Histopathological and immunohistochemical features of early hydatidiform mole in relation to subsequent development of persistent gestational trophoblastic disease.

OBJECTIVE: To examine histomorphological and immunohistochemical findings in hydatidiform moles to determine whether any features can reliably predict clinical behavior. STUDY DESIGN: Blinded semiquantitative review of histological and immunohistochemical findings in cases of partial hydatidiform mole (PHM) (N = 50) and complete hydatidiform mole (CHM) which either spontaneously resolved (N = 50) or required chemotherapy (N = 50). Immunostains assessed included MLH1, MSH2, nm23, TERT, p53, EGFR, and CerbB2 based on previous data. RESULTS: There were marked morphological differences in various criteria between CHMs and PHMs, including the proportion of villi with abnormal trophoblast hyperplasia (29% vs. 6%, respectively). However, there were no significant differences in any morphological parameters between CHMs that spontaneously resolved and those that subsequently required chemotherapy. Similarly, there were no clinically useful differences regarding any immunostaining scores between CHM groups. CONCLUSION: Neither morphological nor immunohistochemical features can reliably predict subsequent requirement of chemotherapy in CHMs.

Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: morphology, p57 immnohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease.

Recent studies have demonstrated the value of ancillary techniques, including p57 immunohistochemistry and short tandem repeat genotyping, for distinguishing hydatidiform moles (HM) from nonmolar specimens and for subtyping HMs as complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM). With rare exceptions, CHMs are p57-negative and androgenetic diploid; partial hydatidiform moles are p57-positive and diandric triploid; and nonmolar specimens are p57-positive and biparental diploid. Androgenetic/biparental mosaic/chimeric conceptions can have morphologic features that overlap with HMs but are genetically distinct. This study characterizes 11 androgenetic/biparental mosaic/chimeric conceptions identified in a series of 473 products of conception specimens subjected to p57 immunohistochemistry and short tandem repeat genotyping. Fluorescence in situ hybridization was performed on 10 to assess ploidy. All cases were characterized by hydropically enlarged, variably sized and shaped villi. In 5 cases, the villi lacked trophoblastic hyperplasia, whereas in 6 there was a focal to extensive villous component with trophoblastic hyperplasia and features of CHM. The villi lacking trophoblastic hyperplasia were characterized by discordant p57 expression within individual villi (p57-positive cytotrophoblast and p57-negative stromal cells), whereas the villous components having trophoblastic hyperplasia were uniformly p57-negative in both cell types. Short tandem repeat genotyping of at least 2 villous areas in each case demonstrated an excess of paternal alleles in all regions, with variable paternal:maternal allele ratios (usually >2:1); pure androgenetic diploidy was identified in those cases with a sufficiently sized villous component having trophoblastic hyperplasia and features of CHM. Fluorescence in situ hybridization demonstrated uniform diploidy in 7 cases, including 4 of 5 tested cases with trophoblastic hyperplasia and 3 of 5 cases without trophoblastic hyperplasia. Two cases without trophoblastic hyperplasia had uniformly diploid villous stromal cells but 1 had triploid and 1 had tetraploid cytotrophoblast; 1 case with trophoblastic hyperplasia had uniformly diploid villous stromal cells but a mixture of diploid, triploid, and tetraploid cytotrophoblast. In 3 cases with a CHM component, persistent gestational trophoblastic disease developed. These results indicate that androgenetic/biparental mosaic/chimeric conceptions are most often an admixture of androgenetic diploid (p57-negative) and biparental diploid (p57-positive) cell lines but some have localized hyperdiploid components. Recognition of their distinctive p57 expression patterns and genotyping results can prevent misclassification as typical CHMs, PHMs, or nonmolar specimens. The presence of androgenetic cell lines, particularly in those with a purely androgenetic CHM component, warrants follow-up because of some risk of persistent gestational trophoblastic disease.

Loss of p57 Expression in Conceptions Other Than Complete Hydatidiform Mole: A Case Series With Emphasis on the Etiology, Genetics, and Clinical Significance.

Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum ß-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.

Immune cell profiling in normal pregnancy, partial and complete molar pregnancy.

OBJECTIVES: Cytotoxic T cells (Tc) and natural killer (NK) cells may play a role in controlling trophoblast invasion. This study was undertaken to determine the level of infiltration and antigen profile of immune cells and explore their relationship in normal placenta (NP) and molar tissues to better understand the biology of gestational trophoblastic diseases. MATERIALS AND METHODS: Immunolocalization of CD8, Granzyme B (GrB), and FoxP3 was performed on sections prepared from 11 gestational age-matched NP, 19 partial moles (PM), and 18 complete moles (CM) to characterize effector (GrB+CD8+) and GrB- (GrB-CD8+) Tc cells, GrB+ NK cells (GrB+CD8-), and Treg (FoxP3+) cells. RESULTS: Immune cells infiltrated into the implantation site of normal placenta, PM, and CM with increasing frequency. Effector and GrB- Tc, GrB+ NK and Treg infiltration in the CM were significantly stronger than seen in the normal placenta (p=0.002, p=0.007, p=0.002, respectively). Immune cell infiltration was not detected in the villi or trophoblast of gestational tissues. Treg infiltration in the implantation site was only observed in PM and CM. In CM and PM Tc infiltration positively correlated with Treg infiltration (p=0.035), but Treg infiltration did not correlate with the Tc effector ratio (effector Tc cells/all Tc cells). CONCLUSION: In CM the cellular immune response in the implantation site was significantly more vigorous than seen in normal placenta. These observations demonstrate that in the implantation site of CM, the number of effector Tc and GrB+ NK cells are increased and Treg cells may negatively regulate T lymphocyte activation.

Nuclear beta-catenin and Ki-67 expression in choriocarcinoma and its pre-malignant form.

OBJECTIVE: To study the expression of nuclear beta-catenin and Ki-67 in patients with normal gestation products (NGP), complete hydatidiform moles (CHM), and choriocarcinoma to elucidate their roles in carcinogenesis and their interrelations. METHODS: Expression of nuclear beta-catenin and Ki-67 was studied by immunohistochemistry using paraffin embedded blocks. Sixty NGP, 60 CHM, and 10 choriocarcinomas were analysed. In addition, approximately 400 trophoblasts each in 40 NGP, 40 CHM, and 10 choriocarcinomas from the same batch of samples were microdissected for quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) to compare beta-catenin mRNA concentration among them. RESULTS: In the chorionic villi of NGP, beta-catenin was consistently expressed in the nuclei of cytotrophoblasts but not syncytiotrophoblasts. Nuclear beta-catenin expression was comparatively reduced in CHM trophoblasts and was absent in choriocarcinoma. By contrast, Ki-67 expression was increased from cytotrophoblasts but not in syncytiotrophoblasts in the chorionic villi of NGP to CHM trophoblasts and choriocarcinoma. Using Q-RT-PCR, beta-catenin mRNA was detected in 10 NGP, 13 CHM, and three choriocarcinoma specimens, with median copy numbers of 43,230, 18,229, and 17,334 per 400 trophoblasts, respectively. A housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was detected as a control in the NGP, CHM, and choriocarcinoma specimens, with median copy numbers of 51,300, 54,270, and 97,150 per 400 trophoblasts, respectively. Thus median beta-catenin mRNA values after normalisation were 0.85 in NGP (n = 10), 0.31 in CHM (n = 13), and 0.16 in choriocarcinoma (n = 3). CONCLUSIONS: Decreased nuclear beta-catenin expression and increased Ki-67 expression may be involved in choriocarcinoma carcinogenesis. The findings also suggest that nuclear beta-catenin may play a role in trophoblast differentiation during normal placental development.

Successive activation of the platelet-derived growth factor beta receptor and platelet-derived growth factor B genes correlates with the genesis of human choriocarcinoma.

The hydatidiform mole is a benign disease of the placenta characterized by the absence of the maternal genome. Approximately 3% of the reported cases will develop into malignant choriocarcinoma. In situ hybridization analysis reveals that the paternal platelet-derived growth factor (PDGF) beta receptor gene is up to 2 orders of magnitude more active in cytotrophoblasts of the complete hydatidiform moles than in normal placentae. The transition between hyperplasia (complete hydatidiform mole) and neoplasia (choriocarcinoma) in these cells correlates with at least a 10- to 20-fold activation of the PDGF-B gene. Since the neoplastic cytotrophoblasts have maintained an abnormally high level of PDGF beta receptor expression, we propose that a deregulated PDGF autostimulatory loop is involved in the genesis of human choriocarcinoma from hydatidiform moles.

The importance of immunohistochemistry in the differential diagnosis of molar disease.

The differential diagnosis among complete moles, partial moles and hydatidiform abortions may be challenging during routine diagnostic activity. These entities share the histological aspect of enlarged villi, but here we summarize also some peculiar features of all of them. If histology does not clarify this distinction, the immunohistochemistry is the most important tool for pathologists to complete such diagnosis. The correct management of immunohistochemistry and of further possible analysis is also reviewed. Lastly, the most important antibodies, starting from p57, are presented.

Immunohistochemical Expression and Clinical Significance of Wnt11 and BCL2A1 in Complete Moles.

OBJECTIVE: To investigate Wnt11 and BCL2A1 immunohistochemical expression in complete moles and normal villi. STUDY DESIGN: The expression of Wnt11 and BCL2A1 in 84 complete moles and 30 normal first-trimester villi were detected by Envision immunohistochemistry. Quantitative evaluation according to color deconvolution and immunoreactive score was performed. Data was analyzed using Kruskal-Wallis test, Pearson test, and ROC curve. RESULTS: Of 84 complete moles, 14 developed to post-molar gestational trophoblastic neoplasia, and the others regressed spontaneously. Both proteins showed cytoplasmic pattern, whereas the DAB wt% of BCL2A1 and Wnt11 expression was highest in moles that developed to GTN, gradually reduced in spontaneously regressed moles and normal villi (all p < 0.01). We considered a 23.17% cutoff valuefor Wnt11 DAB wt% and 16.31% for BCL2A1 DAB wt% to assess molar progression to GTN. There was positive correlation between expressions of the 2 proteins (r = 0.403). CONCLUSION: Our findings demonstrated immunohistochemical expression of Wnt11 and BCL2A1 in complete moles and normal villi. Both proteins may be included as part of an immunohistochemical panel to identify postmolar outcome when other trophoblastic markers yield ambiguous results.

Specific expression patterns of epithelial to mesenchymal transition factors in gestational molar disease.

INTRODUCTION: The epithelial to mesenchymal transition, a well-known and re-emerging model in pathology, has not been completely investigated in the field of gestational pathology. This study aims at improving the comprehension of this process in molar disease, even looking for new possible immunohistochemical markers. MATERIALS AND METHODS: We have analysed the immunohistochemical expression of Twist1 and Snai2, two of the most important transcription factors involved in epithelial to mesenchymal transition, in formalin-fixed paraffin-embedded samples of 23 spontaneous abortive pregnancies, 22 molar pregnancies (10 partial and 12 complete) and 7 term placentas. RESULTS: Twist1 and Snai2 were highly expressed in stromal villi cells of molar disease. Particularly, Twist1 was highly expressed in complete moles compared to both abortive pregnancies (p < 0.001) and partial moles (p < 0.05). Also Snai2 was more expressed by complete moles, differentiating them from non-molar abortions (p < 0.05). DISCUSSION: On the basis of the known cadherins and claudins expression in these pathologies, our new findings reinforce the hypothesis of the involvement of epithelial to mesenchymal transition in early molar pregnancies and above all in complete moles. Furthermore, we highlighted that in molar disease not only the trophoblast, but even the villi stromal cells, are involved. Thanks to their specificity, furthermore, these Twist1 and Snai2 could be used as additional immunohistochemical tool in the diagnosis of complete molar disease, with Twist1 as the first choice.

Decreased type III and V collagen expression in chorionic villi of hydatidiform mole.

To investigate the characteristic structure of hydatidiform mole, various types of collagen expression were determined in human villous tissues obtained from normal pregnancies (n = 17) and complete hydatidiform moles (n = 10). Indirect immunofluorescent staining was performed to detect type I, III, and VI collagen with specific monoclonal antibodies. Collagens were also extracted from the villous tissues obtained from normal pregnancy and hydatidiform mole by the salt precipitation method. Immunohistochemical staining for type I, III, and VI collagen revealed weak staining of the villous stroma in hydatidiform mole compared with that in normal pregnancy. Both the ratios of type III to type I collagen and the ratios of type V to type I collagen in the villous tissues were significantly decreased (P < 0.05) in molar pregnancy compared with those in normal pregnancy. These results suggest that alterations in the distribution and composition of collagen might play an important role in determining the pathophysiology and structure of hydatidiform mole.

Thyrotropic activity of basic isoelectric forms of human chorionic gonadotropin extracted from hydatidiform mole tissues.

hCG is known to have thyroid-stimulating activity and may cause hyperthyroidism in patients with trophoblastic diseases. hCG occurs in normal and molar pregnancy with breaks or nicks in the alpha- or beta-subunit peptide linkage and with substantial heterogeneity in the composition and degree of branching within the oligosaccharide side-chains. The bioactivity of hCG is markedly influenced by these structural variations. We purified hCG from five hydatidiform moles, using chromatofocusing separation after gel filtration. The hCG molecules were fractionated according to their isoelectric points, with a linear pH gradient from 3.2-6.1 and a final 1.0 mol/L NaCl step elution. The hCG immunoreactivity of each fraction was measured by RIA, and the thyroid-stimulating activity of hCG was determined by means of the cAMP response in Chinese hamster ovary cells expressing functional human TSH receptors (Chinese hamster ovary-JP09 cells). The chromatofocusing profile showed that hCG from the moles was eluted in six or seven major peaks at pH 6.1, 5.5, 5.3, 4.8, 3.8, and 3.2 and with 1.0 mol/L NaCl, whereas hCG extracted from serum of hydatidiform moles and standard hCG preparation CR-127 extracted from pregnancy urine showed only small peaks at pH greater than 5.3. Each fraction increased cAMP production significantly in Chinese hamster ovary-JP09 cells. The relative bioactivity/immunoreactivity, represented as the ratio of cAMP/hCG (picomoles per IU), was significantly higher in basic components (pI 6.1, 6.2 +/- 1.2; pI 5.5, 4.4 +/- 2.7; pI 5.3, 5.8 +/- 0.3) than in hCG CR-127 (bioactivity/immunoreactivity, 0.42; P < 0.05). The difference in pI of each hCG isoform was attributable to the extent of sialylation; basic hCG isoforms contained less sialic acid by immunological detection using lectins. These results indicate that isoforms of hCG with more thyrotropic activity were produced by trophoblastic tissues in patients with hydatidiform mole. We speculate that these isoforms of hCG may be responsible for the hyperthyroidism in some patients with hydatidiform moles.

Increased in vitro thyrotropic activity of partially sialated human chorionic gonadotropin extracted from hydatidiform moles of patients with hyperthyroidism.

The intrinsic thyrotropic activity of hCG purified from normal pregnancy urine has been demonstrated in several laboratories. hCG has a specific thyrotropic potency of about 0.04-0.5 microU bovine (b) TSH/IU hCG, depending on the bioassay system. The corresponding potency for hCG derived from pathological sources, such as hydatidiform moles and choriocarcinoma tissue, or from the serum of these patients has not been studied as extensively. Since the biological activity of glycoproteins can be strongly influenced by variations in the oligosaccharide side-chain composition, we have investigated the effect of anion exchange chromatography on the thyrotropic potency of hCG derived from the hydatidiform mole and serum of three hyperthyroid patients with molar pregnancy. The activity for the fraction of total molar hCG immunoreactivity that was not retained by an anion exchange column (0.18-0.90 microM bTSH/IU hCG) was about twice that of the corresponding serum and molar hCG fraction eluting during the NaCl gradient elution (0.08-0.40 microU bTSH/IU hCG). The unretained hCG fraction corresponds to a previously described hCG precursor that is partially desialated in the C-terminal region of the beta-subunit.

Diagnostic considerations in molar gestations.

Hydatidiform moles (HMs) are classified as partial or complete based on a combination of gross, histologic, and karyotypic features. Adherence to strict and reproducible diagnostic criteria is needed to ensure accurate diagnosis and minimize interpathologist variability. Using the kappa statistic as a measure of agreement, the morphologic, flow cytometric, and clinical features of 80 cases of HM or suspected HM were analyzed sequentially by three pathologists to evaluate intrapathologist and interpathologist variability. Poor interpathologist agreement was obtained when histology alone was used for diagnosis. The combination of gross morphology and histology resulted in poor to good agreement. Good interpathologist agreement was obtained, however, when objective data (DNA content determined by flow cytometry) were included in the analysis. Our data indicate that pathologist concordance is maximized when the diagnosis is based on a combination of morphology and DNA content.

Placental iron deposits: significance in normal and abnormal pregnancies.

The extent of iron deposition in the placenta during the various stages of pregnancy, as well as its significance, has not been clearly established. There often is confusion with regard to calcium deposits. To address this issue 82 placentas (60 from normal pregnancies and 22 from abnormal pregnancies) were examined by light microscopy, including iron and calcium stains, and immunoperoxidase stains for ferritin. Seven cases also were studied ultrastructurally, including x-ray microanalysis. With these modalities we could unequivocally differentiate between iron and calcium deposits. It was concluded that in normal pregnancies the placenta stores iron mainly in two forms: first, at least as soon as the seventh week of gestation Hofbauer cells and the syncytiotrophoblast contain ferritin, which is particularly prominent in the syncytiotrophoblast's brush border; and second, during the first two trimesters of gestation iron also is present as linear granular deposits in the trophoblastic basement membrane. In the presence of anomalies in fetal development the iron deposition in the form of linear granular deposits is markedly increased to a statistically significant degree during the second and third trimesters of pregnancy. It is concluded that granular iron deposits in the trophoblastic basement membrane are normally present, gradually decreasing in the progress of normal pregnancies. Their presence in excess (> 7.5% of villi), however, is a pathologic finding associated with fetal growth anomalies.

Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles.

The differentiation of complete mole (CM), an aberrant androgenetic conceptus, from partial mole (PM) and hydropic abortion (HA) in early gestations is very important for patient management. In this study, 10 diploid voluntary artificial abortions (ABs), 20 diploid HAs, 20 triploid PMs, and 44 diploid CMs (including 4 persistent diseases), all of which were in the first trimester, were evaluated by immunohistochemistry of formalin-fixed tissues using a monoclonal antibody against p57(KIP2) protein (p57), a putative paternally imprinted inhibitor gene. DNA ploidy in all cases was analyzed by flow cytometry. In all ABs, nuclear p57 was strongly expressed in cytotrophoblasts, intermediate trophoblasts, villous stromal cells, and decidual stromal cells but was absent in syncytiotrophoblast. In diploid CMs, p57 expression in cytotrophoblasts and villous stromal cells was either absent (37 cases) or very low (7 cases). Villous intermediate trophoblasts stained for p57 in 12 cases of CM. On the other hand, 16 HAs and 19 PMs showed p57 levels comparable to those observed in ABs. Decidual stromal cells provided a reliable internal control in all cases. These findings support the hypothesis that misexpression of p57 is involved in the abnormal development of androgenetic CMs. This immunohistochemical analysis is a useful tool for the differential diagnosis of CMs.

p53 and Bcl-2 oncoprotein expression in placentas with hydropic changes and partial and complete moles.

Forty molar and non-molar placentas with hydropic changes (14 complete moles, 14 partial moles, and 12 hydropic non-molar placentas) were examined immunohistochemically for expression of oncoproteins p53 and Bcl-2. The data were evaluated to determine if p53 and Bcl-2 expression could aid in differentiating molar from non-molar pregnancies on the one hand and complete mole from partial mole on the other. Thirteen out of fourteen complete moles showed p53 expression (93%), 8 of the 14 partial moles expressed p53 (57%), and none of the non-molar pregnancies expressed p53 in the extravillous intermediate trophoblasts. Regarding Bcl-2, the syncytiotrophoblasts of most molar and non-molar placentas showed strong and diffuse positivity. These results suggest that p53 expression can be used as a distinguishing parameter between complete moles and placentas with hydropic changes on the one hand and to a lesser extent between partial moles and placentas with hydropic changes on the other hand. Bcl-2 cannot be used in the same way as p53.

Proliferative activity in placentas with hydropic change and hydatidiform mole as detected by Ki-67 and proliferating cell nuclear antigen immunostaining.

Complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM) represent different clinicopathologic entities. To obtain prognostic and therapeutic information about both entities, it is important that pathologic classification be as accurate as possible. The distinction of molar pregnancy and an abortus with hydropic changes (AHC) can sometimes be very difficult. The acquisition of 2 antibodies against nuclear antigens expressed in cycling cells, Ki-67 and proliferating cell nuclear antigen (PCNA), allow the study of trophoblastic proliferation in CHM, PHM, and AHC. The purpose of this study is to determine whether immunocytochemical stains can help in the distinction between those entities. All materials were obtained by curettage from 95 patients with hydropic villi evident on microscopic examination. The 95 cases included 33 cases of CHM, 42 cases of PHM, and 20 cases of AHC. In the case of the Ki-67 staining, the mean was much lower in the ACH group (8.7%) than in the PHM group (65.3%) or in the CHM group (84.6%). In the case of PCNA staining, the mean differences among the 3 groups (AHC, 23.1%; PHM, 80%; and CHM, 89.2%) were all statistically significant. On the basis of the means and the Gaussian results, it appears that the Ki-67 distribution gives a better separation among the 3 groups. In conclusion, proliferative activity is an additional useful parameter for evaluation of molar pregnancies and hydropic changes, with Ki-67 staining allowing better separation than PCNA staining does.

Expression of c-myc and c-fms oncogenes in trophoblastic cells in hydatidiform mole and normal human placenta.

AIMS: To compare the expression of c-myc and c-fms proto-oncogenes in the placenta and hydatidiform mole. METHODS: Twelve hydatidiform moles and six induced abortion cases were collected. c-myc and c-fms proto-oncogene expression was analysed by northern blot hybridisation and immunohistochemical staining. RESULTS: The results of northern blot hybridisation analysis showed that c-fms was expressed more strongly in hydatidiform moles compared with normal placenta of similar gestational age. Moreover, c-fms mRNA concentrations increased with more advanced gestational age in moles but not in normal placentas. c-myc expression was very low in hydatidiform moles and normal placentas. Both oncogenes, however, had no direct correlation with the clinical course of the molar pregnancies. CONCLUSION: The difference in c-fms expression between hydatidiform moles and normal placentas suggests that c-fms may have a role in the development of molar pregnancies.

Immunohistochemical localization of inhibin-activin subunits in hydatidiform mole and invasive mole.

OBJECTIVE: To examine the cellular localization of each inhibin subunit in hydatidiform mole and invasive mole. METHODS: Tissues were collected and fixed in Bouin's solution and studied with the immunohistochemical technique avidin-biotin-peroxidase complex. RESULTS: In the villous trophoblasts of hydatidiform mole and invasive mole, distinct immunostaining for inhibin alpha-subunit was observed in proliferative syncytiotrophoblasts, but not in the cytotrophoblasts. Positive immunostaining for beta A- and beta B-subunits was observed in both syncytiotrophoblasts and cytotrophoblasts. In extravillous trophoblasts of the invasive mole, staining for beta A- and beta B-subunits was observed, whereas staining for alpha-subunit was not detected. CONCLUSION: Inhibin-activin subunits may be produced in the trophoblasts of hydatidiform mole and invasive mole, and inhibin and activin may play a role in trophoblastic proliferation and invasion.

Insulin-like growth factor-I in women with hydatidiform mole and in normal pregnancy.

OBJECTIVE: To compare molar and placental tissue insulin-like growth factor-I (IGF-I) levels and IGF-I messenger RNA (mRNA) expression and maternal serum IGF-I levels in molar and normal pregnancies of the same gestational length. METHODS: Tissue and serum total IGF-I were measured by radioimmunoassay, and tissue IGF-I mRNA expression was measured by a solution hybridization technique in samples from seven patients with hydatidiform mole in gestational weeks 8 through 14 and from 12 women with normal placentas undergoing induced abortion during weeks 8 through 12. RESULTS: Tissue and serum total IGF-I levels and tissue IGF-I mRNA expression were significantly lower in molar pregnancies than in pregnancies with normal placenta. CONCLUSION: The lower levels of both IGF-I mRNA and of the IGF-I protein itself in hydatidiform mole indicates that the regulation of expression of IGF-I is on the transcriptional level. This finding may reflect a decreased production of the placental growth hormone variant in molar tissue.