Gestational trophoblastic diseases(GTD) Dr. Bushra m majeed

It is a benign neoplasm of the chorionic villi

Incidence: 1:2000 pregnancies in United States and Europe 1:200 in Asia 10 times more in women over 45 years old. The increasing use of ultrasound in early pregnancy has probably led to the earlier diagnosis of molar pregnancy

1-Maternal age : Young mothers (under age 20 years) have a slightly higher prevalence of GTD, although not nearly so great as those mothers over age 35 years. 2-Women who have had a previous molar gestation. 3- Women with blood type A may be more likely to develop choriocarcinoma (but not hydatidiform mole); RISK FACTORS:

What Is A Hydatidiform Mole? A hydatidiform mole is an abnormality of fertilization It is the result of fertilisation of anucleated ovum ( has no chromosomes) with a sperm which will duplicate giving rise to 46 chromosomes of paternal origin only. It is the result of fertilisation of an ovum by 2 sperms so the chromosomal number is 69 chromosomes COMPLETE MOLE PARTIAL MOLE

Comparative Pathologic Features of Complete and Partial Hydatidiform Mole Feature Complete Mole Partial Mole Karyotype Usually diploid 46XX Usually triploidy 69XXX most common. Villi All villi hydropin; no normal adjacent villi Normal adjacent villi may be present vessels present they contain no fetal blood cells blood cells Fetal tissue None present Usually present Trophoblast Hyperplasia usually present to variable degrees Hyperplasia mild and focal

Three components make up the trophoblast: cytotrophoblast,syncytiotrophoblastintermediate trophoblast The cytotrophoblast is a stem cell with high mitotic activity but without hormonal synthesis. The syncytiotrophoblast, which constitutes the villous trophoblast, has low mitotic activity. The syncytiotrophoblast is responsible for the synthesis of the (beta-hCG) The intermediate trophoblast has features of the other two components and is responsible for endometrial invasion and implantation

There is trophoblastic proliferation, with mitotic activity affecting both syncytial and cytotrophoblastic layers. This causes excessive secretion of hCG,chorionic thyrotrophin and progesterone.. Pathology microscopic evaluation shows trophoblastic hyperplasia

( hydropic) villi The uterus is distended by thin walled, translucent, grape-like vesicles of different sizes. At histologic analysis, Uniformly edematous (hydropic) villi with dissolution of central stroma (cavitation/cistern Pathology

There is no vasculature in the chorionic villi leads to early death and absorption of the embryo. At histologic analysis Occasionally, necrosis is seen Pathology

High hCG causes: multiple theca lutein cysts in the ovaries in about 50% of cases. exaggeration of the normal early pregnancy symptoms and signs Pathology

1.Uniformly edematous (hydropic) villi with dissolution of central stroma (cavitation/cistern) 2.Villous vessels absent (usually) 3.Trophoblastic hyperplasia – circumferential, haphazard involves 4.Trophoblastic atypia Pathology

Symptoms and Signs Usually occur in first 20 ­ 24 weeks of gestation. Bleeding. pain. toxemia (25% ). hyperemesis (25%). absent fetus, LGA. hyperthyroidism (7%). passage of tissue with vesicles. bilateral thecalutein cysts (30%).

GTD MOST COMMON: complete hydatidiform mole, invasive mole, choriocarcinoma. Partial hydatidiform moles placental site trophoblastic tumor LESS COMMON:

U/S evaluation. Complete Hydatidiform Mole allows identification of numerous, discrete, anechoic (cystic) spaces within a central area of heterogeneous echotexture

Complete hydatidiform mole demonstrating enlarged villi of various size

Hydatidiform mole: specimen from suction curettage

A large amount of villi in the uterus.

The microscopic appearance of hydatidiform mole: Hyperplasia of trophobasitc cells Hydropic swelling of all villi Vessles are usually absent

Complete Hydatidiform Mole Theca lutein cysts multiloculated, often bilateral resolve after treatment of the intrauterine process Occasionally seen in twin gestations, fetal hydrops, pharmacologic stimulation (especially with human maternal gonadotropin) U/S evaluation.

the ultrasound diagnosis of a complete mole is often reliable, the diagnosis of a partial molar pregnancy is more complex. The finding of multiple cystic spaces in the placenta is suggestive of a partial molar pregnancy. * When there is diagnostic doubt about the possibility of a combined molar pregnancy with a viable fetus then ultrasound examination should be repeated before intervention. Partial Hydatidiform Mole. Ultrasound has limited value in detecting partial molar pregnancies. U/S evaluation.

Diagnosis of hydatidiform mole Quantitative beta-HCG Ultrasound is the criterion standard for identifying both complete and partial molar pregnancies. The classic image is of a “snowstorm” pattern

A sonographic findings of a molar pregnancy. The characteristic “snowstorm” pattern is evident.

Transvaginal sonogram demonstrating the “ snow storm” appearance.

Color Doppler image of a hydatidiform mole and surrounding vessels. The uterine artery is easily identified from its anatomical location.

The clues for the sonographer in this diagnosis are the presence of a fetus (although usually with severe, but nonspecific, abnormalities) in combination with a formed placenta containing numerous cystic spaces U/S evaluation. Partial Hydatidiform Mole

Partial hydartidiform mole

Microscopic image of partial molar pregnancy.

Here is a partial mole in a case of triploidy. Note the scattered grape-like masses with intervening normal- appearing placental tissue.

Large bilateral theca lutein cysts resembling ovarian germ cell tumors. With resolution of the human chorionic gonadotropin(HCG) stimulation, they return to normal-appearing ovaries.

Treatment Suction dilation and curettage :to remove benign hydatidiform moles When the diagnosis of hydatidiform mole is established, the molar pregnancy should be evacuated. An oxytocic agent should be infused intravenously after the start of evacuation and continued for several hours to enhance uterine contractility

Evacuation of Molar Pregnancies Suction curettage is the method of choice of evacuation for complete molar pregnancies.

Medical termination of complete molar pregnancies, including cervical preparation prior to suction evacuation should be avoided where possible. because of the potential to embolise and disseminate trophoblastic tissue through the venous system. Evacuation of Molar Pregnancies

oxytocic infusions are only commenced once evacuation has been started. If the significant haemorrhage prior to evacuation and some degree of control is required then use of these agents will be necessary according to the clinical condition. Evacuation of Molar Pregnancies

Therapy: dilatation and suction curettage (at which time the diagnosis is confirmed). 15% of women with complete hydatidiform mole will develop recurrent disease in the form of invasive mole or choriocarcinoma. all patients are followed up with successive serum beta-hCG measurements to allow early detection of persistent gestational trophoblastic neoplasia SO IF serial testing shows progressive decrease in the serum beta-hCG level The clinical diagnosis of complete hydatidiform mole is reached. Avoid pregnancy

Because persistent trophoblastic disease may develop after any pregnancy it is recommended that all products of conception obtained after repeat evacuation, performed because of persisting symptoms, should undergo histological examination. Evacuation of Molar Pregnancies

Removal of the uterus (hysterectomy) : used rarely to treat hydatidiform moles if future pregnancy is no longer desired. Treatment

 Treatment  Remove the intrauterine contents promply  Hysterectomy in the older reproductive group who have no interest in further childbearing  Management of luteinizing cyst

Chemotherapy with a single- agent drug Prophylactic (for prevention) chemotherapy at the time of or immediately following molar evacuation may be considered for the high-risk patients( to prevent spread of disease ) Treatment

 Preventive chemotherapy  Age more than 40  Level of serum HCG increased significantaly(more than 100KIU/L)  Titer of HCG has not returned to normal after 12 weeks postevacuation  Re-elevated HCG level  Uterus larger than expected  Diameter of luteinizing cyst more than 6cm  Trophoblast hyperproliferation still after second curettage  Has no condition to follow-up

 Follow-up  Pelvic examination, ultrasound examination  Assessment of HCG Serum quantitative HCG level every 1 week until normal  Every 1 week(three month)  Every 2 weeks(three month)  Every 1 month( half year)  Every half year(one year)  Contraception for 1-2 years

Choriocarcinoma  Hyper-malignant tumor  50% of patients follow molar pregnancy  25% of patients follow abortion  25% of patients follow term pregnancy  few of patient follow ectopic pregnancy

Gross specimen of choriocarcinoma

Microscopic image of choriocarcinoma absence of chorionic villi

Doppler image of choriocarcinoma

 Clinical presentation  Vaginal bleeding  Abdominal pain  Pelvic mass  Presentation of metastasis Lung, vagina, brain, liver et al

 Diagnosis  Clinical presentation If the symptom and sign follow abortion, term birth and ectopic pregnancy companing HCG level increased, the diagnosis can be considered  Assessment of HCG titer  Ultrasound and doppler examination  Histology

WHO Prognostic Scoring System Score Prognostic factor 0124 Age(years)≤39>39—— Pregnancy history Hydatidiform mole Abortion,ectopic Term pregnancy — Interval (months) of treatment < >12 Initial hCG(mIU/ml) < >10 5 Largest tumor(cm) <33-5>5— Sites of metastasis LungSpleen, kidney kidney GI tract, liver Brain No. of metastasis — Previous (treatment) —— Single drug 2 or more 0-4 low risk, 5-7 intermediate risk, >8 high risk for death

FIGO Staging System for Gestational Trophoblastic Tumors StageDescription Ⅰ Limited to uterine corpus Ⅱ Extends to the adnexae, outside the uterus, but limited to the genital structures Ⅲ Extends to the lungs with or without genital tract Ⅳ All other metastatic sites

IIb IIa

IIIa<3cm or locate in half lung IIIb disease beyond IIIa

Diagnosis and evaluation Gestational trophoblastic tumor is diagnosed by rising hCG following evacuation of a molar pregnancy or any pregnancy event Once the diagnosis established the further examinations should be done to determine the extent of disease ( X-ray, CT, MRI)

Treatment Nonmetastatic GTD Low-Risk Metastatic GTD High-Risk Metastatic GTD

Treatment of Nonmetastatic GTD Hysterectomy is advisable as initial treatment in patients with nonmetastatic GTD who no longer wish to preserve fertility This choice can reduce the number of course and shorter duration of chemotherapy. Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate any occult metastases and reduce tumor dissemination.

Single-agent chemotherapy is the treatment of choice for patients wishing to preserve their fertility. Methotrexate(MTX) and Actinomycin-D are generally chemotherapy agents Treatment is continued until three consecutive normal hCG levels have been obtained and two courses have been given after the first normal hCG level. Treatment of Nonmetastatic GTD To prevent relapse or metastasis

Single-agent chemotherapy with MTX or actinomycin- D is the treatment for patients in this category If resistance to sequential single-agent chemotherapy develops, combination chemotherapy would be taken Approximately 10-15% of patients treated with single- agent chemotherapy will require combination chemotherapy with or without surgery to achieve remission Treatment of Low-Risk Metastatic GTD

Multiagent chemotherapy with or without adjuvant radiotherapy or surgery should be the initial treatment for patients with high-risk metastatic GTD EMA-CO regimen formula is good choice for high-risk metastatic GTD Treatment of High-Risk Metastatic GTD

EMA-CO Chemotherapy for poor Prognostic Disease Etoposide(VP-16) 100mg/M 2 IV daily×2 days (over minutes) Methotrexate 100mg/M 2 IV losding dose, then 200mg/M2 over 12 hours day 1 Actinomycin D 0.5mg IV daily×2 days Folinic acid 15mg IM or p.o. q 12 hours×4 starting 24 hours after starting methotrexate Cyclophosphamide 600mg/M 2 IV on day8 Oncovin (vincristine) 1mg/M 2 IV on day8 (Repeat every 15 days as toxicity permits)

Prognosis Cure rates should approach 100% in nonmetastatic and low-risk metastatic GTD Intensive multimodality therapy has resulted in cure rates of 80-90% in patients with high-risk metastatic GTD

Follow-up After Successful Treatment Quantitative serum hCG levels should be obtained monthly for 6 months, every two months for remainder of the first year, every 3 months during the second year Contraception should be maintained for at least 1 year after the completion of chemotherapy. Condom is the choice.

 Treatment  Chemotherapy  Operation  Follow-up  Every 1 month first year  Every 3 months 2 years  Every 1 year 2 years  Then every 2 yeas ……