Expressions of p53, proliferating cell nuclear antigen, and Ki-67 in gestational trophoblastic diseases

OBJECTIVE: This study was done to determine whether the expressions of p53, PCNA, and Ki-67 could differentiate spontaneous abortions with hydropic changes from gestational trophoblastic diseases. MATERIALS AND METHODS: Twenty partial hydatidiform moles, 21 complete hydatidiform moles, nine invasive hydatidiform moles, three choriocarcinomas and 19 first trimester hydropic spontaneous abortions were evaluated by means of immunohistochemical methods with antibodies to p53, PCNA, and Ki-67 in this study. RESULTS: The Ki-67, PCNA, and p53 immunoreactivity was significantly higher in the gestational trophoblastic disease group than in the spontaneous abortion group with hydropic changes. None of the three parameters provided reliable discrimination among gestational trophoblastic disease subgroups. CONCLUSION: Our findings suggest that expressions of Ki-67, proliferating cell nuclear antigen and p53 can be used to differentiate between spontaneous abortion with hydropic changes and gestational trophoblastic disease when all three markers are used together.     

Expressions of proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein in gestational trophoblastic disease

OBJECTIVE: This study was undertaken to determine whether the expressions of 3 proliferation markers (Ki-67, proliferating cell nuclear antigen, and silver-staining nucleolar organizer regions) and of p53 tumor protein could differentiate spontaneous abortions from gestational trophoblastic diseases and also discriminate among gestational trophoblastic disease subgroups. STUDY DESIGN: Twenty-two partial hydatidiform moles, 17 complete hydatidiform moles, 6 invasive hydatidiform moles, and 20 nonhydropic spontaneous abortions (control group) were evaluated by means of immunohistochemical techniques with antibodies to Ki-67, proliferating cell nuclear antigen, and p53. One-step silver staining was used to detect silver-staining nucleolar organizer regions. RESULTS: The expressions of Ki-67, proliferating cell nuclear antigen, silver-staining nucleolar organizer regions, and p53 were significantly higher in the gestational trophoblastic disease group than in the control group. The results of linear discriminant analysis showed that silver-staining nucleolar organizer region count had the highest sensitivity and specificity (93.3% and 100%, respectively) for distinguishing gestational trophoblastic disease from spontaneous abortion. Sensitivity and specificity for discriminating gestational trophoblastic disease from spontaneous abortion increased to 100% when all four markers were used together. Proliferating cell nuclear antigen was found to be the best discriminating variable for differentiating among gestational trophoblastic disease subgroups. CONCLUSION: Our findings suggest that expressions of Ki-67, proliferating cell nuclear antigen, silver-staining nucleolar organizer regions, and p53 may aid in the diagnosis of gestational trophoblastic diseases. These fairly rapid, simple, and economic techniques could serve as a useful adjunct to conventional methods in the diagnosis of gestational trophoblastic diseases.     

Expression of topoisomerase IIalpha,Ki-67, proliferating cell nuclear antigen,p53, and argyrophilic nucleolar organizer regions in vulvar squamous lesions

OBJECTIVE: It was the aim of this study to investigate the expression of topoisomerase IIalpha (topo IIalpha), Ki-67, proliferating cell nuclear antigen (PCNA), p53, and argyrophilic nucleolar organizer region (AgNOR) staining in normal vulvar epithelia (NE, N = 10), vulvar condylomas (VC, N = 24), vulvar intraepithelial neoplasia (VIN, N = 26), as well as squamous cell carcinomas (SCC, N = 22) of the vulva. METHODS: Formalin-fixed, paraffin-embedded archival tissue sections were immunostained with monoclonal antibodies against topo IIalpha, p53, and PCNA, as well as an affinity-isolated prediluted ready-to-use Ki-67 antibody using a standard immunohistochemical method, and stained with a colloid silver solution for AgNORs. Immunostaining was quantitated by determining the percentage of positively staining nuclei in each sample to express the labeling indices (LIs) by counting the immunoreactive nuclei in 1000 epithelial cells per case for each antibody. In each specimen 200 nuclei were examined using a x100 oil emersion lens, and the mean number of AgNORs per nucleus (AC) was calculated. RESULTS: The LIs for topo IIalpha, Ki-67, and PCNA as well as ACs increased stepwise from NE to VCs, VIN lesions, and SCCs. In contrast to PCNA LIs and ACs, a consistent correlation in all four groups was found for Ki-67 and topo IIalpha, suggesting that the latter is a proliferation-associated marker in these tissues. p53 expression was seen 8.3% of VCs, 30.8% of VIN lesions, and 54.45% of SCCs. p53 LIs were not correlated with LIs for topo IIalpha or Ki-67 in SCCs. The LIs for topo IIalpha, Ki-67, PCNA, p53, and ACs were not related to tumor progression, FIGO stage, or tumor grade in SCCs. CONCLUSIONS: This study presents topo IIalpha and Ki-67 as useful proliferation-associated markers of vulvar epithelia.     

Expression of the proliferation marker Ki-67 and of p53 tumor protein in trophoblastic tissue of preeclamptic, HELLP, and intrauterine growth-restricted pregnancies.

The human placenta owns the biochemical machinery to proliferate throughout gestation. The aim of this study was to investigate the expression of the proliferation marker Ki-67 in trophoblastic tissue of intrauterine growth retarded (IUGR) placentas, preeclamptic, HELLP, and in normal trophoblastic tissue. Slides of paraffin-embedded trophoblastic tissue of patients with IUGR, preeclamptic patients, HELLP patients, and normal term placentas were incubated with monoclonal antibodies against Ki-67 and p53. Staining reaction was performed with the ABC reagent. Intensity of immunohistochemical reaction on the slides was analyzed using a semiquantitative score. Identification of Ki-67-expressing cells was done by immunofluorescence double staining with Ki-67 and cytokeratin antibodies. Expression of Ki-67 and p53 are significantly elevated in cytotrophoblastic cells of placentas with HELLP as investigated by immunohistochemistry and double immunofluorescence. However, preeclamptic cytotrophoblastic tissue on the other hand showed no significantly different expression intensity of Ki-67 compared with normal placental tissue controls and no changes in p53 expression compared with controls. In IUGR cytotrophoblastic cells, we found no statistically significant change in Ki-67 expression but a statistically significant down-regulation of p53. An elevated proliferation of cytotrophoblastic cells seems to be related to HELLP, and this enhanced proliferation seems to be controlled by p53.     

Impact of p53 immunostaining in predicting advanced or recurrent placental site trophoblastic tumors: a study of 12 cases

OBJECTIVES: To identify an indicator that can predict tumor cell spread beyond the uterine corpus. METHODS: We studied clinicopathology and immunohistochemistry of 12 cases of PSTT. Two cases of epithelioid trophoblastic tumor (ETT) were included as reference cases. For immunohistochemistry, antibodies against Ki-67, p53, human chorionic gonadotropin (hCG), human placental lactogen (hPL), carcinoembryonic antigen (CEA, polyclonal antibodies; pCEA), carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), and bcl-2 were used. PSTT cases were divided as confined and non-confined groups (CG and NCG, respectively). CG consisted of stage I cases with no evidence of recurrence during the follow-up, while NCG consisted of either advanced (stage II or higher) or recurrent stage I lesions. RESULTS: Age, the interval from the latest pregnancy, serum hCG/hPL levels, tumor size, mitotic figures, Ki-67 labeling indices, and bcl-2 did not discriminate NCG from CG. CEACAM1 and CEA-related antigens as determined by polyclonal anti-CEA antibodies were specifically stained in PSTT cells, but they could not discriminate groups. p53 was positive in PSTT cells in NCG (6/6, 100%), while it was positive in only one case of CG (1/6, 16.7%), indicating a possible usefulness of p53 immunostaining in predicting an invasive or recurrent propensity of PSTT cells (p=0.015). CONCLUSIONS: This finding also suggests the importance of p53 function in the biology of PSTT cells.     

Immunohistochemical study of SP1, HPL and HCG in chorionic tissue with early spontaneous and induced abortions

Using an indirect enzyme-labeled antibody method, localization of SP1, HPL and HCG in spontaneous abortions (29 cases) was compared with those in induced abortions (39 cases). At the same time, histological changes were examined in the same specimens. 1) Histologically, the fibrinoid degeneration in cytotrophoblastic mass was more often found in spontaneous abortions than in induced abortions. Stromal fibrosis frequently existed in spontaneous abortions (6-10 weeks: 53%, 11-16 weeks: 93%). Stromal edema was rare in induced abortions, but was detected in spontaneous abortions (6-10 weeks: 13%, 11-16 weeks: 50%). These findings were increased with gestational age. 2) Horseradish peroxidase (HRP) reaction products from SP1, HPL and HCG located mainly in the syncytiotrophoblast. The intensity of HRP reaction was not always uniform in each villus. 8% in induced abortions and 59% in spontaneous abortions showed reaction with anti-HCG in some stromas in syncytiotrophoblast. Most of them also showed stromal fibrosis. In spontaneous abortions, the intensity of HRP reaction on HPL was relatively increased in comparison with that on HCG or SP1. In some severe degenerated specimens, SP1 and HPL were found in syncytiotrophoblast, but HCG seemed to be located on the outer part of the stroma adjacent to syncytiotrophoblast.     

Human chorionic gonadotropin and free beta subunit secretion in three events of pregnancy.

Serum hCG and free beta hCG subunit were measured in intrauterine pregnancies (n = 21), ectopic pregnancies (n = 20) and spontaneous abortions (n = 19) matched for gestational age. Significantly higher concentrations of both dimer and free beta subunit hCG were detected in normal pregnancies (86,336 IU/L) and 21.02 IU/L respectively) compared to abortions (10,460 IU/L and 3.73 IU/L) and ectopic pregnancies (3,900 IU/L and 3.73 IU/L) (p less than .05). When the ratio of free beta hCG/intact hCG (%) was studied, however, EP had significantly higher ratios (0.09 +/- 0.09) than IUP (p less than .05). Assessment of the relative distributions of these ratios revealed that 100% of IUP and AB and 65% of EP had ratios less than 0.10. Most notably, 35% of EP were uniquely characterized by ratios greater than 0.10. This ratio was sufficiently higher in 35% of EP to define a profile completely unique to EP. These data suggest that an increased free beta to dimer hCG ratio of greater than 0.10 may assist in the differentiation of ectopic from intrauterine pregnancies of spontaneous abortions and provide insight into a possible trophoblastic mechanics in these clinical events.     

Expression pattern of the cell cycle promoter cyclin e in benign extravillous trophoblast and gestational trophoblastic lesions: correlation with expression of Ki-67.

In this study, a specific monoclonal antibody was used to immunohistochemically investigate correlated expression of the cell cycle promoter cyclin E and the proliferation marker Ki-67 in benign extravillous trophoblast and gestational trophoblastic lesions. Our data show that cyclin E is expressed in the normal extravillous trophoblast, with strongest levels of expression in the cell columns of anchoring villi. Differences could be observed in expression of Ki-67 in both normal extravillous trophoblast and gestational trophoblastic lesions. In the extravillous trophoblast of the cell columns, expression of cyclin E started more distal compared with Ki-67 and was maintained (with less intensity) into the deeper layers of interstitial trophoblast. In the benign trophoblastic lesions (exaggerated placental site [EPS] and placental site nodule [PSN]) and in the trophoblast proliferations on the surface of hydropic villi of hydatidiform moles (HM), the percentage of cells expressing cyclin E was higher than of those expressing Ki-67. The same observation could be made for a case of placental site trophoblastic tumor (PSTT). In contrast, choriocarcinomas (N=8), which are definitely malignant tumors, showed an opposite pattern, with a much higher percentage of strongly Ki-67-positive cells compared with cyclin E-positive cells. We conclude that cyclin E is expressed in benign extravillous trophoblast and gestational trophoblastic lesions, where a ratio cyclin E/Ki-67<1 characterizes choriocarcinomas, whereas PSTT and the benign lesions (HM, EPS, PSN) show expression of cyclin E in a higher percentage of cells than Ki-67 (cyclin E/Ki-67 ratio >1).     

Immunohistochemical and mutational analysis of p53 tumor suppressor gene in gestational trophoblastic disease: correlation with mdm2, proliferation index, and clinicopathologic parameters

The role of p53 in the pathogenesis of gestational trophoblastic disease (GTD) was investigated. Immunohistochemical studies for p53, its regulator mdm2, and proliferation marker Ki67 were performed on paraffin-embedded tissues of 28 partial moles (PM), 57 complete moles (CM), 14 choriocarcinomas (CCA), and 31 normal placentas. Three antibodies to p53 (DO-7, Ab-2, Ab-3) were used and demonstrated immunoreactivity for wild-type p53 protein predominantly in the nuclei of cytotrophoblasts. Direct DNA sequencing of 36 hydatidiform moles using frozen tissues confirmed an absence of mutational changes in exons 5–8. CCA was found to have the highest p53 protein expression, followed by CM, PM, and normal placenta ( P < 0.001). In normal placentas ( P = 0.0001), PM, and CM ( P = 0.016), an inverse correlation between their gestational age and p53 expression was observed. p53 expression was found to correlate with proliferation index in normal placenta ( P = 0.0001) and all three groups of GTD ( P = 0.012). Significant correlation between p53 and mdm2 expression was also observed ( P < 0.01). The distinctive expression of p53 wild-type protein in the cytotrophoblasts and its positive correlation with the proliferative index suggests that its overexpression in GTD may be related to its effect on cell proliferation. The parallel expression of mdm2 and p53 also supports the presence of an autoregulatory feedback loop in the control of this process. No correlation could be found between clinical progress of the patients with hydatidiform moles, and the p53 ( P = 0.78) or mdm2 protein ( P = 0.54) expression suggesting that neither of them carries any prognostic significance.     

Comparative studies on the biological significance of the marker for proliferation Ki-67-Antigen and PCNA in primary ovarian carcinoma

OBJECTIVE: It was shown in experimental and clinical investigations, that the biological behavior of malignant tumors is reflected by their proliferative activity. PCNA and Ki-67-Antigen are two nuclear antigens and considered to represent important markers of proliferation. We investigated their proliferation index in primary ovarian carcinomas and correlated the results with tumor stage, grading, histological type and survival. MATERIAL AND METHODS: The expression of PCNA and Ki-67-Antigen was immunohistochemically evaluated using the monoclonal antibodies MIB-1 and PC 10 on formalin-fixed, paraffin-embedded tissue of 49 patients. Statistical data were calculated by means of Fisher's Exact Test and Pearson's Chi 2 Test, survival was estimated by Kaplan Meier Curves. RESULTS: PCNA-expression was shown in all ovarian carcinomas and Ki-67-Antigen-expression was detected with one exception (98%) in all tumors, too. No correlation could be found between Ki-67-Antigen-expression and the prognostic factors mentioned above, whereas a high PCNA-expression was significantly correlated with the tumor grading (G3), (p < 0.05). Patients with ovarian carcinomas with high PCNA proliferation index showed the tendency of a shorter overall survival. DISCUSSION: Ki-67-Antigen and PCNA-expression could be detected in almost all primary ovarian carcinomas. PCNA compared to Ki-67-Antigen is considered to be more useful for the determination of the proliferative activity of ovarian carcinomas, although there was shown just a tendency of overall survival dependent on PCNA-expression, and there was a significant correlation only between PCNA-proliferation index and tumor grading.     

Differential diagnosis of smooth muscle tumors utilizing p53, pTEN and Ki-67 expression with estrogen and progesterone receptors

BACKGROUND/AIM: To investigate the expression and value for diagnosis of the genes, p53 and pTEN, the protein, Ki-67, and the receptors, estrogen and progesterone, in differentiating smooth muscle tumors of the uterus. MATERIAL AND METHOD: Seventeen samples of leiomyosarcoma, 2 smooth muscle tumors with uncertain malignant potential (STUMP), 9 atypical myomas and 15 leiomyomas were stained immunohistochemically. The chi(2) test was used for the statistical analysis of the data. RESULTS: The malignant side of the spectrum was strongly stained for Ki-67 and p53 while uniformly decreasing toward the benign tumors. The results were found to be statistically significant (p < 0.0001). The staining for progesterone receptor was also statistically significant, but the tumors that were considered benign, such as leiomyoma and atypical myoma, were the ones strongly stained (p = 0.005). The expression of estrogen receptor was significant in these tumors, but the p value was very close to the cut-off value (p = 0.07). As the degree of differentiation of the tumor increased, the trend showed stronger staining for estrogen receptor. However, no difference was detected in the staining properties of the tumors for pTEN (p = 0.2457). CONCLUSION: The expression of Ki-67, p53 and progesterone receptors is promising in immunodifferentiation of smooth muscle tumors of the uterus with malignant potential.     

Influence of chemotherapy on the expression of p53, HER-2/neu and proliferation markers in ovarian cancer.

OBJECTIVE: Mutated p53 and HER-2/neu play a role in the etiology of ovarian cancer. It is important to know whether the expression of these proteins is affected by platinum-containing chemotherapy. STUDY DESIGN: Together with the cell proliferation markers Ki-67 and PCNA, the expression of p53 and HER-2/neu was assessed before and after chemotherapy. Paraffin-embedded tumor sections from 20 patients with ovarian cancer and four patients with benign disorders of the ovaries (controls) were analyzed. The expression of p53 was determined by the antibodies DO-1 and BP53-12. In addition to HER-2/neu and PCNA specific antibodies, MIB-1 was used to detect Ki-67. RESULTS: The expression of all markers was higher in ovarian cancer patients than in non-malignant controls. MIB-1 showed a significant increase of expression after chemotherapy (P=0.002). HER-2/neu, p53 and PCNA also showed a clear increase after treatment, but this was not statistically significant. HER-2/neu is of prognostic relevance with respect to the response to chemotherapy (P=0.005) and survival (P=0.0002). CONCLUSION: The different markers tested all increase after chemotherapy, but the differences are not statistically significant. Low HER-2/neu expression correlates with good outcome at second look.     

Expression pattern of the adhesion molecule CEACAM1 (C-CAM, CD66a, BGP) in gestational trophoblastic lesions.

CEACAM1 (CD66a, BGP, C-CAM) is an adhesion molecule of the carcinoembryonic antigen (CEA) family which has been shown to be normally expressed at the apical pole of epithelial cells and to show a dysregulated expression pattern in tumors derived from the latter. The purpose of the present study was to investigate the expression pattern of CEACAM1 in gestational trophoblastic lesions and to compare this expression with the one observed in the normal trophoblast. For this purpose, we performed immunohistochemistry using the 4D1/C2 monoclonal antibody which specifically recognizes CEACAM1 and does not interact with other members of the CEA family. Immunohistochemistry was performed on a total of 20 cases of gestational trophoblastic lesions including complete hydatidiform moles, one placental site trophoblastic nodule (PSN), one placental site trophoblastic tumor (PSTT), and three choriocarcinomas. Immunostaining for cytokeratin, hPL, hCG, and Ki-67 was also performed. Normal placental samples served as a control. CEACAM1 was absent from villous cyto- and syncytiotrophoblast in both normal placenta and hydatidiform molar samples. It was present in the benign extravillous trophoblast, with stronger expression in the proximal extravillous trophoblast of anchoring villi, but was also observed in interstitial and endovascular intermediate trophoblast and chorionic intermediate-like trophoblast. Partial expression was observed in the trophoblast proliferating from the surface of molar villi. In choriocarcinomas, areas of weak expression could be observed along with large areas without CEACAM1 expression. In the PSN and especially in the PSTT, CEACAM1 expression was stronger and more diffuse. The specific localization to extravillous trophoblast and its expression pattern in gestational trophoblastic lesions indicate that CEACAM1 can potentially be a helpful additional diagnostic marker in the differential diagnosis of such lesions.     

Borderline tumors of the ovary: a clinico-pathologic and immunohistochemical study of 54 cases

OBJECTIVE: To study EGF-R, HER-2/neu (p185), p53, Mib-1 (Ki-67), Bax, Bcl-2, ras expression and ploidy in borderline tumors of the ovary by assessing their frequency, and relationship to histologic type, tumor recurrence and survival. METHODS: Fifty-four patients with borderline tumors were followed 3-140 months (median: 38 months). Paraffin-embedded sections were stained using monoclonal antibodies against EGF-R, HER-2/neu (p185), p53, Mib-1 (Ki-67), Bax, Bcl-2, and ras. The immunohistochemical findings were correlated to histologic subtype, tumor recurrence, and survival. RESULTS: Positivity for EGF-R was found in 24% (13/54), in 22% (12/54) p185 was positive, 9% (5/54) of tumors were p53-positive, Mib-1 (Ki-67)-positivity was demonstrable in 46% (25/54). Expression of Bax, Bcl-2, and ras was found in 37% (20/54), 28% (15/54) and in 7% (4/54) of the cases, respectively. CONCLUSION: The data demonstrate expression of EGF-R, p185/HER-2/neu, p53, Mib-1 (Ki-67), Bax, Bcl-2, and ras in a subgroup of patients with ovarian borderline tumors. Further studies to evaluate their prognostic value are warranted.     

Immunohistochemical staining for Ki-67 and p53 helps distinguish endometrial Arias-Stella reaction from high-grade carcinoma, including clear cell carcinoma.

The distinction of the Arias-Stella reaction from clear cell carcinoma of the endometrium is usually straightforward; however, this differential diagnosis can be difficult when the Arias-Stella reaction occurs outside the setting of pregnancy or in older patients. The differential diagnosis also is problematic when serous or clear cell carcinoma focally arises within an endometrial polyp, as part of "endometrial intra-epithelial carcinoma" (EIC), or in younger patients. The goal of this study was to determine whether immunohistochemical staining can distinguish the Arias-Stella reaction from endometrial high-grade carcinoma, particularly clear cell carcinoma. Cases of endometrial Arias-Stella reaction (n = 27), clear cell carcinoma (n = 11), serous carcinoma (n = 7), and EIC (n = 4) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, estrogen receptor (ER), and progesterone receptor (PR). Composite immunohistochemical scores based on the percentage and intensity of stained cells were calculated, as was the overall positivity (percentage positive cases), using a cutoff value of >/=5% stained cells and at least weak intensity. Appropriate statistical tests were performed. Ki-67 and p53 immunostaining was significantly less in Arias-Stella reaction than in clear cell carcinoma (p < 0.0001 for both) or serous carcinoma/EIC (p < 0.0001 for both), measured by the composite immunohistochemical scores or overall positivity. ER showed a significant difference only between Arias-Stella reaction and clear cell carcinoma; PR showed a significant difference only between Arias-Stella reaction and serous carcinoma/EIC. When clinical or histologic features cannot facilitate the differential diagnosis, immunohistochemical staining for Ki-67 and p53 may help distinguish endometrial Arias-Stella reaction from clear cell carcinoma and other types of high-grade carcinoma.     

Ki-67、PCNA及HPV在宫颈癌和宫颈上皮内瘤变的表达及意义

目的:研究Ki-67,增殖细胞核抗原(PCNA)在早期宫颈癌(IA~IIA期高分化)、宫颈上皮内瘤变(CINI、CINII、CINIII)及慢性宫颈炎中的表达,及其与HPV感染的关系,探究3者联合应用的诊断价值。方法:应用免疫组织化学S-P法检测宫颈病变中Ki-67、PCNA抗原的表达,PCR反应检测HPV感染,结合临床病理特点分析。结果:慢性宫颈炎、CIN、宫颈鳞癌中Ki-67阳性表达率分别为33.33%、89.19%、100%。PCNA阳性表达率分别为66.67%、97.30%、100%。HPV阳性率分别是13.33%、54.05%、1000%。CINI和CINII/III中Ki-67阳性表达率分别为85.00%、94.12%;PCNA阳性表达率分别为95.00%、100.00%。HPV阳性率分别是30%、82.35%。CIN和宫颈癌中的Ki7、PCNA及HPV的阳性表达与宫颈炎相比,差异均有显著性(P<0.05)。Ki-67及PCNA过表达率在CINII/III组与CINI组间差异显著(P<0.05)。HPV阳性率在CINII/III与CINI之间差异显著(P<0.01)。Ki-67及PCNA表达与HPV感染有相关性(P<0.05)。结论:Ki-67、PCNA抗原过表达与CINII/III和早期宫颈癌显著相关。Ki-67、PCNA表达与HPV感染率相关,联合检测宫颈组织中Ki-67、PCNA的过表达及HPV感染,有助于判断细胞的增殖活性,可作为诊断早期宫颈癌和CINII/III的标记物。     

Correlation of c-erbB-2 oncogene and p53 tumor suppressor gene with malignant transformation of hydatidiform mole

AIM: Considering the roles of c-erB-2 and p53 oncoproteins in tumor progression, we aimed to evaluate their expression in hydatidiform moles, and the possible predictive value of this immunoexpression in postmolar follow-up. METHODS: Group I comprised 35 patients with progression to gestational trophoblastic tumor, and group II included 32 patients with progression to spontaneous remission. Immunohistochemical tests were performed by streptavidin-peroxidase method. c-erbB-2 immunoexpression was evaluated according to quantitative and semiquantitative criteria; p53 according to percentage of cells with stained nuclei. Data were analyzed by Student t-test, Mann-Whitney test, ROC curve and logistic regression analysis. RESULTS: c-erbB-2 and p-53 expressions were significantly increased in group I. Quantitative and semiquantitative analysis of c-erb-2 showed that its expression may be associated with mole hydatidiform progression to gestational trophoblastic tumor. Taking into account cells with complete membranous delineation we proposed a cut-off value of 10.8%. Similarly, considering the percentage of cells presenting nuclei marked by p53 we suggested a cut-off value of 40.1% for the prediction of malignant transformation of mole hydatidiform. CONCLUSIONS: c-erbB-2 and p53 immunoexpression in hydatidiform mole are usually increased with malignant transformation. In addition to beta-fraction of human chorionic gonadotropin, they could possibly help the establishment of a therapeutic protocol.     

Pregnancy outcome after treatment with etoposide (VP-16) for low-risk gestational trophoblastic tumor

The aim of this study was to evaluate subsequent fertility and pregnancy in patients treated for persistent trophoblastic tumors with single-agent VP-16. Records of all patients treated for persistent trophoblastic tumors at the Chiba University Hospital between January 1, 1986 and December 31, 1997 were reviewed. Of these, 85 patients were initially treated with single-agent VP-16. Subsequent pregnancy outcome of these patients was investigated. After remission with VP-16, 36 patients (92.3%) of those who wished for a pregnancy (45.9% of all patients studied) conceived, and 91.7% had at least one live birth. A total of 56 conceptions resulted in 42 (75.0%) term live births, seven (12.5%) first-trimester spontaneous abortions, one (1.8%) second-trimester spontaneous abortion, four (7.1%) therapeutic abortions, and two (3.6%) repeated moles. There were no congenital anomalies, no stillbirths, and the neonates' physical growth was comparable to that of the standard population in Japan. Single VP-16 regimen for patients with low-risk gestational trophoblastic tumor appears to have no adverse effects on fertility potential and pregnancy outcome.     

Analysis of the relationship between cancer procoagulant activity and PCNA and Ki-67 expression in cases of common and cellular uterine leiomyomas

PURPOSE: Histological subtypes of uterine leiomyomas may substantially differ in their cellular biology, including the intensity of synthesis of cancer markers and expression of cell proliferation markers. The present investigation aimed to determine the activity of cancer procoagulant (CP) in subtypes of leiomyomas, including cellular leiomyomas, and to verify whether these activities correlate with immunoexpression of cell proliferation markers: the proliferating cell nuclear antigen (PCNA) and Ki-67. MATERIALS AND METHODS: Preoperative peripheral venous blood and postoperative tissue material were obtained from 24 women operated on in a tertiary referral academic department. The activity of CP in serum was measured with the use of a coagulative method according to Gordon and Benson, and in tissue homogenates with the use of a spectrophotometric method according to Colucci et al. The control serum values were obtained from 20 healthy women without any gynecological disease, and the control solid tissue values from histologically confirmed postoperative normal reproductive tissues obtained from six patients. PCNA and Ki-67 expression were determined immunohistochemically using monoclonal antibodies. RESULTS: Both the tissue and serum activity for CP was considerably higher for common leiomyomas and cellular leiomyomas than for control tissues, but did not differ significantly between the leiomyoma subtypes. Intratumor CP activity significantly correlated with PCNA expression but not with Ki-67 expression. CONCLUSIONS: Cellular leiomyomas do not differ substantially in the serum and intratumor CP activity from common leiomyomas. There is a relationship of intratumor CP activity with PCNA expression, a finding which requires further investigation.     

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.