Persistent trophoblast disease following partial molar pregnancy

OBJECTIVE: Human chorionic gonadotrophin (hCG) follow-up data were analysed retrospectively in all patients registered in the Hydatidiform Mole Registry at the Royal Women's Hospital, Melbourne from January 1992 to January 2001 to determine the risk of persistent trophoblast disease following partial molar pregnancy and to review the present follow-up protocol of patients suffering from partial hydatidiform molar pregnancy (PHM). METHODS: Demographic factors were determined for all 344 cases with a review diagnosis of PHM, included age, history of previous hydatidiform mole, gestation length, hCG levels and compliance with follow-up. FINDINGS: Six of the 344 patients diagnosed with PHM required treatment with single-agent methotrexate and folinic acid rescue. All six patients achieved and maintained a complete biochemical remission after chemotherapy. hCG regression assays were analysed for 235 patients: 225 patients had at least one normal hCG measurement during follow-up, of whom 152 (64.7%) patients obtained normal values within 2 months after evacuation. All patients obtained normal levels within 32 weeks after evacuation of the partial hydatidiform mole. Only 63 (25.6%) patients completed the recommended follow-up program. No patient who achieved normal hCG levels required chemotherapy because of a recurrent gestational trophoblastic tumour. RECOMMENDATIONS: This study indicates that 1.7% of all partial mole pregnancy patients needed treatment for malignant sequelae. In contrast, no patient diagnosed with partial mole had a biochemical or clinical relapse after achieving normal levels of hCG, consistent with previous studies. Patients who have had a partial hydatidiform mole should be followed by hCG assays until normal levels are achieved and then follow-up can be safely discontinued.     

Evidence for the luteal source of circulating relaxin in molar pregnancy

Serum levels of relaxin rapidly decreased in patients with hydatidiform mole who underwent hysterectomy and bilateral salpingo-oophorectomy. However, the disappearance pattern of relaxin in patients with hydatidiform mole who underwent hysterectomy only was delayed and similar to that after evacuation of mole. The findings constitute evidence of the luteal source of circulating relaxin in molar pregnancy.     

Gestational trophoblastic diseases: the ratio of choriogonadotropin to specific pregnancy protein, hCG/SP1, provides useful diagnostic and prognostic evidence

Serum levels of human chorionic gonadotropin (hCG), specific pregnancy protein (SP1), and hPL were measured in 675 samples from women with uneventful pregnancy, and serially from the time of presentation in 125 patients with hydatidiform mole (HM), 43 with invasive mole (IM), and 34 with choriocarcinoma (CC). In HM serum levels of hCG and SP1 declined steadily from presentation to remission; when gestational age at the time of molar evacuation was shorter than 11 weeks, hCG declined to the normal range later than SP1 (57% patients), and when the age was longer--at the same rate as SP1 (26% patients) or earlier (17% patients). Serum levels of either marker were higher in IM than in HM and tended to increase, and in CC were either lower or higher than in IM. Treatment was followed by parallel decline of either marker, although SP1 declined to the normal range later than hCG in 12% of patients with IM and in 10% with CC. The hCG/SP1 ratios in normal pregnancy declined exponentially between the beginning and 23rd week of gestation and stayed level thereafter. The ratios calculated for the gestational age at the time of initial evacuation of the uterus or delivery were close to those of normal pregnancy in 80%, slightly increased in 20% of patients with spontaneously regressing HM, and markedly increased in 70% of patients with IM and in 74% of patients with CC. The ratios tended to increase during chemotherapy. An increase in the hCG/SP1 ratio seemed to be a characteristic sign of malignant change when compared with this ratio in normal pregnancy and hydatidiform mole. Determination of SP1 for monitoring therapy seemed redundant, and hPL assay was useful for discrimination between relapse and pregnancy.     

Factor VIII related antigen in gestational trophoblastic disease

Serum factor VIII related antigen (factor VIII R:Ag) levels were determined in 34 patients with hydatidiform mole at diagnosis and at 2, 4 and 6 weeks after evacuation of uterus and in 272 normal pregnant women. Serum factor VIII R:Ag levels in molar pregnancies before evacuation of the uterus were significantly higher than those in normal pregnancies of the same gestation age. Serum factor VIII R:Ag levels in the group of patients with residual trophoblastic disease were significantly higher than those in the group without residual trophoblastic disease before evacuation and at 6 weeks after evacuation of uterus, but there is considerable overlap in the levels of factor VIII R:Ag between the two groups of patients especially before evacuation of uterus. Factor VIII R:Ag level does not appear to be an useful marker in predicting the outcome of hydatidiform mole.     

Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in The Netherlands

OBJECTIVES: To determine the risk for recurrent trophoblastic disease after spontaneous normalization of human chorionic gonadotropin (hCG) levels in patients with hydatidiform mole and to determine the risk for tumor relapse after apparent remission following chemotherapy in patients with low- and high-risk persistent trophoblastic disease. METHODS: From 1994 until 2004, 355 patients with hydatidiform mole were registered at the Dutch Central Registry of Hydatidiform Mole and were monitored by sequential hCG assays in serum at the department of Chemical Endocrinology of the Radboud University Nijmegen Medical Centre. HCG regression curves were analyzed together with clinical information collected from the Hydatidiform Mole Database. RESULTS: Among the 355 registered hydatidiform mole patients, 265 patients attained spontaneous normalization following evacuation. Of the 265 patients, one patient (0.38%) subsequently required chemotherapeutic treatment for recurrent trophoblastic disease (95% confidence interval 0.0% to 2.1%). HCG levels did not decline to normal (<2.0 ng/ml) spontaneously in 90 patients; those patients were subsequently treated. Relapse rates were 8.1% (6/74) and 6.3% (1/16) for the low- and high-risk category respectively. CONCLUSION: Our analysis indicates that relapse risk in hydatidiform mole patients with spontaneous normalization is extremely low (one in 265 patients) after two normal hCG levels (<2.0 ng/ml) are achieved. Our results support the suggestion that two subsequent normal hCG levels may be sufficient to ensure sustained remission after hydatidiform mole evacuation. In contrary, in order to assure sustained remission, the relapse rates after chemotherapy in the current study emphasize the need for surveillance of trophoblastic tumor patients even after complete remission has apparently been achieved.     

Differential production of human chorionic gonadotropin and free subunits in gestational trophoblastic disease

Serum levels of human chorionic gonadotropin (hCG) and its free subunits (alpha hCG and beta hCG) were determined by means of highly sensitive and specific monoclonal and antipeptide-based monoclonal immunoradiometric assays. During normal pregnancy, the beta hCG to hCG ratio appears constant at approximately 0.5% after 5 weeks of gestation. In contrast, gestational choriocarcinoma was characterized by absolute serum beta hCG levels varying from three to 280 times greater than the maximum values observed during pregnancy and by exceedingly high beta hCG to hCG ratios. In complete hydatidiform mole, this ratio was intermediate between normal pregnancy and choriocarcinoma. The ratios of free beta hCG to hCG will distinguish normal from complete molar pregnancy (p less than 10(-8)), hydatidiform mole from choriocarcinoma (p less than 10(-4)), and choriocarcinoma from normal pregnancy (p less than 10(-8)) with high probability. Finally, it was found by means of the high sensitivity hCG immunoradiometric assays (less than 0.02 ng/ml) that this assay predicted very early tumor recurrence in patients with gestational choriocarcinoma.     

Immunological parameters in gestational trophoblastic neoplasia

Immunological function were studied in 22 patients with hydatidiform mole and 29 patients with malignant trophoblastic disease before and after treatment; normal pregnant and post-pregnant women served as controls. The only significant abnormality in hydatidiform mole was a low granulocyte chemotaxis before evacuation. In malignant trophoblastic disease the total lymphocyte counts, T-cell counts. B-cell counts, lymphocyte responses to mitogens and serum IgA levels were significantly lower than in normal women 6 wk after pregnancy. In those who responded to chemotherapy, these indices rose to the levels of post-pregnancy controls. An 'immune profile score' based on these indices was found to be a useful prognostic index. All patients with hydatidiform mole who had a score of 7 or less developed malignant trophoblastic disease, while the two patients with malignant trophoblastic disease who died had the lowest scores of the series.     

Plasma human chorionic gonadotropin disappearance in hydatidiform mole: a central registry report from the Netherlands

The disappearance time of serum human chorionic gonadotropin (hCG) after the evacuation of hydatidiform mole, partial mole, and hydropic degeneration was investigated. A statistically significant difference existed between the disappearance time of serum hCG after the evacuation of hydatidiform mole as compared with partial mole and hydropic degeneration. The average disappearance time of serum hCG after hydatidiform mole was 99.3 days, after partial mole 58.9 days, and after hydropic degeneration 50.7 days. It is not recommended to start chemotherapy for persistent trophoblastic disease before 100 days after the evacuation of hydatidiform mole, provided there is a steady downward course of the serum hCG level. It is advised to submit cases of supposed hydatidiform and partial moles to a tissue committee for a second opinion.     

Guidelines following hydatidiform mole: a reappraisal

OBJECTIVE: The aim of this study was to determine how often patients with complete hydatidiform mole (CHM) who spontaneously achieve normal human chorionic gonadotrophin (hCG) levels subsequently develop persistent or recurrent gestational trophoblast disease. METHODS: Four hundred and fourteen cases of CHM registered at the Hydatidiform Mole Registry of Victoria were reviewed retrospectively after molar evacuation. Maternal age, gestational age, gravidity and parity were determined for each patient, as well as the need for chemotherapy. RESULTS: Among the 414 patients, 55 (13.3%) required chemotherapy for persistent trophoblastic disease. None of the patients whose hCG levels spontaneously fell to normal subsequently developed persistent molar disease. CONCLUSION: Weekly hCG measurements are recommended for all patients until normal levels are achieved. For patients who attain normal hCG levels within 2 months after evacuation, it seems safe to discontinue monitoring once normal levels are achieved. Patients who fail to achieve normal hCG levels by 2 months after evacuation should be monitored with monthly hCG measurements for 1 year after normalisation to assure sustained remission.     

Factor VIII related antigen in gestational gestational trophoblastic disease

Summary. Serum factor VIII related antigen (factor VIII R:Ag) levels were determined in 34 patients with hydatidiform mole at diagnosis and at 2, 4 and 6 weeks after evacuation of uterus and in 272 normal pregnant women. Serum factor VIII R:Ag levels in molar pregnancies before evacuation of the uterus were significantly higher than those in normal pregnancies of the same gestation age. Serum factor VIII R:Ag levels in the group of patients with residual trophoblastic disease were significantly higher than those in the group without residual tropho-blastic disease before evacuation and at 6 weeks after evacuation of uterus, but there is considerable overlap in the levels of factor VIII R:Ag between the two groups of patients especially before evacuation of uterus. Factor VIII R:Ag level does not appear to be an useful marker in predicting the outcome of hydatidiforin mole.     

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.     

Application of the radioreceptor assay for human chorionic gonadotropin in pregnancy testing and management of trophoblastic disease.

A commercially prepared radioreceptor assay (RRA) for human chorionic gonadotropin (hCG) has been evaluated as a pregnancy test and in a quantitative assay to follow patients with hydatidiform mole. The RRA demonstrated almost 100% agreement in comparison with radioimmunoassay (RIA) and urinary hCG tests. In the quantitative assay, a limiting reliable concentration of 70 mIU/ml of hCG in serum could be obtained. Extremely good correlation was achieved between the RRA and RIA test for hCG in 2 patients with hydatidiform mole over a span of 3 months of followup after evacuation of the mole. The usefulness of the RRA as a replacement of RIA tests for hCG is discussed.     

On the results of hydatidiform mole managed by Niigata method

We have managed 518 cases of total mole patients in our Ob-Gyn clinic in the past 13 years by the Niigata postmole management method. Serial urinary hCG determination by sensitive assay (Higonavis and RIA) is the key examination in it. There are two critical points of urinary hCG determination: 1,000iu/L at the 5th week and 100iu/L at the 8th week after the termination of hydatidiform mole. The urinary hCG patterns are classified into type I if the hCG regression curve falls below both of them, and into type II if it follows curves other than type I. Among 89 cases of postmole patients who were administered no anti-cancer chemotherapy, 73 cases (82%) showed a type I hCG regression pattern, eight cases of which (11%) were complicated mole such as metastatic mole and invasive mole. Sixteen cases (18%) showed type II, but 8 of them (50%) were diagnosed as uncomplicated mole. The rate of complication among 118 cases of hydatidiform mole who had a molar pregnancy terminated and were followed up totally in our clinic was 24.6% and that of referral cases after molar evacuation was 21.3%, which is significantly higher than others reported in literature. There occurred no postmolar choriocarcinoma from uncomplicated mole patients who had their LH level confirmed in their urinary hCG determination, but 1 case (2.7%) did occur from LH level confirmed metastatic mole, and 3 cases (3.9%) from LH level confirmed metastatic invasive mole. It was shown that lung shadows on chest roentgenogram mostly take about 40 days to appear after D & C of hydatidiform mole and after surgery for uterine invasive mole.(ABSTRACT TRUNCATED AT 250 WORDS)     

葡萄胎患者合并妊高征后恶变的临床分析

对１６１例葡萄胎合并妊娠进行分析，其中合并妊高征３３例（妊高征组），１５例发生恶变，恶变率为４５．５％（１５／３３）。在非妊高征１２８例（非妊高征组）中，１２例发生恶变，恶变率为９．４％，两组恶变率比较，差异有极显著性（Ｐ〈０．０１），提示：葡萄胎合并妊高征时预后不良，应引起临床医师重视。     

Androgenetic complete mole coexistent with a twin live fetus.

OBJECTIVE: The aim of this study was to evaluate the clinical course and the management policy of complete mole coexistent with a twin live fetus confirmed with DNA polymorphism in a single hospital. METHODS: From 1981 to 1995, six patients with androgenetic complete hydatidiform mole coexistent with a twin live fetus were diagnosed by DNA polymorphism analysis. The clinical course of these six patients was analyzed. RESULTS: Two patients chose to terminate pregnancies and four patients desired to continue the pregnancy. However, the pregnancy had to be interrupted in two patients because of severe preeclampsia and sudden intrauterine fetal death. In two patients, fetuses were growing unremarkably and normal babies were delivered at term. The development of persistent trophoblastic tumor (PTT) in these rare pregnancies was higher (50.0%: 3/6) than that of single complete mole. In three patients, serum hCG titers during pregnancy were monitored. Although serum hCG levels progressively decreased during pregnancy in one patient without PTT, hCG levels initially decreased, but subsequently increased or showed a plateau with advancing gestational age in two patients with PTT. CONCLUSIONS: In patients with complete mole coexistent with a live fetus, the pregnancy may be allowed to continue when the fetal karyotype and development are normal and serum hCG titers are constantly falling with advancing gestational age.     

Complete hydatidiform mole in a perimenopausal woman with a subsequent severe thyriotoxicosis

Introduction  Gestational trophoblastic disease is one form of abnormal pregnancy, with a median maternal age of 27–28 years. One complication of trophoblastic disease is the development of a secondary hyperthyroidism, which resolves rapidly after evacuation of the hydatidiform mole. Case report  We report a case of a 53-year-old woman presenting with a complete hydatidiform mole and who developed a severe thyrotoxicosis after suction evacuation of the hydatidiform mole. Conclusion   A severe thyriotoxicosis can occur even after surgical evacuation of the mole. Therefore, evaluation of the thyroid function prior to operation, especially with a high quantitative hCG, should be performed to avoid severe complications.     

Levels of placenta-specific tissue protein 12 (PP12) in serum during normal pregnancy and in patients with trophoblastic tumour

A sensitive radioimmunoassay method has been developed to measure soluble placental protein 12. Using this method trace amounts of PP12 have also been detected in the sera of healthy non-pregnant subjects (24.0 +/- 6.15 micrograms/l). During normal pregnancy serum PP12 levels rose rapidly reaching a peak value of 139.90 +/- 40.26 micrograms/l at 18 weeks. Serial determinations of PP12 have been made in 31 patients with trophoblastic tumours (16 hydatidiform moles, 10 invasive moles and five choriocarcinomas). It has been found that in patients with hydatidiform and invasive moles its initial values are extremely high (342.9 +/- 257.9 micrograms/l and 279.3 +/- 103.1 micrograms/l, respectively), much exceeding the non-pregnant and normal pregnant values. After evacuation of hydatidiform moles serum-PP12 rapidly fell to the upper limit of normal at 21-28 days, and to normal values at 8-12 weeks after operation. In patients with invasive mole requiring chemotherapy the rate of fall of PP12 level was slower. In patients with choriocarcinoma serum-PP12 levels were moderately raised (59-132 micrograms/l) and followed the clinical course of the disease. Serum-PP12 levels would seem to be of less value in monitoring patients with trophoblastic tumours than other tumour-markers (hCG, and SP1).     

Plasma prolactin, progesterone, estradiol, and human chorionic gonadotropin in complete and partial moles before and after evacuation

Plasma prolactin, progesterone, and 17 beta-estradiol were measured by radioimmunoassay in 58 patients with complete moles, 17 patients with partial moles, and the same number of maturity-matched pregnant control subjects. In both complete and partial moles in the first trimester, the pre-evacuation plasma levels of these hormones were similar to those of pregnant control subjects, but in the second trimester they were all significantly lower than those of pregnant controls. There was no significant difference in the regression patterns of these hormones between complete and partial moles, but the serum beta-subunit of human chorionic gonadotropin (beta hCG) was higher in complete moles. Patients who subsequently developed persistent gestational trophoblastic tumors had higher plasma estradiol, prolactin, and serum beta hCG than those without persistent gestational trophoblastic tumors both before and after evacuation, but the difference in plasma estradiol and prolactin disappeared by nine weeks after evacuation. The levels of these hormones in patients with theca-lutein cysts were higher than those without theca-lutein cysts in the first few weeks after evacuation. Plasma estradiol, progesterone, and prolactin returned to normal nonpregnant levels before serum beta hCG, and they were not useful as tumor markers.     

Studies on the viability of trophoblast after termination of various kinds of pregnancies (author's transl)

Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years.     

Extraluminal hyperechogenic echo detected by transvaginal ultrasonography as a prognostic factor in recurrent hydatidiform mole.

Measuring beta hCG titers by either bioassay or radioimmunoassay has become the cornerstone in the management and treatment of hydatidiform mole. It is this very determination which will indicate either spontaneous remission or the need for chemotherapy treatment due to rising or plateauing titers. Herein, we report on the potential assistance of a unique ultrasonographic appearance of a hyperechogenic shadow located in the uterine wall, before and after an attempt for full evacuation of hydatidiform mole. The behavior of this echogenic area was more sensitive in predicting the course of the disease than did the beta hCG titers. Thus, using transvaginal sonography may serve as another predictor and indicator in evaluating the treatment of hydatidiform mole.