Gestational Trophoblastic Disease

YASHODHARA PRADEEPProf., OBGYN

QMH CSMMU LKO2014

• Classification of GTT• GTD Epidemiology, Pathogenesis, Aetiology, β hCG, • Clinical Features of Premalignant(GTD) Complete Mole(CM);

Partial Mole• Management of Complete Mole, or Partial Mole• Post evacuation Follow up , Chemotherapy• Contraception• Clinical Features of Malignant (GTN) Invasive Mole, Placental

site tropho blastic tumor( PSTT) Chorio CA • Investigations • GTN ChorioCA Diagnosis, Investigation, Management• Chemotherapy• Follow up

Introduction

• Gestational Trophoblastic disease is a term used to describe the heterogeneous group of interrelated lesions that arise from abnormal proliferation of placental trophoblast. GTD Lesions are histologically different and can be Benign and malignant.

WHO Classification

GTDPremalignant Diseases• Complete Hydatidiform Mole ( C M )• Partial Hyadatidiform Mole ( P M ) Malignant Diseases (Gestational Trophoblastic Neoplasia) Nonmetastatic• Invasive Mole• Placental site trophoblastic tumor ( PSTT )• Epitheloid tumour • Metastatic• Gestational Choriocarcinoma

Epidemiology• It is common in oriental countries- Philippines, China, Indonesia, Japan,

India, Central and Latin America and Africa.• Highest incidence- Philippines- 1 in 80 pregnancies• Lowest incidence- Europe- 1 in 752 pregnancies• India- 1 in 400 pregnancies• Calculated Incidence of complete mole- 1 in 1945 pregnancies partial mole- 1 in 695 pregnancies

• Age C Ms most common at the extremes of reproductive age• The incidence of CM rises fm I:1000 to 1:76; 1:6.5 in subsequent

pregnancies• CM is the most common antecedent to Chorio CA. But it can occur after

any type of pregnancy 3% after invasive mole; 16% after CM

Homozygous 85%

Pathogenesis of complete H Mole

Pathogenesis of complete H Mole

Heterozygous 15%

Pathogenesis of Partial H. Mole

Genetic & Pathology • C M Always contains Paternal DNA alone so androgenic Macroscopically

like bunch of grapes• P M are Triploidy two paternal & one maternal sets of chromosomes

hyperplasia of chorionic villi with embryo usually dies 8-9 weeks of gestation

• P57 cycline dependent kinase inhibitor paternally imprinted gene which is maternally expressed

• P57 kip2 immunostaining is negative in CM in contrast to PMs Hydropic abortions & normal placenta

• Invasive mole can be diagnosed by USG & rising titers of hCG• Presence of chorionic villi distinguish Invasive mole from

Choriocarcinoma• Chorio CA. Grossly abnormal karyotypes with diverse ploidies• PSTT are rare slow growing malignant tumor; intermediate trophoblast

from cytotrophoblast produce little hCG

Gestational Trophoblastic Disease

Aetiological factors

• Genetic factor: Autosomal recessive Genomic Imprinting; Abnormal Methylation

• In cases of Familial recurrent molar pregnancy; Defective locus at 19q 13.4 at single gene NALP7 , it is member of CATERPILLAR family involved in inflammation & Apoptosis in genetic CM

• Three other genes H19, P57, IGF-2• Chorio CA. heterozygosity at specific genes deletion 7p12-

q11.2; Amplification of 7q21-q31 region ; loss of 8p12-p21 • Breast & ovarian cancer also show the abnormalities in

heterozygosity in amplification at 7q21-q31 , & loss of 8p12-p21

Human chorionic gonadotrophin

• Beta hCG is pituitary/ placental glycoprotein• Commercially available Beta hCG test based on sandwich

assay principle & rely on two antibodies• Rare chance of false negative or false positive results with

Rabit polyclonal antibodies RIA used in both serially diluted urine & blood samples .

• Sensitivity of this test in serum is 1 IU/L, in urine 20 IU/L• Beta h CG is tumor marker• New Assay are in research Hyperglycosylated hCG (hCG-H )

specific for cases subsequently require chemotherapy (Clinical GTDs ) Cole etal 2006a

Beta h CG as Tumor marker

• Half life is 24-36 hrs• Marker for pregnancy ,GTD, Germ cell tumors & 15% of

epithelial ovarian malignancies• H CG levels are also associated with tumor volume 5 IU/l

corresponds to 104-105 viable tumor size• Beta hCG used as prognostic marker & progression of disease

or response to therapy, drug resistance at earlier stage.• hCG is best tumor marker known

Clinical features

Complete Mole• Most common in first trimester or early Second trimester• Vaginal bleeding is the most common symptom (84-97%)• Uterus is larger than POG (28%)• Presents with the features of threatened abortion; Amenorrhea, pain &

bleeding P/V• Associated features of Hyperemesis Gravidarum Requires Antiemetic , IV

fluids etc• Toxaemia or PET 10-15% • hyperthyroidism 7%

Clinical features

• Theca leutin cysts• Beta h CG levels > 100.000• O/E• Passage of grapes like vesicle or spontaneous expulsion of entire mole• Pulmonary , cervical, Vaginal metastasis may occur disappears after

evacuation of mole• The presence of metastasis does not necessarily imply invasive mole or

chorio CA• Macroscopic features: Bunch of grapes due to villous swelling• Branching contain hyperplastic cyto & syncytio trophoblast with many

vessels

Complete Molar Pregnancy

High Risk For Developing Post molar tumor

• Patients presenting with any of the following signs of marked trophoblastic proliferations

• hCG Levels > 100,000 mIU/L• Excessive Uterine Enlargement• Theca leutin cyst 6cm or larger

Clinical features

PARTIALMOLE• Findings not as characteristic as in CM• Most commonly presents in late Ist or second trimester• Uterus is often not enlarged more than POA• More often presents as Missed or incomplete abortion • Pre evacuation h CG levels are not more than 100,000IU/ L• Macoscopic : villous swelling is less intense • Embryo is present• Microscopic: Trophoblastic hyperplasia, indented outlines & round

inclusions• Presence of nucleated RBS of embryo in villous structure• Due to Early demise of embryo less documentation of PM

Management Of Molar Pregnancy

There are 2 important basic lines:1. Evacuation of the mole2. Regular follow up to detect persistent Trophoblastic

disease

If both basic lines are done appropriately, mortality rates can be reduced to zero.

Management of Molar Pregnancy

For complete mole: Suction CurettageProcedure:1. Emergency tray should be ready and blood

should be handy.2. Oxytocin infusion: begun before induction of

anaesthesia.3.Cervical dilation

Management

4. Suction curettage: Suction canula up to a maximum of 12 mm is usually sufficient to evacuate all complete molar pregnancies.

If the uterine size is larger than 14 weeks of gestation, one hand should be placed on top of fundus and uterus should be massaged to stimulate uterine contraction and reduce the risk of perforation.

5. Sharp curettage: gentle sharp curettage is done to remove any residual molar tissue.

Cervical preparation with prostaglandins or misoprostol should be avoided to reduce the risk of embolisation.

Should products of conception be examined histologically?

Histological examination is indicated in:• Failed pregnancies (missed or molar): all medically or

surgically managed cases• Products of conception obtained after all repeat

evacuations (post abortive or post partum).There is no need after therapeutic termination: provided

that foetal parts are identified on USGA urine pregnancy test should be performed 3 weeks after

medical management of failed pregnancy if products of conception are not sent for histological examination.

Anti-D Prophylaxis (RCOG)

NOT required in Complete Mole: because of poor vascularisation of the chorionic villi and absence of the D-antigen.

Required in: -partial mole: due to presence of RBCs -complete mole: if diagnosis is not confirmed

histopathologically.

Second uterine evacuation

• There is NO clinical indication for the routine use of second uterine evacuation.

• It may be useful for symptom control in selected patients with heavy bleeding or curative if the recurrent molar tissue is confined to the uterine cavity, particularly in those with hCG levels <1500 IU/L.(Recent Advances)

Post Evacuation Surveillance• Done to detect persistent trophoblastic disease (GTN)• A baseline serum βhCG is obtained within 48 hours after

evacuation• Levels are monitored every 2 weeks until normalisation

and urine βhCG levels analysed monthly after this.• These levels should progressively fall to an undetectable

level (<5 mu/ml).• The average time to achieve the first normal β-hCG level

after evacuation is about 9 weeks.• If symptoms are persistent, more frequent βhCG estimation

and USG examination ± second evacuation is advised.

Optimum follow up period following normalization of β hCG

If βhCG has reverted to normal in• ≤56 days (8 weeks) of the pregnancy event: follow up

is for 6 months from the date of uterine evacuation.• >56 days of the pregnancy event: follow up is for 6

months from normalisation of hCG level.All women should notify at the end of any future

pregnancy, whatever the outcome of the pregnancy. β hCG levels are measured 6-8 weeks after the end of pregnancy to exclude disease occurrence.

Contraception

• Should NOT conceive until follow up is complete.• Use Barrier method until hCG revert to normal (?

OCPs may act as growth factor for trophoblastic tissue).

• Once hCG has normalised, the combined oral contraceptive pill may be used.

• IUCD should not be used until hCG levels are normal to reduce the risk of uterine perforation.

Role of hysterectomy

• If the patient desires surgical sterilization, a hysterectomy may be performed with the mole in situ.

• Hysterectomy does not prevent metastasis; therefore, patients will require follow up with assessment of hCG levels.

• The ovaries may be preserved at the time of surgery, even in the presence of prominent theca luiten cysts.

Role of prophylactic chemotherapy

• The long term prognosis for women with a H. Mole is not improved with prophylactic chemotherapy. Because toxicity- including death- may be significant, it is not recommended routinely (ACOG 2004).

• It may be useful in the high-risk cases when follow up are unavailable or unreliable.

HIGH RISK FACTORS: hCG level >100,000 mIU/ml Excessive uterine enlargement Theca lutien cysts 6 cm in diameter

Chances of malignant transformation

• Complete H.Mole 16%

• Partial H.Mole 0.5%

Gestational trophoplastic NeoplasiaNonmetastatic

Invasive Mole:

Clinical features• Clinical diagnosis by persistence or rising titers of Beta h CG in the weeks

after molar evacuation & USG• Persistent bleeding p/v • Lower abdominal pain due to invasion in myometrium, vulva, vagina or intra

abdominal metastasis• It may spread to adjacent pervic structures bladder , rectum; hematuria,

bleeding P/ R• Pulmonary metastasis• Mostly due to initial diagnosis of CM is missed & not on Beta h CG follow up

Clinical features

Placental Site Trophoblastic Tumor (PSTT):

• it is rare slow growing tumor• Women mainly presents with menstrual irregularities & lower abdominal pain,

galactorrhea due to hyperprolactinemia increased h PL• Little or no h CG is produced ( Free B hCG fragment )• Rarely presents as nephrotic syndrome, hematuria or DIC• Spread is late local Infiltration & metastasis is through lymphatic• Microscopically: In the normal placenta it is distinct from villous trophoblast &

infiltrates the decidua, myometrium, & spiral arteries.• Mainly from intermediate trophoblast derived fm cytotrophoblast

Metastatic Gestational Trophoblastic Neoplasia

Second most common GTN 1 in 30,000 pregnancies Early haematogenous spread is characterstic of

choriocarcinoma 40% after molar pregnancy: Easily Diagnosed 60% non-molar pregnancy: Difficult to Diagnose

GTN arises when the normal regulatory mechanisms controlling the proliferation and invasiveness of trophoblastic tissue are lost.

Diagnosis of the GTN is made on Clinical presentation Elevated HCG Evidence of metastasis Imaging Tissue for Histology- Seldom obtained(Definitive Histological Diagnosis of type of GTN is not made in

most cases).

Metastatic Gestational Trophoblastic Neoplasia

Metastatic Gestational Trophoblastic Neoplasia

CHORIOCARCINOMA:

Clinical features• Occurs mainly following any form of pregnancy, mainly after CM• Difficult to differentiate from Invasive mole as H/P is not possible• Clinical features of bleeding p/v , lower abdominal pain, or in

1/3 of cases no pelvic symptoms but symptoms of distant metastasis lungs , brain ,liver, skin, cauda equina & the heart may present

• Highly malignant , appears as soft purple largely hemorrhagic mass

Clinical features of chorio CA

• Microscopic: implanting blastocyst with central cores of mononuclear cytotropho surrounded by rim of multinucleated syncytiotrophoblast & distinct absence of chorionic villi extensive areas of necrosis & haemorrage &frequent evidence of tumor in the sinuses

• The hypervascularity & absence of connective tissue support are the reason for its highly malignant behaviour

• DIAGNOSIS IS ALWAYS BY BETA h CG

investigations

• Quantitative beta hCG• X Ray Chest• Pelvic Doppler USG• Abdominal doppler USG to rule out liver & renal metastasis• CT chest , abdomen• MRI brain• Beta h CG in cerebrospinal fluid• PET • FD PET• Genetic studies

Which women should be investigated for Persistent GTD after a non molar pregnancy?

(RCOG Guideline)

• Any women who develops persistent vaginal bleeding after a pregnancy event.

• A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event.

• Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely.

FIGO REQUIREMENT FOR MAKING DIAGNOSIS OF GTN

1. Four values or more of plateaue hCG over at least 3 weeks: days 1, 7, 14 and 21.

2. A rise of hCG of 10% or greater for 3 values or more over at least 2 weeks: days 1, 7, and 14.

3. Histologic diagnosis of choriocarcinoma.4. Persistence of hCG beyond 6 months after

mole evacuation.

Invasive H. Mole

Myometrial invasion

Sometimes involving the peritoneum, parametrium, or vaginal vault. Originate almost always from H. mole

Vesicles

Metastatic disease

Sites: Symptoms:

a. Pulmonary- 80% Chest pain, dyspnoeab. Vagina- 30% Vagina bleeding , purulent

discharge and nodule.c. Liver- 10% Epigastric pain, jaundice, hepatic

rupture leading to intraperitoneal haemorrhage.

d. Brain- 10% Focal neurological deficit.

If the pelvic examination & chest X-ray are negative, it is very uncommon to have metastatic involvement of other sites.

Metastatic Disease

Chest X ray: widespread metastatic lesions.

GTN Vaginal Metastasis

Cranial MRI scan: Large metastasis on the left (black arrows)

Brain MRI of a patient with a solitary brain metastasis in remission

Autopsy specimen Multiple hemorrhagic hepatic metastasis

CT Scan: Liver metastsis

Prognostic score is central to the management of GTN.

A single universally accepted, anatomical staging and prognostic scoring system for GTN was developed by FIGO in 2000.

Management of GTN

ANATOMIC FIGO STAGING SYSTEM FOR GTN (2000)

Stage Criteria

I. Disease confined to the uterus

II. Disease outside of uterus but is limited to the genital structures

III. Disease extends to the lungs with or without known genital tract involvement

IV. All other metastatic sites

FIGO prognostic score (2000) O 1 2 4

Age (years) <39 >39

Antecedent pregnancy Hydatidi form mole

Abortion Term pregnancy

Interval from index pregnancy, months

< 4 4-6 7-12 > 12

Pretreatment hCG (mlU/ml)

< 103 103-104 > 104-105 > 105

Largest tumour size, including uterus

3-4 cm 5 cm

Site of metastases Spleen, kidney

GI tract Brain, liver

Previous failed chemotherapy

Single Two or more drugs

Low risk (Score 0-6) and high risk (score> 7)

WORK UP OF GTN

History & physical examinationSerial weekly hCG measurement in serum.Hemogram, LFT, KFT Chest X-ray USG whole abdomen pelvis to rule out hepatic and renal metastasis CT or MRI brain CSF analysis – in metastatic disease.PETFDG PETCurette to be done if there is uterine bleeding. There is grave dangerous of hemorrhage at the biopsy site.

GTN

FIGO scoring

Low risk (<6) High risk (> 6)

Single-agent chemotherapy

Combination chemotherapy

Serial hCG levelsResolution

Life-long hCG follow-up

Relapsed/resistant diseaseSecond-line chemotherapy+ surgical debulking

Low Risk GTN

FIGO score 6 or less. FIGO stage I, II & III. Drugs schedules: single agent chemotherapyMost commonly used regimen.Methotrexate: 1 mg/kg 1M on days 1, 3, 5, 7Folinic acid 0.1 mg/kg 1M on days, 2, 4, 6 and 8.Side Effects: Stomatitis, conjunctivitis, abdominal and

chest pain.Actinomycin- D: (primary therapy in case of abnormal

liver function)

Role of hysterectomy in non metastatic disease i.e. Stage-I

If patient does not wish to preserve fertility hysterectomy with adjuvant single agent chemotherapy given.

In case of stage-I PSTT. Role of adjuvant chemotherapy.

1. Decrease dissemination of viable tumor cells at surgery.2. Maintain cytotoxic level of chem.3. To treat any occult metastasis.

Follow up in Low risk GTN

Weekly hCG titre until normal for 3 consecutive weeks.

Monthly HCG level until normal for 12 consecutive months.

Effective contraception during the follow up (OCP) FIGO recommends additional 2 courses of

chemotherapy after initial negative hCG.

High Risk GTN

Stage I, II, III With FIGO score 7 or greater or Stage IV .

Primary intensive combination chemotherapy and selective use of radiation and surgery.

Regimes given : MAC. Modified Bagshawe (CHAMOCA) EMA-CO EMA-EP.

.

MAC-III Regime

Mtx 1 mg/kg IM/1V Days 1, 3, 5, 7

Folinic acid 0.1 mg/kg IM Days 2, 4, 6, 8

Actinomycin-D 12 g/kg IV Days 1-5

Cyclophosphamide 3 mg/kg IV Days 1-5

To be repeated every 15 days if toxicity permits.

EMA-CO RegimeEtoposide, methotrexate, actinomycin D, alternating weekly with cyclophosphamide and oncovin.Day 1 Actinomycin D 500 micrograms IV push new IV. Etoposide 100 mg/m2 over 30-50 min.

Methotrexate 100 mg/m2 IV infusion over 1 hr and then

Methotrexate 200 mg/m2 IV infusion over 12 hrs

Day 2 Actinomycin D 500 micrograms IV push new IV Etoposide 100 mg/m2 over 30-50 min.Folinic acid 15 mg IV push Q 6 hrs for 8 doses

beginning 24 hrs after methotrexate bolus. Day 8 Vincristine (Oncovin) 1 mg/m2 IV

Cyclophosphamide 600 mg/m2 IVSIDE EFFECT:- Myelosuppresion ,Mucositis , Neuropathy ,Reversible alopecia

EMA-EP

In patient resistant to EMA-COOn day 8 Etoposide- 10 mg/m2 iv. Cisplatin- 80 mg/m2 iv treatment – until 3 consecutive weekly titres

normal. 2-4 cycles given further after initial normal

H.C.G.

.

Chemotherapy Should Not Be Repeated Unless

WBC > 3000/cu mmPolymorph > 1500/ cu mmPlatelets > 100,000/ cu mmBUN, SGOT, SGPT are normal

No febrile course No oral or GIT ulceration

Follow up OF High risk GTN

Weekly HCG until normal for 3 consecutive weeks.

Monthly HCG for 24 consecutive months.

Contraception in follow up period.

Management of sites of metastasis

VAGINAL &PELVIS -30%Single agent chemotherapy –Low risk Combination chemotherapy –High riskIf bleeding occurs- Vaginal packingWide local excision Arteriographic embolisation of hypogastric

arteries

PULMONARY-80%

Present as – Chest pain, cough, hemoptysis dyspnoea. X-ray features- Snowstorm Discrete round densities. Pleural effusion Embolic pattern RxSingle agent chemotherapy-low risk.Combination – high risk.Thoracotomy-viable pulmonary Metastasis following

combination chemotherapy.

HEPATIC-10%

Worse prognosis. Usually associated with widespread metastasis Intraperitoneal

bleeding may occur.Rx Chemo & concurrent radiation (2000-3000 cGy). Hepatic resection to excise resistant foci.

Cerebral-10% Acute focal neurological deficits. Combination chemo + WBRT (2000-3000). Patients with metastasis on initial evaluation respond better

than who develop Lesion during therapy. During period of WBRT- Mtx in EMA-CO be increased to 1 g/m2

with Folinic.Acid rescue.

.

SURVEILLANCE DURING AND AFTER THERAPY OF GTN

Monitor serum quantitative hCG levels every week during chemotherapy:

1. Response: >10% decline in hCG during one cycle

2. Plateau: ±10% change in hCG during one cycle

3. Resistance: >10% rise in hCG during one cycle or plateau for two cycles of chemotheraphy

- evaluate for new metastasis- consider alternative chemotherapy- consider extirpation of drug-resistant sites of disease

. (DISAIA Gynaecolog oncology 2007)

REMISSION: 3 consecutive normal weekly hCG values

1. Maintenance chemotherapy

Surveillance of remission:

1. hCG values every 2 weeks x 3 months

2. hCG values every months to complete one year of follow-up

3. hCG values every 6-12 months indefinitely; at least 3-5 years

Schedule for hCG surveillance after chemotherapy

Urine SerumYear 1 Weeks 1-6 after

chemotherapyWeekly Weekly

Months 2-6 2- weekly 2-weekly

Months 7-12 2-weekly -

Year 2 4-weekly -

Year 3 8-weekly -

Year 4 3-monthly

-

Year 5 4-monthly

_

Year 6 and above

Life-long monitoring

6-monthly

-

CONTRACEPTION

During follow up periodI. OCP’s Safe Started soon after evacuation of H. mole. Given during the entire period of follow up. No increased risk of postmolar GTN or rate of decline

of hCG titre with OCPs use.II. Barrier methods Safe alternative to OCP’s in patients whom OCP are

contraindicated.III. IUCD Contraindicated due to an increased risk of uterine

perforation .

. DISAIA Gynaecology oncology 2007

Future Child Bearing

Pregnancy outcomes in patient with history of molar gestation are similar to patient with no such history with respect to live birth 1st and 2nd trimester abortion, anomalies, Stillbirth, pre-maturity and Caesarean rate.

Pregnancy outcome is similar irrespective of complete or partial mole.

For subsequent pregnancy. Ist trimester TVS to confirm normal pregnancy. HCG 6 wks after termination of pregnancy . After effective treatment for non-malignant GTN molar

pregnancy occur in 1-2% subsequent pregnancies.

.DISAIA Gynaecology oncology 2007

Treatment of malignant GTN with Chemotherapy is compatible with preservation of fertility and not assess with increased risk of congenital malformations.

Women undergoing I.U.I. after previous molar gestations, occasionally develops repeated moles.

This is due to an oocyte defect predisposing to abnormal fertilization.

Therapeutic alterations are:o ICSI with pre-implementation genetic diagnosiso Donor oocyte IVF

Co-Existence of normal pregnancy and GTN Described in both spontaneous & IVF gestations. Estimated incidence of twin pregnancy with 1 mole

and 1 fetus 1 per 221,000-1,00,000 or > 125 cases reported.

Diagnosis difficult based on imaging alone. In many cases diagnosis made only after

termination of pregnancy. Increased risk for haemorrhage persistent GTN and

medical complications. Pregnancy coexistent with H. mole need be

termination. Usually preterm delivery is often required because

of complications like bleeding or preeclampsia.

Thank You