Gestational trophoblastic disease

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Definition Gestational Trophoblastic Disease is spectrum of proliferative abnormalities of trophoblasts associated with pregnancy. It covers both benign & malignant conditions like H ydatidiform mole, Invasive mole, Placental site trophoblastic tumour & Choriocarcinoma.


Classification Histological Hydatidiform mole Complete Partial Invasive mole Choriocarcinoma. Placental site trophoblastic tumour (PSTT).

Modified WHO Classification(1998):

Modified WHO Classification(1998) 1 Benign GTD Hydatidiform mole Complete Partial 2 Non-metastatic malignant GTD. Persistent GTD Invasive mole, Local choriocarcinoma. 3 Metastatic malignant GTD

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Metastatic Disease Low Risk (Good Prognosis) High Risk (Poor Prognosis) Disease present of < 4 mts duration. Disease present of > 4 mts duration. Initial serum HcG < 40,000 mIu/ml Initial serum HcG > 40,000 mIu/ml. Metastasis limited to lung & vagina Brain or liver metastasis. No prior chemotherapy Failure of prior chemotherapy No preceding term delivery Following term pregnancy. WHO score ≥ 8



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Definition - abnormal condition of placenta with partly degenerative & partly proliferative changes in young chorionic villi. They are cluster of small cysts of varying size, superficial resemblance to hydatid cyst so named as hydatidiform mole.

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Incidence - Wide range in geographical & ethic variation of prevalence. Common in oriental countries. Highest in Philippines 1:80 Lowest in European countries 1: 750 India 1:400

Etiology :

Etiology Geographical distribution Racial factors Age -Early teenage pregnancies < 15yrs or -In pregnancies of > 35yrs. Nutritional factors- low socio-economic status, carotene & animal fat soluble vitamin deficiency. Disturbed maternal immune mechanism  ↑ in γ globulin level in absence of hepatic disease ↑ ed association with AB blood group which possesses no ABO antibody.

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h/o previous H.mole– recurrence chance 1-4% High parity, malnourished & Debilitated diseases like TB. Cytogenic Abnormality.


Pathology Mass of large edematous villi typically described as resembling a cluster of grapes. No trace of embryo or amniotic sac.


Histopathology Marked proliferation of syncitial & cytotrophoblastic epithelium. Marked thinning of stromal tissue due to hydropic degeneration. Absence of blood vessels in villi which seems primary rather than due to pressure atrophy.

Ovarian changes:

Ovarian changes b/l lutein cyst in about 50% cases. Regress spontaneously within 2 months after expulsion of mole. Fluid is rich in Chorionic gonadotrophin. Also in estrogen & progesterone.

Clinical features:

Clinical features Symptoms  Vaginal bleeding (90%)- blood mixed with gelatinous fluid from ruptured cysts– white current in red current juice. Lower abdominal pain (70%)  overstretching of uterus, concealed hemorrhage, rarely perforation of uterus by invasive mole, infection or uterine contractions to expel out contents.

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Constitutional symptoms- Pt is sick without any apparent reason. Hyperemesis gravidarum ( 15%) Breathlessness. Thyrotoxic features. Expulsion of grapes like vesicles per vaginum.

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Signs  Features of early months of pregnancy. Pallor P/A- Uterine size > period of gestation (70%) - Corresponding (20%) - Smaller (10%) Feel doughy. Fetal parts/movements not felt. Absence of FHS

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P/V- Internal ballotment cannot be elicited. Both ovaries palpable (25-50%) Theca lutein cyst Vesicles in vaginal discharge. Features of – Pre- Eclampsia , Hyperthyroidism, Respiratory insufficiency.

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Investigations Routine blood investigations Liver function tests Renal function tests Thyroid function tests. USG  molar pregnancy shows snow storm appearance Helpful in pre-evacuation diagnosis. Definitive diagnosis by HPR only.(D)

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Quantative estimation of Chorionic Gonadotrophin. Serum β hCG > 1,00,000 mIu/ml Plain X-Ray abdomen  negative fetal shadow. Chest X-ray  to R/O pulmonary embolism. CT & MRI  to detect metastasis. Dilution Normal Molar Pregnancy Multiple Pregnancy 1:100 + + + 1:200 - + + 1:300 - + -


DIFFERENTIAL DIAGNOSIS Threatened abortion Fibroid uterus with pregnancy. Ovarian tumour with pregnancy Multiple pregnancy.


MANAGEMENT Principles in management Suction evacuation of uterus (safe upto 28 wks of gestation)Evidence level 4 Supportive therapy – correction of anemia, infection if any. Counseling for regular follow-up.


SUCTION EVACUATION Negative pressure upto 200-250 mmHg under Sedation/Short GA. Alternately dilatation & evacuation. Digital exploration & removal of mole with ovum forceps under Short GA. After completing evacuation  Inj Methergin 0.2 mg IM. Prolonged cervical preparation with prostaglandins avoided to reduce risk of embolisation of trophoblastic cells (evidence level 4).

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Oxytocin helps in evacuation & reduces blood loss, its routine use not recommended due to risk of embolism.(Evidence level 3) HPR should be done for material obtained from medical or surgical management of failed pregnancies, to exclude trophoblastic neoplasia (D).

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Complications of suction evacuation. Injury to uterus  perforation, infection. Hemorrhage. Shock Acute pulmonary insufficiency. Thyroid storm.

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Hysterectomy (↓ risk of GTN by 5%) Indicated in  Patient with age > 35 yrs Completed family irrespective of age. Uncontrolled hemorrhage/perforation during suction evacuation.

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Hysterotomy Rarely done. Indicated in Profuse vaginal bleeding. Cervix unfavorable for immediate vaginal evacuation. Accidental perforation of uterus during evacuation.

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Theca Lutein Cyst Regress following removal of mole. Complications Pain & Pressure symptoms  USG guided or Laproscopic percutaneous aspiration. Torsion, Infarction or Hemorrhage  Laproscopic /Open Cystectomy . Risk of post molar GTN is high.

Follow Up:

Follow Up Objective  to diagnose persistent trophoblastic disease that is considered malignant If hCG revert to normal within 56 days of pregnancy event  follow up will be for 6 months from date of uterine evacuation.(D) If not within 56 days of pregnancy then follow up will be for 6 months from normalisation of hCG level.(D) Woman with chemotherapy should follow up for 1 year after hCG has been normal.

Follow up protocol:

Follow up protocol History Physical examination hCG assay Chest X-ray

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History h/o irregular P/V bleeding. Hemoptysis Breathlessness CNS disturbance like headache, blurring of vision, neurological deficit. Epigastric pain, hematuria , jaundice

Physical examination :

Physical examination General examination P/A  Sub-involution of uterus, Palpation of mass Tenderness Hepatomegaly P/S  Vaginal metastasis P/V  Sub-involution of uterus, regression of theca lutein cyst

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Quantative serial β hCG level. Chest X-ray If pre- evacuation shows metastasis  Repeat at 4 wk interval until remission confirmed  then 3 mt interval during rest of follow-up. If pre-evacuation chest x-ray normal  repeated only when hCG titre plateaus or rises.


PROPHYLACTIC CHEMOTHERPHY Prevent metastasis & reduce morbidity. 80% pts  spontaneous regression. Sensitive β hCG assay can identify rest that develop malignancy. Chemotherapy is toxic  ↑ chance of premature ovarian failure & menopause.

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Advised in hCG level fails to become normal by stipulated time (10-12 wk) or re-elevation at 4-8 wk. Rising β hCG level after reaching normal level. Post evacuation hemorrhage. Follow up facilities not adequate. Evidence of metastasis, irrespective of β hCG level. When malignant sequelae is higher.

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Single drug regimen Course is to be repeated at interval of 7 days. Alternatively IV Actinomycin -D 12 μ gm/kg x 5 days. Methotrexate 1-1.5mg/kg IM/IV Day 1,3,5,7 Folinic Acid 0.1-0.15 mg/kg IM Day 2,4,6,8

Contraception after molar evacuation:

Contraception after molar evacuation Advised not to conceive until their follow up is complete (D) For minimum of 6 months & preferably for 12months. Methods  Hormonal - combined OC pills, Depot medroxy progesterone. Barrier – ideal but with high failure rates. Safe to advice to use barrier method till β hCG becomes negative & then OC pills.(D) Surgical sterilization if family is completed.

Pregnancy after H.Mole:

Pregnancy after H.Mole Risk of recurrence 1-2% in 2 nd pregnancy 25% in 3 rd pregnancy Current recommendation 1 st trimester  Pelvic USG  confirm intra-uterine normal gestation. Chest X-ray  to find occult metastasis masked by hCG titre rise of pregnancy. HPE  of placenta & products of conception done after delivery for occult trophoblastic disease. hCG titre after 6 wks of delivery to exclude occult trophoblastic disease.


RH ISSOIMMUNISATION If <12 wks gestation  50 μ gm Anti-D If >12 wks gestation  300 μ gm. In complete mole poor vascularisation of chorionic villi & absence of anti-D antigen so Anti –D prophylaxis not required. BUT required in partial mole.(D)

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Hormonal replacement therapy may be used once hCG levels have returned to normal.(Evidence level 4)


PARTIAL OR INCOMPLETE MOLE Affection of Chorionic Villi is focal. Fetus/Amniotic sac is present. Karyotype triploid is either 69XXY, 69XYY with 1 maternal but usually 2 paternal haploid chrosomes.

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Microscopy Dilated chorionic villi. Predominant hyperplasia of Syncytotrophoblast. Presence of fetal blood vessels with fetal red blood cells.

Clinical features:

Clinical features Same as H.Mole hCG is not markedly raised. Uterus is generally not large for dates. Malignant potential is low.

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USG Gestational sac must be present  empty, amorphous echoes. Increase in transverse to Antero-posterior diameter of gestational sac > 3:2 (90% positive predictive value). If fetus present, it is often growth retarded. Placenta is excessively large, relative to size of uterine cavity & contain focal cystic spaces.

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Management If fetus is not alive  termination of pregnancy. If fetus is alive  woman counseled about ↑ ed risk of perinatal morbidity & outcome of GTN. Terminate the pregnancy.(D)

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Twin pregnancy of Fetus & co-existent molar pregnancy. Prenatal invasive testing for fetal karyotyping. If it is unclear  Pregnancy is complete mole with normal twin or partial mole. Abnormal placenta (mesenchymal hyperplasia of placenta). (Evidence level 3)

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Williams Obstetrics 22 nd ed.

Placental Site Trophoblastic Tumour (PSTT):

Placental Site Trophoblastic Tumour (PSTT) Rare Histological Diagnosis  syncytotrophoblastic cells are generally absent  persistent low level of serum or urinary HcG. Tumor  from intermediate trophoblasts of placental bed composed mainly of cytotrophoblastic cells.

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C/ F  Vaginal bleeding. Local invasion of Myometrium & Lymphatics. PSTT is not responsive to chemotherapy. Rx  Hysterectomy.

Persistent Gestational Trophoblastic Disease:

Persistent Gestational Trophoblastic Disease Definition  it is the persistence of trophoblastic activity as evidenced by clinical, imaging, pathological &/or hormonal study following initial treatment. Post Molar GTD  Benign. Malignant. Post Molar GTD after non-molar pregnancy is always choriocarcinoma. After complete H.mole -chances of GTD – 15-20%

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Incidence 50% following H.Mole 25% following abortion or ectopic pregnancy. 25% following normal delivery.


DIAGNOSIS During post-evacuation follow-up period  Continued vaginal bleeding. Persistent Theca Lutein Cysts. Persistent soft & enlarged uterus. hCG titer either fail to become negative or plateau or re-elevation after initial fall by 8 wk post molar evacuation. Local, systemic metastasis ruled out by x-ray chest, CT, MRI of brain, Liver etc.

FIGO Anatomic Staging of GTT :

FIGO Anatomic Staging of GTT

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All stages subdivided as No risk factors One risk factor Two risk factors Risks hCG > 1,00,000 mIu/ml Duration of disease > 6 mts from termination of antecedent pregnancy.

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WHO prognostic scoring system of GTT as modified by FIGO (2000) Score Characteristic 0 1 2 4 Age <40 ≥40 - - Antecedent preg Mole Abortion Term - Interval from index pregnancy <4 months 4-6 months 7-12 months >12 months Pretreatment HcG <10 3 10 3 - 10 4 10 4 -10 5 >10 5 Largest tumor size (including uterus) < 3cm 3-4 cm ≥5cm - Site of metastases Lung Spleen, kidney GI tract Liver, brain Number of metastases - 1-4 5-8 >8 Previous failed chemotherapy - - Single drug ≥2 drugs


TREATMENT Patients are classified into high/low risk categories. Prognostic scoring system for GTT was modified by FIGO in 2000. Here Interval  time between antecedent pregnancy & start of chemotherapy. Total score < 6  low risk. ≥7  High risk.

MAC protocol in low risk cases:

MAC protocol in low risk cases Methotrexate Folinic Acid Actinomycin D Cyclophosphamide 1-1.5mg/kg 0.1-0.15mg/kg 12mcg/kg 3mg/kg IM/IV IM IV IV Day 1,3,5,7 Day 2,4,6,8 Day 1-5 Day 1-5

EMA-CO Protocol in poor prognosis metastatic disease:

EMA-CO Protocol in poor prognosis metastatic disease Day 1 Etoposide Actinomycin D Methotrexate 100 mg/m2 in 200ml saline infused over 30 min. 0.5mg IV bolus 100mg/m2 bolus followed by 200mg/m2 IV infusion over 12 hr. Day 2 Etoposide Actinomycin D Folinic Acid 100mg/m2 in 200ml saline infused over 30 min. 0.5 mg IV bolus. 15mg IM every 12 hrs x 4 doses beginning 24 hrs after starting Methotrexate . Day 8 Cyclophospamide Vincristine ( Oncovin ) 600mg/m2 IV in saline over 30 min. 1mg/m2 IV bolus. Course will restart in 7-14 days if possible. 2 additional course given after hCG level is normal.

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During Chemotherapy serum hCG level checked weekly. Chemotherapy should be changed if no fall in hCG titer by atleast 25% after treatment cycle. Place of Hysterectomy  Reduce trophoblastic tumour burden. Decrease no. of courses of chemotherapy. Total Hysterectomy Ovaries usually not involved. If involved- actively cured with post-op chemotherapy. Radiation Brain Metastasis  whole brain radiation therapy 3000cGy over 10 days. Liver Metastasis  whole liver radiation therapy 2000cGy over 10 days.

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Prognosis Low risk  almost 100% High risk  70%. Recurrence Non-metastatic GTN  2-3% Good prognosis metastatic disease  3-5% Poor prognosis disease  21%. Recurrence following 12 mts of normal hCG level  < 1%.

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