7 The immune system in disease: gestational trophoblastic tumours E D W A R D S. N E W L A N D S ROSEMARY A. FISHER FRANCES SEARLE
INTRODUCTION Gestational trophoblastic tumours (GTI') are unique in that by definition they must follow a normal or abnormal pregnancy and the tumours express paternal genes and are therefore an allograft in the maternal host. GTI" occur most commonly after the abnormal pregnancy, hydatidiform mole (HM), but can also occur after a normal pregnancy (Table 1). Trophoblast in a normal pregnancy shares some characteristics with malignancy in that the trophoblast invades the myometrium and forms intimate connections with the maternal circulation. Trophoblast from a normal pregnancy can on occasion embolize to the lungs. Sufficient trophoblast cells may be present in the circulation to allow antenatal diagnosis of genetic disorders, using the polymerase chain reaction (Mueller et al, 1990). Table 1. Gestational trophoblastic tumours. Antecedent pregnancy
Outcome
Hydatidiform mole Normal pregnancy ] Ectopic pregnancy [ Stillbirth / Spontaneous abortionJ
~ Spontaneous regression Persistent trophoblastic disease "~ FChoriocarcinoma ~ LPlacental site trophoblastic tumour
Since GTT express not only paternal genes but paternally derived antigens, it might be anticipated that the immune system plays a major role in eliminating these diseases. However, it has been hypothesized that the process whereby the mother does not reject a normal fetus may operate in the situation where there is a trophoblastic tumour. The ABO blood group system influences the outcome of patients developing trophoblastic tumours Baillidre's Clinical Obstetrics and Gynaecology--
Vol. 6, No. 3, September 1992 ISBN 0-7020-1634-9
519 Copyright © 1992, by Bailli~re Tindall All rights of reproduction in any form reserved
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and patients with B or AB whose partners are either group O or A may have a worse prognosis (Bagshawe, 1976). Lawler (1978) studied the development of anti-HLA antibodies in a large group of patients with GTT. Her results showed that (1) choriocarcinoma can follow the birth of an HLA incompatible infant but that these patients as a group had more compatible offspring than would be expected; and (2) that anti-HLA antibodies were present in a greater proportion of, and in higher titres in, pregnancies with a hydatidiform mole than in normal pregnancies. The antibodies also persisted for longer in patients with tumours than following normal pregnancies. Her conclusion was that the HLA system did not appear to exert any major influence on the chance of a woman developing a trophoblastic tumour. All GTT synthesize varying amounts of a range of pregnancy hormones including human chorionic gonadotrophin (hCG) and its subunits and fragments (see below, Tumour markers and the role of hCG and its fragments), hCG is produced throughout a normal pregnancy and its synthesis is switched on not only in GTTs but in certain other tumours such as germ cell tumours and, less commonly, other malignancies such as bladder carcinoma. Its function both in normal pregnancy and in those tumours which produce it remains largely obscure. While hCG may stimulate the synthesis of a range of hormones and may have an immunomodulating effect, its role in malignancy is probably quite complex. On the one hand, while GTT apparently cannot grow clinically without synthesizing hCG, the same molecule can in other circumstances suppress carcinogenesis and tumour growth. This is shown in a recent study where hCG suppressed the development of carcinogen-induced mammary tumours in rats (Russo et al, 1990). Although uncommon, GTT are important since with proper management it should now be rare for a woman to die from her tumour and in most cases fertility can be preserved. The main reasons for this success are threefold: (1) for reasons that are not clearly understood, GT1~are highly sensitive to a range of currently available therapeutic agents; (2) the universal production of a serological tumour marker, hCG, makes possible a sensitivity and accuracy of screening, monitoring, management and follow-up of patients which is unique in clinical cancer; (3) detailed analysis of large groups of patients with these rare diseases has allowed the recognition of a range of prognostic factors, permitting the adjustment of intensity of treatment so that each patient only receives the minimum treatment necessary to eliminate her disease. PATHOLOGY The terminology in GTT and gestational trophoblastic disease (GTD) remains confusing partly due to the interchangeable use of histopathological and clinical terms. Since the management of patients at risk of developing a GTT is focused on the behaviour of the serum concentration of hCG, the curability of most of these patients means that frequently clinical decisions are made without further pathological specimens being obtained.
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Hydatidiform moles (HM) HM are premalignant conditions and in most cases remit spontaneously once the HM has been evacuated from the uterus. Molar pregnancies are now clearly distinguished both on morphological and cytogenetic grounds into complete and partial HM (Szulman and Surti, 1978a,b).
Complete hydatidiform mole A complete HM forms a multivesicular mass composed of grossly distended chorionic villi without a gestational sac or fetus. Hydropic change usually affects all the villi and trophoblastic hyperplasia is present to a variable extent.
Partial hydatidiform mole A partial HM is one in which only a proportion of the chorionic villi are affected by vesicular change, the abnormal villi being admixed with normal villi. The vesicular villi tend to be smaller than those in the complete HM, frequently showing a deeply indented outline. The presence of a fetus may be recognized either macroscopically or by the presence of nucleated red cells. It is likely that many partial HM are classified as 'products of conception' at uterine evacuation for a 'miscarriage'. Without genetic analysis to confirm that a specimen is a partial HM, underdiagnosis will continue. The natural history of partial HM has recently been better defined. While the malignant sequelae following partial HM is much less than after complete HM, a small number (approximately 1 in 200) of patients with partial HM require chemotherapy for a GTI" and therefore all patients need to be registered and followed up in the same way as for complete HM (Bagshawe et al, 1990).
Invasive hydatidiform mole This term is applied when a HM (complete or partial) invades into the myometrium. Since this is part of the normal behaviour of molar trophoblast, this is common, as is confirmed both on ultrasound examination of the uterus and by the hCG profile following evacuation of the uterine cavity. Pathologically this condition can only be confirmed by either having curettings containing a significant amount of myometrium or in the occasional case where a hysterectomy is performed rather than evacuation of the uterine cavity for a molar pregnancy.
Choriocarcinoma Choriocarcinoma is composed of both cyto- and syncytiotrophoblastic cells, characteristically surrounded by necrosis and haemorrhage. Choriocarcinoma is unusual in stimulating virtually no connective tissue support for the tumour
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and this is reflected by its clinical behaviour in its rapid haematogenous spread and haemorrhagic complications at sites where the tumour is growing. In the past choriocarcinoma was a rapidly lethal neoplasm but with proper management and modern chemotherapy, most patients should achieve complete remission. Placental site trophoblastic tumour This rare tumour is composed mainly of cytotrophoblast with very little syncytiotrophoblast. It can occur after both normal and molar pregnancies (Fisher et al, 1992b). The tumour tends to grow locally with a lower metastatic potential than choriocarcinoma. In most cases described so far its spread is mainly by local infiltration rather than widespread dissemination. The management of these tumours is different from other GTT in that they are less chemosensitive and if localized to the uterus the treatment of choice is surgery. Occasional long-term remissions have been obtained with intensive chemotherapy (Dessau et al, 1990). EPIDEMIOLOGY The epidemiology of GTT is still poorly understood although major progress in this area is likely to come from modern molecular genetics. The identification of the abnormal gene expression associated with the different clinical and pathological syndromes is fundamental to further progress in our understanding of these conditions. Many reports in the past, before the recognition by Szulman and Surti (1978a,b) that there are two different pathological syndromes of complete and partial HM, contain patients with both conditions and makes the earlier published data difficult to interpret. However, there is considerable evidence in the literature that the incidence of HM in different parts of the world varies considerably. In a number of countries including Japan and the Far East the incidence would appear to be much higher than it is in Europe and North America. Matsuura et al (1984) analysed the incidence of HM in Hawaii between 1968 and 1981. In 278 cases, 69.4% were complete HM, 24.5% were partial HM and 6.1% were non-molar pregnancies. This is a complete : partial HM ratio of 2.9 : 1. The population studied was of particular interest since several different racial groups live in Hawaii and have more or less equal access to hospital facilities. In Table 2 the incidence in the different racial groups in Hawaii are shown. This study confirms that molar pregnancies are more common in Filipino, Japanese and Oriental groups. The fact that the incidence is similar in Caucasians and native Hawaiians suggests that an environmental cause does not explain this difference in incidence between racial groups. Molar pregnancies are more common at the extremes of the reproductive age range. In a study of over 8000 cases of HM registered in England and Wales between 1973 and 1983 the relative risk of a HM in patients under 15 years was 6 and in patients over 50 years was 411 (when compared with the incidence in patients aged between 25 and 29 years) (Bagshawe et al, 1986).
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GESTATIONAL TROPHOBLASTIC TUMOURS Table 2. Incidence of complete hydatidiform moles by maternal race in Hawaii (1968-1981).
White Filipino Japanese Hawaiian Orientals (Chinese, Koreans) All
Rate/10 000
Incidence
8.0 17.5 16.5 7.7 17.5 12.1
1 : 1256 1 : 571 1 : 607 1 : 1304 1 : 571 1 : 825
Modified with permission from Matsuura et al, 1984.
Analysis of this large group of patients confirmed the increased risk of a second HM with an incidence of 1 in 76 and of a third HM of 1 in 6.5. This increased risk of further GTT following subsequent pregnancies is an important feature in their follow-up in that they need confirmation that the hCG returns to normal following each subsequent pregnancy. GT-I" occur after approximately 1 in 50 000 full-term pregnancies. Where histology is available, these tumours are choriocarcinoma or occasionally placental site trophoblastic tumours. In Charing Cross Hospital, London, a referral centre for trophoblastic tumours, this pattern of disease accounted for 137 (12.9%) of 1058 patients treated between 1968 and 1985. GTT following a full-term pregnancy behave aggressively and form that subgroup described in the older literature of women presenting with fulminating disease and dying within a matter of weeks. The clinical pattern in the patients presenting with choriocarcinoma following a full-term pregnancy is intriguing. In all the patients in the Charing Cross series the pregnancy reached term normally and no abnormality was noted in any placenta, yet the patient frequently presented with widespread disease within a matter of weeks of delivery. This raises the possibility that the presence of the fetus may suppress the malignant trophoblast until after delivery. We have attempted to identify an inhibitory factor in cord serum from pregnancies using normal adult serum as a control. No inhibitory factor has been identified in vitro or in vivo with choriocarcinoma xenografts. However, in a recent review of the literature Flam et al (1989) identified nine cases in which both mother and infant have had tumour invasion with choriocarcinoma. The influence of exogenous hormones on the behaviour of molar trophoblast is an area of considerable interest. Stone and Bagshawe (1976) suggested that patients who were exposed to oestrogen and/or progesterone had an increased incidence of malignant sequelae following a molar pregnancy. We have recently analysed the patients registered between 1973 and 1989 (Table 3). These data indicate that there is probably very little effect of exogenous hormones in patients whose hCG has already returned to normal, indicating minimal or no residual abnormal trophoblast. However, in patients given exogenous hormones while their hCG is still raised, the proportion requiring chemotherapy is 30.7%, compared with 8-9% in the overall population (Bagshawe et al, 1986). This subgroup of patients should not, therefore, receive oral contraceptives owing to the
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E. S. NEWLANDS ET AL Table 3. Effects of taking oral contraceptives within 6 months of evacuation of a hydatidiform mole, Charing Cross Hospital (1973-1989). Total number of patients Total number of patients requiring chemotherapy Numbers who received oral contraceptive A. Patients with normal hCG prior to oral contraceptive Number requiring chemotherapy (0.0047%) B. Patients with raised hCG given oral contraceptives Number requiring chemotherapy A versus B, P12
< 103 AxO O×A OorA x unknown 1-4 Spleen Kidney
104-105 B × A or O AB×AorO
> lOs
4-8 GI tract Liver
>8 Brain
3-5 cm
> 5 cm Single drug
2 or
more drugs Low risk, 0-5; medium risk, 6-9; high risk, >9; CXH, Chafing Cross Hospital, London. assessment of the volume of viable tumour in the body; (3) failure of previous c h e m o t h e r a p y to eliminate the G T T . A purely anatomical staging system is included in the World Health Organisation report ( W H O , 1983) but, although the above scoring system appears complex, a detailed comparison (Smith et al, 1992) has confirmed that it can identify a small subgroup of patients who would be either underor overtreated if their treatment was based solely on anatomical staging. This scoring system can also be applied in centres without high technology equipment since the important variables include only the history, examination, chest X-ray and a quantitative h C G estimation.
TREATMENT A t the Charing Cross Hospital, L o n d o n we have used the prognostic scoring system in Table 7 and have subdivided the patients into low, m e d i u m and high risk categories. W e have retained the medium risk category of patients since this allows the assessment of a new anticancer agent in a patient population where the survival is already 100%, but without compromising their subsequent treatment (for discussion, see Newlands et al, 1986). H o w e v e r , for m a n y centres it is probably simpler to have two risk categories, low and high risk, since the toxicity with our current high risk schedule (the E M A / C O regimen; see below) is only moderately m o r e than our m e d i u m risk schedule and m a y induce complete remission m o r e rapidly. Our m a n a g e m e n t of these three risk categories has each been reviewed recently: the results with the low risk patients in Bagshawe et al (1989), the m e d i u m risk patients in Newlands et al (1986) and the high risk patients in Newlands et al (1991). These results are summarized briefly here.
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Low risk patients Since 1964 these patients have been treated with a simple schedule of methotrexate 50mg i.m. given on days 1, 3, 5 and 7, and folinic acid 6mg i.m. on days 2, 4, 6 and 8, with a 6-day interval between courses. This schedule is, in general, well tolerated although 5% of patients need to change treatment because of toxicity (usually severe pleuritic chest pain or drug-induced hepatitis). However, even in correctly stratified patients 20% will need to change because of the development of drug resistance. This means that methotrexate is not a simple 'wonder drug' for this group of patients since a total of 25 % will need to change treatment because of either drug resistance or toxicity. Therefore these patients need to be carefully monitored to ensure that they achieve complete remission. The survival in these patients is excellent even though they may need to change treatment and the only deaths in patients treated with this schedule
Figure 1. Patient presenting several months after a normal pregnancywith symptomsof a subarachnoid haemorrhageand a hemianopia. CT scan confirmedthree cerebral metastases (arrowed).
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following the introduction of the prognostic scoring system were one from concurrent but not therapy-induced non-Hodgkin's lymphoma and one from hepatitis (Bagshawe et al, 1989). Medium risk patients These patients need to be treated with chemotherapy either using drugs in sequence or in combination. Between 1974 and 1979 2 patients out of 75 (3%) in this category died from their tumours despite intensive treatment. Following the introduction of etoposide (Newlands and Bagshawe, 1980), there have been no further deaths in this subgroup of patients. High risk patients Since 1979 we have used a weekly chemotherapy schedule, trying to
Figure 2, Same patient as in Figure 1. An additional complication in this paticnt was increasing obstructive jaundice due to a pancreatic mass of tumo~tr obstructing the c o m m o n bite duct (CT showing dilated bile ducts and pancreatic mass. arrowed). This required stcnting so that intensive chemotherapy with E M A / C O was not delayed by the impaired liver function.
Fortnightly x 20 Monthly × 20 2-Monthly x 20
Then every 6 months
Fortnightly x 5 Monthly × 10 Then only if necessary
Urine
Then every 6 months
As for low risk
Blood
3-Monthly x 20
Fortnightly × 5 Monthly x 5 Then only if necessary
Fortnightly x 10 Monthly x 10 2-Monthly x 10
Urine
Then only if necessary
Fortnightly x 20 Monthly x 10 2-Monthly x 10
Blood
Score value > 9
High risk
3-Monthly x 10
Blood
Score value 6--9
Score value 0-5
Urine
Medium risk
Table 8. Follow-up for gestational trophoblastic tumour patients who have received chemotherapy.
Low risk
Lit t~ 4~
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maximize dose intensity in order to minimize the development of drug resistance. The EMA/CO schedule contains etoposide, methotrexate and actinomycin D, cyclophosphamide and vincristine (Oncovin). In our recent analysis (Newlands et al, 1991) of 148 patients receiving this schedule, the overall survival was 85 %. There were two subgroups of patients: 76 who had received no prior chemotherapy and whose survival was 82%. Ten of the 14 patients who died in this group died early from the following causes: respiratory failure (five), cerebral metastases (three), hepatic failure (one), pulmonary embolism (one). Some of the clinical problems presented by this variant of GTT are illustrated in Figures 1 and 2. In none of these cases was the antecedent pregnancy a HM (they were: livebirth, six; stillbirth, one; spontaneous abortion, three). It will be difficult to improve the survival in this particular subgroup of patients since there was no immediate antecedent pregnancy to allow them to be entered into a screening programme such as that for patients who have had a HM. The ready awareness that widespread malignancy in a young woman may possibly be choriocarcinoma which can be confirmed by a very high hCG will minimize the number of patients presenting with this disease extent and consequent mortality. The second group of high risk patients are those relapsing after previous chemotherapy, either our own treatment failures or those referred from centres abroad. The survival in these 72 patients was 89%. These patients were all on follow-up and therefore their disease extent was less than in the previous group. The cause of death in these patients was usually the development of drug-resistant disease and these patients could not be saved either by extensive surgery or by the addition of cis-platinum (cisplatin) to the chemotherapy (Newlands et al, 1991). POST-TREATMENT FOLLOW-UP AND FERTILITY Following completion of their chemotherapy, patients need to be followed up regularly with hCG estimations to confirm that their disease is in remission. Initially the follow-up is with serum and urine samples (Table 8). In due course the follow-up is only on urine samples. In the UK this is computerized and automatic reminders are sent to patients so that they do not get lost to follow-up. Patients are advised to avoid a subsequent pregnancy until 12 months after completing their chemotherapy, in order to minimize the potential teratogenicity of the treatment. Even in the high risk patients receiving intensive chemotherapy, patients return to normal activity within a few months and most side-effects of the treatment are reversible. Chemotherapy-induced alopecia is always reversible. To date, late sequelae from chemotherapy have been remarkably rare. Two patients receiving extensive treatment (lasting more than 6 months) developed acute myeloid leukaemia which was probably therapy-induced. This emphasizes the importance of achieving complete remission as rapidly as possible to minimize this recognized complication of intensive chemotherapy. In the population analysed between 1968 and 1978 there was no increase in second tumours in 457 long-term survivors (Rustin et al, 1983).
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The outcome of subsequent pregnancies following chemotherapy is usually successful. In an analysis of 445 long-term survivors treated at the Charing Cross Hospital, London, 90% of those who wished to become pregnant succeeded and 86% of these had at least one livebirth (Rustin et al, 1984). However, there was a tendency for patients who had received three or more drugs to be less likely to have a livebirth than those who had received only one or two drugs. There was no increase in the incidence of congenital malformation compared with the normal population.
SUMMARY
Trophoblastic tumours form a spectrum of disease from the borderline malignancy of HM to highly aggressive choriocarcinoma. Their management requires the integration of the information derived from serial hCG estimations, the clinical history and pattern of spread of the disease, so that our understanding of the prognostic variables can be applied appropriately. This maximizes the patient's chances of complete remission from her disease with the minimum of toxicity. Given our knowledge of this group of diseases and an integrated approach to management, it should be uncommon for any woman to die from her trophoblastic tumour.
REFERENCES Bagshawe KD (1976) Risk and prognostic factors in trophoblastic neoplasia. Cancer 38: 1373-1385. Bagshawe KD & Lawler SD (1982) Choriocarcinoma. In Schottenfeld D & Fraumeni JF (eds) Cancer Epidemiology and Prevention, pp 909-924. Philadelphia: Saunders. Bagshawe KD, Dent J & Webb J (1986) Occasional survey: hydatidiform mole in England and Wales 1973-83. Lancet ii: 6734577. Bagshawe KD, Dent J, Newlands ES et al (1989) The role of low dose methotrexate and folinic acid in gestational trophoblastic tumours (GTr). British Journal of Obstetrics and Gynaecology 96: 795-802. Bagshawe KD, Lawler SD, Paradinas FJ et al (1990) Gestational trophoblastic tumours following initial diagnosis of partial hydatidiform mole. Lancet 335: 1074-1076. Birken S, Armstrong EG, Kolks MAG et al (1988) Structure of the human chorionic gonadotrophin beta subunit fragment from pregnancy urine. Endocrinology 123(1): 572-583. Boorstein WR, Vamkakopoulos NC & Fiddes JC (1982) Human chorionic gonadotrophin beta subunit is encoded by at least eight genes arranged in tandem and inverted pairs. Nature 300: 419-422. Braunstein GD (1983) HCG expression in trophoblastic and non-trophoblastic tumours. In Braunstein GD (ed.) Oncodevelopmental Markers. Biologic, Diagnostic and Monitoring Aspects, pp 351-357. New York: Academic Press. Campbell RK, Dean-Emig DM & Moyle WR (1991) Conversion of human chorionic gonadotrophin into a follitropin by protein engineering. Proceedings of the National Academy of Sciences (USA) 88: 760-764. Chaganti RSK, Kodura PRK, Chakraborty R et al (1990) Genetic origin of a trophoblastic choriocarcinoma. Cancer Research 50: 6330-6333. Cole LA & Birken S (1988) Origin and occurrence of human chorionic gonadotrophin beta subunit core fragment. Molecular Endocrinology 2: 825-830. Cole LA, Kardana A & Birken S (1989) The isomers, subunits and fragments of hCG. Serono Symposia Publications 65: 59-78.
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Lathrop JC, Lauchlan S, Nayak R & Ambler M (1988) Clinical characteristics of placental site trophoblastic tumor (PSST). Gynecologic Oncology 31: 32-42. Lawler SD (1978) HLA and trophoblastic tumours. British Medical Bulletin 34(3): 305-308. Lawler S & Fisher RA (1986) Genetic aspects of gestational trophoblastic tumours. In Ichinoe K (ed.) Trophoblastic Diseases, pp 23-33. Tokyo, New York: Igaku-Shoin. Lawler SD, Klouda PT & Bagshawe KD (1976) The relationship between HLA antibodies and the causal pregnancy in choriocarcinoma. British Journal of Obstetrics and Gynaecology 83: 651-655. Lawler SD, Pickthall VJ, Fisher RA et al (1979) Genetic studies of complete and partial hydatidiform moles. Lancet ii: 58. Lawler SD, Fisher RA, Pickthall VJ et al (1982a) Genetic studies on hydatidiform moles. I. The origin of partial moles. Cancer Genetics and Cytogenetics 5: 309-320. Lawler SD, Povey S, Fisher RA & Pickthall VJ (1982b) Genetic studies on hydatidiform moles. II. The origin of complete moles. Annals of Human Genetics 46: 209-222. Lawler SD, Fisher RA & Dent J (1991) A prospective study of hydatidiform mole. American Journal of Obstetrics and Gynecology 164: 1270-1277. Matsuura J, Chiu D, Jacohs P e t al (1984) Complete hydatidiform mole in Hawaii: an epidemiological study. Genetic Epidemiology 1: 271-284. Mueller UW, Hawes CS, Wright AE et al (1990) Isolation of fetal trophoblast cells from peripheral blood of pregnant women. Lancet 336: 197-200. Newlands ES & Bagshawe KD (1980) Antitumour activity of the epipodophyllin derivative VP16-213 (etoposide: NSC-141540) in gestational choriocarcinoma. European Journal of Cancer 16: 401-405. Newlands ES, Bagshawe KD, Begent RHJ et al (1986) Developments in chemotherapy for medium and high risk patients with gestational trophoblastic tumours (1979-1984). British Journal of Obstetrics and Gynaecology 93: 63~69. Newlands ES, Bagshawe KD, Begent RHJ et al (1991) Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. British Journal of Obstetrics and Gynaecology 98: 550-557. Ohama K, Kajii T, Okamoto E et al (1981) Dispermic origin of XY hydatidiform moles. Nature 292: 551-552. Osada H, Kawata M, Yamada M, Okumura K & Takamizawa H (1991) Genetic identification of pregnancies responsible for choriocarcinomas after multiple pregnancies by restriction fragment length polymorphism analysis. American Journal of Obstetrics and Gynecology 165: 682-688. Park WW (1957) The occurrence of sex chromatin in chorionepitheliomas and hydatidiform moles. Journal of Pathology and Bacteriology 74: 197-206. Policastro PF, Daniels-McQueen S, Carle G e t al (1986) A map of the hCG beta-LH beta gene cluster. Journal of Biological Chemistry 261: 5907-5916. Russo IH, Koszalka M & Russo J (1990) Human chorionic gonadotrophin and rat mammary cancer prevention. Journal of the National Cancer Institute 82: 1286-1289. Rustin GJS, Rustin F, Dent J e t al (1983) No increase in second tumours after cytotoxic chemotherapy for gestational trophoblastic tumours. New England Journal of Medicine 308: 473--476. Rustin GJS, Booth M, Dent J et al (1984) Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. British Medical Journal 288: 103-106. Sasaki S, Katayama PK, Roesler M e t al (1982) Cytogenetic analysis of choriocarcinoma cell lines. Acta Obstetrica et Gynecologica Japonica 34: 2253-2256. Seckl MJ, Rustin GJS, Newlands ES et al (1991) Pulmonary embolism, pulmonary hypertension, and choriocarcinoma. Lancet 338: 1313-1315. Sheppard DM, Fisher RA, Lawler SD & Povey S (1982) Tetraploid conceptus with three paternal contributions. Human Genetics 62- 371-374. Sheppard DM, Fisher RA & Lawler SD (1985) Karyotypic analysis and chromosome polymorphisms in four choriocarcinoma cell lines. Cancer Genetics and Cytogenetics 16: 251-259. Smith DB, Holden L, Newlands ES & Bagshawe KD (1992) Correlation between clinical staging (FIGO) and prognostic groups in gestational trophoblastic disease. Submitted to British Journal of Obstetrics and Gynaecology.
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Stone M, Dent J, Kardana A et al (1976) Relationship of oral contraception to development of trophoblastic tumour after evacuation of a hydatidiform mole. British Journalof Obstetrics and Gynaecology 83: 913-916. Surti U, Szulman AE, Wagner K et al (1986) Tetraploid partial hydatidiform moles: two cases with a triple paternal contribution and a 92,XXXY karyotype. Human Genetics 72" 15--21. Szulman A & Surti U (1978a) The syndromes of hydatidiform mole. I. Cytogenetic and morphologic correlations. American Journal of Obstetrics and Gynecology 131: 665--671. Szulman A & Surti U (1978b) The syndromes of hydatidiform mole. II. Morphologic evidence of the complete and partial mole. American Journal of Obstetrics and Gynecology 132: 20-27. Tormey DC, Waalkes PT & Simon RM (1977) Biological markers in breast carcinoma. Cancer 39: 2391-2396. Vejerslev LO, Fisher RA, Surti U & Wake N (1987) Hydatidiform mole: cytogenetically unusual cases and their implications for the present classification. American Journal of Obstetrics and Gynecology 157: 180-184. Wake N, Takaqi N & Sasaki M (1978) Androgenesis as a cause of hydatidiform mole. Journal of the National Cancer Institute 60: 51-57. Wake N, Tanaka K-I, Chapman V, Matsui S & Sandberg A A (1981) Chromosomes and cellular origin of choriocarcinoma. Cancer Research 41: 3137-3143. Wake N, Fujino T, Hoshi S e t al (1987) The propensity to malignancy of dispermic heterozygous moles. Placenta 8: 319-326. Wallace DC, Surti U, Adams CW & Szulman AE (1982) Complete moles have paternal chromosomes but maternal mitochondrial DNA. Human Genetics 61: 145-147. Wehmann RE & Nisula BC (1980) Characterization of a discrete degradation product of hCG beta subunit in humans. Journal of Clinical Endocrinology and Metabolism 51: 101-107. World Health Organisation (1983) Gestational trophoblastic diseases. Report of a WHO scientific group. Technical Report Series 692. Geneva: WHO.
INTRODUCTION Gestational trophoblastic tumours (GTI') are unique in that by definition they must follow a normal or abnormal pregnancy and the tumours express paternal genes and are therefore an allograft in the maternal host. GTI" occur most commonly after the abnormal pregnancy, hydatidiform mole (HM), but can also occur after a normal pregnancy (Table 1). Trophoblast in a normal pregnancy shares some characteristics with malignancy in that the trophoblast invades the myometrium and forms intimate connections with the maternal circulation. Trophoblast from a normal pregnancy can on occasion embolize to the lungs. Sufficient trophoblast cells may be present in the circulation to allow antenatal diagnosis of genetic disorders, using the polymerase chain reaction (Mueller et al, 1990). Table 1. Gestational trophoblastic tumours. Antecedent pregnancy
Outcome
Hydatidiform mole Normal pregnancy ] Ectopic pregnancy [ Stillbirth / Spontaneous abortionJ
~ Spontaneous regression Persistent trophoblastic disease "~ FChoriocarcinoma ~ LPlacental site trophoblastic tumour
Since GTT express not only paternal genes but paternally derived antigens, it might be anticipated that the immune system plays a major role in eliminating these diseases. However, it has been hypothesized that the process whereby the mother does not reject a normal fetus may operate in the situation where there is a trophoblastic tumour. The ABO blood group system influences the outcome of patients developing trophoblastic tumours Baillidre's Clinical Obstetrics and Gynaecology--
Vol. 6, No. 3, September 1992 ISBN 0-7020-1634-9
519 Copyright © 1992, by Bailli~re Tindall All rights of reproduction in any form reserved
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and patients with B or AB whose partners are either group O or A may have a worse prognosis (Bagshawe, 1976). Lawler (1978) studied the development of anti-HLA antibodies in a large group of patients with GTT. Her results showed that (1) choriocarcinoma can follow the birth of an HLA incompatible infant but that these patients as a group had more compatible offspring than would be expected; and (2) that anti-HLA antibodies were present in a greater proportion of, and in higher titres in, pregnancies with a hydatidiform mole than in normal pregnancies. The antibodies also persisted for longer in patients with tumours than following normal pregnancies. Her conclusion was that the HLA system did not appear to exert any major influence on the chance of a woman developing a trophoblastic tumour. All GTT synthesize varying amounts of a range of pregnancy hormones including human chorionic gonadotrophin (hCG) and its subunits and fragments (see below, Tumour markers and the role of hCG and its fragments), hCG is produced throughout a normal pregnancy and its synthesis is switched on not only in GTTs but in certain other tumours such as germ cell tumours and, less commonly, other malignancies such as bladder carcinoma. Its function both in normal pregnancy and in those tumours which produce it remains largely obscure. While hCG may stimulate the synthesis of a range of hormones and may have an immunomodulating effect, its role in malignancy is probably quite complex. On the one hand, while GTT apparently cannot grow clinically without synthesizing hCG, the same molecule can in other circumstances suppress carcinogenesis and tumour growth. This is shown in a recent study where hCG suppressed the development of carcinogen-induced mammary tumours in rats (Russo et al, 1990). Although uncommon, GTT are important since with proper management it should now be rare for a woman to die from her tumour and in most cases fertility can be preserved. The main reasons for this success are threefold: (1) for reasons that are not clearly understood, GT1~are highly sensitive to a range of currently available therapeutic agents; (2) the universal production of a serological tumour marker, hCG, makes possible a sensitivity and accuracy of screening, monitoring, management and follow-up of patients which is unique in clinical cancer; (3) detailed analysis of large groups of patients with these rare diseases has allowed the recognition of a range of prognostic factors, permitting the adjustment of intensity of treatment so that each patient only receives the minimum treatment necessary to eliminate her disease. PATHOLOGY The terminology in GTT and gestational trophoblastic disease (GTD) remains confusing partly due to the interchangeable use of histopathological and clinical terms. Since the management of patients at risk of developing a GTT is focused on the behaviour of the serum concentration of hCG, the curability of most of these patients means that frequently clinical decisions are made without further pathological specimens being obtained.
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Hydatidiform moles (HM) HM are premalignant conditions and in most cases remit spontaneously once the HM has been evacuated from the uterus. Molar pregnancies are now clearly distinguished both on morphological and cytogenetic grounds into complete and partial HM (Szulman and Surti, 1978a,b).
Complete hydatidiform mole A complete HM forms a multivesicular mass composed of grossly distended chorionic villi without a gestational sac or fetus. Hydropic change usually affects all the villi and trophoblastic hyperplasia is present to a variable extent.
Partial hydatidiform mole A partial HM is one in which only a proportion of the chorionic villi are affected by vesicular change, the abnormal villi being admixed with normal villi. The vesicular villi tend to be smaller than those in the complete HM, frequently showing a deeply indented outline. The presence of a fetus may be recognized either macroscopically or by the presence of nucleated red cells. It is likely that many partial HM are classified as 'products of conception' at uterine evacuation for a 'miscarriage'. Without genetic analysis to confirm that a specimen is a partial HM, underdiagnosis will continue. The natural history of partial HM has recently been better defined. While the malignant sequelae following partial HM is much less than after complete HM, a small number (approximately 1 in 200) of patients with partial HM require chemotherapy for a GTI" and therefore all patients need to be registered and followed up in the same way as for complete HM (Bagshawe et al, 1990).
Invasive hydatidiform mole This term is applied when a HM (complete or partial) invades into the myometrium. Since this is part of the normal behaviour of molar trophoblast, this is common, as is confirmed both on ultrasound examination of the uterus and by the hCG profile following evacuation of the uterine cavity. Pathologically this condition can only be confirmed by either having curettings containing a significant amount of myometrium or in the occasional case where a hysterectomy is performed rather than evacuation of the uterine cavity for a molar pregnancy.
Choriocarcinoma Choriocarcinoma is composed of both cyto- and syncytiotrophoblastic cells, characteristically surrounded by necrosis and haemorrhage. Choriocarcinoma is unusual in stimulating virtually no connective tissue support for the tumour
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and this is reflected by its clinical behaviour in its rapid haematogenous spread and haemorrhagic complications at sites where the tumour is growing. In the past choriocarcinoma was a rapidly lethal neoplasm but with proper management and modern chemotherapy, most patients should achieve complete remission. Placental site trophoblastic tumour This rare tumour is composed mainly of cytotrophoblast with very little syncytiotrophoblast. It can occur after both normal and molar pregnancies (Fisher et al, 1992b). The tumour tends to grow locally with a lower metastatic potential than choriocarcinoma. In most cases described so far its spread is mainly by local infiltration rather than widespread dissemination. The management of these tumours is different from other GTT in that they are less chemosensitive and if localized to the uterus the treatment of choice is surgery. Occasional long-term remissions have been obtained with intensive chemotherapy (Dessau et al, 1990). EPIDEMIOLOGY The epidemiology of GTT is still poorly understood although major progress in this area is likely to come from modern molecular genetics. The identification of the abnormal gene expression associated with the different clinical and pathological syndromes is fundamental to further progress in our understanding of these conditions. Many reports in the past, before the recognition by Szulman and Surti (1978a,b) that there are two different pathological syndromes of complete and partial HM, contain patients with both conditions and makes the earlier published data difficult to interpret. However, there is considerable evidence in the literature that the incidence of HM in different parts of the world varies considerably. In a number of countries including Japan and the Far East the incidence would appear to be much higher than it is in Europe and North America. Matsuura et al (1984) analysed the incidence of HM in Hawaii between 1968 and 1981. In 278 cases, 69.4% were complete HM, 24.5% were partial HM and 6.1% were non-molar pregnancies. This is a complete : partial HM ratio of 2.9 : 1. The population studied was of particular interest since several different racial groups live in Hawaii and have more or less equal access to hospital facilities. In Table 2 the incidence in the different racial groups in Hawaii are shown. This study confirms that molar pregnancies are more common in Filipino, Japanese and Oriental groups. The fact that the incidence is similar in Caucasians and native Hawaiians suggests that an environmental cause does not explain this difference in incidence between racial groups. Molar pregnancies are more common at the extremes of the reproductive age range. In a study of over 8000 cases of HM registered in England and Wales between 1973 and 1983 the relative risk of a HM in patients under 15 years was 6 and in patients over 50 years was 411 (when compared with the incidence in patients aged between 25 and 29 years) (Bagshawe et al, 1986).
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GESTATIONAL TROPHOBLASTIC TUMOURS Table 2. Incidence of complete hydatidiform moles by maternal race in Hawaii (1968-1981).
White Filipino Japanese Hawaiian Orientals (Chinese, Koreans) All
Rate/10 000
Incidence
8.0 17.5 16.5 7.7 17.5 12.1
1 : 1256 1 : 571 1 : 607 1 : 1304 1 : 571 1 : 825
Modified with permission from Matsuura et al, 1984.
Analysis of this large group of patients confirmed the increased risk of a second HM with an incidence of 1 in 76 and of a third HM of 1 in 6.5. This increased risk of further GTT following subsequent pregnancies is an important feature in their follow-up in that they need confirmation that the hCG returns to normal following each subsequent pregnancy. GT-I" occur after approximately 1 in 50 000 full-term pregnancies. Where histology is available, these tumours are choriocarcinoma or occasionally placental site trophoblastic tumours. In Charing Cross Hospital, London, a referral centre for trophoblastic tumours, this pattern of disease accounted for 137 (12.9%) of 1058 patients treated between 1968 and 1985. GTT following a full-term pregnancy behave aggressively and form that subgroup described in the older literature of women presenting with fulminating disease and dying within a matter of weeks. The clinical pattern in the patients presenting with choriocarcinoma following a full-term pregnancy is intriguing. In all the patients in the Charing Cross series the pregnancy reached term normally and no abnormality was noted in any placenta, yet the patient frequently presented with widespread disease within a matter of weeks of delivery. This raises the possibility that the presence of the fetus may suppress the malignant trophoblast until after delivery. We have attempted to identify an inhibitory factor in cord serum from pregnancies using normal adult serum as a control. No inhibitory factor has been identified in vitro or in vivo with choriocarcinoma xenografts. However, in a recent review of the literature Flam et al (1989) identified nine cases in which both mother and infant have had tumour invasion with choriocarcinoma. The influence of exogenous hormones on the behaviour of molar trophoblast is an area of considerable interest. Stone and Bagshawe (1976) suggested that patients who were exposed to oestrogen and/or progesterone had an increased incidence of malignant sequelae following a molar pregnancy. We have recently analysed the patients registered between 1973 and 1989 (Table 3). These data indicate that there is probably very little effect of exogenous hormones in patients whose hCG has already returned to normal, indicating minimal or no residual abnormal trophoblast. However, in patients given exogenous hormones while their hCG is still raised, the proportion requiring chemotherapy is 30.7%, compared with 8-9% in the overall population (Bagshawe et al, 1986). This subgroup of patients should not, therefore, receive oral contraceptives owing to the
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E. S. NEWLANDS ET AL Table 3. Effects of taking oral contraceptives within 6 months of evacuation of a hydatidiform mole, Charing Cross Hospital (1973-1989). Total number of patients Total number of patients requiring chemotherapy Numbers who received oral contraceptive A. Patients with normal hCG prior to oral contraceptive Number requiring chemotherapy (0.0047%) B. Patients with raised hCG given oral contraceptives Number requiring chemotherapy A versus B, P12
< 103 AxO O×A OorA x unknown 1-4 Spleen Kidney
104-105 B × A or O AB×AorO
> lOs
4-8 GI tract Liver
>8 Brain
3-5 cm
> 5 cm Single drug
2 or
more drugs Low risk, 0-5; medium risk, 6-9; high risk, >9; CXH, Chafing Cross Hospital, London. assessment of the volume of viable tumour in the body; (3) failure of previous c h e m o t h e r a p y to eliminate the G T T . A purely anatomical staging system is included in the World Health Organisation report ( W H O , 1983) but, although the above scoring system appears complex, a detailed comparison (Smith et al, 1992) has confirmed that it can identify a small subgroup of patients who would be either underor overtreated if their treatment was based solely on anatomical staging. This scoring system can also be applied in centres without high technology equipment since the important variables include only the history, examination, chest X-ray and a quantitative h C G estimation.
TREATMENT A t the Charing Cross Hospital, L o n d o n we have used the prognostic scoring system in Table 7 and have subdivided the patients into low, m e d i u m and high risk categories. W e have retained the medium risk category of patients since this allows the assessment of a new anticancer agent in a patient population where the survival is already 100%, but without compromising their subsequent treatment (for discussion, see Newlands et al, 1986). H o w e v e r , for m a n y centres it is probably simpler to have two risk categories, low and high risk, since the toxicity with our current high risk schedule (the E M A / C O regimen; see below) is only moderately m o r e than our m e d i u m risk schedule and m a y induce complete remission m o r e rapidly. Our m a n a g e m e n t of these three risk categories has each been reviewed recently: the results with the low risk patients in Bagshawe et al (1989), the m e d i u m risk patients in Newlands et al (1986) and the high risk patients in Newlands et al (1991). These results are summarized briefly here.
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Low risk patients Since 1964 these patients have been treated with a simple schedule of methotrexate 50mg i.m. given on days 1, 3, 5 and 7, and folinic acid 6mg i.m. on days 2, 4, 6 and 8, with a 6-day interval between courses. This schedule is, in general, well tolerated although 5% of patients need to change treatment because of toxicity (usually severe pleuritic chest pain or drug-induced hepatitis). However, even in correctly stratified patients 20% will need to change because of the development of drug resistance. This means that methotrexate is not a simple 'wonder drug' for this group of patients since a total of 25 % will need to change treatment because of either drug resistance or toxicity. Therefore these patients need to be carefully monitored to ensure that they achieve complete remission. The survival in these patients is excellent even though they may need to change treatment and the only deaths in patients treated with this schedule
Figure 1. Patient presenting several months after a normal pregnancywith symptomsof a subarachnoid haemorrhageand a hemianopia. CT scan confirmedthree cerebral metastases (arrowed).
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following the introduction of the prognostic scoring system were one from concurrent but not therapy-induced non-Hodgkin's lymphoma and one from hepatitis (Bagshawe et al, 1989). Medium risk patients These patients need to be treated with chemotherapy either using drugs in sequence or in combination. Between 1974 and 1979 2 patients out of 75 (3%) in this category died from their tumours despite intensive treatment. Following the introduction of etoposide (Newlands and Bagshawe, 1980), there have been no further deaths in this subgroup of patients. High risk patients Since 1979 we have used a weekly chemotherapy schedule, trying to
Figure 2, Same patient as in Figure 1. An additional complication in this paticnt was increasing obstructive jaundice due to a pancreatic mass of tumo~tr obstructing the c o m m o n bite duct (CT showing dilated bile ducts and pancreatic mass. arrowed). This required stcnting so that intensive chemotherapy with E M A / C O was not delayed by the impaired liver function.
Fortnightly x 20 Monthly × 20 2-Monthly x 20
Then every 6 months
Fortnightly x 5 Monthly × 10 Then only if necessary
Urine
Then every 6 months
As for low risk
Blood
3-Monthly x 20
Fortnightly × 5 Monthly x 5 Then only if necessary
Fortnightly x 10 Monthly x 10 2-Monthly x 10
Urine
Then only if necessary
Fortnightly x 20 Monthly x 10 2-Monthly x 10
Blood
Score value > 9
High risk
3-Monthly x 10
Blood
Score value 6--9
Score value 0-5
Urine
Medium risk
Table 8. Follow-up for gestational trophoblastic tumour patients who have received chemotherapy.
Low risk
Lit t~ 4~
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maximize dose intensity in order to minimize the development of drug resistance. The EMA/CO schedule contains etoposide, methotrexate and actinomycin D, cyclophosphamide and vincristine (Oncovin). In our recent analysis (Newlands et al, 1991) of 148 patients receiving this schedule, the overall survival was 85 %. There were two subgroups of patients: 76 who had received no prior chemotherapy and whose survival was 82%. Ten of the 14 patients who died in this group died early from the following causes: respiratory failure (five), cerebral metastases (three), hepatic failure (one), pulmonary embolism (one). Some of the clinical problems presented by this variant of GTT are illustrated in Figures 1 and 2. In none of these cases was the antecedent pregnancy a HM (they were: livebirth, six; stillbirth, one; spontaneous abortion, three). It will be difficult to improve the survival in this particular subgroup of patients since there was no immediate antecedent pregnancy to allow them to be entered into a screening programme such as that for patients who have had a HM. The ready awareness that widespread malignancy in a young woman may possibly be choriocarcinoma which can be confirmed by a very high hCG will minimize the number of patients presenting with this disease extent and consequent mortality. The second group of high risk patients are those relapsing after previous chemotherapy, either our own treatment failures or those referred from centres abroad. The survival in these 72 patients was 89%. These patients were all on follow-up and therefore their disease extent was less than in the previous group. The cause of death in these patients was usually the development of drug-resistant disease and these patients could not be saved either by extensive surgery or by the addition of cis-platinum (cisplatin) to the chemotherapy (Newlands et al, 1991). POST-TREATMENT FOLLOW-UP AND FERTILITY Following completion of their chemotherapy, patients need to be followed up regularly with hCG estimations to confirm that their disease is in remission. Initially the follow-up is with serum and urine samples (Table 8). In due course the follow-up is only on urine samples. In the UK this is computerized and automatic reminders are sent to patients so that they do not get lost to follow-up. Patients are advised to avoid a subsequent pregnancy until 12 months after completing their chemotherapy, in order to minimize the potential teratogenicity of the treatment. Even in the high risk patients receiving intensive chemotherapy, patients return to normal activity within a few months and most side-effects of the treatment are reversible. Chemotherapy-induced alopecia is always reversible. To date, late sequelae from chemotherapy have been remarkably rare. Two patients receiving extensive treatment (lasting more than 6 months) developed acute myeloid leukaemia which was probably therapy-induced. This emphasizes the importance of achieving complete remission as rapidly as possible to minimize this recognized complication of intensive chemotherapy. In the population analysed between 1968 and 1978 there was no increase in second tumours in 457 long-term survivors (Rustin et al, 1983).
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The outcome of subsequent pregnancies following chemotherapy is usually successful. In an analysis of 445 long-term survivors treated at the Charing Cross Hospital, London, 90% of those who wished to become pregnant succeeded and 86% of these had at least one livebirth (Rustin et al, 1984). However, there was a tendency for patients who had received three or more drugs to be less likely to have a livebirth than those who had received only one or two drugs. There was no increase in the incidence of congenital malformation compared with the normal population.
SUMMARY
Trophoblastic tumours form a spectrum of disease from the borderline malignancy of HM to highly aggressive choriocarcinoma. Their management requires the integration of the information derived from serial hCG estimations, the clinical history and pattern of spread of the disease, so that our understanding of the prognostic variables can be applied appropriately. This maximizes the patient's chances of complete remission from her disease with the minimum of toxicity. Given our knowledge of this group of diseases and an integrated approach to management, it should be uncommon for any woman to die from her trophoblastic tumour.
REFERENCES Bagshawe KD (1976) Risk and prognostic factors in trophoblastic neoplasia. Cancer 38: 1373-1385. Bagshawe KD & Lawler SD (1982) Choriocarcinoma. In Schottenfeld D & Fraumeni JF (eds) Cancer Epidemiology and Prevention, pp 909-924. Philadelphia: Saunders. Bagshawe KD, Dent J & Webb J (1986) Occasional survey: hydatidiform mole in England and Wales 1973-83. Lancet ii: 6734577. Bagshawe KD, Dent J, Newlands ES et al (1989) The role of low dose methotrexate and folinic acid in gestational trophoblastic tumours (GTr). British Journal of Obstetrics and Gynaecology 96: 795-802. Bagshawe KD, Lawler SD, Paradinas FJ et al (1990) Gestational trophoblastic tumours following initial diagnosis of partial hydatidiform mole. Lancet 335: 1074-1076. Birken S, Armstrong EG, Kolks MAG et al (1988) Structure of the human chorionic gonadotrophin beta subunit fragment from pregnancy urine. Endocrinology 123(1): 572-583. Boorstein WR, Vamkakopoulos NC & Fiddes JC (1982) Human chorionic gonadotrophin beta subunit is encoded by at least eight genes arranged in tandem and inverted pairs. Nature 300: 419-422. Braunstein GD (1983) HCG expression in trophoblastic and non-trophoblastic tumours. In Braunstein GD (ed.) Oncodevelopmental Markers. Biologic, Diagnostic and Monitoring Aspects, pp 351-357. New York: Academic Press. Campbell RK, Dean-Emig DM & Moyle WR (1991) Conversion of human chorionic gonadotrophin into a follitropin by protein engineering. Proceedings of the National Academy of Sciences (USA) 88: 760-764. Chaganti RSK, Kodura PRK, Chakraborty R et al (1990) Genetic origin of a trophoblastic choriocarcinoma. Cancer Research 50: 6330-6333. Cole LA & Birken S (1988) Origin and occurrence of human chorionic gonadotrophin beta subunit core fragment. Molecular Endocrinology 2: 825-830. Cole LA, Kardana A & Birken S (1989) The isomers, subunits and fragments of hCG. Serono Symposia Publications 65: 59-78.
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Cole LA, Kardana A, Andradegordon P et al (1991) The heterogeneity of human chorionic gonadotrophin (hCG). 3. The occurrence and biological and immunological activities of nicked hCG. Endocrinology 129(3): 1559-1568. Dessau R, Rustin GJS, Dent J e t al (1990) Surgery and chemotherapy in the management of placental site tumor. Gynecologic Oncology 39: 56--59. Eckstein RP, Russell P, Friedlander ML et al (1985) Metastasizing placental site trophoblastic tumor: a case study. Human Pathology 16: 632-636. Edwards YH, Jeremiah SJ, McMiUan S e t al (1984) Complete hydatidiform moles combine maternal mitochondria with a paternal nuclear genome. Annals of Human Genetics 48: 119-127. Fiddes JC & Goodman HM (1981) The gene encoding the common beta-subunit of the four human glycoprotein hormones. Journal of Molecular and Applied Genetics 1: 13-18. Fisher RA, Lawler SD, Povey S & Bagshawe KD (1988) Genetically homozygous choriocarcinoma following pregnancy with hydatidiform mole. British Journal of Cancer 58: 788-892. Fisher RA, Povey S, Jeffreys AJ et al (1989) Frequency of heterozygous complete hydatidiform moles, estimated by locus-specific minisatellite and Y chromosome-specific probes. Human Genetics 82: 259-263. Fisher RA, Newlands ES, Jeffreys AJ et al (1992a) Gestational and non-gestational trophoblastic tumours distinguished by DNA analysis. Cancer 69: 839-845. Fisher RA, Paradinas F J, Newlands ES & Boxer GM (1992b) Genetic evidence of placental site trophoblastic tumours originating from hydatidiform mole or a normal conceptus. British Journal of Cancer 65: 355-358. Flam F, Lundstrom V & Silfversward C (1989) Choriocarcinoma in mother and child. Case report. British Journal of Obstetrics and Gynaecology 96: 241-244. Graham MY, Otani T, Boime Iet al (1987) Cosmid mapping of hCG beta subunit genes by field inversion gel electrophoresis. Nucleic Acids Research 15: 4437-4448. Hunter V, Raymond E, Christensen C et al (1990) Efficacy of the metastatic survey in the staging of gestational trophoblastic disease. Cancer 65: 1647-1650. Iles RK, Czepulkowski BH, Young BD et al (1989) Amplification or rearrangement of the beta-hCG-human LH cluster is not responsible for the ectopic production of beta-hCG by bladder tumour cells. Journal of Molecular Endocrinology 2: 113-117. Jacobs RA, Wilson CM, Sprenkle JA et al (1980) Mechanisms of origin of complete hydatidiform moles. Nature 286: 714-716. Jacobs PA, Szulman AE, Funkhouser J e t al (1982) Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Annals ofltuman Genetics 46: 223-231. Jameson JL, Lindell CM & Habener JF (1987) Gonadotrophin and thyrotrophin and subunit gene expression in normal and neoplastic tissues characterized by using specific mRNA hybridization probes. Journal of Clinical Endocrinology and Metabolism 64:319-326. Kajii T & Omaha K (1977) Androgenetic origin of hydatidiform mole. Nature 268: 633-634. Kajii T, Kurashige H, Ohama K & Uchino F (1984) XY and XX complete moles. Clinical and morphologic correlations. American Journal of Obstetrics and Gynecology 150: 57-64. Kardana A & Cole LA (1990) Serum hCG beta core fragment is masked by associated macromolecules. Journal of Clinical Endocrinology and Metabolism 71(5): 1393-1395. Kardana A & Cole LA (1991) Polypeptide nicks cause erroneous results in assays of human chorionic gonadotrophin free beta subunit. Clinical Chemistry 38: 26--33. Kardana A, Taylor M, Southall P e t al (1988) Urinary gonadotrophin peptide: isolation and purification and its histochemical distribution in normal and neoplastic tissues. British Journal of Cancer 58: 281-286. Kardana A, Elliott MM, Gawinowicz MA et al (1991) The heterogeneity of human chorionic gonadotrophin (hCG). 1. Characterization of peptide heterogeneity in 13 individual preparations of hCG. Endocrinology 129(3): 1541-1551. Keutmann HT, Charlesworth MC, Mason KA et al (1987) A receptor-binding region in human gonadotrophin/lutropin beta subunit. Proceedings of the National Academy of Sciences (USA) 84: 2038-2042. Keutmann HT, Mason KA, Kitzmann K et al (1989) Role of the 93-100 determinant loop sequence in receptor binding and biological activity of human luteinizing hormone and chorionic gonadotrophin. Molecular Endocrinology 3: 526--531.
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