Introduction:

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 event like abortion ,ectopic or term pregnancy.

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 diameterThese 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 moleInvasive 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 of both anatomic and non anatomic factors.

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.

Cont.

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 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 0 1 2 4

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

Site of metastasis Lung vagina

Spleen kidney

Gastrointestinal tract

Liver Brain

Number of metastases - 1-4 5-8 >8

Previous failed chemotherapy

- - Single drug

2 or > dmgs

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 achieve normal titres without treatment.

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. Inj methotrexate 50mg on alternate days for four days andInj. 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.

2. 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 and gastrointestinal disturbance.

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, prenatal loss or neonatal morbidity.

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.