Concentrations of SP1 and beta-hCG in serum and cerebrospinal fluid and concentrations of hCG in urine in patients with trophoblastic tumour

Using immunological techniques urinary hCG, pregnancy-specific beta 1-glycoprotein (SP1) and beta-subunit of hCG (beta-hCG) levels were measured in the serum and cerebrospinal fluid of patients with trophoblastic tumours. After removal of hydatidiform moles, urinary hCG, beta-hCG and SP1 levels were similar, but SP1 levels tended to exceed serum beta-hCG levels. SP1 usually disappeared first. In patients with metastatic choriocarcinoma, SP1 levels appeared to be lower than beta-hCG values in serum and cerebrospinal fluid, but urinary hCG, beta-hCG and SP1 concentrations all decreased during chemotherapy. Measurements of SP1 levels may well be useful in the monitoring of patients being treated for trophoblastic tumours.     

恶性滋养细胞肿瘤肺转移患者肺叶切除术指征的探讨

目的探讨肺叶切除术治疗恶性滋养细胞肿瘤肺转移患者的手术指征。方法通过医院病案数据库,调用1990—2003年北京协和医院收治的629例Ⅲ~Ⅳ期恶性滋养细胞肿瘤患者的治疗记录,收集肺转移行肺叶切除术的患者及化疗后血人绒毛膜促性腺激素β亚单位(βhCG)降至正常(<2IU/L)后肺内带瘤随诊的患者,对符合入选条件的95例患者的临床病理资料进行回顾性分析。结果侵蚀性葡萄胎肺转移患者41例中,行肺叶切除术者6例,病理检查病灶全为坏死结节;化疗后血βhCG正常后肺内带瘤随诊者35例,随诊6个月~11年,病情均稳定。绒毛膜癌肺转移患者54例中,行肺叶切除术者29例,其中病理检查病灶为出血坏死组织、无活性肿瘤细胞者(定为病理阴性)17例,病灶内仍有活性肿瘤细胞残留者(定为病理阳性)12例;化疗后血βhCG正常未手术的带瘤随诊者25例,其中病情进展5例,病情稳定20例。绒毛膜癌肺叶切除术后病理阳性及带瘤随诊病情进展患者在年龄、临床分期、末次妊娠性质等方面与肺叶切除术后病理阴性及带瘤随诊病情稳定患者比较,差异无统计学意义(P>005);但两者血βhCG从10IU/L降到2IU/L以下所需的化疗疗程数及总疗程数比较,前者却明显多于后者(P=001,P=0001)。结论侵蚀性葡萄胎肺转移可经化疗治愈,化疗后未完全消失的肺部阴影可随诊观察。     

Result of registration and follow-up system of gestational trophoblastic disease in Shizuoka Prefecture (from 1977 to 1988)--recent trend and choriocarcinoma following term gestation

The remission rate of choriocarcinoma has greatly improved since the introduction of effective multiagent chemotherapy combined with aggressive surgical therapy and radiotherapy. In addition to these, the registration and follow-up of gestational trophoblastic disease (GTD) also has been playing an important role in the early detection and treatment of choriocarcinoma following hydatidiform mole. The system for the registration and follow-up of GTD was started in 1977 in Shizuoka Prefecture. In the present series, the results obtained with this registration and follow-up system from 1977 to 1988 in Shizuoka Prefecture were reviewed and analysed. 1) One thousand, nine hundred and twenty-five cases of hydatidiform mole, 68 cases of invasive mole, 70 cases of persistent trophoblastic disease and 48 cases of choriocarcinoma were registered in 12 years. The overall registration rate was 97.4%. 2) The number of cases of hydatidiform mole registered has decreased from about 180 cases to about 140 cases per year, probably due to the decreasing birth rate. 3) The number of cases of choriocarcinoma registered has recently been decreasing significantly and the number of cases of registered invasive mole and persistent trophoblastic disease has decreased slightly. 4) Antecedent pregnancy with choriocarcinoma including clinical choriocarcinoma has been changing from "post-molar" to "post-term" in the past 12 years. The prognosis of the patient with choriocarcinoma following hydatidiform mole has improved by the early detection and treatment since the introduction of the registration and follow-up system. More attention should be paid to choriocarcinoma following term gestation not yet included in the registration and follow-up system to facilitate early detection and treatment.     

Measurement of CA-125 in trophoblastic disease

OBJECTIVES: Physicians treating hydatidiform mole are still seeking means of identifying those patients who will require chemotherapy. The standard accepted method is to follow human chorionic gonadotropin levels but CA-125 measurement has been suggested as a supplement that may be clinically useful. This study was undertaken to validate or refute the one previous study that addresses this issue. CA-125 was measured at the time of hydatidiform mole evacuation to determine (1) whether it would predict the need for chemotherapy and (2) whether it correlated with human chorionic gonadotropin and tumor load in following patients with hydatidiform mole and metastatic gestational trophoblastic disease. PATIENTS AND METHODS: CA-125 was measured in serial weekly samples selected from diagnostic groups of patients with trophoblastic disease. Sixteen patients had hydatidiform mole with spontaneous resolution, fourteen had nonmetastatic gestational trophoblastic tumor, and four had low-risk metastatic disease. Six patients had high-risk metastatic disease. Ten patients had partial hydatidiform mole and one of these required chemotherapy. One patient had primary ovarian choriocarcinoma and three had placental site tumor. RESULTS: The mean preevacuation CA-125 among the 15 patients with complete hydatidiform mole was 40.9 U/ml: 52.5 U/ml for 5 patients who required chemotherapy and 36.2 U/ml for 10 patients who did not require chemotherapy. There was no statistical difference between these values. There was no correlation of CA-125 with hCG. Frequently CA-125 became negative when hCG was still elevated. Among six patients with high-risk disease, CA-125 was elevated in four but in all six patients hCG remained elevated when CA-125 became negative. In nine patients with partial hydatidiform mole CA-125 was elevated prior to mole evacuation and then became negative. The patient with a tetraploid conceptus who required chemotherapy had negative CA-125. With placental site tumor CA-125 was negative, but it was elevated with ovarian choriocarcinoma. CONCLUSION: CA-125 levels do not provide reliable information in the management of patients with gestational trophoblastic disease.     

Serum SP1 and hCGβ-subunit (hCGβ) levels in choriocarcinoma, invasive mole, and hydatidiform mole—Clinical significance of ratio

Serum SP₁ (pregnancy-specific β₁, glycoprotein) levels in patients with choriocarcinoma, invasive mole, and hydatidiform mole were radioimmunoassayed and compared with simultaneously measured serum hCGβ-subunit (hCGβ) levels in order to evaluate the clinical significance of SP₁ determination. Serum SP₁ levels at the time of admission ranged from 6.4 to 1660 ng/ml in choriocarcinoma patients, 16.3 to 540 ng/ml in invasive mole, and 720 to 58,000 ng/ml in hydatidiform mole. ratios were under 1.0 in choriocarcinoma (0.3 ± 0.2, mean ± SD), over 1.0 in hydatidiform mole (10.9 ± 8.3), and intermediate in invasive mole (1.5 ± 0.3). In normal pregnancy, the ratio increases as pregnancy progresses, that is, from 15.25 in 7-week gestation to 14,090.90 in 40-week gestation. The mean ratio differs significantly among choriocarcinoma, invasive mole, and hydatidiform mole. ratio is likely to represent the degree of differentiation of trophoblastic cells. The ratio may be useful in differentiating between choriocarcinoma and invasive mole.     

Gestational trophoblastic disease in women aged 50 or more

Twenty cases of gestational trophoblastic disease in women aged 50 or more are reported. The lesions were 7 hydatidiform mole (35%), 8 invasive mole (40%), and 5 choriocarcinoma (25%). The most common presenting symptom was abnormal vaginal bleeding. Three choriocarcinoma patients were postmenopausal and all of them had choriocarcinoma. None of the patients with hydatidiform mole or invasive mole died of the disease, but 4 of 5 choriocarcinoma patients died of the disease. Because of the high rate (56.3%) of malignant sequelae after molar evacuation, a primary hysterectomy for the treatment of hydatidiform mole in this age group is recommended. It is important to maintain a high level of suspicion for the diagnosis of gestational trophoblastic disease in the elderly women.     

The serum pregnancy-specific beta 1-glycoprotein to beta-human chorionic gonadotrophin ratio as an index of prognosis in patients with choriocarcinoma

The ratio of serum pregnancy-specific beta 1-glycoprotein (SP1) to the beta-subunit of human chorionic gonadotrophin (beta-hCG) before and after chemotherapy was measured in 12 patients with metastatic choriocarcinoma. The ratios before chemotherapy ranged between 0.03 and 0.75, with a mean value of 0.34 (SD 0.21). The ratio increased to over 1.0 (1.05-53.3) after one or two courses of chemotherapy in seven of the 12 patients. These women achieved complete remission. In the other five patients who died of the disease due to drug resistance of the tumour, the ratio after chemotherapy was low (0.04-0.74) and tended to decline. These data suggest that the serum SP1/beta-hCG ratio can be used to predict the prognosis of patients with choriocarcinoma.     

Statistical analysis of trophoblastic disease in Kanagawa prefecture

Two thousand one hundred and thirty-five cases of trophoblastic disease were registered in Kanagawa Prefecture in 7 years (from 1978 to 1984). The incidence of trophoblastic diseases, hydatidiform mole, partial mole, invasive mole, choriocarcinoma and persistent trophoblastic disease (PTD) was 3.22, 1.67, 1.20, 0.07, 0.06 and 0.20, respectively, per 1,000 live births. The incidence was constant for 7 years, and did not differ significantly from that of 16 prefectures in Japan. In Kanagawa, the incidence of hydatidiform mole was less and that of partial mole was more than those in the 16 prefectures. The incidence of invasive mole and choriocarcinoma was lower and that of PTD was higher than those in the 16 prefectures. Total incidence of invasive mole, choriocarcinoma and PTD was higher in the western part of Japan, and lower in the eastern and northern parts. Kanagawa Prefecture is between these two regions. The distribution by age of hydatidiform mole was high in 25-29 y.o. and over 40 y.o. The distribution by age of partial mole tended to be similar to that of hydatidiform mole, but less remarkable. The distribution by age of invasive mole and choriocarcinoma had 2 peaks of 30-34 y.o. and 45-49 y.o. The distribution by age of PTD was between that of hydatidiform mole and choriocarcinoma.     

Gestational Trophoblastic Disease in Port Moresby, Papua New Guinea

A retrospective study was performed at Port Moresby General Hospital covering the period 1.1.81-31.3.86. There were 37 cases of hydatidiform mole, 2 of choriocarcinoma and 4 of metastasizing gestational trophoblastic disease of unknown histology, During the study period there were 35,630 deliveries in the same hospital. The incidence of hydatidiform mole was found to be 1:963 deliveries. Among the patients with hydatidiform mole 1 death was recorded whilst in the group with choriocarcinoma and unclassified disease there were 4 deaths. Of the patients treated for hydatidiform mole 48.5% made no follow-up visits to the hospital.     

Expression of nm23-H1 in hydatidiform mole and its relationship with the development of postmolar disease.

The aim of the present study was to investigate the expression of nm23-H1 in human placenta, hydatidiform mole and choriocarcinoma cells. Nm23-H1 protein was localized in the cytotrophoblast, but not in the syncytiotrophoblast. In the hydatidiform mole cases with subsequent spontaneous remission, nm23-H1 mRNA levels were significantly lower than those in first-trimester placentas. However, its levels were elevated in the hydatidiform mole cases that progressed to persistent gestational trophoblastic disease and were comparable to those of first-trimester placentas, and they were further elevated in choriocarcinoma cells. The present data suggest an association of nm23-H1 for the proliferation activity of trophoblast, and its increased expression may influence the development of persistent trophoblastic disease.     

Ultrasonographic study of trophoblastic neoplasms. A report of 185 cases]

B-scan ultrasonography was used in 94 cases of hydatidiform mole (benign group), 62 cases of invasive mole and 29 cases of choriocarcinoma (malignant group). A correct diagnosis was made in 91.5% of cases of the benign group and 91.3% of the malignant group. Chemotherapy was given to all patients with invasive mole or choriocarcinoma, and hysterectomy was done in 47 cases after chemotherapy. During chemotherapy a gradual regression of the intramural lesions was demonstrated by ultrasonography with fall of hCG titer. The authors suggest that the B-scan ultrasonography is a safe and useful method in monitoring the response of the trophoblastic tumors to chemotherapy.     

Telomerase activity in complete hydatidiform mole.

OBJECTIVE: To investigate whether telomerase is activated in complete hydatidiform mole and whether it could predict the development of persistent gestational trophoblastic tumors (GTTs). STUDY DESIGN: For this prospective study, 21 patients with complete hydatidiform mole were recruited. Molar tissue was obtained for telomerase activity measurement using the telomeric repeat amplification protocol assay. Patients' clinical characteristics, telomerase activity and subsequent clinical outcome were analyzed. RESULTS: Telomerase activity was detected in 12 cases (57.1%) with varied intensity. Two of four patients who had telomerase activity, uterine size larger than expected and preevacuation serum beta-human chorionic gonadotropin (beta-hCG) levels > 10(6) mIU/mL developed persistent GTT. CONCLUSION: Telomerase activity is detectable in some complete hydatidiform moles and might be useful for predicting persistent GTT when combined with uterine size and preevacuation serum beta-hCG level.     

The natural history of theca lutein cysts

The histories of 386 patients with untreated hydatidiform mole were reviewed to define the clinical aspects of accompanying theca lutein cysts. These cysts occurred in 102 patients (26.4%), with three patients experiencing cyst-related complications. Mean cyst size at diagnosis was 7.3 cm (3-20 cm), and did not correlate with post-molar trophoblastic disease development. Bilateralism occurred more often in patients developing post-molar trophoblastic disease. In patients with post-molar trophoblastic disease, 83% (45 of 54) experienced theca lutein cyst regression and 16.7% an increase in cyst size with falling beta-hCG titers. Post-molar trophoblastic disease developed in 44 patients. Theca lutein cyst growth occurred in 31.8% of the patients with beta-hCG plateau/rise and in 4.5% with falling titers. Disappearance of theca lutein cysts before diagnosis of post-molar trophoblastic disease occurred in 31.8%. Theca lutein cysts persisted in three patients for long periods (15-18 weeks) after beta-hCG regression. We conclude that theca lutein cysts commonly accompany hydatidiform mole and are associated with an increased risk of post-molar trophoblastic disease, a risk that is higher with cyst bilateralism or severe complications of hydatidiform mole. Theca lutein cysts uncommonly have serious complications; their clinical behavior does not depend entirely on changes in beta-hCG levels, as cysts may persist for long periods after beta-hCG regression.     

Ultrasonic evaluation of trophoblastic disease and the response to chemotherapy

Ultrasound is an established method of confirming the presence of a hydatidiform mole in utero. However, in agreement with other investigations, we have often noted that the appearance of this entity is less specific than originally reported. To elucidate this, the ultrasonic patterns of 26 patients with trophoblastic disease and 27 with other entities were reviewed. Since there is a paucity of literature with regard to the response of choriocarcinoma to chemotherapy, determined by ultrasound, we simultaneously studied the relationship between findings of the ultrasonograms and the levels of hCG-beta-subunit in sera. We noted variable ultrasonic features in trophoblastic disease, and the sonograms of the choriocarcinoma have occasionally been confused with those of hydatidiform mole. If special attention is directed to the thickness of the placenta-like echoes as well as the sonolucent areas within it, the diagnosis of partial hydatidiform mole may be feasible. We also noted a rough correlation between ultrasonic appearances and the hCG-beta-subunit value, determined during chemotherapy for choriocarcinoma.     

P63 expression in hydropic abortion and gestational trophoblastic diseases

Gestational trophoblastic diseases are a group of interrelated diseases of trophoblastic tissue that include partial hydatidiform mole, complete hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic tumor. P63 is a p53 homologue that, in normal placentas, is expressed in the cytotrophoblast cells. The role of p63 in gestational trophoblastic diseases, however, merits further investigation. Immunohistochemistry with the p63 antibody (clone 4A4) was performed in formalin-fixed paraffin-embedded samples of hydropic abortion (n=10), partial hydatidiform mole (n=12), complete hydatidiform mole (n=12) and choriocarcinoma (n=5). P63 expression was quantitatively assessed as 0 (no stained cells), + (less than 10% positive cells), ++ (10-50% positive cells), and +++ (more than 50% positive cells). The intensity was scored as 0 (absence), + (weak), ++ (moderate), or +++ (strong). Statistical analysis was carried out by the Fisher test. In contrast to the other diagnoses, none of the choriocarcinomas analyzed exhibited p63-positive cells. There was no difference in distribution of p63 positive cells between hydropic abortion, partial hydatidiform mole, and complete hydatidiform mole. Concerning the intensity of immunostaining, there was difference only between partial hydatidiform mole and complete hydatidiform mole. According to our results, p63 might be useful to differentiate a choriocarcinoma from other gestational trophoblastic diseases. Besides, since the intensity of p63 expression was much stronger in partial hydatidiform mole and complete hydatidiform mole than in hydropic abortion, this feature may be helpful in distinguishing these two diagnoses in challenging cases.     

Human chorionic gonadotropin and its subunits in hydatidiform mole and choriocarcinoma.

Serum human chorionic gonadotropin (hCG) was measured by a radioreceptorassay (RRA) and radioimmunoassay (RIA) and serum hCG-beta and hCG-alpha by RIA in 10 patients with intact mole, 3 patients with choriocarcinoma, and 4 patients with hydatidiform mole during treatment. hCG levels by RRA were higher in 5 of 10 molar pregnancies and ranged from 20,900 to 100,000 ng/ml and from 30,000 to 100,000 ng/ml by RIA. hCG levels by RRA and RIA paralleled one another closely during treatment of hydatidiform mole. hCG-alpha was higher than hCG by RRA and RIA and hCG-beta in molar pregnancies, in the uterine venous blood draining a uterine choriocarcinoma, and during chemotherapy of choriocarcinoma. In 2 of 3 choriocarcinoma patients who eventually developed cerebral metastases, hCG-alpha increased while hCG and hCG-beta were declining or negative. hCG-beta was usually lower than hCG or hCG-alpha in all the cases studied. These results demonstrate the production of free alpha and beta subunits in trophoblastic disease. Further, due to the biospecificity, simplicity, and rapidity, the RRA of hCG is a sueful diagnostic aid during treatment of trophoblastic neoplasia until the levels fall to within the sensitivity range of the assay. Finally, the RIA of hCG, hCG-beta, and hCG-alpha, which requires several days, should be performed until they become negative or fall within normal range.     

Epidemiology of hydatidiform mole in Finland, 1975 to 2001

PURPOSE: Broad variations in the incidence of gestational trophoblastic diseases have been reported in different parts of the world. Recent time trends in the incidence of hydatidiform mole in Western countries have not been elucidated. We studied the epidemiology of hydatidiform mole in Finland over a period of 27 years. METHODS: Women reported to have hydatidiform mole from 1975-2001 were identified from the National Research and Development Center for Welfare and Health. Women with choriocarcinoma were identified from the Finnish Cancer Registry. RESULTS: We identified 1659 cases of hydatidiform mole between 1975 and 2001. This gives an incidence of 73/10(6) women or 984/10(6) deliveries. The overall incidence remained fairly constant over the study period. The incidence was higher in women below 20 years and above 39 years than in women in the other age groups. Forty-nine percent of choriocarcinomas identified during the study period were associated with a preceding hydatidiform mole. The risk of choriocarcinoma after a hydatidiform mole was 2.2%. CONCLUSIONS: The incidence of hydatidiform mole in Finland follows the same patterns as in other Western countries. The incidence has not changed considerably in recent decades.     

Levels of placenta growth factor in gestational trophoblastic diseases

OBJECTIVE: The aim of the current study was to investigate levels of placenta growth factor in the tissues and sera of the patients with gestational trophoblastic disease and to determine its usefulness for the treatment of gestational trophoblastic disease. STUDY DESIGN: Placenta growth factor concentrations were measured in the tissue homogenates of 12 normal placentas, 33 complete hydatidiform moles, and 6 gestational choriocarcinomas. Serum placenta growth factor levels were determined in 59 women with normal pregnant course, in 30 women with complete hydatidiform mole, in 36 women with persistent gestational trophoblastic disease, and 100 nonpregnant healthy volunteers. RESULTS: Serum and tissue placenta growth factor levels in the patients with mole tended to be decreased compared with the levels in normal pregnancy; the levels were increased significantly in patients with choriocarcinoma. When serum placenta growth factor levels were >20 pg/mL (normal upper limit in nonpregnant women), placenta growth factor-to-human chorionic gonadotropin ratios were increased significantly in patients with persistent gestational trophoblastic disease. CONCLUSION: Serum placenta growth factor levels are not of any predictive value in patients with hydatidiform mole. However, elevated serum placenta growth factor levels with increased placenta growth factor-to-human chorionic gonadotropin ratios are suggestive of persistent gestational trophoblastic disease.     

妊娠滋养细胞疾病中Th1/Th2类细胞因子的表达与葡萄胎恶变关系的探讨

目的：探讨妊娠滋养细胞疾病中Th1/Th2类细胞因子的表达及与葡萄胎恶变的关系。方法：以IL-2、IFN-γ代表Th1类细胞因子,以IL-4、IL-10、IL-13代表Th2类细胞因子,以β-actin为内参照,用逆转录聚合酶链反应(RT-PCR)方法检测未恶变的葡萄胎12例,发生恶变的葡萄胎及绒癌38例中不同细胞因子的表达模式。结果：非恶变组IL-2及IFN-γ的表达率较恶变组高(P＜001),细胞因子的表达以Th1类占优势,而恶变组IL-4、IL-10及IL-13的表达率较非恶变组高(P＜005),细胞因子的表达以Th2类占优势。恶变组恶变前后相比较,恶变后IL-4、IL-10、IL-13的表达均有增高的趋势(P＜005)。侵蚀性葡萄胎与不同来源的绒癌之间细胞因子的表达差异无显著性(P＞005)。结论：Th2类细胞因子的高表达在妊娠滋养细胞疾病的发生、发展中起一定作用,Th1/Th2漂移对滋养细胞肿瘤的早期发现、患者预后判断及治疗有一定价值。     

Radioimmunoassay of free beta-subunit of human chorionic gonadotropin in diagnosis of high-risk and low-risk gestational trophoblastic disease

A radioimmunoassay was performed with monoclonal antibody 1E5, which distinguishes free beta-subunit of human chorionic gonadotropin in the presence of intact human chorionic gonadotrophin. Serum samples were obtained from 68 pregnant women, 9 with hydatidiform mole who underwent spontaneous remission, 12 with hydatidiform mole who developed gestational trophoblastic disease, 5 with metastatic gestational trophoblastic disease of high-risk category, and 1 with choriocarcinoma concomitant with pregnancy. The concentrations of free beta-subunit of human chorionic gonadotropin and total beta-subunit were determined on the sera. The assay data were expressed as a ratio of nanograms of free beta-subunit per 1000 mIU of total beta-subunit. The ratios, analyzed by the Wilcoxon two-sample test, indicated a highly significant correlation between high ratios and the eventual diagnosis of high-risk gestational trophoblastic disease (p = 0.0019). This study suggests that the excessive production of free beta-subunit of human chorionic gonadotrophin may identify patients with high-risk gestational trophoblastic disease much earlier and identify gestational trophoblastic disease in patients during pregnancy.