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

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

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

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

Hydatidiform mole

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

Partial moles Complete moles

Hydatidiform mole Related Factors Complete moles Area common in Latin America, Asia uncommon in North America and Europe Race differences of the same race in different regions Nutrition and Economy lack of Vit A Age < 20 or >35 years The fertilization of an empty egg the fertilization of an empty egg by a haploid sperm Diploid genome 90% of the time (usually 46,XX) Genomic imprinting disorder

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

Comparison of complete and partial hydatidiform moles Karyotype 46, XX(90%) 46, XY(10%) Triploid (69XXY, 69XXX) Embryo Absent Present Villi Hydropic Few hydropic Trophoblasts Diffuse hyperplasia Mild focal hyperplasia Villus outline regular irregular Blood vessel absence presence

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

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

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

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

a “snowstorm” pattern

Hydatidiform mole 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

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

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

Gestational Trophoblastic Neoplasia

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

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

Invasive mole Choriocarcinoma Invasive mole Choriocarcinoma Invasive mole Choriocarcinoma

invades the myometrium Lung metastases Brain metastases cervical metastases

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

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

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

Gestational Trophoblastic Neoplasia HCG assay Most important and sometimes only diagnostic evidence Diagnostic criteria for post- HM GTN (FIGO2000) hCG plateau for >4 values （±10％）， over 3 weeks hCG increase of ≥10% over 2 weeks 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

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

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

Anatomy staging of GTN (FIGO, 2000) Gestational Trophoblastic Neoplasia 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 StageⅣ Other metastasis Stage III Stage I Stage II Stage IV

Prognostic scoring system for GTT (FIGO,2000) score 1 2 4 Age(y) ＜40 ≥40 - Antecedent mole abortion term Interval (mo) ＜4 4～6 7～12 ≥13 Pretreatment b-hCG (mIU/ml) ＜10３ 10３～10４ ＞ 10４～10５ ＞ 10５ Largest tumor (cm) － 3～4 cm ≥5cm Site of metastases Lung Spleen, Kidney Gastrointestinal Liver, brain Number of metastases 1～4 5～8 ＞8 Prior chemotherapy failed single ＞2 * Total score≤6 low risk, ≥7 high risk

Gestational Trophoblastic Neoplasia Treatment Chemotherapy combining surgery, radiotherapy and other treatment 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) High-risk patients commonly use combined chemotherapy (EMA-CO)

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

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

Combined chemotherapy EMA-CO Interval 2weeks the first part EMA 1st day VP16 100mg/m2 ivgtt Act-D 0.5mg ivgtt MTX 100 mg/m2 ivgtt MTX 200mg/m2 ivgtt for 12hours 2nd day VP16 100mg/m2，ivgtt Act-D 0.5mg ivgtt CF15mg，im （after 24hours from the use of MTX， once every 12hours，twice） 3rd CF15mg，im，once every 12hours，twice。 4th to 7th rest（no drug） the second part CO 8th day VCR1.0mg/m2， ivgtt CTX600mg/m2， ivgtt

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

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

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