[Gestational trophoblastic disease--literature review].

Gestational trophoblastic disease is characterized by abnormal proliferation of pregnancy-associated trophoblastic tissue with malignant potential. Gestational trophoblastic disease covers a spectrum of conditions including hydatidiform mole, invasive mole, choriocarcinoma and placental site trophoblastic tumour. It is very important to understand the pathophysiology and natural history of the disease in order to achieve faster recognition and effective treatment. The presence and course of the disease can be monitored with quantitative levels of human chorionic gonadotrophin in all cases. Clinical signs and symptoms are usually insufficient to diagnose and predict the extent of disease. Nowadays, gestational trophoblastic diseases are the best treated gynaecological malignancy thanks to modern technology. This review covers various aspects of gestational trophoblastic disease: its development, epidemiology, aetiology and pathogenesis, as well as its classification, clinical manifestations and diagnostic methods.

Recent advances in gestational trophoblastic disease.

Recent advances have increased our understanding of gestational trophoblastic disease, and epidemiologic studies have demonstrated that there are important differences in risk factors for complete and partial mole. Complete moles are now increasingly being diagnosed in the first trimester, affecting their clinical presentation and pathologic characteristics. While important advances have been made in chemotherapy, it is now recognized that etoposide is associated with a risk of second tumors. Several studies have advanced understanding of the molecular biology of gestational trophoblastic disease, and this is important for the eventual development of new and innovative therapy.

Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors.

There is abundant evidence that human chorionic gonadotropin (hCG) is a weak thyrotropin (TSH) agonist. In FRTL-5 rat thyroid cells, hCG increases cyclic adenosine monophosphate (cAMP), iodide transport, and cell growth. hCG has thyroid-stimulating activity in bioassays in mice and in clinical studies in man. In cultured cells transfected with the human TSH receptor, hCG increases generation of cAMP. Molecular variants of hCG with increased thyrotropic potency include basic molecules with reduced sialic acid content, truncated molecules lacking the C-terminal tail, or molecules in which the 47-48 peptide bond in the beta-subunit loop is nicked. In normal pregnancy, when hCG levels are highest at 10 to 12 weeks gestation, there is suppression of serum TSH levels, presumably due to slight increases in free thyroxine (T4) concentration. In twin pregnancies, hCG levels tend to be higher and suppressed TSH levels are more frequent. Hyperemesis gravidarum, defined as severe vomiting in early pregnancy that causes 5% weight loss and ketonuria, is usually associated with increased hCG concentration. A high proportion of patients with hyperemesis gravidarum, about one-third to two-thirds in different series, have evidence of increased thyroid function. Only a small proportion of these patients have clinical hyperthyroidism, termed gestational thyrotoxicosis. These patients probably secrete a variant of hCG with increased thyroid-stimulating activity. Trophoblastic tumors, hydatidiform mole, and choriocarcinoma often cause hyperthyroidism because they secrete very large amounts of hCG. When the serum hCG exceeds about 200 IU/mL, hyperthyroidism is likely to be found. There is a correlation between the biochemical severity of hyperthyroidism and the serum hCG in these patients. Removal of the mole or effective chemotherapy of the choriocarcinoma cures the hyperthyroidism. In conclusion, hCG has thyroid-stimulating activity that influences thyroid function early in pregnancy when hCG levels are high. Excessive hCG secretion may cause hyperthyroidism in patients with hyperemesis gravidarum or trophoblastic tumors.

Changes in gestational trophoblastic tumors over four decades. A Korean experience.

OBJECTIVE: To review changes that occurred in gestational trophoblastic tumor (GTT) patients treated over four decades and to identify factors leading to the changes. STUDY DESIGN: A retrospective study of 287 cases treated during 1961-1967, 1975-1979, 1980-1986 and 1990-1994. The method of diagnosis, incidence and outcome in each decade and factors that may have had an influence, on incidence, outcome or both, were reviewed. RESULTS: Diagnosis shifted from pathologic (1960s) to clinical (1990s). The incidence per 1,000 births decreased from 4.4 (1960s) to 1.6 (1990s). The incidence showed a 26-fold increase in women aged 40 and over and 13.4-fold increase in women para 3 and over. The obstetric population showed a decrease in the high-risk group of greater age and higher parity. Assessment by the 1983 World Health Organization prognostic score showed an increase in low-risk and decrease in high-risk disease. Prognostic score changes are related to a decrease in GTT in older women, increase in GTT with a short interval and increase in nonmetastatic disease. Overall mortality decreased from 32.6% to 2.6%. CONCLUSION: The decreased incidence and improved outcome of GTT in Korea are related to improved medical care and to social, economic and educational changes.

A invasao trofoblastica e suas repercussoes fisiopatologicas: contribuicao da dopplervelocimetria / Trophoblastic invasion and its phisiopathological findings: a dopplervelocimetry contribution

O fluxo sanguineo utero-placentario aumenta gradativamente durante a gestacao, associado a uma diminuicao progressiva da resistencia nas arterias uterinas e espiraladas. Controversias existem de quando a circulacao no espaco interviloso comecaria a existir. Atualmente, acredita-se que so a partir da decima segunda semana gestacional se iniciaria a circulacao no espaco interviloso e que estaria diretamente relacionada a invasao trofoblastica. Atraves de estudos dopplervelocimetricos foi possivel melhor compreensao da fisiopatologia desta invasao nas das arterias utero-placentarias na gestacao. Assim, observou-se que existia uma relacao entre as alteracoes da invasao trofoblastica e o prognostico da gestacao...

Human chorionic gonadotrophin-beta gene sequences in women with disorders of HCG production.

Women with recurrent abortion, primary unexplained infertility, and gestational trophoblastic neoplasia (GTN) manifest disordered human chorionic gonadotrophin (HCG) secretion. Mutations in the HCG beta/luteinizing hormone (LH) beta gene complex could cause aberrant HCG production in these disorders. The purpose of this study was to determine whether HCG beta gene deletions occur in women with recurrent abortion or primary unexplained infertility, and whether HCG beta gene duplications are present in women with GTN. DNA was extracted from 10 patients with unexplained recurrent abortion, 10 patients with unexplained primary infertility, 12 patients with GTN, three partners of women with GTN, and 30 controls. Southern blots were constructed and hybridized with DNA probes for HCG beta-5 and the LH beta gene. No gene deletions were identified in patients with recurrent abortion or primary unexplained infertility. Likewise, no gene duplications were identified in women with GTN. A previously described Mbol restriction fragment length polymorphism (RFLP) was identified in both patients and controls. A new Pstl RFLP was also characterized, but was present in patients and controls. Deletion/duplication mutations in the HCG beta/LH beta gene complex do not appear to be common causes of aberrant HCG production in humans with these disorders.

Reproductive status in GTD treated with etoposide.

OBJECTIVE: To investigate the mechanism and degree of ovarian dysfunction in gestational trophoblastic disease (GTD) patients treated with etoposide alone. STUDY DESIGN: Forty-seven patients with low-risk GTD were treated with etoposide alone, and pituitary-ovarian function was evaluated by measuring basal serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and progesterone and by recording basal body temperature. Moreover, the responses of LH and FSH to the administration of LH-releasing hormone (LHRH) and the responses of prolactin to thyrotropin-releasing hormone (TRH) were analyzed after the completion of etoposide treatment. RESULTS: Increased basal LH and FSH levels were found in approximately 50% of patients, especially those over 40 years old. Although the LH and FSH responses to LHRH were exaggerated in patients with high basal FSH levels, the prolactin responses to TRH were normal. Ovulation resumed within 121 days after the cessation of chemotherapy in women under 39 years. However, five of nine patients over 40 years remained anovulatory during the follow-up period. CONCLUSION: Ovarian function was impaired in approximately 50% of patients treated with etoposide at the time of LHRH study, though pituitary function was preserved. This complication is age related but not related to the amount of etoposide exposure. Therefore, we must consider the possibility of permanent anovulation when we treat patients 40 years old and older.

Pulmonary function in patients with trophoblastic disease treated with low-dose methotrexate.

The Sheffield Trophoblastic Disease Centre treats about 25 patients with persistent trophoblastic disease each year. A total of 75% of patients are classified as low risk according to the Charing Cross Hospital prognostic scoring system and receive methotrexate (MTX) 50 mg, i.m., on days 1, 3, 5, 7 with folinic acid 7.5 mg orally 24 h after each methotrexate injection. There is a 7-day rest between treatment cycles. Remission is achieved in 85% of cases. Approximately 20% of patients experienced pleuritic chest pain and dyspnoea. We have evaluated prospectively lung function in 16 low-risk patients receiving methotrexate. All patients had pulmonary function tests [spirometry-forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), and transfer factor - TLCO, kCO] performed before and after completed treatment. A mean of 7.5 cycles of MTX were administered (range 4-11). There was a significant reduction in the mean TLCO (mean pre/post 8.15/7.38 mmol min-1 kPa-1, P = 0.01), but there were no other statistically significant changes. Three patients experienced respiratory symptoms and were found to have a 39%, 28%, and 11% reduction in TLCO from baseline, improving on follow up to pretreatment levels. Low-dose MTX is an effective therapy but may cause troublesome pulmonary toxicity.

[Effects of ACM sequential chemotherapy on ovarian function in trophoblastic tumors].

OBJECTIVE: To study the changes of ovarian function during and after ACM sequential chemotherapy on trophoblastic tumors. METHODS: 17 patients with trophoblastic tumors, received totally 48 cycles of ACM chemotherapy. Of these, 7 underwent hysterotomy and focal ectomy and ovarian biopsy. Changes of menstruation and BBT were observed. beta-hCG, E2, FSH and LH were assayed and histological and immunohistochemical studies in ovaries biopsied were made. RESULTS: Amenorrhea and anovulatory BBT were predominant at the onset of chemotherapy and high level of beta-hCG. Following chemotherapy and decrease of beta-hCG, menstruation recovered with less amount and BBT transformed into ovulatory types with shorter luteal phase. The E2 level appeared to be lower and the FSH and LH level higher. The different kinds of follicles were decreased, but estrogen receptors unchanged. Follow-up showed that ovarian function of 12 of the 17 patients returned to normal in one year. CONCLUSION: ACM chemotherapy suppresses ovarian function mildly and temporarily. Trophoblastic tumor also affects ovarian function. ACM chemotherapy seems to be suitable for young patients with trophoblastic tumors who desire child-bearing.

Enfermedad trofoblástica gestacional: experiencia de 6 años en el Instituto Nacional de Perinatología / Gestational trophoblastic disease: six years experience al Instituto Nacional de Perinatología

De enero de 1988 a marzo de 1994, 83 pacientes con diagnóstico de Enfermedad Trofoblástica Gestacional fueron identificadas. La incidencia fue de 2.4 por 1000 nacimientos. La edad promedio de las pacientes fue de 28.9 años. El 44.5 fueron multíparas y en 25.3 por ciento existió el antecedente de embarazo molar. El 77.1 por ciento de los casos pertenece al estrato socioeconómico bajo. El diagnóstico se hizo mediante ultrasonido en 89.1 por ciento. Se realizó legrado uterino instrumental en 89.1 por ciento con confirmación histológica en 100 por ciento de los casos. De los 83 casos de embarazo molar, 74 se clasificaron como molas completas, cuatro incompletas, cuatro invasoras y un coriocarcinoma. Se realizó seguimiento en todas las pacientes con fracción beta de hormona gonadotrofina coriónica, que fue negativa en la mayoría de los casos en la semana 8 posterior a la evacuación. Se indicaron anticonceptivos orales en 73.4 por ciento de las pacientes

Persistent nonmetastatic gestational trophoblastic disease.

The management of GTD has developed as a result of an accurate and sensitive serologic marker, effective chemotherapeutic agents, and the judicious treatment of patients with evidence of persistence. Treatment and intervention guidelines are well established and will lead to a successful outcome for nearly all patients. Reproductive potential can be preserved and chemotherapy toxicity has been made quite manageable in the minority of patients requiring its administration. However, as demonstrated in the patient whose case is presented, violation or deviation from these guidelines for monitoring and intervention can lead to the unnecessary sacrifice of reproductive capability and the administration of potentially toxic multiagent chemotherapy regimens.

Correlation of uterine hemodynamics with chemotherapy response in gestational trophoblastic tumors.

OBJECTIVE: To assess the uterine hemodynamics in gestational trophoblastic tumors and to correlate them with response to chemotherapy. METHODS: Using transvaginal color Doppler ultrasound, we measured the peak systolic velocity and the resistance index (RI) of the uterine arteries in 23 women with gestational trophoblastic tumors before each course of chemotherapy. Fifty-five nonpregnant women and another 15 women who had uneventful molar evacuation were enrolled as controls. Two-tailed Student t test was used for statistical analysis. RESULTS: A hyperdynamic uterine circulation was noticed at diagnosis in all gestational trophoblastic tumors, manifested as higher peak systolic velocity (mean +/- standard deviation 57.5 +/- 20.4 cm/second) of the uterine arteries compared to nonpregnant (28.3 +/- 3.41 cm/second; P < .0001) and uneventful post-mole uteri (26.8 +/- 3.08 cm/second; P < .0001). The RI values of the uterine arteries in gestational trophoblastic tumors at diagnosis ranged from 0.21-0.80. However, the mean value (0.56 +/- 0.19) was lower than those of nonpregnant (0.80 +/- 0.05; P < .0001) and post-mole uteri (0.75 +/- 0.06; P < .0001). A higher pre-treatment uterine artery RI (mean 0.71 +/- 0.09) was noted in ten patients with gestational trophoblastic tumors requiring fewer than five courses of chemotherapy, compared with the mean in 13 patients requiring longer courses of treatment (0.47 +/- 0.14; P < .0001). There was a marked decrease of peak systolic velocity during the first three courses of treatment in the former group (54.2 to 23.6 cm/second; P < .001), in contrast to no change in the latter group (60.1 to 60.5 cm/second). CONCLUSION: Uterine hemodynamic characteristics assessed by color Doppler ultrasound might predict and monitor the response to chemotherapy in gestational trophoblastic tumors.

Cell proliferative activity and mutation of P53 suppressor gene in human gestational trophoblastic disease

Cell proliferative activity and the over accumulation of P53 suppressor gene were evaluated in 26 cases of gestational trophoblastic disease and five cases with normal placentae. Formalin-fixed, paraffin-embedded histological sections were used for immunohistochemistry, utilizing the avidin-biotin-peroxidase technique and antibodies to PCNA (proliferative cell nuclear antigen) and to P53 (product of suppressor gene). Positive reactions for PCNA were graded from 1+ to 3+ (1+ - less than 10 percent of cells; 2+ - 10 - 50 percent; 3+ - more than 50 percent). Eight of 10 cases of choriocaricinoma (80 percent) showed moderate to strong reactivity for PCNA (2+ and 3+). All 9 cases with hydatidiform mole and 6 of 7 cases with partial mole also demonstrated 2+ and 3+ reactions for PCNA. There was minimal or no PCNA straining in the trophoblastic cells of normal placentae. Five of 10 cases with choriocarcinoma (50 percent) exhibited P53 overaccumulation as did 7 of 9 cases with hydatidiform mole (78 percent). In hydatidiform moles, P53 staining was limited to the areas of trophoblastic proliferation separate from chorionic villi. None of the partial moles or normal placentae showed P53 overaccumlation. It is concluded that the cell proliferative activity of choriocarcinomas as well as complete and partial hydatidiform moles are comparable. On the other hand, the mutation of P53 suppressor gene, as demonstrated by the overaccumulation of P53 protein, is seen only in true trophoblastic neoplasms, namely choriocarcinomas and hydatidiform moles (AU)

Cell proiferative actitiy and mutation of P53 suppressor gene in human gestational trophoblastic disease

Cell proliferative activity and the over accumulation of P53 suppressor gene were evaluated in 26 cases of gestational trophoblastic disease and five cases with normal placentae. Formalin-fixed, paraffin-embedded histological sections were used for immunohistochemistry, utilizing the avidin-biotin-peroxidase technique and antibodies to PCNA (proliferative cell nuclear antigen) and to P53 (product of suppressor gene). Positive reactions for PCNA were graded from 1+ to 3+ (1+ - less than 10 per cent of cells; 2+ - 10 - 50 per cent ; 3+ - more than 50 per cent ). Eight of 10 cases of choriocaricinoma (80 per cent ) showed moderate to strong reactivity for PCNA (2+ and 3+). All 9 cases with hydatidiform mole and 6 of 7 cases with partial mole also demonstrated 2+ and 3+ reactions for PCNA. There was minimal or no PCNA straining in the trophoblastic cells of normal placentae. Five of 10 cases with choriocarcinoma (50 per cent ) exhibited P53 overaccumulattion as did 7 of 9 cases with hydatidiform mole (78 per cent ). In hydatidiform moles, P53 staining was limited to the areas of trophoblastic proliferation separate from chorionic villi. None of the partial moles or normal placentae showed P53 overaccumlation. It is concluded that the cell proliferative activity of choriocarcinomas as well as complete and partial hydatidiform moles are comparable. On the other hand, the mutation of P53 suppressor gene, as demonstrated by the overaccumulation of P53 protein, is seen only in true trophoblastic neoplasms, namely choriocarcinomas and hydatidiform moles.

[Hysterotomy and focal ectomy of malignant trophoblastic tumor].

Hysterotomy and focal ectomy were performed on 25 patients with malignant trophoblastic tumor during 1979-1991, owing to the patients and their husbands desiring strongly to have reproductive function preserved. Each of the foci of malignant trophoblastic tumor was found to be single nodule with 1-4 cm in diameter and located within the myometrium. The incision of uterus was sutured interuptly with "2-0" catgut. The pregnant rate was 80% among the patients who had received this surgical therapy. The results showed that hysterotomy and focal ectomy were an effective management for some patients without children.