层粘蛋白及受体在正常妊娠及妊娠滋养细胞疾病中的表达

目的探讨层粘蛋白(LN)及其受体(LN-R)在正常妊娠及妊娠滋养细胞疾病中的表达及其与恶性滋养细胞肿瘤侵袭的关系。方法收集1991年1月至2003年12月温州医学院附属一院正常妊娠、葡萄胎、侵蚀性葡萄胎及绒毛膜癌(绒癌)石蜡包埋组织,应用免疫组织化学SP方法检测各组中LN、LN-R的表达情况。结果LN、LN-R在正常妊娠、葡萄胎、侵蚀性葡萄胎及绒癌中的表达差异有非常显著性意义(P<0·01)。LN、LN-R在侵蚀性葡萄胎及绒癌中的表达与正常妊娠、葡萄胎比较差异有非常显著性意义(P<0·01)。结论LN、LN-R在妊娠滋养细胞疾病中的表达异常与恶性滋养细胞的高侵袭力密切相关。     

葡萄胎清宫前发生侵蚀性葡萄胎肺转移患者的临床分析

目的 探讨葡萄胎清宫前发生侵蚀性葡萄胎肺转移患者的临床特点及治疗效果.方法 回顾性分析2004年1月至2006年1月间,北京协和医院诊治的葡萄胎患者及侵蚀性葡萄胎肺转移患者的病历资料.首先将葡萄胎清宫前无肺转移患者的临床特点与葡萄胎清宫前发生侵蚀性葡萄胎肺转移的患者进行比较;然后,将葡萄胎清宫前发生侵蚀性葡萄胎肺转移患者的治疗效果与葡萄胎清宫后进展为侵蚀性葡萄胎肺转移的患者进行比较.结果 葡萄胎清宫前有胸部CT检查的37例初治葡萄胎患者中,发现存在肺部转移灶的患者有11例,占30%.葡萄胎清宫前有肺转移患者的停经时间[(15.0±4.0)周]、完全性葡萄胎所占的比例(91%),均显著高于葡萄胎清官前无肺转移的患者[(10.0±2.5)周和50%],两者分别比较,差异均有统计学意义(P值分别为0.026、0.027);而年龄、子宫体积较相应停经时间大4周、卵巢黄素化囊肿直径≥6 cm、葡萄胎清宫前血人绒毛膜促性腺激素β亚单位(β-hCG)水平等比较,差异均无统计学意义(P＞0.05).葡萄胎清宫前发生侵蚀性葡萄胎肺转移患者的血β-hCG水平降至正常水平距第1次清宫术的时间间隔,明显短于葡萄胎清宫后发生侵蚀性葡萄胎肺转移的患者,分别为(83±18)、(126±31)d,两者比较,差异有统计学意义(P＜0.01);而血β-hCG水平降至正常水平的化疗疗程数、肺部转移灶完全消失或明显吸收后不再改变所需的化疗疗程数、治疗所需总化疗疗程数以及完全缓解率等比较,差异均无统计学意义(P＞0.05).结论 葡萄胎一经诊断应尽早行清宫术,清宫术实施的时间越晚,发生侵蚀性葡萄胎肺转移和需要进行化疗的概率就越大.若葡萄胎清宫前发生了侵蚀性葡萄胎肺转移,其治疗效果与葡萄胎清宫后发生侵蚀性葡萄胎肺转移的相同,均可治愈.     

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.     

Serum relaxin in patients with hydatidiform mole

Human chorionic gonadotropin (hCG) is considered to be one of the factors that regulates relaxin secretion in humans. However, the secretory pattern of relaxin has not been evaluated in pregnancy complicated by hydatidiform mole, where circulating hCG levels are higher than in normal pregnancy. In the present study, relaxin, progesterone, and hCG levels were determined by radioimmunoassay in patients with hydatidiform mole before and after evacuation of the mole. Serum immunoreactive relaxin and progesterone levels in patients with hydatidiform mole were similar to those in normal women at corresponding weeks of pregnancy before evacuation of the mole, though hCG levels were significantly higher. The fall of relaxin levels after evacuation of the mole was slower than that of hCG or progesterone. This finding may reflect a continued stimulation of the corpus luteum by lower, but still effective, hCG levels persisting after evacuation of the mole. An extraluteal source of relaxin cannot be excluded.     

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.     

妊娠滋养细胞疾病Cyclin B1、PCNA表达的研究

目的 :检测CyclinB1和增殖细胞核抗原 (PCNA)蛋白在妊娠滋养细胞疾病(GTD)中的表达 ,探讨二者的相关性及与GTD的关系。方法 :采用免疫组化S P法检测 1 5例正常绒毛、38例葡萄胎 (HM)、42例侵蚀性葡萄胎 (IM)和 1 8例绒毛膜癌 (CC)组织中Cy clinB1和PCNA蛋白表达情况。结果 :葡萄胎、IM、CC组织中的CyclinB1和PCNA蛋白表达水平显著高于正常绒毛。术前未化疗的IM和CC组织中CyclinB1的表达水平明显高于葡萄胎。CC组织PCNA的表达水平高于葡萄胎 (P =0 .0 0 5)。葡萄胎恶变者CyclinB1和PCNA的表达显著高于未恶变者。术前未化疗的滋养细胞肿瘤患者 (包括IM和CC)Cy clinB1表达显著高于术前化疗≥3疗程者 (P =0 .0 0 2 )。WHO预后评分为高危者及中危者的CyclinB1表达显著高于低危者 (P =0 .0 0 5)。PCNA的表达与滋养细胞肿瘤是否化疗、WHO分期、WHO评分无关。PCNA与CyclinB1的表达呈正相关 (P =0 .0 0 0 )。结论 :GTD中存在CyclinB1的调节紊乱 ,CyclinB1异常表达可能与葡萄胎滋养细胞的增生、恶变及滋养细胞肿瘤的恶性生物学行为有关     

Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies.

Partial or complete hydatidiform mole (HM) affects approximately 1 in 500 to 1,000 pregnancies. Previous small series suggest that histopathologic diagnosis of HM may be difficult in tubal ectopic pregnancies. The histopathology database of a regional Trophoblastic Disease Unit was searched to identify cases with a referral diagnosis of tubal HM, and the histopathologic findings were reviewed. During the study period (1986-2004 inclusive), there were 132 cases. After central review by specialist histopathologists, the final diagnosis was ectopic partial mole in two, ectopic complete mole in five, and ectopic hydatidiform mole (not otherwise specified) in one. The final diagnosis of definite hydatidiform mole was made in eight (6%) cases, significantly less than in referred uterine curettage specimens, in which approximately 90% have a confirmatory diagnosis of HM (Z = 12.9; p < 0.0001). No cases in this series developed persistent gestational trophoblastic disease, the human chorionic gonadotropin concentration spontaneously returning to normal. Ectopic pregnancies, where managed surgically, should be submitted for histopathologic examination; however, the pathologist should be aware that the degree of extravillus trophoblastic proliferation may appear more florid compared with evacuated uterine products of conception. Molar pregnancy should only be diagnosed when strict criteria regarding morphologic abnormalities previously described in uterine evacuation material are applied.     

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。     

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.     

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.     

Study of serum SP1 levels in early normal and abnormal pregnancies

The pregnancy-specific beta 1 glycoprotein (SP1) levels in the serum of normal and abnormal pregnancies were determined by radioimmunoassay in the first trimester. The results indicated that serum SP1 levels of normal pregnancies increased with the advancing gestational week; 67% of threatened abortions with low SP1 levels would finally abort and only 7% of those with normal SP1 levels would abort. Serum SP1 levels were of lower values in ectopic pregnancy and hydatidiform mole. Serum SP1 might be taken as a better index for estimating the fetal prognosis in threatened abortion and an auxiliary diagnostic means for ectopic pregnancy and hydatidiform mole.     

Immunocytochemical localization of chorionic gonadotropin, placental lactogen, and placental alkaline phosphatase in the diagnosis of complete and partial hydatidiform moles

Complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) represent different clinicopathologic entities with characteristic morphologic and cytogenetic findings. In the absence of cytogenetic data, the histologic distinction between these lesions and abortuses showing hydropic swelling (AHS) may be difficult. An immunocytochemical study analyzing the distribution of human chorionic gonadotropin (hCG), human placental lactogen (hPL), and placental alkaline phosphatase (PlAP) in CHMs, PHMs, and AHS was undertaken to determine whether the expression of these trophoblastic proteins might assist in the differential diagnosis. A total of 24 CHMs, 22 PHMs, and 13 AHS were selected on the basis of established morphologic criteria. Thirty-four specimens of abortuses without hydropic swelling and normal placentas, ranging from 6 to 24 weeks gestational age, were similarly analyzed. The immunocytochemical localization of the three trophoblastic proteins, predominantly in syncytiotrophoblast (ST), was scored using a semiquantitative scoring system. In CHMs hCG is widely distributed and PlAP is patchily distributed in ST regardless of the gestational age, whereas hPL tends to increase with increasing gestational age. In contrast, in PHMs hPL is more widely distributed in ST compared with CHMs regardless of gestational age, while PlAP increases with increasing gestational age; in PHMs the distribution of hCG is markedly less than in CHMs except early in the first trimester when the staining patterns are similar. The different patterns of distribution of hCG, hPL, and PlAP may reflect differences in the pathobiology of trophoblast in CHMs and PHMs and appear to be useful in the differential diagnosis of these conditions.     

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.     

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.     

Molecular biological analysis of the DNA in trophoblastic disease--with special reference to genetic information of hPL and hCG(alpha, beta)

Genomic DNAs extracted from normal placenta, while blood cells, hydatidiform mole and choriocarcinoma were examined to see if they had the same coding structure for hPL, hCG alpha and hCG beta using each of the complementary DNAs. The restriction analysis of these genomic DNAs showed the same pattern even for the DNA of choriocarcinoma that transcribed no hPL mRNA but a relatively high level of hCG(alpha,beta)mRNA. We considered that during trophoblastic malignant transformation, neither the gene deletion for hPL nor the gene amplification for hCG occurred. Moreover, the genomic DNA sequence in hCG alpha gene has polymorphic restriction sites designated as R+/- and H+/-. Using these polymorphisms, we confirmed the hypothesis that a hydatidiform mole develops from an androgenetic origin. We also observed that it is possible that a hydatidiform mole having R- and H+ homozygous DNA may develop into a choriocarcinoma. These observation suggested that some intervening sequence between these polymorphic sites is related to the tumorigenesis of choriocarcinoma.     

In vitro secretory patterns of human chorionic gonadotrophin, placental lactogen and pregnancy-specific beta 1-glycoprotein

The control of secretion of the placental hormones human chorionic gonadotrophin (hCG) and human placental lactogen (hPL), and the trophoblastic protein pregnancy-specific beta-glycoprotein (SP1), is not well understood. During pregnancy, the hCG concentrations peak in the first trimester then decrease, while hPL and SP1 increase steadily throughout gestation. In order to determine whether the discordance between hCG secretion and that of hPL and SP1 observed in vivo also occur in vitro, we cultured placental explants with and without dibutyryl cyclic AMP (dbcAMP) and theophylline. Between 5 and 12 explants were used for each treatment in each experiment. The concentration of the proteins secreted into the media each day was measured by specific radioimmunoassays. The quantities of hPL and SP1 secreted per day declined in a parallel fashion after 24 hours under both basal and dbcAMP-stimulated conditions. The hCG output progressively decreased in the unstimulated cultures until 48 hours, at which time an increase in hCG secretion was observed. The dbcAMP-stimulated placentae significantly increased their hCG output at both 48 and 72 hours. These data show that hCG secretion is regulated differently from that of hPL and SP1. The results do not negate the possibility that term placental tissue may contain an inhibitor of hCG release that is removed by experimental manipulation in vitro.     

What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients

Objective

To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines.

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.     

Serum testosterone and dihydrotestosterone in patients with trophoblastic disease.

Serum testosterone (T) and dihydrotestosterone (DHT) were measured by radioimmunoassay in 14 patients with unaborted hydatidiform mole and in 16 patients with normal pregnancy of similar gestational age. Serum human chorionic gonadotropin (hCG) was measured by the radioreceptor assay in patients with hydatidiform mole. Serum T ranged from 0.27 to 5.39 ng/ml with a mean +/- SE of 2.21 +/- 0.45 ng/ml in patients with hydatidiform mole mole and from 0.20 to 2.40 ng/ml with a mean +/- SE of 0.80 +/- 0.14 ng/ml in patients with normal pregnancy, the difference being statistically significant (P = less than 0.005). Similarly, patients with molar pregnancies had a significantly higher (P = less than 0.005) serum DHT (range: 0.09 to 0.62 ng/ml; mean +/- SE: 0.29 +/- 0.05 ng/ml) than patients with normal pregnancies (range: 0.04 to 0.28 ng/ml; mean +/- SE 0.12 +/- 0.02 ng/ml). There was no significant correlation between uterine size or serum hCG and serum T or DHT. The possible sources of the elevated serum T and DHT and the lack of hirsutism or virilization in patients with trophoblastic disease are discussed.     

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).