GESTATIONAL TROPHOBLASTIC DISEASE

INTRODUCTION

Spectrum of diseases formed by abnormal proliferation of gestational trophoblastic tissues ( syncitiotrphoblasts and cytotrophoblast). Develop from fetal allografts in maternal tissues and are not very common. Ranges from benign Hydatidiform mole to malignant Choriocarcinoma. Its malignant form is the most curable gynaecological malignancy. Secretion of high tumour marker HCG has made the disease management quite interesting.

EPIDEMIOLOGY

Incidence has regional / racial distribution. Higher in Africa and Asia. In USA, incidence is about 1 in 500 -2000 pregnancies among the white population and 1 in 800 among the African population. In W/A , incidence rates between 0.87 and 4.88 per 1000 deliveries were reported in Nigeria and a rate of 0.8 per 1000 deliveries reported in Ghana.

Incidence higher in the following:

Age less than 20 and over 40 years. Previous molar pregnancies. Increased number of spontaneous abortions. Rhesus D blood group A. Multiparity Artificial insemination Low protein, low fat and vit A ?Familial tendencies.

CLASSIFICATION

1. Benign ( Pre-malignant ).

a) Hydatidiform mole.

Partial H/mole Complete H/mole.

2. Malignant.(GTT)

a) Invasive mole ( Chorioadenoma destruens) b) Choriocarcinoma c) Placental site trophoblastic tumour

HYDATIDIFORM MOLE

Characterised by vesicular swelling of villi and varying degrees of trophoblastic proliferation.

Aetiology

Unclear Thought to be due to abnormal gametogenesis and fertilization. TYPES

Complete H/mole Partial H/mole

COMPLETE H/MOLE

There is marked hydropic swelling of chorionic villi with diffuse trophoblastic hyperplasia (cytotrophoblast and syncitiotrophoblast) Absence of intact fetus. 90% chromosomal pattern is 46xx Karyotype (paternal origin ). A haploid sperm (23x) fertilizes an empty ovum and duplicates its own chromosomes. 6 -10% have 46xy chromosomes all paternal. Results from fertilization of empty ovum by 2 separate sperms.

PARTIAL H/MOLE

An abnormal conceptus with an embryo/fetus that tends to die early. There is focal hydropic swelling of the chorionic villi with focal trophoblastic proliferation usually of syncitiotrophoblast only. Chromosomal pattern is triploid karyotype, usually 69xxy resulting from fertilization of an apparently normal ovum by 2 sperms. May have a diploid karyotype ( 46xx or 46xy )

Clinical Presentation of H/mole

Amaenorrhea Vaginal bleeding Recurrent altered bloody discharge Anaemia Passage of vesicular tissues per vagina Exaggerated pregnancy symptoms Signs and symptoms of thyrotoxicosis Enlarged uterus which may be larger than the gestational age Luteal cysts may be present and palpable Early onset of pre-eclampsia

Investigations

FBC including platelet count. Blood coagulation profile Serum Bhcg assay usually very high ( up to 100,000iu/l ) Blood grouping and cross matching of 2 -4 unites of blood. Urine for PT in neat and dilution ( if serum Bhcg assay is not available ) Abdominopelvic USS snow storm Establishes diagnosis and reveals characteristic or foam bubble appearance. C-XRay LFT RFT

Treatment

Done in specialist units Correct anaemia if any by blood transfusion Suction evacuation of uterus

Done in theatre Use oxytocics Send sample for histology Curative in > 80% of cases TAH for patients who have completed family

Follow-up

Most important aspect of management. May transform to malignancy in 5% of cases. Bhcg assay is the key to monitoring. Patient seen 1- 2 weekly until Bhcg becomes normal ( < 5iu/l ) for 3 consecutive visits, 2 monthly for 1 year, and 6 monthly for the next year.

At Each Visit

History taking to ascertain : irregular vag bleeding, cough, chest pain, breathlessness, and vomiting. Clinical examination to exclude anaemia, chest congestion, abdominal mass and vaginal lession. C-XRay done every month.

Contraception

Avoid pregnancy for at least one year. Use barrier contraceptives, depo provera, or low dose OCP.

Reason: hcg difficult to interpret.

Indications for Chemotherapy during follow up.

High level of hcg > 4wks post evacuation ( 20,000 iu/l ). Progressive increase in hcg. Persisting uterine haemorrhage. Clinical or radiological evidence of metastases. Histological evidence of choriocarcinoma.

CHORIOCARCINOMA

Malignant trophoblastic disease and it is not common. It is the only gynaecological cancer that is curable with chemotherapy. It is rapidly fatal without treatment.

AETIOLOGY - Follows H/mole in 50% of cases. - Abortion or ectopic pregnancy in 25% - Normal pregnancy in 25%

Pathology

Usually found in the uterine wall. May be found in cervix, vagina, fallopian tube or broad ligament. Lesion is usually soft, necrotic and haemorrhagic. On microscopy, there is characteristically no villi. The chorion maintains its invasive nature and shows extensive proliferation. Large volumes of hcg ( tumour marker ) are excreted about 100,000 400000 units daily. This causes extensive stimulation of the ovaries with theca lutein cyst formation. Human placental lactogen may also be secreted.

Metastases

Direct spread to fallopian tubes,broad ligament, paracolpus and the cervix. Haematogenous spread to the vagina, lungs, brain, liver, kidneys and GIT.

Clinical presentation

Hx of antecedent pregnancy. When it follows H/mole, hcg level during follow up shows characteristic persistent rise, or plateau. Vaginal bleeding with or without abdominal masses. Bleeding suburethral nodules from vaginal metastases. Cough, dyspnoea with or without haemoptysis from lung metastases. Cerebral haemorrhage with increased intracranial pressure from CNS metastases. Right hypochondrial pain. Bloody stools from GIT metastases.

Diagnosis

Hx Physical examination Histopathology samples obtained during suction evacuation of H/mole

Investigation

FBC LFT Serum E/U/Cr. Bhcg serum levels. Grouping and crossmatching Abdominopelvic USS May indicate infiltration of the disease into uterine wall and metastatic lesion in the liver. C-XRay Characteristic cannon ball secondaries. May show milliary pattern or large solitary lesions. Computerized Tomography ( CT ) More sensitive than XRay and USS. Useful in cerebral metastases. Magnetic Resonance Imaging Arteriography Radio-immunoscintigraphy

FIGO STAGING

Stage O - H /mole Stage 1 - Persistently elevated hcg levels and tumour confined to uterine corpus. Stage II - Patients with metastases to the vagina or pelvis or both. Stage III Lung metastases Stage IV - Patient with advanced diseases and involvement of the brain, liver, kidney, or GIT.

SCORING SYSTEM BASED ON PROGNOSTIC FACTORS

1 >39 Abortion 4-6

Term 7-12 >12

HCG(miu/ml

<103

103 - 104

104 - 105

>105

ABO group(F & M) Largest tumour(cm) Site of Metatases No of Metatases Prior Chemotherapy

OXA AXO

B AB 35 Spleen, Kidney 13 >5 GIT, Liver 48 1 drug Brain >8 2 drugs

Score 6 = Low Risk

= High Risk

Treatment

Multi disciplinary with emphasis on individualized treatment. Proper counselling is essential. Treatment depends on the prognostic scores and stage of the disease. WHO prognostic scoring system gives good prognosis of treatment.

Low Risk

Single agent chemotherapy im Methotrexate 1mg/kg/day on days 1,3,5, & 7 plus Folinic acid, 0.1mg/kg/day on days 2,4,6. & 8. or iv Actinomycin D 10 -12g/kg/day for 5 days or iv Etoposide 200mg/m2/day for 5 days.

NB methotrexate is the most effective & most widely used.

Complications

Mucositis Allergy Photosensitivity Myelosuppression Alopecia Diarrhoea Nausea and Vomiting

Treatment is repeated when patient is fit as in the following:

No evidence of oral or GIT ulcerations WBC > 3 x 109/L Platelet count over 100 x 109/L Normal Liver and Renal function tests.

Treatment is continued till the weekly B-HCG titre is normal (<5iu/L) for 3 consecutive times. When the HCG is normal, continue treatment for 1 3 more courses.

FOLLOW-UP

Monthly B-HCG for 12 months, then every 2 months for another 12 months, then every 6 months for life.

PROGNOSIS

With Methotrexate/Folinic Regime

75% have complete remission 20% have drug resistance 5% - Regime changed to alternate regime because of intolerance.

HIGH RISK

Combination Therapy with ;

Etoposide, Methotraxate, and Actinomycin D, in the 1st week, and Cyclophosphomide and Vincristine ( Oncovin) administered in the 2nd week of a two week cycle. EMA-CO regimen.

HIGH RISK

EMA CE regimen for failed EMA-CO. -- Substituting Cisplatin and Etoposide for Cyclophosphomide and Vincristine during the second week

At least 2 additional courses of EMA-CO or EMA-CE are administered after after a normal serum Hcg level.

ROLE OF SURGERY

Management of acute complications

GI/Urinary tract obstructions Intra-peritoneal haemorrhage Haemorrhage from vaginal or suburethral nodules.

Removal of known focus of disease

Hysterectomy for placental site trophoblastic tumours Thoracotomy & removal of solitary lung nodules Hysterectomy for isolated focus or resistant tumour

ROLE OF RADIOTHERAPY

Radiation to brain and liver metastases as adjunct to chemotherapy

FOLLOW-UP

As in low risk Allow at least 1 yr after treatment before attempting pregnancy

INVASIVE MOLE (chorioadenoma destruens)

Nearly always arise from H/mole Has similar histologic appearance to complete mole, but characterized by ability to invade the myometrium & local structures May metastasize to vagina and lungs Lesions may remit spontaneously Treatment is hysterectomy

PLACENTAL SITE TROPHOBLASTIC TUMOUR

First described in 1976 Least common type of GTD; <2% of cases May arise from normal pregnancy (most commonly), non-molar abortions or H/mole after 1 4 years Develop from the placental bed trophoblast & cells are predominantly intermediate trophoblast Secrete low quantities of B-HCG and large amount of HPL Rarely metastasize beyond uterus Most frequent presentation is vaginal bleeding following amenorrhoea Treatment is hysterectomy

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