Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 17, No. 6, pp.

925 942, 2003

doi:10.1016/S1521-6934(03)00097-X, www.elsevier.com/locate/jnlabr/ybeog

8 Management of gestational trophoblastic disease in developing countries

V. Sivanesaratnam*
MBBS, FRCOG, FICS, FACS, FAMM

Professor, Head and Senior Consultant Department of Obstetrics and Gynaecology, University of Malaya, 50603 Kuala Lumpur, Malaysia

In Malaysia, the incidence of molar pregnancy and gestational trophoblastic neoplasia is 2.8 and 1.59 per 1000 deliveries, respectively; the disease is more common among the Chinese compared to the Malays and Indians. While uterine suction is the preferred method of uterine evacuation of hydatidiform mole, complete evacuation was not achieved at the rst attempt in 25% of cases. Partial moles comprise 30% of all moles; these need follow up similar to that for complete moles as they are potentially malignant. In the management of invasive moles, chemotherapy should not be withheld in the presence of metastases or failure of regression of hCG. Placental site tumours are rare. Prophylactic hysterectomy and prophylactic chemotherapy are not recommended. However, in those patients with unsatisfactory hCG regression curves indicating at risk in developing gestational trophoblastic neoplasia (GTN), selective preventive chemotherapy appears appropriate. Chemotherapy remains the main modality of treatment for GTN. As tumour bulk and location of disease are important determinants in outcome, we categorized our patients into low, medium- and high-risk groups with survivals of 100, 98 and 61.7% respectively. Surgery and radiotherapy have a limited role. Key words: gestational trophoblastic disease; gestational trophoblastic neoplasia; incidence; chemotherapy; surgery; radiotherapy; selective preventive chemotherapy; hydatidiform mole; invasive mole; placental site tumour.

Gestational trophoblastic disease (GTD) is a common gynaecological problem in Malaysia and other South-East Asian countries. Because of the lack of a Tumour Register in many of these countries, the true incidence of the disease is unknown. The University of Malaya Medical Centre is a major referral centre for gynaecological malignancies in Malaysia. During the 12-year period 19912002 a total of 3125 cases of gynaecological malignancies were managed; gestational trophoblastic disease was the third most common problem (9.1%) after carcinoma of the cervix (47%) and ovarian cancer (30.7%). Hydatidiform mole is more prevalent in Indonesia (12.9 per 1000 pregnancies)1, and the Philippines (seven per 1000 deliveries).2 In Malaysia the incidence was reported as 2.8 per 1000 deliveries3; a signicantly higher incidence of 5.52 per 1000 deliveries P , 0:001 was observed among the Chinese compared to Malay (2.65) and Indian (0.89). The risk of choriocarcinoma is 1000-fold greater after hydatidiform mole than after an abortion or normal pregnancy;
* Tel.: 60-3-7950-2059; Fax: 60-3-7955-1741. E-mail address: sivanes@um.edu.my 1521-6934/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.

926 V. Sivanesaratnam

choriocarcinoma is thus more prevalent in the countries of South-East Asia. An incidence of gestational trophoblastic neoplasia occurring in 1.59 per 1000 deliveries was reported in our centre4; a signicantly higher incidence of 4.59 per 1000 deliveries P , 0:001 was seen among the Chinese compared to the Malays and Indian. The risk of choriocarcinoma will be increased without optimal management and follow up of hydatidiform mole.

MANAGEMENT OF MOLAR PREGNANCY Once the diagnosis of hydatidiform mole is conrmed (by ultrasound) the uterine cavity must be emptied; the preferred method is suction curettage. An oxytocin infusion (20 units in 500 ml saline) commenced soon after induction aids in the uterine evacuation and helps to minimize the risk of uterine perforation. The aim in the management is to prevent malignant sequelae; hence, complete emptying of the uterus is essential. In 25% of our cases, complete evacuation was not achieved at the rst attempt.3 An ultrasound assessment 1 week later should be routinely performed to ensure that the uterus has been emptied. If this is not so a second evacuation needs to be done; the uterus is now rm and can be curetted more boldly without fear of perforation.5 The danger of repeated curettage is the development of Ashermans syndrome; fertility in these cases can be restored by lysis of intra-uterine adhesion.6 We have not encountered acute respiratory distress occurring after uterine evacuation; an incidence of 2% has been reported by others.7 With cardiovascular and respiratory support, response is usual within 72 hours.

PROPHYLAXIS AGAINST CHORIOCARCINOMA Uterine contraction, stimulation by oxytocics and evacuation of the uterus are known to result in embolization of trophoblasts. The role of chemotherapy at the time of molar evacuation remains controversial.8 In the early 1970s at our centre, our patients received prophylactic methotrexate (50 mg in 500 ml of 5% dextrose) infusion during evacuation of a mole or hysterectomy for mole, and this was continued for 3 to 4 hours thereafter; we felt that this would help to eliminate these emboli and thus help to solve the problems of follow up and late diagnosis. Of the 41 patients so treated all had no evidence of choriocarcinoma at 3 years; however, two presented subsequently after 6 and 7 years with metastatic disease.9 The disadvantage of routine chemotherapy is that a large number of patients (80-90%) who are unlikely to develop persistent gestational trophoblastic neoplasia (GTN) will be unnecessarily exposed to the potential toxicity of these drugs. Further, as our study above9 has shown, the neoplasia takes longer to be detected and is often resistant to treatment.10 We have now stopped the above practice and instead follow these patients after evacuation with serial hCG and practise selective preventive chemotherapy in those identied at risk of developing GTN/choriocarcinoma, i.e: (i) those with a very slow decline in hCG levels; (ii) those with an initial fall but subsequent rise in hCG levels; (iii) those in whom an initial fall is followed by a plateau.

GTD in developing countries 927

Table 1. Chemotherapy regimes in low- and medium-risk GTN. Low-risk cases Medium-risk cases

Methotrexate (MTX) 50 mg in 200 ml 5% dextrose I.V. on days 1, 3, 5, 7, 9 Folinic acid 12 mg oral 24 30 hours after each dose of methotrexate Course repeated after 710 days

Methotrexate 50 mg in 200 ml 5% dextrose I.V. on days 1, 3, 5, 7, 9 Folinic acid 12 mg oral 24 30 hours after each dose of methotrexate Actinomycin D 0.5 mg I.V on days 2, 4, 6, 8, 10 Course repeated after 7 10 days

These patients will receive our low risk regime chemotherapy (Table 1). The justications for such an approach are: Our patients have difculty in accepting a long period of observation without treatment; many are likely to seek traditional native treatment which is non-effective so that we may see them only when the disease is already well advanced. Single-agent methotrexate (MTX) with folinic acid rescue has minimal toxicity in our experience; the risk of such therapy, if any, is denitely less than that of metastatic GTN. In all instances full courses of chemotherapy are given until biochemical remission is achieved; this helps to obviate the theoretical risk of development of tumour resistance. Long-term follow-up studies after chemotherapy have shown normal reproductive function and normal offspring.11 Fifty-one patients receiving selective preventive chemotherapy have now been followed up for more than 10 years; none have developed choriocarcinoma, indicating the value of such therapy.

Role of prophylactic hysterectomy In 1966 Tow12 pointed out that the rate of subsequent malignancy in patients with molar pregnancy at 40 years of age or more, or in those para 3 or more, was signicantly increased 3 1 2 times. He, therefore, advocated prophylactic hysterectomy in such patients. Similar studies in the Far East13,14 seemed to suggest that prophylactic hysterectomy did reduce the risk of malignancy and mortality. Hence, it is not unusual to see this practice adopted in many developing countries of Asia. In our own institution, routine prophylactic hysterectomy was practised prior to 1978. Since the availability of radio-immunoassay for hCG from 1979, such routine prophylactic hysterectomy has ceased. We believe that this is too major a procedure to serve a prophylactic purpose: it removes the opportunity for further childbearing. One of our patients had a hysterectomy for molar pregnancy at the age of 40 years at a District Hospital in Malaysia in 1980, only to present 9 years later with widespread metastatic disease to brain, lungs and porta-hepatis (Figures 1 4). After chemotherapy

928 V. Sivanesaratnam

Figure 1. Choriocarcinoma metastasis in (R) frontal lobe.

with cisplatinum and etoposide initially followed by the modied CHAMOCA regime (see Table 4) she responded (Figures 5 and 6). Thus, hysterectomy for a mole is no guarantee that all trophoblastic elements have been removed. PARTIAL HYDATIDIFORM MOLE (PHM) As a result of lack of awareness and the lack of detailed routine histopathological evaluation of the placenta and products of conception evacuated at abortion, which result in under-reporting, the true incidence of PHM in Malaysia is unknown. In our own institution we reported that 30% of all molar pregnancies were, in fact, PHM.15 Although it is said that there is no discrepancy in uterine size, one of our patients3 at 19 weeks gestation had a 24 weeks enlarged uterus; a mole and a co-existent fetus were seen on ultrasound. The hCG levels have been said to be not higher than in normal

Figure 2. Choriocarcinoma metastasis in (R) occipital lobe.

GTD in developing countries 929

Figure 3. Choriocarcinoma lung metastases.

pregnancies; yet in one of our cases the urinary pregnancy test was positive at a dilution of 1:4096. It has often been said in the past that PHM is always benign. As recently as 1988 Szulman16 and Bagshawe17 claimed that no choriocarcinoma has been associated with PHM. This is in spite of the rst documented case as early as 198118 by us of malignant evolution with fatal outcome in a patient with PHM. The partial mole is, thus, part of a spectrum of GTD and not an entity by itself and is potentially malignant. It therefore requires close follow up as for complete moles.

INVASIVE MOLE The diagnosis of an invasive mole cannot be made on evacuation of the uterus alone; the exact incidence is thus unknown. Acosta-Sison19, at a time when hysterectomy was

Figure 4. Choriocarcinoma metastasis in porta hepatis; patient was intensely jaundiced.

930 V. Sivanesaratnam

Figure 5. Choriocarcinoma the frontal lobe lesions have resolved after chemotherapy.

considered proper treatment for molar pregnancy, reported 18 histologically proven cases in a series of 210 an incidence of 8.6%. Recent advances in treatment and the modern practice of conserving the uterus in a majority cases of molar pregnancy mean that a pathological diagnosis of invasive moles cannot be made; the diagnosis of myometrial invasion is not always possible with abdominal or vaginal ultrasound. Deep myometrial invasion in these cases can result in uterine perforation and massive intraperitoneal haemorrhage. The gross appearance of haemorrhage and necrosis in the uterine wall can be

Figure 6. Choriocarcinoma the large lesion in porta-hepatis has resolved after chemotherapy.

GTD in developing countries 931

confused with choriocarcinoma. This was seen in one of our patients; detailed histological evaluation showed persistence of villous structures, conrming an invasive mole.20 Although invasive mole is generally less malignant than choriocarcinoma, 3.4% of documented cases of invasive mole have subsequently died from histologically veried choriocarcinoma.21 Thus, in the presence of metastasis, or failure of hCG regression and persistence of the theca-luteal cysts as occurred in one of our patients20, chemotherapy should not be withheld.

PLACENTAL SITE TUMOUR This very rare tumour can follow any type of pregnancy. It is composed predominantly of only one type of trophoblastic cell (cytotrophoblast); hCG production is variable or absent (because syncytial cells are the source of hCG). Curettage is needed to conrm the diagnosis. The clinical course is variable but, once diagnosed, hysterectomy is the recommended treatment. In the past 25 years, only one case has been seen at our centre. This was in a 28-yearold lady who, 3 months after her last delivery, developed features of nephrotic syndrome and was managed by the physicians with various drugs. Her condition deteriorated with marked oedema of legs, severe ascites and oedema of anterior abdominal wall. She had also been complaining of prolonged intermittent bleeding since her last delivery. After 3 months of treatment she was referred to us. Endometrial curettage revealed placental site tumour. After hysterectomy a remarkable clinical and biochemical response was observed.

CHORIOCARCINOMA/GTN The most common sites of disease we observed were the uterus and lungs (Table 2). Chemotherapy remains the main modality of treatment. The severity of the disease has been graded according to various prognostic factors by Bagshawe22 and more recently by FIGO.23 The criteria used appear rather complicated for routine use.

Table 2. Choriocarcinoma (n 98) sites (University Hospital, Kuala Lumpur 19801990). Genital Uterus Vagina Paravaginal Cervix Fallopian tube Number 36 8 8 3 2 Extragenital Lungs Brain Liver Porta-hepatis Kidney Stomach Spleen Para-aortic nodes Number 78 14 11 2 1 1 1 1

932 V. Sivanesaratnam

Table 3. Choriocarcinoma risk groups. University Hospital, Kuala Lumpur classication. Low risk Persitent trophoblastic disease after molar evacuation (no radiological evidence of disease) Medium risk Lesion in uterus (uterus size , 8 weeks) Vaginal nodule , 3 lung nodules (each , 2 cm size) High risk . 3 lung nodules metastasis to brain, liver or kidneys uterine tumour (uterine size . 8 weeks) Paravaginal masses Failed chemotherapy

Risk groups For purposes of assigning appropriate chemotherapy we have categorized our patients into low, medium and high risk groups (Table 3). The low-risk group has been described earlier; they received selective preventive chemotherapy. Patients in the medium-risk group (Table 3), received a combination of MTX and actinomycin D as shown in Table 1. Survival in this group of patients (51 in all) was 98%4,24; eight required the high-risk regime to achieve biochemical remission. One died from hepatitis B infection during clinical remission. The chemotherapy regimes used in the high-risk cases are shown in Table 4. Eighteen out of 47 patients in the high-risk group died, giving an overall survival of 61.7%; six of them died within 7 days of admission.4,24 The survivals according to FIGO staging are shown in Table 5. The reasons for the poor survival in high-risk cases were multifactoral multiorgan involvement and large bulky disease at the time of presentation, late referrals, previous failed chemotherapy and poor patient compliance in some instances. Although survival appeared to be worse in those whose antecedent pregnancy was a normal pregnancy4, there was no statistical difference in the type of previous pregnancy and outcome. Similarly, although survival among the Malays was the lowest (75%), there was no statistical signicance to suggest that a racial factor had a role in survival. However, we observed a signicantly lower survival (50%) when the interval between the antecedent pregnancy (mole) and the development of GTN exceeded 24 months.4 This nding would suggest that the current advocation of discontinuing follow-up after 2 years may not be appropriate; the follow up of moles may, thus, need to be indenite. Side-effects of chemotherapy The side-effects we encountered, apart from nausea and vomiting, included severe mucositis, marrow depression, alopecia, extravasation of drugs causing sloughing of skin etc. Patient compliance will be enhanced if these side-effects are minimized. We

Table 4. Chemotherapy regimes in high-risk cases. Regime 1 (Modied CHAMOCA) Treatment 10 am Vincristine 1 mg/m2 MTX 100 mg/m2 i.v. bolus 200 mg/m2 in 500 ml dextrose infusion over 12 h Patients with brain metastases receive intrathecal MTC 12.5 mg Regime 2 (EMA-PE) Treatment 8 am 8 am 9 am Etoposide 100 mg/m2 i.v. in 200 ml saline (30 min) Actinomycin D 0.5 mg bolus MTX 100 mg/m2 i.v. bolus 200 mg/m2 in 500 ml dextrose infusion over 12 h Patients with brain metastases receive intrathecal MTC 12.5 mg) Etoposide 100 mg/m2 i.v. infusion Actinomycin D 0.5 mg i.v. bolus Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Rest Cisplatinum 60 mg/m2 Etoposide (VP16) 100 mg/m2 Repeat course day 21 Regime 3 (PEB) Treatment Cisplatinum 100 mg/m2 Etoposide (VP16) 100 mg/m2 Bleomycin 10 mg/m2 Etoposide 100 mg/m2

Day 1

Day 1

Day 1

2 3

3 pm 8 am 10 am 8 pm 8 am 10 am 8 pm 10 am 10 am

5 6,7 8

Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Cyclophosphamide 600 mg i.v. bolus Actinomycin D 0.5 mg bolus Folinic acid 33 mg i.v./oral Folinic acid 33 mg i.v./oral Actinomycin D 0.5 mg bolus Folinic acid 33 mg i.v./oral Actinomycin D 0.5 mg bolus Rest Adriamycin 30 mg/m2 i.v. bolus Cyclophosphamide 400 mg/m2 i.v. bolus Repeat course day 21

3 4 5 7 8

8 am 8 am 9 am 9 pm 9 am 9 pm 9 am 8 am

2&3 7 & 14

Bleomycin 10 mg/m2 Repeat course day 21

GTD in developing countries 933

934 V. Sivanesaratnam

Table 5. Survival according to FIGO staging. Medium or high risk Number of cases 15 5 56 22 98

FIGO stage 1 2 3 4 Total

Alive 15 4 44 15 79

% 100 80 78.6 68.2 80.6

found that the recommended dose of folinic acid of 15 mg advocated by Bagshawe25 was inadequate; increasing the dose to 33 mg gave satisfactory results. We also reported4 transient premature menopause occurring in three patients after chemotherapy; all had amenorrhoea and elevated FSH and LH levels. Return of normal ovulatory cycles was seen in all three after completing six cycles of the oral contraceptive (Nordette) with return of FSH and LH to normal levels; one of them subsequently conceived with successful pregnancy outcome.

THE JAUNDICED PATIENT In the presence of severe jaundice due to multiple liver secondaries or obstructive jaundice, it would not be wise to use combinations containing methotrexate. In these situations we have found the PEB regime (Table 4) to be effective and safe, switching to the EMA-CO regime if necessary after the jaundice has resolved. One of our intensively jaundiced patients had extensive disease involving the cervix (with extension to uterus and parametrium), liver, lungs and brain (see Figures 7 13). This case illustrates the effectiveness of carefully selected chemotherapy in such severely ill patients.

Figure 7. A 38-year-old lady with an irregular enlarged uterine mass and enlarged liver.

GTD in developing countries 935

Figure 8. Notice the large haemorrhagic/blackish tumour (choriocarcinoma) in the cervix.

Another patient had obstructive jaundice due to choriocarcinoma of the common bile duct; percutaneous drainage failed, resulting in intra-peritoneal haemorrhage requiring laparotomy. A T-tube drainage of the common bile duct above the obstruction resulted in clearance of the jaundice. When chemotherapy was started, the tumour resolved and the T-tube was removed. Today, with advances in endoscopy, stenting of the bile duct via the endoscope/gastroscope will relieve the obstruction.

Figure 9. Choriorcarcinoma involving the liver.

936 V. Sivanesaratnam

Figure 10. Choriocarcinoma extensive uterine involvement.

CEREBRAL METASTASES Patients with central nervous system metastases have one of the worst prognoses, with variable survival rates from various centres (Table 6). Primary surgery craniotomy has been advocated by others in the region.26 Our main modality of treatment has been chemotherapy (with intrathecal MTX). In the presence of raised intracranial pressure dexamethasone has been useful. Sudden intracranial haemorrhage following chemotherapy in one of our patients required craniotomy with successful outcome.

Figure 11. Choriocarcinoma with lung metastasis.

GTD in developing countries 937

Figure 12. Choriocarcinoma biochemical response seen.

We reported a survival rate of 84.6%.3,24 One patient who had extensive disease (brain, liver, stomach, spleen, and lungs) died from severe gastrointestinal bleeding before effective chemotherapy could be instituted. Two patients presented to the neurosurgeon initially and were referred to us after craniotomy had conrmed choriocarcinoma; one of these patients (Figures 1 and 2) had multiple brain metastases and had bulky disease in lungs and abdomen and was clearly not a suitable case for surgical intervention. One of our patients refused chemotherapy after two cycles; she received wholebrain irradiation instead. She is alive and well 20 years later and has had three subsequent normal pregnancies with satisfactory outcome.33 Two other patients

Figure 13. Choriorcarcinoma a normal cervix after successful treatment (cf. Figure 8).

938 V. Sivanesaratnam

Table 6. Choriocarcinoma with metastases survivals. Number of cases/number alive 15/2 34/7 27/6 9/6 4/3 27/22 13/11 Survivals (%) 13.3 20.5 22.2 66.0 75.0 81.0 84.6

Author Kanazawa & Takeuchi27 Lin et al28 Ishizuka et al29 Bagshawe & Begent30 Stilp et al31 Athanassiou32 Sivanesaratnam3

successfully treated with chemotherapy alone have each had two subsequent normal pregnancies.3

ROLE OF SURGERY Because chemotherapy is effective as primary treatment, surgery has only a limited role. The types of surgery performed at our centre are shown in Table 7. Solitary lesions in the lungs not responding to chemotherapy were excised at thoracotomy in 5% of our cases. Similarly, hysterectomy need not be performed routinely; less than 10% of our cases needed hysterectomy for resistant disease or severe haemorrhage (Figures 14 and 15). As haemorrhage can be a problem when hysterectomy is performed, an extra-fascial approach will allow ligation of the major vessels with ease and ensures complete removal of the tumour which could have invaded through the uterine/cervical wall. Two of our patients developed A-V malformation in the uterus, conrmed on pelvic arteriography, resulting in prolonged vaginal bleeding long after biochemical remission had been achieved. Figures 16 and 17 illustrate the features seen in one of these patients. At

Table 7. Choriocarcinoma surgical intervention (University Hospital, Kuala Lumpur, 19811990). Type of surgery Thoracotomy excision of lung nodules Excision of vaginal nodules Craniotomy Hysterectomy Laparotomy Excision of tubal choriocarcinoma Arrest of bleeding from liver nodules Arrest of bleeding after percutaneous cholangiostomy
a

Number 5a 4 3 3 2 1 1

One had bilateral lung nodes excised.

GTD in developing countries 939

Figure 14. Resistant choriocarcinoma. Hysterectomy specimen shows lesion in wall of uterus. Biochemical response was achieved soon after.

laparotomy, the right uterine artery was ligated at its origin. The bleeding ceased soon after. Both patients have subsequently had two successful full-term deliveries.

CONCLUSION Gestational trophoblastic neoplasia are highly curable. It is obvious that unless these cases are referred to specialized centres where appropriate facilities are available to

Figure 15. Large uterus with extensive involvement by tumour. Surgery in these instances should be via an extra-fascial approach to ensure complete removal of tumour.

940 V. Sivanesaratnam

Figure 16. Persistent bleeding occurred in this patient after biochemical remission.

determine the correct diagnosis, the extent of the disease land to institute effective chemotherapy regimes and optimal followup the best results will not be achieved. Timely referral to such centres is important if these potentially curable patients are to be salvaged. Patient compliance is also essential.

Figure 17. Arrow indicates the A-V malformation at pelvic arteriography.

GTD in developing countries 941

Practice points hysterectomy for hydatidiform mole does not guarantee that all trophoblastic elements have been removed; it does not serve as prophylaxis against choriocarcinoma selective preventive chemotherapy in those patients at high risk after molar evacuation prevents the development of choriocarcinoma subsequently choriocarcinoma can follow partial hydatidiform mole; close follow-up of PHM is thus essential nephrotic syndrome is a manifestation of placental-site tumour the commonest extra-genitial site for GTT; tumour bulk present will inuence the choice of regimes in the jaundiced patient avoid drugs that are hepato-toxic; the PEB regime (cisplatinum, etoposide and bleomycin) is most appropriate therapy uterine A-V malformation may rarely follow successful treatment of GTT; embolization or ligation of uterine artery stops the continued per vaginal bleeding

REFERENCES
1. Farid Aziz N, Kampono N, Moegmi EM et al. Epidemiology of gestational trophoblastic neoplasm at the Dr Cipto Mungun Peusmo Hospital, Jakarta. Advances in Experimental Medicine and Biology 1984; 176: 166. 2. Panililo HB. Gestational trophoblastic disease newer concepts and approaches. In Proceedings of the Seventh Congress of Indonesian Obstetrics and Gynaecology, Semerang, Indonesia 5 10 July, 1987; 73 80. * 3. Sivanesaratnam V. The Presidents Lecture: Gestational trophoblastic disease the Malaysian experience. Proceedings of the 3rd Malaysian Congress of Obstetrics and Gynaecology, Kuala Lumpur 1991. 4. Sivanesaratnam V. Gestational trophoblastic disease in Malaysia and the Pacic Basin. Contemporary Reviews in Obstetrics and Gynaecology 1995; 7: 179 184. 5. Chun D, Braga C, Chow C et al. Clinical observation on some aspects of hydatidiform mole. Journal of Obstetrics & Gynaecology of the British Commonwealth 1964; 71: 180184. * 6. Sivanesaratnam V. Ashermans syndrome successfully treated by insertion of a multiload copper 250 device. Journal of Obstetrics & Gynecology 1986; 7: 22 23. 7. Kohorn El, McGinn RC, Bunard J et al. Pulmonary embolisation of trophoblastic disease in molar pregnancy. Obstetrics & Gynecology 1978; 51 (Suppl.): 165 205. 8. Goldstein DP. Prevention of gestational trophoblastic disease by use of actinomycin D in molar pregnancies. Obstetrics & Gynecology 1974; 43: 475479. 9. Sivanesaratnam V & Ng KH. Prophylaxis against choriocarcinoma. Medical Journal of Malaysia 1977; 3: 219231. 10. Begent RHJ. Trophoblastic disease. In Sheplard JH & Monaghan JM (eds) Clinical Gynaecologic Oncology, 2nd edn. Oxford: Blackwell, 1990, pp 299332. 11. Rustin GJ, Booth M, Dent J et al. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. British Medical Journal 1984; 288: 103106. * 12. Tow WSH. The inuence of the primary treatment of hydatidiform mole on its subsequent course. Journal of Obstetrics & Gynaecology of the British Commonwealth 1966; 77: 544 552. 13. Chun D, Braga C, Chow C et al. Treatment of hydatidiform mole. Journal of Obstetrics & Gynaecology of the British Commonwealth 1964; 71: 185. 14. Soma H, Takayama M, Saito T et al. Management of hydatidiform mole in women over 45 years old. AsiaOceania Journal of Obstetrics and Gynecology 1983; 9: 393 397. 15. Cheah PL, Looi LM & Sivanesaratnam V. Hydatidiform molar pregnancy in Malaysian women, a histopathological study from University Hospital, Kuala Lumpur. Malaysian Journal of Pathology 1993; 15: 5963. 16. Szulman AE. Trophoblastic disease: clinical pathology of hydatidiform mole. Obstetrics & Gynecology Clinics of North America 1988; 15: 443 456.

942 V. Sivanesaratnam 17. Bagshawe KD. Trophoblastic neoplasia current results and therapeutic issues. In Magreth I (ed.) New Direction in Cancer Treatment. London: Springer, 1988, p 514. 18. Looi LM & Sivanesaratnam V. Malignant evolution with fatal outcome in a patient with partial hydatidiform mole. Australia & New Zealand Journal of Obstetrics & Gynaecology 1981; 21: 5152. 19. Acosta-Sison H. Indications for immediate hysterectomy with curettage in cases of hydatidiform mole. American Journal of Obstetrics & Gynecology 1961; 81: 715 717. 20. Goh JYL, Sivanesaratnam V & Peh SC. Perforating invasive mole with subsequent metastasis. Singapore Journal of Obstetrics & Gynecology 1987; 18: 151153. 21. Obir WB. The pathology of choriocarcinoma. Annals of the New York Academy of Sciences 1971; 172: 299426. * 22. Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. Cancer 1976; 30: 13731385. * 23. Ngan HYS, Benedit JI, Bender HG et al. FIGO staging for gestational trophoblastic neoplasia. International Journal of Gynecology and Obstetrics 2002; 77: 285287. 24. Sivanesaratnam V, Looi LM & Ching SL. Gestational trophoblastic tumour results of treatment at the University Hospital, Kuala Lumpur. Proceedings of the VI World Congress on Gestational Trophoblastic Disease, Sydney, 1992. 25. Bagshawe KD. High risk metastatic trophoblastic disease. Obstetric & Gynecologic Clinics of North America 1988; 15: 531543. 26. Ratnam SS & Chew SC. The modern management of trophoblastic disease. In: J. Stalworthy, G. Bourne (Eds). Recent Advances in Obstetrics and Gynaecology. London: Churchill Livingstone, 1979; pp. 237255. 27. Kanazawa K & Takeuchi S. Clinical analysis of intracranial metastases in gestational choriocarcinoma. Australia & New Zealand Journal of Obstetrics & Gynecology 1985; 25: 16 20. 28. Lin TL, Deppe G, Chang OT & Tan TT. Cerebral metastases of choriocarcinoma in Peoples Republic of China. Gynecologic Oncology 1983; 15: 166170. 29. Ishizuka T, Tomoda Y, Kazekis T et al. Intracranial metastases of choriocarcinoma. Cancer 1983; 52: 18961903. 30. Bagshawe KD & Begent RHJ. In Coppleson M (ed.) Gynaecological Oncology. London: Churchill Livingstone, 1981, pp 770. 31. Stilp TJ, Bucy PC & Brewer JI. Cure of metastases choriocarcinoma of the brain. Journal of the American Medical Association 1972; 221: 276 279. 32. Athanassiou A, Begent RHJ, Newlands ES et al. Central nervous system metastases of choriocarcinoma. Cancer 1983; 52: 17281735. 33. Sivanesaratnam V & Sen DK. Normal pregnancy after successful treatment of choriocarcinoma with cerebral metastases. Journal of Reproductive Medicine 1988; 33: 402403.