Hydatidiform moles and trophoblastic neoplasms

A patient with a hydatidiform mole is commonly under 20 or over 40; she usually presents before the 18th week of pregnancy with: (1) Rapid enlargement of her uterus, which feels abnormally soft. (2) Excessive nausea and vomiting. (3) Vaginal bleeding which is typically dark red, or brownish, and starts at the 6th to 8th week. (4) The passage of vesicles though her cervix. (5) Enlarged cystic ovaries (50% of cases), which may be palpable. (6) Signs of gestational hypertension (17.4). She may show any combination of these signs, and if her pregnancy exceeds 18 weeks, inability to palpate the fetal parts and the absence of fetal movements are other suggestive features.

After you have evacuated her mole three things can happen: (1) She may recover completely (80% or even 95%). (2) She may develop a non-metastasizing trophoblastic neoplasm (invasive mole). (3) She may develop a metastasizing trophoblastic neoplasm (choriocarcinoma), either high risk or low risk.

Early diagnosis, effective treatment, and energetic follow- up are essential. You can treat a hydatidiform mole without too much difficulty, but you should refer a choriocarcinoma. If this is impossible, you may have to treat her yourself. As always with cancer chemotherapy, treat patients properly or not at all.

The method which follows makes no allowance for the fact that she may want more children, nor does it advise hysterotomy. Unfortunately, the use of an oxytocin drip increases the risk of her requiring chemotherapy, but is the method of choice under your circumstances.

Fig. 32-23 TUMOURS OF THE TROPHOBLAST. A, a choriocarcinoma has metastasized to the lungs. B, a hydatidiform mole. C, a choriocarcinoma invading the wall of the uterus. Adapted from drawings by Frank Netter, with the kind permission of CIBA-GEIGY Ltd, Basle (Switzerland).

TUMOURS OF THE TROPHOBLAST HYDATIDIFORM MOLE HISTORY and EXAMINATION. Enquire exactly about the times of bleeding, and look at the colour of the blood. Ask about the passage of tissue (''grapes') vaginally. Note the size and feel of the patient's uterus, especially changes after 2 weeks. Measure her fundal height. Listen to the fetal heart; you should hear it at 18 weeks in a normal pregnancy. Doppler fetal heart monitoring is useful (if you have it). The presence of a fetal heart reduces the probability of a mole, but does not exclude the much rarer occurrence of a partial mole, with a complete fetus, or twin pregnancy. Look for signs of gestational hypertension (17.4).

X-RAY her abdomen and look for fetal parts. You should see them at 16 weeks. Their absence is strongly suggestive, but their presence does not exclude hydatidiform mole.

CAUTION ! Never X-ray a fetus less than 14 weeks. Most fetuses that need X-raying are more than 22 weeks. A suspected mole and acute hydramnios are the only exceptions.

TESTS FOR GONADOTROPHIN are not ideal for diagnosing a mole, but you are unlikely to have ultrasound, which is better. If possible, measure the human chorionic gonadotrophin (HCG) in a 24 hour urine sample (normal 40 000 u/24 hours). Suspect titres above 100,000; they may reach 1 or 2 million. Unfortunately, values in the normal pregnancy range do not exclude hydatidiform mole.

Do a standard qualitative immunological pregnancy test using a test kit. If this is positive, do serial dilutions of a 24 hour urine specimen, to detect the greatest dilution showing a positive result. This is an inexpensive way of doing a quantitative test, and although it is not ideal, it is likely to be the best that you can do, but it must be done carefully! The standard quantitative test uses much test solution and is expensive. Some way of doing a quantitative test is important because: (1) the clinical and X-ray signs may be inconclusive, (2) during follow-up, it is the only way of knowing if trophoblastic tissue is still present.

THE DIFFERENTIAL DIAGNOSIS includes: (1) a multiple pregnancy, (2) an abortion, especially a missed abortion, (3) acute polyhydramnios, (4) retention of urine with a retroverted gravid uterus, (5) a subacute or chronic ectopic pregnancy.

IMMEDIATE COMPLICATIONS. The important one is bleeding, especially during, or after abortion, or evacuation of her uterus.

LONG TERM SEQUELAE. There is a 15% chance of a non- metastasizing neoplasm, and a 5% chance of a metastasizing one.

THE MANAGEMENT [s7]OF HYDATIDIFORM MOLE ANAEMIA. Correct her anaemia by blood transfusion. If her haematocrit is [lt]15% (haemoglobin 50 g/l), give her packed cells slowly, and precede each unit with frusemide 20 mg. Watch carefully for cardiac failure, and replace any sudden blood loss rapidly.

EVACUATE HER UTERUS. You have four choices:

(1) You can start by setting up an oxytocin drip of 10 u/500 ml, running at 30 drops a minute during the procedure, and for 1 or 2 hours afterwards. Avoid combining this with ergometrine if you can, because it increases the risk of trophoblastic tissue embolizing to her lungs.

(2) You can avoid oxytocin: give her ergometrine alone, and accept its risks as being necessary. If you decide to do this, give her ergometrine 0.25 mg intramuscularly or intravenously. When her cervix is sufficiently dilated, evacuate her uterus under sedation and a paracervical block (A 6.14), or under general anaesthesia or ketamine. Avoid subarachnoid and epidural anaesthesia if she is hypovolaemic. If possible use suction, if not, use your fingers or a blunt curette. The standard suction apparatus for terminating pregnancy is satisfactory (See Primary Mother Care).

(3) Prostaglandin pessaries are better if you have them (16.4).

CAUTION ! (1) Don't start to evacuate her uterus until her cervix is sufficiently dilated to admit your finger, or she will be more likely to bleed. (2) Take great care not to perforate her uterus. If you think that evacuation is incomplete, or if bleeding continues, accept this, and repeat the curettage in a week. (3) Torrential bleeding can occur, so have 2 units of blood available, but don't give it unless she bleeds.

After you have evacuated her uterus, you may feel her cystic ovaries[md]leave them. Repeat the curettage in 7 to 10 days.

(4) Consider doing a hysterectomy if: (1) You cannot control bleeding (tying her uterine or internal iliac arteries is preferable, and may be effective; see ''Stop Press'). (2) You cannot control infection. (3) She is over 40, and is unreliable, particularly if she already has several children.

FOLLOW UP is essential to identify those patients (up to 20%) who need cytotoxic drugs early. If you can diagnose choriocarcinoma early, you have a 95% chance of curing her.

See her every 2 weeks for 3 months, and then every month for the next 3 months. This may be difficult, but is imortant if she is to get the best results from cytotoxic drugs. Follow her for at least 2 years.

At each visit: (1) Examine the size of her uterus. (2) Do a speculum examination. A haemorrhagic nodule near her urethral meatus, or on the vault of her vagina, or on her cervix may be the first sign of progression to a trophoblastic neoplasm. (3) Note any bleeding. (4) X-ray her chest monthly. If you can do HCG assays, X-rays can be done less often. (4) From 8 weeks do an HCG qualitative test as above. If this is positive, do a quantitative one. The standard qualitative test should become negative by 8 weeks after the evacuation of the mole. Use a test capable of detecting 1000 to 2000 units in a 24 hour specimen.

She must use some family planning method for a year. Don't use contraceptive pills, because they increase the risk of a lesion requiring chemotherapy. If her husband cannot be relied on to use a condom (usual), you may have to insert an IUD, even though its side effects may be confused with choriocarcinoma.

Suspect a trophoblastic neoplasm if during follow up: (1) dark vaginal bleeding continues, or (2) her uterus remains large after evacuation or delivery, or (3) amenorrhoea continues. Establish it by measuring her HCC levels and by X-raying her chest (see below).

NON-METASTASIZING [s7]TROPHOBLASTIC NEOPLASM (invasive mole) DIAGNOSIS. If the above symptoms lead you to suspect a trophoblastic neoplasm: (1) Measure her HCG titre. A titre above 2000 units in a 24 hour specimen after 3 months, or a rising titre after 2 months is abnormal. (2) Look for evidence of metastases in her pelvis, liver, brain, and chest. The differential diagnosis includes the incomplete evacuation of a normal placenta, placenta accreta, and a fibromyoma.

If you make the diagnosis within 4 months of delivery you have a 95% chance of curing her.

Give her methotrexate tablets by mouth 15 mg/m['2] in courses of 4 days. Repeat the courses every 14 days for 2 courses after her HCG is normal, to a maximum of 6 courses.

If her HCG is still above 2000 u/24 hours, after 6 courses of methotrexate, start actinomycin D 2 mg/m['2] (or 1 mg on days 1 and 3), one course every 3 weeks. Repeat this every 3 weeks for 2 courses after her HCG test is negative.

If her HCG test remains positive, start her on triple therapy, as below.

METASTASIZING [s7]TROPHOBLASTIC NEOPLASM (choriocarcinoma) PRESENTATION. (1) A history of heavy irregular bleeding, sometimes following an ''abortion', especially the need for repeated evacuation. (2) Persistent amenorrhoea following hydatidiform mole. (3) A haemorrhagic nodule in her vagina or on her cervix (see above). (4) Cough, chest pain, ''unresolved pneumonia'', or symptoms suggesting tuberculosis. (5) An acute haemoperitoneum like a ruptured ectopic pregnancy, due to perforation of her uterus by the tumour. (6) Neurological symptoms.

X-RAYS of her chest may show ''cannon ball' secondaries.

CAUTION ! If her choriocarcinoma arose from a hydatidiform mole, you will already have evacuated it. If it presented in other ways, don't do a diagnostic curettage, because: (1) A negative one does not exclude the diagnosis. (2) You can easily perforate her uterus, or cause catastrophic bleeding. (3) You may spread the tumour.

PROGNOSIS. All untreated patients die from multiple metastases. Patients must be diagnosed and treated early. Treat ''low risk' and ''high risk' patients separately.

LOW RISK. (1) Following hydatidiform mole. (2) Metastases in the pelvis and lungs (on chest X-ray) only. (3) HCG not above 100 000 u/24 hours. (4) Treatment is started within 4 months of evacuation of the uterus. She is only at low risk if all these criteria are met.

Treat her as for ''non-metastasizing' disease, and expect 95% long-term disease-free survival.

HIGH RISK. (1) The association with a term pregnancy. (2) Treatment starting later than 4 months after evacuation. (3) An HCG titre of more than 100 000 u/24 hours. (4) Metastases in her liver, gut or brain.

CAUTION ! A further cause of a rising titre is a fresh pregnancy, so remember this possibility, even if she is using contraception.

CHEMOTHERAPY [s7]FOR HIGH-RISK CHORIOCARCINOMA Here two regimes: (1) EMA-Co using etoposide, actinomycin D, methotrexate (in high dosage), vincristine, and cyclophosphamide. This is the WHO regime. (2) An alternative regime, using methotrexate, cyclophosphamide, and actinomycin D.

EMA-Co This regime consists of two courses. Give Course 1 on days 1 and 2. Give Course 2 on day 8. Course 1 may require overnight admission, Course 2 does not.

Course 1

Day 1 etoposide 100 mg/m['2] by intravenous infusion in 200 ml of saline. Also actinomycin D 0.5 mg intravenously stat. Also methotrexate 100 mg/m['2] intravenously stat followed by 200 mg/m['2] intravenously over 12 hours.

Day 2 etoposide 100 mg/m['2] by intravenous infusion in 200 ml of saline over 30 min. Also actinomycin D 0.5 mg intravenously stat. Also, calcium folinate 15 mg intramuscularly or orally every 12 hours for 4 doses beginning 24 hours after starting methotrexate.

Course 2

Day 8 vincristine 1 mg/m['2] intravenously stat. Also cyclophosphamide 600 mg/m['2] intravenously in saline.

Give these courses on days 1 and 2, 8, 15, and 16, 22, etc., and don't extend the intervals without cause. Continue until no gonadotrophin has been detectable in the urine for 3 months.

ALTERNATIVE REGIME. Give her: Tablets of methotrexate 15 mg/m['2] daily for 4 days. And, actinomycin D 2 mg/m['2] intravenously on day 1 (or 1 mg on days 1 and 3). And, give her cyclophosphamide 1 g to 1.5 g/m['2] intravenously on day 1. Repeat the course every 3 weeks (on day 21) for two courses after there is no evident disease (HCG [lt]2000 u/24 hours), or up to 6 courses.

Expect long-term disease-free survival in 50 to 75% of patients, depending on how advanced the disease is when treatment starts. Advise her very strongly to have her tubes tied.

CAUTION ! Proper management depends on monitoring the HCG levels in her urine using the appropriate quantitative dilution tests.

DIFFICULTIES [s7]WITH CHORIOCARCINOMA If you DON'T HAVE AN IMMUNOLOGICAL PREGNANCY TEST, refer her. If you have limited supplies of pregnancy tests, give priority to these patients, and don't use them for routine pregnancy diagnosis, which should be made clinically anyway.