Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: evidence for revised protocol of a UK regional trophoblastic disease unit.

Following hydatidiform mole, women are at increased risk of persistent gestational trophoblastic neoplasia (pGTN) and are therefore monitored using serum human chorionic gonadotrophin (hCG) concentration measurements. We retrospectively evaluated the policy of extended (2 year) follow up for women with hCG concentrations returning to normal >56 days after evacuation. Of 6701 women registered for hCG follow up, 422 (6%) developed pGTN, 412 (98%) of these women presented within 6 months after evacuation. Three developed pGTN at 402, 677 and 1267 days after evacuation following spontaneous normalisation of hCG levels. Only one woman was detected by routine extended follow up. Prolonged surveillance after molar pregnancy causes significant anxiety and is not cost-effective. Therefore, the current revised protocol comprises hCG follow up for 6 months after spontaneous return of hCG levels to normal for all women.

Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors.

PURPOSE: No increase in second tumor incidence was found in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT). More patient years at risk enabled a further analysis of the risk of second tumors to be performed in the 1,377 women treated in this until up to 1990. PATIENTS AND METHODS: Health questionnaires were returned on 93.3% of patients who successfully completed chemotherapy and were living in the United Kingdom. The remainder were flagged for death or developing further cancers by the Office of Population Census and Surveys and by the Thames Cancer Registry. Incidence density analysis was performed based on 15,279 person-years of observation available. Standardized incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. RESULTS: An overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1 to 2.1; P < .011) was observed: there were 37 second tumors, when 24.5 were expected. For specific second tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6; 95% CI, 5.4 to 38.9), colon (RR = 4.6; 95% CI, 1.5 to 10.7), and breast cancer when the survival exceeded 25 years (RR = 5.8; 95% CI, 1.2 to 16.9). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3; 95% CI, 0.6 to 2.1). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. CONCLUSION: This study suggests that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This has become apparent since the introduction of etoposide and longer follow-up.

Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000.

PURPOSE: We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen. PATIENTS AND METHODS: Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was < or = 100 IU/L, patients received dactinomycin; if hCG was greater than 100 IU/L, patients received EMA/CO. RESULTS: The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX. CONCLUSION: Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.

Persistent gestational trophoblastic disease is rarely, if ever, derived from non-molar first-trimester miscarriage.

Traditional epidemiologic data suggest that persistent gestational trophoblastic disease (pGTD), may follow, and be derived from, either molar pregnancy, non-molar term pregnancy or first-trimester non-molar miscarriage. We examined a database of cases of possible or probable hydatidiform moles and proven pGTD derived from the Regional Trophoblastic Disease Unit, Charing Cross Hospital, London. There were 424 cases (6%), in whom the initial registered diagnosis was that of PHM or CHM but central histopathological review diagnosed a definite non-molar hydropic abortion (HA). In eight of the 424 (2%), although the histology of the most recent index pregnancy was that of non-molar miscarriage, there was a previous history of pregnancy affected by hydatidiform mole; two of these developed subsequent pGTD. Of a further 86 cases referred for a histopathological opinion prior to registration which demonstrated definite non-molar HA, none developed pGTD (zero of 510 (0%, 95% CI 0-0.7%)). During the same period there were 352 cases with pGTD requiring chemotherapy. In 31 cases, the only known pregnancy was the preceding apparent non-molar HA. However, of these, there were only three cases in whom the preceding histological products of conception had been centrally reviewed and were suggestive of non-molar pregnancy. However, in all three of these cases, the specimens were inadequate for definite exclusion of molar pregnancy. In one case in whom no material was available for review, molecular genetic analysis using restriction fragment length polymorphisms was carried out, and the choriocarcinoma was genetically derived from a previous molar pregnancy rather than the preceding HA. There were therefore no cases identified on the database of the trophoblastic disease unit of pGTD requiring treatment in whom the trophoblastic tumour could be genetically proven to have arisen from the preceding first trimester non-molar HA. We suggest that the risk of pGTD developing from a histologically confirmed non-molar HA is less than 1 in 50,000 and that the majority of pGTD cases previously reported to have been caused by a non-molar miscarriage probably represent disease due to an unrecognised early molar pregnancy.

Prospective analysis of patterns of weight change in stage IV human immunodeficiency virus infection.

Weight loss is a major manifestation of infection with the human immunodeficiency virus (HIV). Prospective analysis of weight change was performed in 30 male subjects with stage IV HIV infection over a period of 9-49 mo and weight change events (> 4 kg) related to contemporaneous clinical events. Two distinct patterns of weight loss were observed: episodes of acute severe weight loss and episodes of chronic unremitting progressive weight loss. Thirty-three acute episodes (median 9.1 kg in 1.7 mo) and 23 chronic episodes (13.2 kg in 9.5 mo) were identified. Twenty-seven of 33 (82%) acute weight-loss episodes were associated with nongastrointestinal opportunistic infections and 15 of 23 (65%) chronic episodes with gastrointestinal disease (P < 0.01). Weight loss was neither inevitable nor unremitting. Periods of weight stability (> 4 mo) occurred in 13 individuals (43%); 35 episodes of weight gain were identified, mostly related to recovery from opportunistic infection. These findings have important implications for our understanding of the natural history of weight loss in HIV infection.

Chemotherapy for gestational trophoblastic tumours hastens menopause by 3 years.

Chemotherapy may induce acute ovarian failure, but in women who retain gonadal function throughout chemotherapy, the late effects upon ovarian function are unknown. A retrospective controlled survey was performed to ascertain whether chemotherapy for gestational trophoblastic tumours (GTT) results in premature menopause. Questionnaires were sent to 1,489 women diagnosed between 1971 and 1990 with GTT, including 1089 who had received chemotherapy and 400 who had not received chemotherapy (controls). Responses were obtained from 972 chemotherapy-treated patients and 327 controls. 124 women were not evaluable for menopause date as they had undergone hysterectomy as part of the treatment for GTT or had developed permanent amenorrhoea during chemotherapy. Overall, 172 women reported that they were postmenopausal, including 157 women who had received chemotherapy. The median age at menopause for the evaluable population was 50 years (range 25-56 years). The age at menopause was significantly earlier in the treated arm (median 50, range 25-56 years) than in the controls (median 53, range 40-57 years) (logrank test chi 2 = 12.6, P = 0.0004). Menopause occurred significantly earlier in women treated with combination chemotherapy (median 49, range 25-56 years) compared with single agent methotrexate (median 51, range 25-56 years) (logrank test chi 2 = 8.3, P = 0.004). However, the age at completion of chemotherapy in the treated arm did not influence the age of menopause (proportional Hazards chi 2 = 1.99, P = 0.16). Chemotherapy for GTT induces menopause 3 years earlier than it occurs in women with GTT who do not receive chemotherapy. Although the difference is statistically significant, the magnitude is modest and most women can be reassured that neither fertility nor postmenopausal osteoporosis will be greatly affected.

Extravillus endovascular implantation site trophoblast invasion is abnormal in complete versus partial molar pregnancies.

This study examines endovascular trophoblast invasion in pregnancies complicated by complete hydatidiform mole (CM), partial hydatidiform mole (PM) and non-molar abortions (HA). Two hundred consecutive cases from a supra-regional referral centre for suspected trophoblastic disease were examined histologically with particular regard to the presence or absence of endovascular trophoblast invasion of decidual vessels. There were 57 CM, 75 PM and 68 HA. The prevalence of normal endovascular invasion of decidual vessels was significantly lower in CM compared to all other clinical groups, amongst which there were no significant differences. Endovascular trophoblast was identified in about 80 per cent of HA and PM moles, compared to only around 25 per cent of CM (Z = -4.0, P< 0.0001). The majority of cases of complete mole demonstrated a similar appearance, of implantation site showing florid interstitial extravascular trophoblast invasion with surrounding of decidual vessels but without normal endovascular trophoblast invasion or 'plugging' seen. In many cases, there also appeared to be destruction of decidual vessels with interstitial haemorrhage and extensive fresh blood clot present in the histological sections. These findings may provide some explanation regarding the mechanism of clinical findings in molar pregnancy.

Triplet pregnancy with hydatidiform mole.

Multiple pregnancies with hydatidiform mole are rare. We describe here a patient who delivered a male fetus and a female fetus together with molar tissue following treatment for infertility. comparing microsatellite polymorphisms in the DNA from the patient, her partner, the two normal placentas and the molar tissue, we were able to show that this was a triplet pregnancy with two normal conceptions and a complete hydatidiform mole of monospermic origin.

Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age.

All cases of first histologically confirmed complete and partial moles registered between 1985 and 1999 were identified from the database of a Trophoblastic Disease Registration Centre. The maternal age distribution at diagnosis was calculated for the 7916 molar pregnancies and compared with the maternal age distribution of an unselected population of women from a routine obstetric database. Likelihood ratios were calculated for complete and partial molar pregnancies by maternal age. A positive relationship was found between the risk of molar pregnancy and both upper and lower extremes of maternal age (> or = 45 years and < or = 15 years, respectively). This association, although present for both complete and partial moles, is much greater for complete mole at all maternal ages, and the degree of risk is much greater with older (> or = 45 years) rather than younger (< or = 15 years) maternal age. This study provides, for the first time, data regarding specific risk of partial versus complete hydatidiform mole with maternal age.

Diploid hydatidiform moles with fetal red blood cells in molar villi. 2--Genetics.

The purpose of this study was to determine the genetic origin of a series of seven diploid hydatidiform moles with fetal red blood cells in the molar villi, normally a characteristic feature of triploid, partial hydatidiform moles. DNA was prepared from formalin-fixed, paraffin-embedded blocks of molar tissue and blood from the patient and her partner. The genetic origin of molar tissue was determined by comparing microsatellite polymorphisms in molar and parental tissue following polymerase chain reaction (PCR) amplification of DNA. In six cases, the hydatidiform mole was shown to be androgenetic in origin and therefore genetically to be a complete hydatidiform mole. In one case, the hydatidiform mole was of biparental origin, having both a maternal and a paternal contribution to the genome. We conclude that fetal red blood cells may be observed in the villi of complete hydatidiform moles. In cases where the degree of trophoblastic hyperplasia and ploidy is suggestive of a complete hydatidiform mole, the presence of fetal red blood cells alone should not be considered indicative of a diagnosis of partial hydatidiform mole.

Choriocarcinoma and partial hydatidiform moles.

BACKGROUND: Partial hydatidiform moles (PMs) rarely require chemotherapy and have never previously been proven to transform into choriocarcinoma, the most malignant form of gestational trophoblastic disease (GTD). Consequently, some have questioned whether women with PMs need human chorionic gonadotropin (hCG) follow-up. Here, we investigate whether PMs can transform into choriocarcinomas. METHODS: Patients with a PM who developed a subsequent choriocarcinoma were identified from our GTD database. The histology of both PM and ensuing choriocarcinoma was reviewed and flow cytometry used to verify the triploid status of the PMs. To determine whether the choriocarcinoma arose from the PM, DNA from the PM and choriocarcinoma in each patient was compared using microsatellite polymorphisms. FINDINGS: Of the 3000 patients with PM, 15 required chemotherapy for persisting GTD. This was identified as choriocarcinoma in three cases. In one patient, the local pathologist could not differentiate between a PM or a hydropic abortion and neither central histological review nor hCG follow-up were obtained. This patient nearly died before the diagnosis of choriocarcinoma was made. Fortunately, the local pathologists correctly diagnosed PM in the two other patients who were then registered for hCG follow-up. Some months later, the hCG was rising and repeat uterine evacuation revealed choriocarcinoma. The PM was confirmed to be triploid in all three cases and genetic analysis showed that the subsequent choriocarcinomas contained identical single maternal and two paternal alleles at several independent loci. INTERPRETATION: Our results show that PMs can transform into choriocarcinoma. All patients with suspected PM should be reviewed centrally and, if confirmed, need hCG follow-up.

Presentation and management of choriocarcinoma after nonmolar pregnancy.

OBJECTIVE: To ascertain the mode of presentation and treatment outcome for women with choriocarcinoma after a nonmolar pregnancy. DESIGN: Retrospective analysis of case records between 1985 and 1994. SETTING: A referral centre for trophoblastic disease. SUBJECTS: One hundred women with choriocarcinoma: 62 after a live birth, six after a live birth preceded by a molar pregnancy and 32 after a nonmolar abortion. RESULTS: Choriocarcinoma after nonmolar pregnancies represent 17% of the total gestational trophoblastic tumours requiring treatment. Vaginal bleeding was the commonest symptom in all groups, but symptoms from metastatic disease were important in the group presenting after a live birth. Metastatic disease was present in 31% of cases after live birth and 43% post-abortion. The median interval between the antecedent pregnancy and choriocarcinoma was five and six months, respectively. High risk multi-agent chemotherapy was required in 82% and 60% of cases, respectively. The mortality rate was significantly higher after a live birth than a nonmolar abortion (21% vs 6%). CONCLUSIONS: Treatment of choriocarcinoma after a live birth is associated with an unacceptably high mortality rate. Vaginal bleeding is an important early symptom and a pregnancy test should be performed if it persists after usual medical treatment.

A clinical, histopathological and flow cytometric study of 149 complete moles, 146 partial moles and 107 non-molar hydropic abortions.

We have compared the clinical and histological features of 149 complete moles with 146 triploid partial moles and 107 diploid non-molar hydropic abortions initially registered as moles for human chorionic gonadotrophin (hCG) follow-up. Forty-one patients with complete moles, five with partial moles and one with hydropic abortion received chemotherapy for hCG elevations interpreted as persistent trophoblastic disease. Complete moles were aborted or were evacuated significantly earlier than partial moles (means of 12.1 and 15.4 weeks; P < 0.001) and hydropic abortions significantly earlier than complete moles (mean 10.7 weeks; P < 0.005). The means of the highest recorded hCG were higher in complete moles (184,056 i.v.) than in partial moles (66,259 i.v.) and hydropic abortion (7942 i.v.). When hCG became normal without chemotherapy, this occurred earlier in patients with hydropic abortion than in those with partial moles (means of 46.7 days and 62.8 days; P < 0.001) and earlier in partial moles than in complete moles (mean 78.3 days; P < 0.005). The incidence of partial moles was comparable throughout fertile years but rose to 1.9 times the average after 40 years. Complete moles were commoner between 14 and 25 years and after 35 years, reaching 4.8 times the average after 40 years. Hydropic abortions were rare before 25 years and increased with age to 12 times the average after 40 years. Stromal karyorrhexis and shape of villi, before they become hydropic, discriminate well between complete and partial mole. Hydrops increased and vascularity decreased with molar age and the presence of non-hydropic villi or vessels did not discriminate between partial mole and the younger complete moles evacuated nowadays.

Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy.

OBJECTIVE: To determine pregnancy outcome, including the rate of repeat molar pregnancy, following histologically confirmed complete or partial hydatidiform mole. DESIGN: Retrospective review of a large supraregional database of registrations for gestational trophoblastic disease. SETTING: Supraregional Trophoblastic Disease Unit, London. SAMPLE: Women with pregnancies affected by complete or partial hydatidiform mole registered between 1992 and 1998. METHODS: All patients with a diagnosis of histologically confirmed complete or partial hydatidiform mole were identified and data on subsequent pregnancies compared between groups using comparison of proportion test. MAIN OUTCOME MEASURES: Pregnancy outcome by partial or complete mole subtype, with particular regard to risk of subsequent molar pregnancy. RESULTS: Of 2578 complete moles, the subsequent pregnancy was affected by hydatidiform mole in 27 (1.9%) cases, including 22 (81%) complete moles and 5 (19%) partial moles. Of 2627 partial moles, the subsequent pregnancy was also molar in 25 (1.7%) cases, including 17 (68%) partial moles and 8 (32%) complete moles. Overall recurrence risk for molar pregnancy was 1.8% (1 in 55), or a 20-fold increase compared with the background risk. Of 27 cases with repeat complete moles, three had further complete moles, suggesting the recurrence risk following two previous complete moles is approximately 10%. There were no other significant differences in pregnancy outcome between cases with previous complete or partial hydatidiform mole and that expected in an unselected obstetric population. CONCLUSIONS: Women having a pregnancy affected by a histologically confirmed complete or partial hydatidiform mole may be counselled that the risk of repeat mole in a subsequent pregnancy is about 1 in 60 and if this were to occur, the majority of cases will be of the same type of mole as the preceding pregnancy. However, >98% of women who become pregnant following a molar conception will not have a further hydatidiform mole and these pregnancies are at no increased risk of other obstetric complications.

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours.

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome. DOI: 10.1038/sj/bjc/6600041 www.bjcancer.comCopyright 2002 The Cancer Research Campaign

Pseudo-partial moles: placental stem vessel hydrops and the association with Beckwith-Wiedemann syndrome and complete moles.

AIMS: To describe the clinical and histological features of a series of cases of placentas originally diagnosed as partial moles in which the final diagnosis was that of placental stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann syndrome. METHODS AND RESULTS: We searched a computerized database containing cases of suspected or proven trophoblastic disease examined at the Trophoblastic Disease Unit at Charing Cross Hospital, London, to identify cases in which stem vessel hydrops was present without other histological features of partial mole. For each case, histological sections were examined and the histological features present recorded. There were 15 cases identified. Placental weight was above the 95th centile of the normal for gestation in all cases in which this information was documented. In an additional five cases the placenta was described as 'large'. All cases had marked stem vessel hydropic change with cyst formation and in the majority of cases some terminal villous hydrops was also present. In 13 of the 15 cases there was marked aneurysmal dilatation of stem villous vessels. Nine had focal chorioangiomatoid change and in four of these extramedullary haematopoiesis was focally present in these areas. No excessive trophoblast proliferation was noted in any case and no trophoblastic inclusions typical of partial mole were identified. CONCLUSIONS: This study has identified cases of stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann spectrum in pregnancies initially diagnosed as partial hydatidiform mole in the second half of pregnancy and has highlighted the need for detailed pathological examination and clinicopathological correlation in all such cases.