Gestational Trophoblastic Disease

Dr U.D.Bafna MD

Professor & Head, Department of Gynecologic Oncology,

Kidwai Memorial Institute of Oncology,

Bangalore

Gestational Trophoblastic Disease (GTD)

GTD :Refers to benign and malignant trophoblastic diseases – Hydatidiform mole Invasive moleChoriocarcinoma (CCA) and Placental site trophoblastic tumor (PSTT)

Gestational Trophobastic tumor or neoplasia – GTT/GTN

GTN (GTT) : Refers to clinical/biochemical evidence of IM, CCA & PSTT

These patients require chemotherapy (&/ or excisional surgery)

GTN

GTN is seen in some patients following evacuation of molar pregnancy (about 80% regress normally and 20 % develop GTN)

GTN may also rarely follow an abortion and very rarely a term delivery (1 in 100,000 term deliveries).

Diagnosis of GTN

Following H. mole is fairly easy due to meticulous follow up and high degree of suspicion

Its difficult to diagnose after an abortion or term delivery as the symptoms are non-specific. Patients may present with non-gynec symptoms like haemoptysis due to lung metastasis.

Risk of progression to GTN following molar pregnancy

Hydatidiform Mole (20% over all)

Partial Complete

Low Risk High Risk

4% 4% 40%

GTN GTN GTN

Gestational Trophoblastic Disease

Hydatidiform Mole

Low Risk (4%) High Risk (40%)

Uterine size > period of gestation

ShCG > 100,00 miu/ml

Large Theca-Lutein cysts ( > 6 cm)

PIH, thyrotoxicosis, pulmonary

embolism, Previous mole (all these indicate high trophoblastic proliferation)

Genetic basis of molar pregnacy

Partial Mole – diandric triploid (69) usually46 maternal chromosomes and 23 paternal chromosomes

Maternal chromosomes are responsible for proper development of embryo and paternal chromosomes for placental development

Complete Mole – diandric diploid (46 chromosomes)

Here all the 46 chromosomes are of paternal origin and therefore there is only trophoblastic proliferation and no development of embryo

Molar pregnancy

Incidence – 1 in 1000 (west) to 1 in 400 (Asia)

More common if maternal age is > 35 or <20 years

Chances of repeat mole is 2% Chances increase to 20% after two molar

pregnancies

Molar pregnancy

Signs and symptoms are due to excessive trophoblastic proliferation – resulting in Increased uterus size, Excessive nausea and vomitingPIHHyperthyroidismEarly vaginal bleedPassage of grape like cysts

Diagnosis is easy by ultrasound and serum hcg

Evacaution of a mole

Suction evacuation Some patients may develop trophoblastic

embolisation causing respiratory distress There is no role of repeat curettage after a

week unless there is residual mole Medical Induction is contraindicated

because of increased risk of embolisation

Management after evacuation of the Mole

Meticulous follow up with serial B hCG estimation to detect persistent trophoblastic disease in the form of GTN is essential

Follow up with serum B hCG

Serum B hcg should be measured weekly for three times till normal and then monthly at least for one to two years after molar pregnancy

hCG

Human chorionic gonadotrophin (hCG): it is a glycoprotein produced by syncytiotrophoblasts. It contains a and b subunits joined by non-covalent bonds. In normal pregnancy, most hCG is intact. In GTD, there is a higher proportion of b-hCG compared with that in normal

pregnancy. b-hCG not only reflects trophoblastic activity but also promotes

tumourigenesis.

hCG

Various forms of b-hCG exist in GTD, including free-b, b-core, nicked free-b and carboxyl-terminal fragment.

Therefore, an ideal hCG assay for GTD should detect all forms of b-hCG.

False-positive and false negative results can occur. Phantom hCG (pseudohypergonadotropinemia ) is a result of the

presence of heterophilic antibodies in serum giving rise to a falsely elevated hCG..

The alternative is to measure the urine hCG level because heterophilic antibodies are not excreted into the urine.

Management after evacuation of mole

Prophylactic Chemotherapy Single agent , single eight day courseof

methotrexate with folinic acid rescue may be given to a patient who is unreliable for follow up following molar pregnancy – especially if it is high risk (excess trophoblastic proliferation)

Prophylactic Hysterectomy With or with out prophylactic chemothrapy may be done for unreliable multi-parous patient aged > 39 years.This is to decrease the risk of development of perforating invasive mole

Contraception after molar

Barrier/IUCD/Oral PillsContraception for a minimum period of six months after B hcg has become normal

Future Conceptions after Molar

Repeat molar pregnancy – 3%,

20-30% after two consecutive molar pregnancy

After three consecutive molar pregnancy normal

pregnancy is very rare

Early USG during the subsequent conceptions

Gestational Trophoblastic Neoplasia (GTN)

Includes IM, CCA and PSTT

1)Invasive Mole : HM that has invaded

the myometrium or metastasised

2)Choriocarcinoma: differs from IM in that

the villous pattern is lost

3)Placental Site Trophoblastic Tumor

Note – all metastatic disease need not be chorioca, it could also be an invasive mole which responds better to chemotherapy.

There is no need for histo-patholgy/biopsy as serum b–hcg is a very sensitive and specific marker

Gestational Trophoblastic Neoplasia (GTN)

3)Placental Site Trophoblastic Tumor

- composed mainly of cytotrophoblasts

- hPL is raised > hCG

- less responsive to chemotherapy

- Follows either a molar pregnancy (50% of cases of PSTT), abortion (25%), term pregnancy (20%), or ectopic (5%)

GTN - Diagnosis

May arise after HM, Abortion or Term delivery High degree of suspicion is required after

abortion or term delivery as symptoms may be highly non-specific/non-gyn symptoms depending on the site of metastasis

Any young woman with metastasis of unknown origin should be screened for GTN

GTN - Diagnosis

Diagnosis after HM evacuation : FIGO

Recommendations (2000)1)4 values or more of plateau of hCG over at

least 3 weeks

2)A rise of hCG of 10% or greater for 3 values over at least 2 weeks

3)The presence of histologic choriocarcinoma

4)Persistence of hCG 6 months after evacuationA single value of high b hcg of 20,000 miu/ml at 4 weeks after evacuation

Mangement of GTN

GTN is mainly managed with chemotherapy as the tumor is highly sensitive to chemotherapy (except PSTT)

(God’s first cancer and man’s first cure) Chemotherapy is either single agent or

combination chemotherapy depending on the FIGO stage and/or WHO risk score

Stage I – confined to uterus Stage II – extension to pelvis and vagina Stage III – Lung metastasis Stage IV – all other mets

FIGO stage

GTN – WHO Score The Scoring System for FIGO 2000

Score 0 1 2 4

Age <39 >39

A.P HM Abortion Term

Interval <4 m 4-6 7-12hCG IU/ml

< 1 1-10 10-100

>100

Tumor Size (CM)

3-4 5

Site Spleen

Kidney

GIT Brain

Liver

No. 0 1-4 4-8 >8Previous failed CT

Single drug

Two or more

GTN FIGO 2000 Score

Low Risk GTN : Score 6 or less High Risk GTN : Score >6

Requirements for Scoring and Diagnosis of Metastases:

Clinical History & Serum hCG estimation

Chest X-ray/CT scan for diagnosis of lung metastases

USG/CT scan for diagnosis of intra-abdominal metastases

MRI/CT scan for Brain metastases* All the patients with lung metastases should have CT/MRI of brain

Management of GTN

General PrinciplesGTN is highly curable even in very

advanced stages as it is highly chemosensitive

Chemotherapy should be used in proper combination, proper schedule, proper

dosage – otherwise tumor may become chemo-resistant very rapidly

Role of surgery for GTN

Surgery is generally not required as the tumor is chemosensitive

However, surgery may be done to decrease the tumor load and reduce the number of chemotherapy cycles in selected patients

Example – hysterectomy in a multiparous women with large uterine tumor and high risk who score

Role of surgery

Surgery is also indicated for removal of chemoresistant tumor any where in the body

Example – Hysterectomy, Pulmonary lobectomy Craniotomy Surgery is done generally for a solitary

chemoresistant tumor which can be excised completely

Management of GTN

General Principles

Low Risk GTN is mostly cured with single agent chemotherapy

High Risk GTN should be always treated with combination chemotherapy

Low Risk GTN- Chemotherapy

Inj. Methotrexate 1 mg/kg on D 1,3,5 & 7

Inj. Leucovorin 0.1 mg/kg oRn D 2,4,6 & 8

Repeat cycle on D 15 ( if no toxicity).

Estimate serum hCG serially weekly.Continue CT for 1-2 cycles after normalization of hCG.

Change CT if hCG values plateau or rise

Low Risk GTN- Chemotherapy

Kidwai Data ( Bafna et al , Int J Gyncol Ca, 1997)

- 100% remission- 78.7% achieved remission with single agent

MTX- 21.3% with comination CT or Actinomycin D

High Risk GTN - Chemotherapy

EMA-CO REGIMEN EMA on D 1 & 2, CO on D8 Repeat cycle on D 15 ( if no toxicity).

Estimate serum hCG serially weekly. Continue CT for 3-4 cycles after normalization of hCG.

Change CT if hCG values plateau or rise/

Consider excisional surgery for localized tumor

High Risk GTN

Kidwai Data (Bafna et al., 1997)83.7 % remissionSite of metastases in this series included -

Pelvis, lung, liver,brain, GIT, Spine, Parotid

Clinical presentation included Gyn symptoms, hemoptysis, hemiplegia, paraplegia, facial nerve palsy etc.

High Risk GTN

Kidwai Data (Bafna et al., 1997)83.7 % remission56.7% achieved remission with first line

chemotherapy*27% achieved remission with second and

third line CT* This series also includes patients before the advent of

EMA_CO regimen.

Follow up after GTN treatment

Meticulous follow up with serial hCG estimation

Contraception for a period of one year after remission has been achieved

No evidence of increased obstetric complications during subsequent normal conceptions.

Contraception for one year as most of the recurrences occur within one year

One year period may also be required to allow recovery of primordial follicles damaged by chemotherapy

Chemotherapy is known to suppress ovarian function and cause amenorrhea for a short period.

High Risk GTN - Chemotherapy

Supportive therapy is important in patients with extensive brain/lung metastases –

Steroids to decrease brain/lung edema Positive pressure ventilation Hemostatic radiotherapy to brain