCG titer after reaching normal levels

29. Gestational Trophoblastic Neoplasia Chest X-ray Chest X-ray lung metastases lung metastases CT CT small lung metastases and brain metastases small lung metastases and brain metastases MRI MRI Liver and brain metastases Liver and brain metastases Ultrasound Ultrasound primary lesions of uterus and pevical metastases primary lesions of uterus and pevical metastases Imaging supports diagnosis, but not necessary

30. Gestational Trophoblastic Neoplasia Histological diagnosis Histological diagnosis villus shape can be found in primary or metastatical lesions villus shape can be found in primary or metastatical lesions Presence of villus shape Invasive mole Presence of villus shape Invasive mole Absence of villus shape Choriocarcinoma Absence of villus shape Choriocarcinoma Histology is not necessary Histology is not necessary for diagnosis of GTN

31. Anatomy staging of GTN (FIGO, 2000) StageI Localized to the uterus StageII Lesion diffused, but Localized to the genitalia (accessory,vagina,broad ligament) StageIII Lung metastasis, with or without genitalia change Stage Ⅳ Other metastasis Gestational Trophoblastic Neoplasia Stage I Stage II Stage III Stage IV

32. Prognostic scoring system for GTT (FIGO,2000) score0124 Age(y) ＜ 40 ≥40-- Antecedentmoleabortionterm- Interval (mo) ＜4＜4＜4＜4 4～64～64～64～6 7 ～ 12 ≥13 Pretreatment b-hCG (mIU/ml) ＜ 10 ３ 10 ３ ～ 10 ４ ＞ 10 ４ ～ 10 ５ ＞ 10 ５ Largest tumor (cm) － 3 ～ 4 cm ≥5cm- Site of metastases Lung Spleen, Kidney Gastrointesti nal Liver, brain Number of metastases － 1～41～41～41～4 5～85～85～85～8 ＞8＞8＞8＞8 Prior chemotherapy failed －－single ＞2＞2＞2＞2 * Total score≤6 low risk, ≥7 high risk

33. Gestational Trophoblastic Neoplasia Treatment Chemotherapy combining surgery, radiotherapy and other treatment Chemotherapy combining surgery, radiotherapy and other treatment Base on the assessment and stage, therapy stratified Base on the assessment and stage, therapy stratified Chemotherapy : Single-agent chemotherapy is applied in low-risk gestational trophoblastic disease (MTX, Act-D, 5-Fu) Single-agent chemotherapy is applied in low-risk gestational trophoblastic disease (MTX, Act-D, 5-Fu) High-risk patients commonly use combined chemotherapy (EMA-CO) High-risk patients commonly use combined chemotherapy (EMA-CO)

34. Single agent chemotherapy DAY Therapy Interval 1-5 MTX 0.4mg/kg im qd 14d 1 、 3 、 5 、 7 MTX1mg/kg im 14d 2 、 4 、 6 、 8 FA 0.1mg/kg im or po 1-5 Act-D10-12ug/kg ivgtt qd 14d 1-8 5-Fu 28-30mg/kg ivgtt qd 12 － 14d

35. Combined chemotherapy Drugs Dose,pathway,periods Interval 5-Fu+KSM 3weeks 3weeks 5-Fu 26-28mg/kg·d ， ivgtt for 8days KSM 6  g/kg·d ， ivgtt for 8days

36. Combined chemotherapy EMA-CO Interval 2weeks the first part EMA the first part EMA 1 st day VP16 100mg/m 2 ivgtt Act-D 0.5mg ivgtt Act-D 0.5mg ivgtt MTX 100 mg/m 2 ivgtt MTX 100 mg/m 2 ivgtt MTX 200mg/m 2 ivgtt for 12hours MTX 200mg/m 2 ivgtt for 12hours 2 nd day VP16 100mg/m 2 ， ivgtt Act-D 0.5mg ivgtt Act-D 0.5mg ivgtt CF15mg ， im CF15mg ， im （ after 24hours from the use of MTX ， once every 12hours ， twice ） （ after 24hours from the use of MTX ， once every 12hours ， twice ） 3 rd CF15mg ， im ， once every 12hours ， twice 。 4 th to 7 th rest （ no drug ） the second part CO the second part CO 8 th day VCR1.0mg/m 2 ， ivgtt CTX600mg/m 2 ， ivgtt CTX600mg/m 2 ， ivgtt

37. PSTT A special type, more rarely in clinic A special type, more rarely in clinic Most of them have a good prognosis Most of them have a good prognosis Form the intermediate trophoblast cells Form the intermediate trophoblast cells Clinical manifestations Clinical manifestations  More common occur at reproductive period women  More common occur following term or ectopic pregnancy  Abnormal bleeding after amenorrhea

38. PSTT Diagnosis Diagnosis HCG was negative HCG was negative HPL mildly elevated Confirmed by histology HPL mildly elevated Confirmed by histology Treatment Treatment Surgery is the preferred treatment Surgery is the preferred treatment Chemotherapy is adjuvant therapy Chemotherapy is adjuvant therapy

39. Thank you ! Thank you !