GESTATIONAL TROPHOBLASTIC DISEASES Prof. M.C.Bansal MBBS,MS,MICOG,FICOG Professor OBGY Ex-Principal & Controller Jhalawar Medical College & Hospital Mahatma Gandhi Medical College, Jaipur.
HYDATIDIFORM MOLE• Epidemiology: ▫ Incidence of GTD vary dramatically in different regions of the world- incidence in Japan (2 per 1000 pregnancies) is about 3 times higher than in Europe or North America(0.6 to 1.1 per 1000 pregnancies) ▫ Incidence of partial mole (about 1 per 695 pregnancies) is 3 times higher than complete mole (about 1 per 1945 pregnancies)• Risk factors of complete molar pregnancy: ▫ Low dietary intake of carotene ▫ Vitamin A deficiency ▫ Higher maternal age(35 yrs)• Risk factor for partial mole: ▫ It has been associated with use of OCPs and history of irregular menstruation. ▫ Not associated with dietary factors or maternal age
Types: (on the basis of gross morphology, histopathology and karyotype) • Complete mole • Partial mole Features Complete Mole Partial MoleFetal or embryonic tissue Absent PresentHydatidiform swelling of Diffuse Focalchorionic villiTrophoblastic hyperplasia Diffuse FocalScalloping of chorionic villi Absent PresentTrophoblastic stromal inclusions Abse nt PresentKaryotype 46XX (90%); 46 XY Triploid
COMPLETE H. MOLE• Complete H. Moles exhibit characterstic swelling and trophoblastic hyperplasia.• Karyotype: 46XX (90% cases); 46XY(10%)• Molar chromosomes- entirely paternal in origin, although mitochondrial DNA is maternal. Complete moles arise from an ovum that has been fertilized by a haploid sperm, which then duplicates its own chromosomes. Ovum nucleus may be either absent or inactivated.
PARTIAL H. Mole• Characterized by:1. Chorionic villi of varying size with focal hydatidiform swelling, cavitation and trophoblastic hyperplasia.2. Marked villous scalloping3. Prominent stromal trophoblastic inclusions4. Identifiable fetal or embryonic tissues.• Karyotype: triploid, the extra haploid set is derived from father.• When a fetus is present with partial mole, it generally exhibits stigmata of triploidy: growth retardation, multiple congenital malformations- syndactyly, hydrocephaly
Clinical features of complete mole:A. Vaginal Bleeding: most common symptom (84% patients)- may cause anaemia.B. Excessive uterine size relative to gestational age: one of the classic symptoms (28% patients). Endometrial cavity may be expanded by both chorionic tissue and retained blood. Is generally asociated with markedly elevated hCG levels.C. Preeclampsia: develops almost exclusively in patients with excessive uterine size and markedly elevated hCG levels.D. Hyperemesis gravidarum: 8% patients, particularly those with excessive uterine size and markedly elevated hCG levels
E. Hyperthyroidism: rare these days. Anaesthesia or surgery may precipitate thyroid storm.• if hyperthyroidism is suspected, beta-adrenergic blocking agents shud be given before induction of anaesthesia for molar evacuation.• Hyperthyroidism develops almost exclusively in patients with very high hCG levels as hCG is thyroid stimulator in women with GTD.F. Respiratory distress due to trophoblastic embolization: occurs rarely these days.G. Theca leutin ovarian cysts: prominent cysts(>=6cm diameter) develop in about half of patients with complete mole.• Result from ovarian hyperstimulation by high serum hCG levels.• Regress spontaneously 2-4 mths after molar evacuation.
Clinical features of Partial H. Mole:• Have signs and symptoms of incomplete of missed abortion. Diagnosis is made after histological review of tissue obtained by curettage.• Vaginal bleeding is main symptom.• Excessive uterine enlargement and pre eclampsia occur rarely.
NATURAL HISTORY:A. COMPLETE MOLE: after molar evacuation: Local uterine invasion(15%) Metastasis(4%) High risk factors for postmolar tumor: hCG levels> 100,000 mIU/ml Excessive uterine enlargement Theca leutin cysts 6cm in diameter Older patients are also at increased risk.B. PARTIAL H.MOLE: persistent tumor usually non- metastatic develops in 2-4% cases. Chemotherapy is required to achieve remission.
DIAGNOSIS: USG-• sensitive and reliable method for complete mole- characteristic vesicular pattern even in 1st trimester.• In partial molar pregnancy-focal cystic spaces in placental tissues and increase in transverse diameter of gestational sac is seen.
Treatment:• Pt should be evaluated carefully for presence of associated medical complications.• Most appropriate method of evacuation:1. Hysterectomy: if patient desires surgical sterilization- hysterectomy with mole in situ. Ovaries may be preserved even in the presence of prominent theca leutin cysts.hysterectomy doesn’t prevent metastasis, so patients still require followup assessment of hCG levels.2. Suction curettage: preferred method of evacuation regardless of uterine size, for patients who desire fertility. Steps: oxytocin infusion started before induction of anaesthesia.2. cervical dilatation. 3. suction curettage. 4. blunt curettage.• Trophoblastic cells express RhD factor, Rh neg patients should receive Rh immunoglobulin at the time of evacuation.
Prophylactic chemotherapy:• Prevents metastasis and local uterine invasion.• It is particularly useful in management of high risk complete molar pregnancy, esp. when hCG assessments for follow-up are unavailable or unreliable
Follow-up:1. hCG: weekly -hCG levels until normal for 3 consecutive weeks, followed by monthly estimations until normal for 6 consecutive months.2. Contraception: patients are encouraged to use effective contraception during entire hCG follow up interval. IUCDs ar not used until patient achieves normal hCG levels because of potential risk of perforation. OCPs or barrier methods are used if patient doesn’t desire surgical sterilization.
PERSISTENT GESTATIONAL TROPHOBLASTIC TUMORA. NONMETASTATIC DISEASE: locally invasive GTT develops in about 15% patients after evacuation of complete mole and infrequently after other gestations. Symptoms:1. Irregular vaginal bleeding2. Theca leutin cysts3. Uterine subinvolution or assymetric enlargement4. Persistently elevated serum hCG levels.After molar evacuation, persistent GTT may exhibit the histological features of either H. Mole or choriocarcinoma.After a non molar pregnancy, persistent GTT always has the histological pattern of choriocarcinoma
B. PLACENTAL SITE TROPHOBLATIC TUMOR:• Placental-site trophoblastic tumor is an uncommon but important variant of choriocarcinoma that consists predominently of intermediate trophoblas. Relative to their masses, these produce small amout of hCG and hPL.• They tend to remain confined to uterus, metastasizing late in their course.• These are relatively insensitive to chemotherapy.
C. METASTATIC DISEASE:• Metastatic GTT occurs in 4% patients after evacuation of complete mole, but it is seen more often when GTT develops after nonmolar pregnancies.• It has tendency towards early vascular invasion and widespread dissemination.• Most common sites are:• PULMONARY(80%)- alveolar or snowstorm appearence, discrete rounded opacities’canon- appearence’, pleural effusion, embolic pattern. respiratory symptoms and sonographic findings may be dramatic, can be confused with primary pulmonary disease.
Contn..• VAGINAL(30%): suburethral, highly vascular and may bleed vigorously when biopsied.• HEPATIC(10%): painful enlargement, intraperitoneal hemorrhage may occur.• CNS(10%): may develop focal neurological deficits.
Staging (FIGO)• Staging 1-persistently elevated hCG& tumorconfined to uterine carpus• Stage2- metastesis to vagina,pelvis or both• Stage3-Pulmonary metastesis with or without uterine,vaginal,pelvic involment• Stage4-advanced desease and Brain,kidneys GIT, liver involment
Prognostic Scoring system (WHO)• Predicts potential for resistance to chemotherapy.• When score is >7- high risk case- requires intensive chemotherapy for remission.• Stage1 disease have low risk score while stage 4 disease have high risk score.
DIAGNOSTIC EVALUATION:• Patients with persistent GTT should be carefully evaluated before starting treatment:1. Complete history and physical examination2. Measurement of serum hCG value3. Hepatic, renal and thyroid function tests4. Determination of baseline TLC and platelet counts.
Metastatic workup:• Includes:• Xray chest and CT scan• USG and CT scan abdomen and pelvis• CT or MRI scan of head• hCG levels can be measured in CSF to exclude cerebral involvement if CT brain is normal.• Ratio of plasma to CSF hCG has to be lower than 60 in presence of cerebral metastasis.• Pelvic USG- useful in detecting extensive trophoblastic uterine involvement and may also add in identifying sites of resistent uterine tumors.
Management contn..• Stage-1: If pt does not wish to preserve fertility ,• Hysterectomy with Adjuvant single agent chemotherapy------• 1. To reduce dissamination of tumor cells• 2.To mantain cytotoxic levelof drug inblood circulation---to kill circulating cancer cells• 3.To treat occult metastesis if any present.Hysterectomy can also be done in all pts with stage1 placental site Trophpblastic tumorSngle drugChemotherapy alone is recomonded to stage1 pt who wants to presrve fertility.in resistant cases ,combination therapy should be administated.
Management of stageII and III• Low risk patients with vaginal and pelvic metastasis respond well(80%) to single agent therapy but high risk cases are are treated with primary intensive combination chemotherapy, bleeding from vaginal metastasis may be controleed by packing or wide local excision.• Pt with pulmonary metastis—Primary intensive combine chemotherapy.• To control genital bleeding and sepsis---- Hysterectomymay be needed.
Follow up of stage1 2 3• It should be done by:-1. Weekly hCG measurement until they are normal for 3 consecutive weeks2. Monthly- for hCG measurement until they are normal for 12 consecutive months3. Effective contraception during the entire interval of hrmonal follow up.
Management of stage 4• Should be treated with intensive combination chemotherapy and and surgery.• Hepatic metastasis- hepatic artery infusion of chemothapy may induce complte remission in selected cases.• Cerebral metastasis: whole brain irradiation(3000cGy) in 10 fractions may be instituated promptly. Crainotomy may be required to provide acute decompression or to control bleeding.
Follow up of stage 41. Weekly determination of hCG levels until they are normal for 3 consecutive weeks2. Monthly determination of hCG until they are normal for 24 consecutive months.3. These patients require gonadotropin follow up because of high risk of recurrence.
CHEMOTHERAPY:• Single-agent treatment: with either Actinomycin D or MTX have achieved comparable and excellent remission rates in both non metastatic and low risk metastatic GTT. Mtx 5mg with folinic acid x 3-5 days orally for 5-6 weeks is safe and effective. ▫ serum hCG level is measured weekly after each course of chemotherapy. ▫ After first treatment: 1. further chemotherapy is withheld as long as hCG level is falling progressively. 2. Additional single agent chemotherapy is not administered at any predetermined or fixed interval. ▫ Second course: If hCG level plateaus for more than 3 consecutive weeks or begins to raose again. If hCG level doesn’t decline by 1 log within 18 days after completion of first treatment. ▫ If response to first treatment is inadequate, dose of MTX is increased from 1mg/kg per day to 1.5mg /kg per day for eack of the 4 treatment days.
Combination Chemotherapy:• Triple therapy: with MTX, Act-D and cyclophosphamide is in• Duration of therapy: patients who require combination chemotherapy must be treated intensively to attain remission. It should be given as often as toxicity permits until patient achieves 3 consecutive normal hCG levels. After normal hCG levels are attained , atleast 2 additional courses of chemotherapy• adequate as an initial treatment in patients with metastasis and a high-risk prognostic score.• are administered to reduce the risk of relapse.
Subsequent pregnancies:A. Pregnancies after H. Mole: increased risk of having a molar gestation in subsequent conceptions. Risk: 1% 1. Pelvic USG during 1st trimester to confirm normal gestational development 2. hCG measurement 6 weeks after completion of pregnancy to exclude trophoblastic neoplasia.B. Pregnancies after persistent GTT: patients who are treated successfully with chemotherapy can expect normal reproduction in future. The frequency of congenital malformations is also not increased.