Introductio

n:
Persistent Gestational Trophoblastic Neoplasia is a

disease in women who have had treatment to remove

a molar or non-molar pregnancy but still have some
trophoblastic tissue left behind.

Persistent GTN follows mostly molar pregnancy but

may follow any gestational

,ectopic or term pregnancy.

event

like

abortion

After molar evacuation local uterine invasion

and
metastasis occurs in 15% and in 4% of patients
respectively. Thus approximately 20% are at risk for
development of persistent GTN after complete mole.

Persistent GTN includes invasive mole, placental site

trophoblastic tumour and choriocarcinoma.

Gestational Trophoblastic
tumour

Definition:
In

United States Persistent Gestational Trophoblastic

Neoplasia is defined as the presence of a re-elevation or
persistent plateau in hCG for at least 3 consecutive weeks.

In Western Europe, the criteria for persistent GTTs are-

- hCG>20,000 IU/L, >4 weeks after evacuation.

- progressively rising hCG levels, with a minimum of three
rising values over 2 to 3 weeks.
- persistent high hCG level 4-6 weeks after evacuation.
- metastasis to the liver, kidney, brain or gastrointestinal
tract.
- metastasis to the lung > 2cm in diameter or three or more
in
number.
Source: J of Gynecol Oncol
1993

Risk factors for Persistent GTN:

Age:
There is increased risk of developing post molar GTTs
in women older then 40 years.
Ethnic group:
Persistent GTN are more common in women from
Asian countries than in women from other ethnic
group.
In Asia and in Asian women living in the UK, the
incidence is 1 in every 380 babies born.
In UK, the incidence is 1 in every 750 babies born.
Type of molar pregnancy:
The risk is 15 out of 100 women (15%) for women
who have had complete mole but only 1 in 200
women (0.5%) for women who have had partial mole.

Repetitive Molar Disease:

There is three fold increased risk of post molar
tumours in patient with repetitive molar disease

Marked trophoblastic proliferation:

Women showing signs of marked trophoblastic
proliferation at presentation- hCG level > 1,00,000 miu/ml
- Uterine size greater than gestational age
- Theca lutein cysts > 6cm in diameter
These patients are categorized as high risk as they
are at increased risk of developing persistent GTTs.

Symptoms:
H/O antecedent pregnancy
Vaginal Bleeding:
It is the must common symptom of persistent

GTN.
Intermittent but heavy PV Bleeding lasting
longer than normal after a molar or normal
pregnancy is suspicious.
Intra peritoneal bleeding following perforation
of trophoblastic tissue through the
myometrium in invasive mole.

Abdominal Swelling:
Theca lutein cysts may cause abdominal

swelling due to high hCG level.

Symptoms

cont.

Metastatic Symptoms:
Metastatic GTT is often associated with choriocarcinoma.
Common metastatic sites are lung (80%), vagina (30%),

brain (10%) and liver (10%).

Patients may present with symptoms of distant
metastasis.

(a) Neurological : Headaches

Dizziness
Seizures
(b) Pulmonary
: Dyspnoea
Hemoptysis
(c) Hepatic
: Epigastric or
Right upper abdominal pain
Massive intra peritoneal hemorrhage
following hepatic rupture.

Signs:
Uterus is often enlarged with bilateral

enlarged cystic ovaries.

Sub-urethral nodule in the vagina is

indicative of vaginal metastasis.

Invasive mole

Invasive GTN develop in 15% of the patients

following evacuation of a complete mole and
infrequently after other gestations.
The patients usually present with one or more
of the followings:
H/o antecedent pregnancy
Irregular vaginal bleeding
Intraperitoneal bleeding
Thecal lutein cyst
Uterine enlargement
Persistently elevated serum hCG levels

Diagnostic Evaluation:
A thorough evaluation of the extent of disease

prior to treatment is essential.

Assessment includes-

- Complete history and physical examination.

- Serum BhCG
- Chest radiography, GTTs produce four principal
radiographic patterns in the lung
(a) Discrete rounded densities- cannon ball
appearance
(b) Alveolar or snow storm appearance
(c) Pleural effusion
(d) Embolic pattern caused by pulmonary arterial
occlusion
.

Diagnostic Evaluation
Cont.
Pelvic USG to determine the extent of

uterine involvement aided by colour flow

Doppler.
CT scans or MRI scans of head and
abdomen to exclude brain and liver
metastasis.
The ratio of serum B-hCG to CSF B-hCG
( Ratio of < 60:1 indicates brain
metastases)
Hepatic, renal and thyroid function tests

Facts:
.
The diagnosis of GTN is usually made by high

level of serum BhCG, following an antecedent

pregnancy.

Diagnostic curettage is not indicated as

(a) it usually gives negative findings because

the growth does not always abut on to the
uterine cavity.
(b) in 1/3 of metastatic choricarcinoma there is

no evidence of disease in the uterus.

Asymptomatic patients with normal pelvic
examination and chest radiograph are very
unlikely to have liver or brain metastases.
However,

patients with vaginal or lung

metastases should undergo CT scans or MRI
scans of head and abdomen to exclude brain
and liver involvement

Cont

Treatment should be instituted whenever

there is raised level of BhCG

with or
without metastasis or there is tissue
diagnosis
of
choricarcinoma.
However,
histological confirmation is unnecessary
because raised BhCG or development of
metastasis is a sufficient justification for
chemotherapy.

Histological pattern:
After

molar pregnancy, persistent

GTN may have histological pattern of
either molar tissue or choricarcinoma.

Following

a non molar gestation

persistent GTN may only have the
histological
features
of
choricarcinoma.

Staging System:
In 2000, FIGO revised the staging system of GTT and

combined the use

anatomic factors.

of

both

anatomic

and

non

A patient is assigned a stage based on the anatomic

location of disease and given a risk factor score

based on WHO prognostic scoring system.

Prior

to commencing treatment patients are

assigned into both staging and risk factor scoring to(a) improve the assessment and assist in selecting
appropriate
chemotherapy, thus avoiding the
likelihood of drug resistance.
(b) It also allows comparable reporting of data which
is critical for comparison of treatment results.

FIGO anatomic staging for GTN:

Stage I

Disease confined to uterus.

Stage II

GTN extends outside the uterus, but

is limited to genital structures
(adnexa, vagina, broad ligament)

Stage III

GTN extends to lungs, with or without

known genital tract involvement.

Stage IV

Advanced disease with involvement

of brain, liver, kidneys or
gastrointestinal.

 Stage I GTN have low risk score while Stage

IV patients have high risk score. Thus

scoring is mainly applicable patients with
stage II or III disease to categories low Cont.
risk
and high risk.
Stage IV disease are likely to be resistant to

chemotherapy. In most cases, the disease

follows the non molar pregnancy and a
histological pattern of choriocarcinoma.

Modified WHO Prognostic Scoring

System as adapted by FIGO
Scores

Age

<40

40

Antecedent pregnancy

Mole

Abortion

Term

Interval from index

pregnancy

<4

4-<7

7-<13

Pretreatment serum
hCG

<103

103-<104

104-<105

105

Largest tumour size

3-<5cm

5cm

Lung
vagina

Spleen
kidney

Gastrointe
stinal tract

Liver
Brain

Number of metastases

1-4

5-8

>8

Previous failed
chemotherapy

Single
drug

2 or >
dmgs

Site of metastasis

A score of 0-6 is considered as low risk while score 7 is categorized as

high risk.

Format for reporting to FIGO annual

Report

Diagnosis = Stage + Risk

score
= Stage II : 4

Placental-site trophoblastic tumour

(PSTT)
PSTT is an uncommon variant of GTN.
Pathologically it is composed almost

entirely of intermediate trophoblast

with no chorionic villi.

It differs from choricarcinoma in that it

produces relatively little hCG and hPL in

relation to the size of tumour. Thus
tumour burden may be present before
hCG levels are detectable.

The tomour tend to remain confined to

uterus, metastasizing late in their course.

Placental-site trophoblastic tumour

(PSTT)
cont.
Diagnosis are made by curettage,

though curettage can lead to uterine

perforation because the tumour
penetrates deeply into the myometrium.
PSTT are relatively insensitive to
chemotherapy, thus hysterectomy is the
recommended treatment.
Conservative surgery with excision of
tumour has been described where
preservation of fertility is desired.

Treatment:
Chemotherapy is treatment of choice in all cases

Persistent GTN, alone or in combination with

surgery.

Choice of chemotherapy depends on the risk

score.

Monitoring of patients to evaluate the

(a) toxicity of drug and

(b) Response to treatment is done in between
the courses of chemotherapy.
Chemotherapy is changed due to toxicity or

drug resistance.

When to start
treatment:

Facts:

70% patients achieve normal B-HCG level

within 8 weeks post-evacuation.
15% patients demonstrate a slow decline in

titers but ultimately

without treatment.

achieve

normal

titres

15% patients who have elevated titers at 8

weeks post-evacuation, demonstrate a rising or

plateau titers. Nearly half of these will have
histological evidence of invasive mole and
other half will have choricarcinoma.
Thus Rx should be instituted when B-HCG levels

are elevated at 15 weeks post-evacuation.

Chemotherapy:
A.

Low Risk GTN:

Single Agent Chemotherapy is recommended

1.

2.

Inj methotrexate 50mg on alternate days for four

days and
Inj. Folinic acid 6mg for four days in-between the
four days.
The cycle is repeated every 2 weeks because tumour
re-growth becomes significant if the gap is > 2
weeks.
One additional course is given after serum BHCG
titer has become negative.
The number of Rx cycles necessary to induce
remission is proportionate to the magnitude of BHCG
at the start of Rx.
An average of 3-4 courses are required.
In patients with severe side effects with
methotrexate, Dactinomycin can be initiated .

B. High Risk GTN:

Combination chemotherapy is recommended.
Currently EMACO ( Etoposide, Methotrexate, Actinomycin

D, Cyclopyosphamide and Vincristine) chemotherapy

provides best response rate (80%) with lowest side
effects.

The cycle is repeated every 2 weeks.

Prior treatment included MAC (Methotrexate,

dactinomycin and chlorambucil or cyclophosphomide)

chemotherapy but remission rate was 50% and patients
experienced high side effects.

Two additional course of chemotherapy is advocated after

BHCG titers have retuned to normal to reduce the risk of

relapse.

Salvage therapy for disease not responsive to EMACO

substitutes cisplatin and etoposide ( EP-EMA) for

cyclophosphamide and vincristine (CO)

Monitoring in between treatment:

A. Evaluation of Response to Rx:
This is done by doing serum BHCG after each course of
chemotherapy.

Complete Response/Remission: It is defined as 3 consecutive

weekly normal BHCG values measured over 2 consecutive
weeks.

Cure: It is said to have occurred after a period of 5 years in

remission.

Plateau: It is defined as any decrease of serum BHCG of <10%

of previous week in 3 consecutive weeks.

Rise: It is considered significant if the rise of serum BHCG is

>10% of previous week.

Failed Response: It is defined as appearance of metastases or

plateau of serum BHCG level.

Drug Resistance: It is diagnosed when there is plateau or rise

of serum BHCG.

B. Evaluation of Toxicity:
The systemic side effects are stomatitis, skin rash,

alopecia,
conjunctivitis
disturbance.

and

gastrointestinal

The organs affected adversely are bone marrow,

liver, and kidney. So regular checks are made on

white cell count, platelet, liver function and Blood
Urea.

Toxicity is diagnosed if there is

- White cell count < 3000/ml

- Platelet count <1,00,000/ml for more than 21
days after the last
cycle.
- Liver function tests arte elevated > twice of
normal.
- Blood Urea is raised
- Systemic side effects are evident.

Surgery:
Total Abdominal Hysterectomy has limited role in

the Rx of GTN. Since the tumours are highly

responsive to chemotherapy the need for
hysterectomy has been obviated attaining 100%
cure rate while retaining fertility.

Current recommendations restrict hysterectomy

to cases
(a) Who are resistant to chemotherapy
(b) Who have uncontrollable uterine bleeding.
(c) Bulky uterine tumour to reduce tumour
burden
and
thereby
limit
the
need
of
chemotherapy.
(d) Placental site trophoblastic tumour.

Surgery
cont.

Hysterectomy

does not eliminate the

need for careful follow up with BhCG
testing.

Hepatic Resection is indicated in stage

IV disease to control bleeding or to

excise resistant tumour.

Craniotomy may be necessary to provide

acute decompression or to control

bleeding or to excise resistant tumour

Radiotherapy:

Brain irradiation is both haemostatic

and tumourocidal.
The

risk of spontaneous cerebral

hemorrhage may be reduced by the
concurrent use of chemotherapy and
brain irradiation.

Follow up:
Patients

with stages I, II & III GTN are

followed with
- Weekly hCG values until they are normal for
3 weeks
- Monthly until they are normal for 12
months.

Patients with stage IV GTN are followed with

- Weekly hCG values until they are normal for

3 weeks
- Monthly until they are normal for 24
months.

Risk of Relapse
Once the hCG has fallen to normal, the

risk of relapse is < 5% for low risk

patients and 3% for high risk patients.
Generally these recurrence occur within
the first 12 months after treatment.
Majority of patients who develop
relapse are subsequently cured with
further chemotherapy and on occasion
surgery.

Pregnancies after GTN:

Patients with GTN who are successfully treated

with chemotherapy can generally expect normal

pregnancy after 2 years.

There is no evidence of sub fertility, abortions,

congenital malformations,
neonatal morbidity.

prenatal

loss

or

The

explanation is that the period of

contraception allows all mature ova affected by
chemotherapy to be eliminated, whilst the
resting oocyts are not affected by drugs.

Following delivery, the placenta should be sent

to pathology and a BHCG level should be

checked at 6 week postpartum visit.