1-s2.0-s152169340300097x-main indonesia

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 and1.59 per 1000 deliveries, respectively; the disease is more common among the Chinese comparedto the Malays and Indians. While uterine suction is the preferred method of uterine evacuation ofhydatidiform mole, complete evacuation was not achieved at the first attempt in 25% of cases.Partial moles comprise 30% of all moles; these need follow up similar to that for complete molesas they are potentially malignant. In the management of invasive moles, chemotherapy should notbe withheld in the presence of metastases or failure of regression of hCG. Placental site tumoursare rare. Prophylactic hysterectomy and prophylactic chemotherapy are not recommended.However, in those patients with unsatisfactory hCG regression curves indicating ‘at risk’ indeveloping gestational trophoblastic neoplasia (GTN), ‘selective preventive chemotherapy’appears appropriate. Chemotherapy remains the main modality of treatment for GTN. Astumour bulk and location of disease are important determinants in outcome, we categorized ourpatients 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 Malaysiaand other South-East Asian countries. Because of the lack of a Tumour Register in many ofthese countries, the true incidence of the disease is unknown. The University of MalayaMedical Centre is a major referral centre for gynaecological malignancies in Malaysia.During the 12-year period 1991–2002 a total of 3125 cases of gynaecological malignancieswere managed; gestational trophoblastic disease was the third most common problem(9.1%) after carcinoma of the cervix (47%) and ovarian cancer (30.7%). Hydatidiform moleis more prevalent in Indonesia (12.9 per 1000 pregnancies)1, and the Philippines (seven per1000 deliveries).2 In Malaysia the incidence was reported as 2.8 per 1000 deliveries3; asignificantly higher incidence of 5.52 per 1000 deliveries ðP , 0:001Þwas observed amongthe Chinese compared to Malay (2.65) and Indian (0.89). The risk of choriocarcinoma is1000-fold greater after hydatidiform mole than after an abortion or normal pregnancy;

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

MANAGEMENT OF MOLAR PREGNANCY

Once the diagnosis of hydatidiform mole is confirmed (by ultrasound) the uterine cavitymust be emptied; the preferred method is suction curettage. An oxytocin infusion(20 units in 500 ml saline) commenced soon after induction aids in the uterineevacuation and helps to minimize the risk of uterine perforation. The aim in themanagement is to prevent malignant sequelae; hence, complete emptying of the uterusis essential. In 25% of our cases, complete evacuation was not achieved at the firstattempt.3 An ultrasound assessment 1 week later should be routinely performed toensure that the uterus has been emptied. If this is not so a second evacuation needs tobe done; the uterus is now firm and can be curetted more boldly without fear ofperforation.5 The danger of repeated curettage is the development of Asherman’ssyndrome; fertility in these cases can be restored by lysis of intra-uterine adhesion.6 Wehave not encountered acute respiratory distress occurring after uterine evacuation; anincidence of 2% has been reported by others.7 With cardiovascular and respiratorysupport, response is usual within 72 hours.

PROPHYLAXIS AGAINST CHORIOCARCINOMA

Uterine contraction, stimulation by oxytocics and evacuation of the uterus are knownto result in embolization of trophoblasts. The role of chemotherapy at the time ofmolar evacuation remains controversial.8 In the early 1970s at our centre, our patientsreceived prophylactic methotrexate (50 mg in 500 ml of 5% dextrose) infusion duringevacuation of a mole or hysterectomy for mole, and this was continued for 3 to 4 hoursthereafter; we felt that this would help to eliminate these emboli and thus help to solvethe problems of follow up and late diagnosis. Of the 41 patients so treated all had noevidence of choriocarcinoma at 3 years; however, two presented subsequently after 6and 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, asour study above9 has shown, the neoplasia takes longer to be detected and is oftenresistant to treatment.10

We have now stopped the above practice and instead follow these patients afterevacuation with serial hCG and practise ‘selective preventive chemotherapy’ in thoseidentified 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.

926 V. Sivanesaratnam

These patients will receive our ‘low risk’ regime chemotherapy (Table 1). Thejustifications for such an approach are:

† Our patients have difficulty in accepting a long period of observation withouttreatment; many are likely to seek traditional native treatment which is non-effectiveso 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 ourexperience; the risk of such therapy, if any, is definitely less than that of metastaticGTN.

† In all instances full courses of chemotherapy are given until biochemical remission isachieved; this helps to obviate the theoretical risk of development of tumourresistance.

† Long-term follow-up studies after chemotherapy have shown normal reproductivefunction and normal offspring.11

Fifty-one patients receiving ‘selective preventive chemotherapy’ have now beenfollowed up for more than 10 years; none have developed choriocarcinoma, indicatingthe value of such therapy.

Role of prophylactic hysterectomy

In 1966 Tow12 pointed out that the rate of subsequent malignancy in patients withmolar pregnancy at 40 years of age or more, or in those para 3 or more, wassignificantly increased 3 1

2 times. He, therefore, advocated prophylactic hysterectomy insuch patients. Similar studies in the Far East13,14 seemed to suggest that prophylactichysterectomy did reduce the risk of malignancy and mortality.

Hence, it is not unusual to see this practice adopted in many developing countries ofAsia. In our own institution, routine prophylactic hysterectomy was practised prior to1978. Since the availability of radio-immunoassay for hCG from 1979, such routineprophylactic hysterectomy has ceased. We believe that this is too major a procedure toserve a prophylactic purpose: it removes the opportunity for further childbearing. Oneof our patients had a hysterectomy for molar pregnancy at the age of 40 years at aDistrict Hospital in Malaysia in 1980, only to present 9 years later with widespreadmetastatic disease to brain, lungs and porta-hepatis (Figures 1–4). After chemotherapy

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

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

Folinic acid 12 mg oral 24–30 hours

after each dose of methotrexate

Course repeated after 7–10 days Actinomycin D 0.5 mg I.V

on days 2, 4, 6, 8, 10

Course repeated after 7 – 10 days

GTD in developing countries 927

with cisplatinum and etoposide initially followed by the modified CHAMOCA regime(see Table 4) she responded (Figures 5 and 6).

Thus, hysterectomy for a mole is no guarantee that all trophoblastic elements havebeen removed.

PARTIAL HYDATIDIFORM MOLE (PHM)

As a result of lack of awareness and the lack of detailed routine histopathologicalevaluation of the placenta and products of conception evacuated at abortion, whichresult in under-reporting, the true incidence of PHM in Malaysia is unknown. In our owninstitution 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 19weeks’ gestation had a 24 weeks’ enlarged uterus; a mole and a co-existent fetus wereseen on ultrasound. The hCG levels have been said to be not higher than in normal

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

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


pregnancies; yet in one of our cases the urinary pregnancy test was positive at a dilution of1:4096.

It has often been said in the past that PHM is always benign. As recently as 1988Szulman16 and Bagshawe17 claimed that no choriocarcinoma has been associated withPHM. This is in spite of the first documented case as early as 198118 by us of malignantevolution with fatal outcome in a patient with PHM. The partial mole is, thus, part of aspectrum of GTD and not an entity by itself and is potentially malignant. It thereforerequires close follow up as for complete moles.

INVASIVE MOLE

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

Figure 3. Choriocarcinoma – lung metastases.

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


considered proper treatment for molar pregnancy, reported 18 histologically provencases in a series of 210 – an incidence of 8.6%.

Recent advances in treatment and the modern practice of conserving the uterusin a majority cases of molar pregnancy mean that a pathological diagnosis ofinvasive moles cannot be made; the diagnosis of myometrial invasion is not alwayspossible with abdominal or vaginal ultrasound. Deep myometrial invasion in thesecases can result in uterine perforation and massive intraperitoneal haemorrhage.The gross appearance of haemorrhage and necrosis in the uterine wall can be

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

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


confused with choriocarcinoma. This was seen in one of our patients; detailedhistological evaluation showed persistence of villous structures, confirming aninvasive mole.20

Although invasive mole is generally less malignant than choriocarcinoma, 3.4% ofdocumented cases of invasive mole have subsequently died from histologically verifiedchoriocarcinoma.21 Thus, in the presence of metastasis, or failure of hCG regressionand 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 predominantlyof only one type of trophoblastic cell (cytotrophoblast); hCG production is variable orabsent (because syncytial cells are the source of hCG). Curettage is needed to confirmthe diagnosis. The clinical course is variable but, once diagnosed, hysterectomy is therecommended treatment.

In the past 25 years, only one case has been seen at our centre. This was in a 28-year-old lady who, 3 months after her last delivery, developed features of nephroticsyndrome and was managed by the physicians with various drugs. Her conditiondeteriorated with marked oedema of legs, severe ascites and oedema of anteriorabdominal wall. She had also been complaining of prolonged intermittent bleeding sinceher last delivery. After 3 months of treatment she was referred to us. Endometrialcurettage revealed ‘placental site tumour’. After hysterectomy a remarkable clinical andbiochemical 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 morerecently by FIGO.23 The criteria used appear rather complicated for routine use.

Table 2. Choriocarcinoma (n ¼ 98) – sites (University Hospital, Kuala Lumpur 1980–1990).

Genital Number Extragenital Number

Uterus 36 Lungs 78

Vagina 8 Brain 14

Paravaginal 8 Liver 11

Cervix 3 Porta-hepatis 2

Fallopian tube 2 Kidney 1

Stomach 1

Spleen 1

Para-aortic nodes 1


Risk groups

For purposes of assigning appropriate chemotherapy we have categorized our patientsinto low, medium and high risk groups (Table 3).

The ‘low-risk’ group has been described earlier; they received ‘selective preventivechemotherapy’.

Patients in the ‘medium-risk’ group (Table 3), received a combination of MTX andactinomycin D as shown in Table 1. Survival in this group of patients (51 in all) was98%4,24; eight required the ‘high-risk’ regime to achieve biochemical remission. Onedied 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 FIGOstaging 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, latereferrals, previous failed chemotherapy and poor patient compliance in some instances.

Although survival appeared to be worse in those whose antecedent pregnancy was anormal pregnancy4, there was no statistical difference in the type of previous pregnancyand outcome. Similarly, although survival among the Malays was the lowest (75%), therewas no statistical significance to suggest that a racial factor had a role in survival.However, we observed a significantly lower survival (50%) when the interval betweenthe antecedent pregnancy (mole) and the development of GTN exceeded 24 months.4

This finding would suggest that the current advocation of discontinuing follow-up after2 years may not be appropriate; the follow up of moles may, thus, need to be indefinite.

Side-effects of chemotherapy

The side-effects we encountered, apart from nausea and vomiting, included severemucositis, marrow depression, alopecia, extravasation of drugs causing sloughing ofskin etc. Patient compliance will be enhanced if these side-effects are minimized. We

Table 3. Choriocarcinoma – risk groups. University Hospital, Kuala

Lumpur classification.

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


Table 4. Chemotherapy regimes in high-risk cases.

Day

Regime 1 (Modified CHAMOCA)

Treatment Day

Regime 2 (EMA-PE)

Treatment Day

Regime 3 (PEB)

Treatment

1 10 am Vincristine 1 mg/m2 1 8 am Etoposide 100 mg/m2 i.v. in

200 ml saline (30 min)

1 Cisplatinum 100 mg/m2

MTX 100 mg/m2 i.v. bolus 200 mg/m2

in 500 ml dextrose infusion over 12 h

8 am Actinomycin D 0.5 mg bolus Etoposide (VP16) 100 mg/m2

Patients with brain metastases receive

intrathecal MTC 12.5 mg

9 am MTX 100 mg/m2 i.v. bolus

200 mg/m2 in 500 ml dextrose

infusion over 12 h

Bleomycin 10 mg/m2

Etoposide 100 mg/m2

Patients with brain metastases

receive intrathecal MTC 12.5 mg)

2 3 pm Folinic acid 33 mg i.v./oral 2 8 am Etoposide 100 mg/m2 i.v. infusion

3 8 am Folinic acid 33 mg i.v./oral 8 am Actinomycin D 0.5 mg i.v. bolus 2 & 3 Bleomycin 10 mg/m2

10 am Cyclophosphamide 600 mg i.v. bolus 9 am Folinic acid 33 mg i.v./oral 7 & 14 Repeat course day 21

Actinomycin D 0.5 mg bolus 9 pm Folinic acid 33 mg i.v./oral

8 pm Folinic acid 33 mg i.v./oral 3 9 am Folinic acid 33 mg i.v./oral

4 8 am Folinic acid 33 mg i.v./oral 9 pm Folinic acid 33 mg i.v./oral

10 am Actinomycin D 0.5 mg bolus 4 9 am Folinic acid 33 mg i.v./oral

8 pm Folinic acid 33 mg i.v./oral 5–7 Rest

5 10 am Actinomycin D 0.5 mg bolus 8 8 am Cisplatinum 60 mg/m2

6,7 Rest Etoposide (VP16) 100 mg/m2

8 10 am Adriamycin 30 mg/m2 i.v. bolus Repeat course day 21

Cyclophosphamide 400 mg/m2 i.v. bolus

Repeat course day 21

GT

Din

develo

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933

found that the recommended dose of folinic acid of 15 mg advocated by Bagshawe25 wasinadequate; increasing the dose to 33 mg gave satisfactory results. We also reported4

transient premature menopause occurring in three patients after chemotherapy; all hadamenorrhoea and elevated FSH and LH levels. Return of normal ovulatory cycles wasseen in all three after completing six cycles of the oral contraceptive (Nordette) withreturn of FSH and LH to normal levels; one of them subsequently conceived withsuccessful pregnancy outcome.

THE JAUNDICED PATIENT

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

Table 5. Survival according to FIGO staging.

Medium or high risk

FIGO stage Number of cases Alive %

1 15 15 100

2 5 4 80

3 56 44 78.6

4 22 15 68.2

Total 98 79 80.6

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


Another patient had obstructive jaundice due to choriocarcinoma of the commonbile duct; percutaneous drainage failed, resulting in intra-peritoneal haemorrhagerequiring laparotomy. AT-tube drainage of the common bile duct above the obstructionresulted in clearance of the jaundice. When chemotherapy was started, the tumourresolved and the T-tube was removed. Today, with advances in endoscopy, stenting ofthe bile duct via the endoscope/gastroscope will relieve the obstruction.

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

Figure 9. Choriorcarcinoma involving the liver.


CEREBRAL METASTASES

Patients with central nervous system metastases have one of the worst prognoses, withvariable survival rates from various centres (Table 6).

Primary surgery – craniotomy – has been advocated by others in the region.26 Ourmain modality of treatment has been chemotherapy (with intrathecal MTX). In thepresence of raised intracranial pressure dexamethasone has been useful. Suddenintracranial haemorrhage following chemotherapy in one of our patients requiredcraniotomy with successful outcome.

Figure 10. Choriocarcinoma – extensive uterine involvement.

Figure 11. Choriocarcinoma with lung metastasis.


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 bleedingbefore effective chemotherapy could be instituted. Two patients presented to theneurosurgeon initially and were referred to us after craniotomy had confirmedchoriocarcinoma; one of these patients (Figures 1 and 2) had multiple brain metastasesand had bulky disease in lungs and abdomen and was clearly not a suitable case forsurgical intervention.

One of our patients refused chemotherapy after two cycles; she received whole-brain irradiation instead. She is alive and well 20 years later and has had threesubsequent normal pregnancies with satisfactory outcome.33 Two other patients

Figure 12. Choriocarcinoma – biochemical response seen.

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


successfully treated with chemotherapy alone have each had two subsequent normalpregnancies.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 atthoracotomy in 5% of our cases. Similarly, hysterectomy need not be performedroutinely; less than 10% of our cases needed hysterectomy for resistant disease orsevere haemorrhage (Figures 14 and 15).

As haemorrhage can be a problem when hysterectomy is performed, an extra-fascialapproach will allow ligation of the major vessels with ease and ensures complete removalof the tumour which could have invaded through the uterine/cervical wall. Two of ourpatients developed A-V malformation in the uterus, confirmed on pelvic arteriography,resulting in prolonged vaginal bleeding long after biochemical remission had beenachieved. Figures 16 and 17 illustrate the features seen in one of these patients. At

Table 6. Choriocarcinoma with metastases – survivals.

Author

Number of

cases/number alive

Survivals

(%)

Kanazawa & Takeuchi27 15/2 13.3

Lin et al28 34/7 20.5

Ishizuka et al29 27/6 22.2

Bagshawe & Begent30 9/6 66.0

Stilp et al31 4/3 75.0

Athanassiou32 27/22 81.0

Sivanesaratnam3 13/11 84.6

Table 7. Choriocarcinoma – surgical intervention (University

Hospital, Kuala Lumpur, 1981–1990).

Type of surgery Number

Thoracotomy – excision of lung nodules 5a

Excision of vaginal nodules 4

Craniotomy 3

Hysterectomy 3

Laparotomy

Excision of tubal choriocarcinoma 2

Arrest of bleeding from liver nodules 1

Arrest of bleeding after percutaneous cholangiostomy 1

a One had bilateral lung nodes excised.


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

CONCLUSION

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

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

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


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

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

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


REFERENCES

1. Farid Aziz N, Kampono N, Moegmi EM et al. Epidemiology of gestational trophoblastic neoplasm at theDr 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 theSeventh Congress of Indonesian Obstetrics and Gynaecology, Semerang, Indonesia 5–10 July, 1987; 73–80.

* 3. Sivanesaratnam V. The President’s 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 Pacific Basin. ContemporaryReviews 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 ofObstetrics & Gynaecology of the British Commonwealth 1964; 71: 180–184.

* 6. Sivanesaratnam V. Asherman’s syndrome successfully treated by insertion of a multiload copper 250device. Journal of Obstetrics & Gynecology 1986; 7: 22–23.

7. Kohorn El, McGinn RC, Bunard J et al. Pulmonary embolisation of trophoblastic disease in molarpregnancy. Obstetrics & Gynecology 1978; 51 (Suppl.): 165–205.

8. Goldstein DP. Prevention of gestational trophoblastic disease by use of actinomycin D in molarpregnancies. Obstetrics & Gynecology 1974; 43: 475–479.

9. Sivanesaratnam V & Ng KH. Prophylaxis against choriocarcinoma. Medical Journal of Malaysia 1977; 3:219–231.

10. Begent RHJ. Trophoblastic disease. In Sheplard JH & Monaghan JM (eds) Clinical Gynaecologic Oncology, 2ndedn. Oxford: Blackwell, 1990, pp 299–332.

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Practice points

† hysterectomy for hydatidiform mole does not guarantee that all trophoblasticelements have been removed; it does not serve as prophylaxis againstchoriocarcinoma

† selective preventive chemotherapy in those patients at ‘high risk’ after molarevacuation prevents the development of choriocarcinoma subsequently

† choriocarcinoma can follow partial hydatidiform mole; close follow-up of PHMis thus essential

† nephrotic syndrome is a manifestation of placental-site tumour† the commonest extra-genitial site for GTT; tumour bulk present will influence

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 vaginalbleeding


17. Bagshawe KD. Trophoblastic neoplasia – current results and therapeutic issues. In Magreth I (ed.) NewDirection in Cancer Treatment. London: Springer, 1988, p 514.

18. Looi LM & Sivanesaratnam V. Malignant evolution with fatal outcome in a patient with partial hydatidiformmole. Australia & New Zealand Journal of Obstetrics & Gynaecology 1981; 21: 51–52.

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. SingaporeJournal of Obstetrics & Gynecology 1987; 18: 151–153.

21. Obir WB. The pathology of choriocarcinoma. Annals of the New York Academy of Sciences 1971; 172:299–426.

* 22. Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. Cancer 1976; 30: 1373–1385.* 23. Ngan HYS, Benedit JI, Bender HG et al. FIGO staging for gestational trophoblastic neoplasia. International

Journal of Gynecology and Obstetrics 2002; 77: 285–287.24. 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 TrophoblasticDisease, Sydney, 1992.

25. Bagshawe KD. High risk metastatic trophoblastic disease. Obstetric & Gynecologic Clinics of North America1988; 15: 531–543.

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. 237–255.

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 People’s Republic ofChina. Gynecologic Oncology 1983; 15: 166–170.

29. Ishizuka T, Tomoda Y, Kazekis T et al. Intracranial metastases of choriocarcinoma. Cancer 1983; 52:1896–1903.

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 AmericanMedical Association 1972; 221: 276–279.

32. Athanassiou A, Begent RHJ, Newlands ES et al. Central nervous system metastases of choriocarcinoma.Cancer 1983; 52: 1728–1735.

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