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PubMed1980

[Trophoblastic gestational diseases. Triploid syndrome, perivillous trophoblastic hyperplasia, trophoblastic pseudotumor, trophoblastic microcarcinoma and carcinoma].

Comparing the cytogenetic and morphological data on cases of hyperplasia and neoplasia of the trophoblast allows some conditions to be better defined and separated. The term partial mole or embryonic mole should be replaced by the term triploid syndrome because of the especially strong correlation between the triploid caryotype and the special aspect of the placenta. Triploidy is usually the result of fecundation of a haploid ovule by two spermatozoids, probably due to the similarity of the haploids of the two parents, as is suggested by the study of HLA antigens. Classical hydatidiform mole, or perivillous trophoblastic hyperplasia, is usually discovered earlier, during an ultrasound examination or abortion and its histological diagnosis is easy. The caryotype of complete hydatidiform mole is diploid, nearly always XX, with the two sex chromosomes coming from the father (the maternal sex chromosome being eliminated). The caryotype of vesicular dystrophia without trophoblastic hyperplasia is, on the other hand, normal. Trophoblastic microcarcinomas have a better known presentation. And trophoblastic carcinomas are distinct from non-trophoblastic neoplasms which secrete HCG and from benign trophoblastic pseudo-tumors which are often non-secretory.

Female↗
PubMed2004

p63 expression is useful in the distinction of epithelioid trophoblastic and placental site trophoblastic tumors by profiling trophoblastic subpopulations.

Human trophoblast is composed of a heterogeneous population of cells, which give rise to a variety of trophoblastic tumors and tumor-like lesions. In this report, we analyzed the expression pattern of the p63 gene, a transcription factor belonging to the p53 family, in different trophoblastic subpopulations and in trophoblastic lesions. p63 has various isoforms that are classified into two groups designated TA and DeltaNp63 isoforms. The TA isoforms have a p53-like suppressor function, whereas the DeltaNp63 isoforms exert an oncogenic effect. Based on immunohistochemistry and RT-PCR, it appears that cytotrophoblast expresses the DeltaNp63 isoform whereas chorionic-type intermediate trophoblast in the fetal membranes, placental site nodules, and epithelioid trophoblastic tumors expresses the TAp63 isoform. Intermediate trophoblast in the implantation site and placental site trophoblastic tumors does not express p63. Based on the expression patterns of p63 and the previously described expression patterns of other trophoblastic markers, including HLA-G, cytokeratin 18, hPL, and Ki-67, we developed an immunohistochemical algorithm to diagnose trophoblastic lesions. A validation set of 22 trophoblastic lesions and 34 nontrophoblastic tumors were classified correctly using this algorithm. In conclusion, the findings in this study demonstrate that different trophoblastic subpopulations and their related trophoblastic lesions are characterized by distinctive patterns of p63 expression. Recognizing these distinctive expression patterns helps to further elucidate the biology of trophoblast and can also provide a useful tool for the differential diagnosis of trophoblastic lesions.

Algorithms↗
PubMed2002

Molecular genetic analysis of placental site trophoblastic tumors and epithelioid trophoblastic tumors confirms their trophoblastic origin.

Trophoblastic tumors represent a unique group of human neoplasms because they are derived from fetal tissue. Except for choriocarcinoma, the neoplasms that develop from human trophoblast are poorly characterized. Placental site trophoblastic tumors and epithelioid trophoblastic tumors are thought to arise from intermediate (extravillous) trophoblasts based on histopathological studies, but direct molecular evidence of a trophoblastic origin has not been established. In this study, we performed molecular analysis in an attempt to confirm their presumable trophoblastic origin. We demonstrated that such tumors contain a Y-chromosomal locus and/or new (paternal) alleles not present in adjacent normal uterine tissue in all 31 informative cases. Loss of heterozygosity was found in 60% of tumors and all 42 tumors assessed contained wild-type K-ras. All of the trophoblastic tumors were heterozygous in at least 1 of 10 single-nucleotide polymorphism markers studied in contrast to homozygosity in all 10 single-nucleotide polymorphism markers in most complete hydatidiform moles indicating that these tumors are not related to complete hydatidiform moles. This study provides the first molecular evidence that placental site trophoblastic tumors and epithelioid trophoblastic tumors are of fetal (trophoblastic) origin.

Embryonal Carcinoma Stem Cells↗
PubMed1984

Immunocytochemical localization of placental lactogen and chorionic gonadotropin in the normal placenta and trophoblastic tumors, with emphasis on intermediate trophoblast and the placental site trophoblastic tumor.

This report presents preliminary observations on the immunocytochemical localization of human chorionic gonadotropin (hCG) and human placental lactogen (hPL) in placental site trophoblastic tumors, hydatidiform moles, and choriocarcinomas and compares the findings with those of a similar immunocytochemical analysis of the placenta at various stages of development. In addition to cytotrophoblast (CT) and syncytiotrophoblast (ST), a third form of trophoblast designated "intermediate trophoblast" (IT) is present during normal pregnancy and in trophoblastic disease. Intermediate trophoblastic cells are mononucleate, larger than CT, and contain more abundant eosinophilic cytoplasm, resulting in a partial resemblance to ST. Intermediate trophoblast has distinctive immunocytochemical features that distinguish it from CT and ST. The localization of hPL and hCG in both IT and ST varies with the age of the placenta, with the type of trophoblastic neoplasm, and from one specimen to another within each category of tumor. Syncytiotrophoblast may contain both hormones in large amounts, whereas IT contains hPL predominantly and hCG focally. Cytotrophoblast is devoid of hCG and hPL except in choriocarcinoma, which may show focal weak staining for hCG. Immunocytochemical identification of hCG and hPL has proved helpful in clarifying the histogenesis of trophoblastic neoplasms and may also be of value in establishing their diagnosis and in determining their prognosis.

Adult↗
PubMed1980

Differential expression of trophoblast-specific membrane antigens by normal and abnormal human placentae and by neoplasms of trophoblastic and non-trophoblastic origin.

Using a specific antiserum to human syncytial trophoblast plasma membrane (TrPM), we have investigated the expression of these antigens on a variety of trophoblastic and non-trophoblastic tissues by a standard peroxidase/anti-peroxidase staining method. Normal placenta (first-trimester as well as full-term), placenta from tubal pregnancy and placenta accreta were all found to express TrPM antigens. However, malignant change in trophoblast neoplasms appeared to by accompanied by a loss of these antigens, with 7 out of 10 specimens of hydatidiform mole staining positively while 3 specimens of invasive mole and 7 specimens of choriocarcinoma were all negative. In contrast, a number of malignant tumours of non-trophoblastic origin such as carcinomas of the colon, cervix, bladder and hepatomas were found to express TrPM antigens. The possible significance of the reversal to a trophoblast phenotype by malignant neoplasms of non-trophoblastic origin is discussed.

Antigens, Neoplasm↗
PubMed2004

[Trophoblastic gestational disease: a placental site trophoblastic tumor and an epithelioid trophoblastic tumor].

Placental site trophoblastic tumor and epithelioid trophoblastic tumor are rare gestational trophoblastic tumors. They both appear in the same context and follow the same course. We report two cases in patients aged 44 and 20 years. These lesions usually affect young women with a history of multiple gestations. Clinical manifestations include vaginal bleeding, uterine mass, and moderate elevation of serum beta human chorionic gonadotrophin levels. These morphologically distinct trophoblastic proliferations usually have a favorable course if complete excision is performed.

Adult↗
PubMed1992

Trophoblast-derived tumor necrosis factor-alpha induces release of human chorionic gonadotropin using interleukin-6 (IL-6) and IL-6-receptor-dependent system in the normal human trophoblasts.

The titer of tumor necrosis factor-alpha (TNF alpha) secreted by placental blocks was determined by enzyme immunoassay. The source of placental TNF alpha was immunohistochemically demonstrated with monoclonal anti-TNF alpha antibody to be only trophoblasts. Purified trophoblasts produced 174.4 ng/L TNF alpha by 24 h of culture in vitro. To investigate the role of TNF alpha in placental hormonogenesis, purified trophoblasts were stimulated with recombinant TNF alpha (rTNF alpha) to determine the hCG titer by enzyme immunoassay. Trophoblasts stimulated with rTNF alpha released hCG in a dose-dependent fashion with kinetics similar to those of recombinant interleukin-1 (rIL-1)-stimulated trophoblasts. The stimulated trophoblasts released IL-6 before hCG, but failed to show hCG release when pretreated with anti-IL-6 receptor (anti-IL-6-R) monoclonal antibody PM-1. However, the pretreatment of trophoblasts with PM-1 did not interfere with rTNF alpha-induced IL-6 release, ruling out the possibility of a nonspecific toxic effect of PM-1 on trophoblasts. These results suggest that trophoblast-derived TNF alpha induced IL-6 release and then activated the IL-6-R system in trophoblasts to release hCG. Since IL-1 has also been demonstrated to induce similar release of IL-6 and hCG from trophoblasts, the effects of TNF alpha and IL-1 on these trophoblast functions were also examined. Simultaneous stimulation of trophoblasts with rTNF alpha and gamma IL-1 alpha resulted in synergistic enhancement of IL-6 release, subsequently leading to enhanced hCG release. Collectively, trophoblast-derived TNF alpha and IL-1 synergistically regulated the level of IL-6 secreted by trophoblasts, the magnitude of which determined the level of hCG released by activating the IL-6-R system in trophoblasts.

Antibodies, Monoclonal↗
PubMed1998

Platelet-endothelial cell adhesion molecule-1 is expressed by a subpopulation of human trophoblasts: a possible mechanism for trophoblast-endothelial interaction during haemochorial placentation.

The terminal event in the establishment of the haemochorial placenta in the human is the invasion of trophoblasts into the maternal vessels, a process in which trophoblasts interact directly with the vascular endothelium and degrade the vascular basement membrane and the tunica elastica of the vessels. To further understand this heterotypic cellular interaction, we investigated the expression by human trophoblasts of the vascular cell adhesion molecule platelet-endothelial cell adhesion molecule-1 (PECAM-1) as a possible mediator of the adhesive interaction between trophoblasts and endothelium. In vitro, human trophoblasts were found to express PECAM-1 mRNA and protein. Indirect immunofluorescence indicated a diffuse staining pattern, which was most intense in a subpopulation of trophoblast cells. Co-incubation of trophoblasts with endothelial cells showed interaction between these two cell types with strong expression of PECAM-1 at points of trophoblast-endothelial cell contact, suggesting that this cell adhesion molecule participates in this heterotypic cell interaction. Immunohistochemical localization of PECAM-1 in chorionic villi and first trimester implantation sites showed that, in vivo, only extravillous interstitial and endovascular trophoblasts were positive. In first trimester placentae, villous trophoblast and extravillous trophoblast in other locations than around or within the decidual vessels did not express this molecule. In term placentae, villous trophoblast did not express these adhesion molecules except for two specimens examined. This study demonstrates that PECAM-1 is expressed by a subset of human trophoblasts in vitro and in vivo. Its tissue localization suggests that PECAM-1 is important in mediating the adhesive interaction between trophoblasts and maternal vascular endothelium during the process of haemochorial placentation. Regulation of PECAM-1 expression by human trophoblasts may play a critical role in normal and abnormal vascular invasion during implantation and placentation.

Cell Adhesion↗
PubMed1998

Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma.

This report describes the clinicopathologic and immunohistochemical features of 14 cases of epithelioid trophoblastic tumor (ETT), a distinctive but rare gestational trophoblastic tumor. The patients with this neoplasm were in the reproductive age group and presented with abnormal vaginal bleeding. Although diagnosis was usually associated with a gestational event, the latter was sometimes remote. Two of the 14 patients presented with extrauterine ETT without evidence of prior gestational trophoblastic disease in the uterus. Serum human chorionic gonadotropin levels were elevated in eight of nine patients in whom this information was available. In the uterus, ETT presented as a discrete, hemorrhagic, solid and cystic lesion that was located either in the fundus, lower uterine segment, or endocervix. Microscopically, the tumor was composed of a relatively uniform population of mononucleate intermediate trophoblastic cells forming nests and solid masses. The cells resemble the trophoblastic cells in the chorion laeve, and we have therefore designated them "chorionic-type intermediate trophoblast." Typically, islands of trophoblastic cells were surrounded by extensive necrosis and were associated with a hyaline-like matrix creating a "geographic" pattern that is quite characteristic of this lesion. The mean mitotic count was two mitoses per 10 high-power fields, and the average Ki-67 nuclear labeling index was 18%. Immunohistochemically, all cases were diffusely positive for inhibin-alpha, cytokeratin (AE1/AE3), epithelial membrane antigen, E-cadherin, prolyl 4-hydroxylase, and epidermal growth factor receptor but were only focally immunoreactive for human placental lactogen, human chorionic gonadotropin, PlAP, and Mel-CAM. The monomorphic growth pattern of ETT resembles placental site trophoblastic tumor to a much greater degree than choriocarcinoma which is characterized by a dimorphic population of trophoblast. In contrast to placental site trophoblastic tumor, the cells of ETT are smaller and display less nuclear pleomorphism. In addition, ETT grows in a nodular fashion compared with the infiltrative pattern of placental site trophoblastic tumor. In some of the cases, the trophoblastic cells in ETT replaced the endocervical surface epithelium, giving the appearance that the tumor was derived from the cervix. Moreover, because the associated hyaline-like material in ETT resembles keratin, the tumor can be misinterpreted as a keratinizing squamous cell carcinoma of the cervix. Ten patients underwent total hysterectomy and two had an endometrial curettage only. The two patients who presented with extrauterine ETT underwent small bowel resection and lung resection. Two of 12 patients with ETT in the uterus developed metastasis in the lungs and bone. One of these patients is alive with disease at 43 months and one patient was lost to follow-up after 2 months. One of the two patients who had extrauterine disease died of widespread tumor 36 months after diagnosis. The remainder of the patients are alive and well from 1 to 120 months. In summary, ETT is a rare trophoblastic tumor that simulates carcinoma and can behave in a malignant fashion. It appears to be less aggressive than choriocarcinoma, more closely resembling the behavior of placental site trophoblastic tumor. Based on the morphologic and immunohistochemical features, it appears that ETT develops from neoplastic transformation of chorionic-type intermediate trophoblast.

Adolescent↗
PubMed1994

Developmental regulation of the expression of 72 and 92 kd type IV collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion.

OBJECTIVE: During early pregnancy fetal cytotrophoblast cells invade the uterus and penetrate the basement membrane, a property that is characteristic of malignant cells. However, unlike tumor invasion, trophoblast invasion of the uterus is under strict control. This control limits invasion, so that it primarily remains confined to the endometrial aspect of the myometrium and continues only until midgestation. The invasive properties of the trophoblast cells are made possible by the activity of proteolytic enzymes that belong to the metalloproteinases and serine proteinases. Type IV collagenase (metalloproteinase) is considered crucial in the extracellular matrix remodeling that takes place during the invasion process. In this study we set out to characterize the invasive properties of trophoblast cells at different stages of pregnancy. STUDY DESIGN: Human trophoblast cells were isolated from first- and third-trimester placentas by trypsin digestion and Percoll fractionation and were then cultured under serum-free conditions. The invasive ability of trophoblast cells was determined by the in vitro invasion assay, in which the ability of cells to penetrate an artificial basement membrane was examined. Metalloproteinase activity was measured by zymography, and the expression of messenger ribonucleic acid transcripts of 72 and 92 kd type IV collagenases was examined by reverse transcriptase polymerase chain reaction. RESULTS: First-trimester trophoblasts were 3.5 time more invasive in vitro than were third-trimester trophoblast cells (p < 0.005). Although first-trimester trophoblasts secreted both species of type IV collagenase, 72 and 92 kd, in large amounts, third-trimester cells secreted the 92 kd and only minimal amounts of 72 kd type IV collagenase. Moreover, first-trimester trophoblasts secreted significantly more (p < 0.05) 92 kd type IV collagenase than did third-trimester trophoblast. The messenger ribonucleic acid transcript expression of 72 and 92 kd type IV collagenases correlated with the activity of these enzymes secreted by first- and third-trimester trophoblasts. CONCLUSION: The described high in situ invasive capacity of first-trimester trophoblast might be explained by the increased expression and production of 72 kd type IV collagenase and the higher expression of 92 kd type IV collagenase by first-trimester trophoblast cells.

Base Sequence↗
PubMed2006

hCMV induced IL-6 release in trophoblast and trophoblast like cells.

BACKGROUND: Human cytomegalovirus (hCMV) infection of the trophoblasts is a crucial event in virus transmission from mother to child, being one responsible factor for intrauterine infection of the unborn. Differences of virus replication in trophoblasts depending on time point of pregnancy and degree of differentiation of trophoblasts might influence this transmission. Furthermore, immunological reactions of the trophoblasts to hCMV infection might be important defence mechanisms too. OBJECTIVES: hCMV replication and interleukin-6 release in trophoblasts and trophoblast like cells (choriocarcinoma cells) was investigated. STUDY DESIGN: Trophoblasts from term and 1st trimester placentas were isolated and infected with hCMV. hCMV production and release to the supernatant as well as interleukin-6 release and interleukin-6 mRNA production by these infected cells was measured. Choriocarcinoma cell lines (JEG-3, JAR) were treated the same. Non-infected trophoblasts were used as controls. RESULTS: In 1st trimester trophoblast, term trophoblasts and JEG-3 permissive hCMV replication was observed, although with different kinetics and efficiency. In JAR no complete virus replication was seen. High levels of interleukin-6 were measured in the supernatants of all hCMV infected cells immediately after infection. IL-6 mRNA upregulation was seen 48 h after infection in those cell types replication of hCMV occurred (1st trimester trophoblasts, term trophoblasts, JEG-3). At that time-point hCMV immediate early proteins appeared. In JARs no virus production and no IL-6 mRNA upregulation was seen, and IL-6 levels in the supernatant of these hCMV infected cells declined significantly until day 6 after infection compared to mock infected cells. CONCLUSION: These observations show that hCMV replication is influenced by the degree of trophoblast differentiation. Interleukin-6 is upregulated by hCMV infection, but is independent of complete virus replication.

Cell Differentiation↗
PubMed2003

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).

Biomarkers, Tumor↗
PubMedDate not supplied

Effects of human trophoblast-induced interferons on the expression of proto-oncogenes c-fms/CSF-1R, EGF-R and c-erbB2 in invasive and non-invasive trophoblast.

The human cytotrophoblast is the first fetal cell type to arise during embryogenesis and differentiate along two pathways to the invasive (extravillous) and non-invasive (villous) populations. The non-invasive villous trophoblast differentiate morphologically and biochemically to form terminally differentiated multinucleated syncytial trophoblast. First trimester invasive and non-invasive trophoblast were isolated from human placentae (5-12 weeks) and were cultured in vitro. The villous trophoblast cells differentiated in vitro to form aggregated syncytial cells which was associated with increased expression of epidermal growth factor receptor (EGF-R). The invasive trophoblast cells expressed colony-stimulating factor receptor (c-fms/CSF-1R) and c-erbB2 proteins but low levels of EGF-R. We studied the effects of human trophoblast-induced interferon (IFN)-alpha/beta on the expression of c-fms/CSF-1R, EGF-R and c-erbB2 whose ligands are reported to be involved in the regulation of growth and differentiation of normal invasive and non-invasive trophoblast cells. Human trophoblast-induced IFN-alpha/beta (100 IU/ml) reduced the expression of EGF-R in both invasive and non-invasive trophoblast cells as determined by quantitative enzyme-linked immunosorbant assay ('ELISA') and western immunoblot methods. The same amount of IFN activity reduced the expression of c-fms/CSF-1R and c-erbB2 proto-oncogene products in invasive trophoblast cells. These results may suggest a possible role of trophoblast-induced IFNs in the regulation of normal trophoblast growth, differentiation and function.

Blotting, Western↗
PubMed1991

Trophoblast-derived interleukin-1 (IL-1) stimulates the release of human chorionic gonadotropin by activating IL-6 and IL-6-receptor system in first trimester human trophoblasts.

Interleukin-1 (IL-1) has a unique activity to stimulate the release of multiple hormones in a number of human and murine endocrine systems. IL-6 also expresses such activities by activating IL-6-receptor (R)-mediated signal transduction pathways. Since the placenta produces both of these cytokines and endocrine hormones such as hCG, we investigated how these cytokines regulate hCG release by normal trophoblasts. Trophoblasts purified by Percoll density gradient released hCG from 120 min after stimulation with recombinant (r) IL-1 alpha, and its release was dependent on the rIL-1 alpha concentration used. The rIL-1 alpha-stimulated trophoblasts released a molecule with IL-6 activity antecedently, as determined by an IL-6-dependent cell line, MH60.BSF2 cells. The IL-6 identity of the released molecule was confirmed by goat anti-IL-6 antiserum. rIL-1-mediated hCG release from trophoblasts was completely abrogated to the basal level by pretreatment of the trophoblasts with PM1, an anti-IL-6-R monoclonal antibody. Identical results were observed with rIL-1 beta. These results showed that rIL-1-induced hCG release was totally dependent on IL-6- and IL-6-R-mediated signal transduction in human trophoblasts. The presence of peripheral monocytes in the purified trophoblast fraction, however, induced a rapid decrease in IL-6 and hCG release after their maximal release, suggesting some regulatory interaction between trophoblasts and the monocytes. In contrast, rIL-1-mediated enhancement of IL-6 and hCG secretion by purified trophoblasts was no longer observed at 24 h compared with that of the unstimulated trophoblasts, while spontaneous hCG secretion was significantly inhibited by pretreatment of trophoblasts with PM1. The results showed that IL-6 and hCG secretion might also be regulated by a number of agents besides IL-1, and that hCG secretion as well as its release is dependent on IL-6 and IL-6-R system in trophoblasts.

Antibodies↗
PubMed2004

[Malignant trophoblastic tumors (MTT) treated in the years 1955-2004 in trophoblastic disease center in the Czech Republic (TDC-CZ): clinical-pathological features, curability, typing, pathogenesis].

OBJECTIVE: Clinical- pathological features, typing, curability and pathogenesis of malignant tumors of trophoblast (MTT). DESIGN: A retrospective analysis. SETTING: Trophoblastic Disease Center in the Czech Republic (TDC-CZ), Mother and Child Care Institute, 3rd Medical Faculty, Charles University, Prague. METHODS: Revision of 379 MITT cases treated at TDC-CZ and comparison of their histological picture with developmental stages of orthologic trophoblast from the standpoint of MTT typing and pathogenesis. The determination of curability of different histological types and risk stages (RS) used in TDC-CZ and a comparison with RS axccording to FIGO, WHO and NIH. Differentiation of undifferentiated choriocarcinoma (CH-Und) alias Epitheloid Trophoblastic Tumor (ETT) from the given cohort of MIT and establishment of its clinical and biological properties, curability and formal pathogenesis. RESULTS: Three hundred and seventy nine MTT cases were classified into 5 histological types onthe basis of analogy with developmental stages of 7 to 14 days old trophoblast. 1: typical "classical" choriocarcinoma - No Special Type (CH-NST), which forms more than 80% of MTT. Moreover, the degree of differentiation of tumorous trophoblast and its prevailing (cytological) type made it possible to define other 4 types, i.e.: 2: CH-syncytio-trophoblastic (CH-Syn), representing 3.8%; 3: CH-cytotrophoblastic CH-Cyt with 3.3%; 4: CH-dissociated (CH-Dis), representing 6%; 5: CH-undifferentiated (CH-Und) with 6.8%. Mortality due to MIT of all mentioned types reached 94% until 1963, decreased to 43% until 1980 and has been 5.8% in the period of 1981-2004. In the latter period of time (1981-2004), mortality due to CH-Cyt proved to be 40%, that due to CH-Dis being 11%, and CH-Und 18%, though. Mortality of s.c. Placental Site Trophoblastic Tumor, which includes our CH-Cyt and CH-Dis therefore forms 21.4%. We have been using four RS in TDC-CZ. The following outline includes only the main features: 1st RT includes CH-NST < 30mm limited to uterus in connection with mole. 2nd RS includes CH-NST > 30mm after birth. 3rd RS includes CH-NST with multiple metastases outside GIT and CNS and MTT with the CH-Cyt, Dis, Und component < 75%. 4th RS includes CH-NST with metastases in CNS or GIT. MTT with CH-Cyt Dis, Ned component < 75% with metasteses and MTT with the same components > 75% In the last 23 years 1st RS and 2nd RS includes 85 % of all MTT in the TDC-CZ and curability is 100%. In the 3rd RS curability decreases to 64.3% and decreases to 55.6% in the 4th RS. According to FIGO classification the 1st RS forms 48%, 2nd RT represents 17% and 100% curability applies for both of them. 3rd a RS includes 20% of 100% curability, 3rd bc RS forms 10% with 67% curability and 4th abc RS includes 5 % with 50% curability. In using the WHO classification with four RS, their percentage representation is similar to our classification with similar curability; nevertheless the 1st RS and 2nd RS did not detect almost 8% of MTT, which ended with exitus. 3rd RS according to FIGO is overestimated in view of 100% curability and the abc degree in 1st and 2nd RS are only of theoretical significance and irrelevant for the choice of treatment. The closest results comparable with our classification were those of NIH. A very careful clinical-pathological analysis of 25 CH-Und-ETT, detected among 379 MTT revealed that CH-Und-ETT is anaggressive malignant form of CH, which is best derived from undifferentiated 7-8 days old trophoblast. It is insidious for its seemingly primary extragenital symptomatology in seven out of 25 cases, low hCG values and poor sensitivity to chemotherapy. CONCLUSION: 1) The comparison of histological pictures of 379 MTT with developmental stages of orthologic trophoblast of 7-14 days old embryo was the basis for classification of 5 types of choriocarcinoma (CH): 1. Differentiated CH "No Special Type" (CH-NST), 2. Syncytiotrophoblastic CH (CH-Syn), 3. Cytotrophoblastic CH (CH-Cyt), 4. Dissociated CH (CH-Dis), and 5. Non-differentiated CH (CH-Und); 2) We have determined their percentual (and absolute) occurrence in the group of 379 MTT treated in CTN in the years 1955-2004. 3) We have described biological properties of individual types of CH and established the way they influence curability. 4) Four degrees of risk (RS) were specified in relation to 7 types of risk factors observed (1. size of tumor, 2. type of preceding pregnancy, 3. interval from pregnancy to the diagnosis, 4. histological type of CH, 5. number of metastases, 6. localization of metastases, 7. values of hCG). It has become obvious how RS influenced curability of CH (1st and 2nd RS forms 85% of all CH's and their curability is 100% (!), 3rd and 4th RS are represented in 15% and their curability is 64% in the 3rd RS and 55% in the 4th RS. 6) The curability reached in CTN was compared with that determined according to FIGO, WHO and NIH, respectively. The results proved to be similar, but in case of FIGO the 3rd degree was overestimated and the degrees abc in the 1st and 2nd RS were of theoretical importance only, therefore being of no values for the choice of treatment. Low and medium score according to WHO did not detect 8% of women who had died. The CH curability according to RS, having been recommended by NIH and used in the American Centers was virtually the same as our results. 7) It has been proved that the histological type of CH significantly influenced the determination of RS in the given patient. 8) CH-Und-ETT represents the least differentiated form of MTT, in other words choriocarcinoma. This is associated with a low production of HCG, mostly between 10(1) and 10(3) mIU/ml. 9) Pathogenesis of CH-Und ETT-ETT we derive from the earliest, undifferentiated stage of orthological trophoblast. The origin from the differentiated intermediate trophoblast chorion leeve we considerei improbable. 10) There are continuous transitions from CH-Und-ETT and PSTT to CH-NST, representing an analogy to grading in other malignant epithelial tumors.

Choriocarcinoma↗
PubMed1996

Altered expression of the tumor suppressor/oncoprotein p53 in SV40 Tag-transformed human placental trophoblast and malignant trophoblast cell lines.

The expression of the tumor suppressor/oncoprotein p53 has been investigated in normal human placental villous trophoblast, in vitro propagated invasive extravillous trophoblast, SV40 tumor antigen (Tag)-immortalized extravillous trophoblast, human cytomegalovirus (hCMV)-infected syncytiotrophoblast and malignant trophoblast (choriocarcinoma) cell lines (JAR, JEG-3 and BeWo) using quantitative enzyme-linked immunosorbent assay (ELISA) and Western immunoblot methods using monoclonal antibodies specific for wild-type and mutant p53. The normal villous and extravillous trophoblast cells expressed low levels of the wild-type p53 protein, whereas normal terminally differentiated multinucleated syncytiotrophoblast cells, as well as hCMV-infected syncytiotrophoblast, showed a higher expression of the wild-type p53 protein. SV40 Tag-immortalized invasive trophoblast cells also showed a high expression of the wild-type p53 protein which remained complexed with the Tag protein. All the choriocarcinoma cell lines over expressed the mutant form of the p53 protein. The increased expression of p53 protein in the SV40 Tag-immortalized invasive trophoblast and choriocarcinoma cells paralleled with increased expression of the mouse double minute 2 (mdm2) oncogenic protein. Transforming growth factor (TGF)-beta inhibited proliferation of normal extravillous trophoblast cells. The antiproliferative effects of TGF-beta were reduced in SV40 Tag-immortalized cells and non-detectable in choriocarcinoma cell lines JAR, BeWo and JEG-3. The inactivation of p53 owing to complexing with Tag in the immortalized premalignant trophoblast and p53 mutation in the malignant trophoblast may be responsible for their aberrant proliferation and refractoriness to antiproliferative effects of TGF-beta observed in these cells as compared to the normal trophoblast. These results may suggest the role of p53 protein in trophoblast differentiation, transformation and tumorigenesis.

Animals↗
PubMed1997

New concepts in trophoblastic growth and differentiation with practical application for the diagnosis of gestational trophoblastic disease.

Human trophoblast in normal implantation and placentation appears to undergo two different pathways of differentiation resulting in the development of villous and extravillous trophoblast. Cytotrophoblast (CT) differentiates abruptly into syncytiotrophoblast (ST) on the villous surface as compared with the spectrum of differentiation exhibited by extravillous trophoblast where CT differentiates into intermediate trophoblast (IT) and then into multinucleated intermediate trophoblastic cells (MITC). The various types of gestational trophoblastic lesions can be defined and related to discrete pathologic aberrations occurring at different stages of trophoblastic differentiation. The rapid advance in the discovery of new trophoblastic markers has facilitated the molecular dissection of the lineage and differentiation stages of trophoblast and related these to various trophoblastic lesions. Furthermore, antibodies against these markers, especially those that are able to recognize formalin-resistant epitopes, have considerable value in the study and differential diagnosis of different types of gestational trophoblastic disease.

Biomarkers, Tumor↗
PubMed1996

Macaque intra-arterial trophoblast and extravillous trophoblast of the cell columns and cytotrophoblastic shell express neural cell adhesion molecule (NCAM).

BACKGROUND: During placental development in higher primates trophoblast cells originating in the cell columns migrate along endometrial surfaces to form the cytotrophoblastic shell. A subpopulation of these cells invades uterine arteries, where they migrate on the surface of endothelium, against the flow of blood. These intra-arterial cells become sequestered in the walls of the arteries where they are referred to as intramural trophoblast. Because migration depends upon binding the cell surface to other cells or to extracellular matrix, we investigated the potential role of neural cell adhesion molecule (NCAM, CD56) in arterial invasion by trophoblast cells. METHODS: Tissues from macaque placentas and endometrium were fixed and embedded in paraffin. Standard immunoperoxidase methods were used to identify NCAM. RESULTS: NCAM labeled cells were present within spiral arteries of the decidua basalis. Trophoblast cells within or adjacent to the arterial lumen were distinctly NCAM positive, whereas most intramural trophoblast cells revealed reduced or no reactivity for NCAM. Maternal endothelial cells and villous trophoblast cells were negative. Uterine veins were tapped by trophoblast but did not contain migratory cells. The cell columns of early pregnancy contained cells outlined by rims of reactivity for NCAM. Labeled cells were also seen in the cytotrophoblastic shell, arranged as discontinuous groups. These groups variably occupied the entire thickness of the shell, or only the proximal (adjacent to the intervillous space) or distal layers of the shell. Later in gestation, the cytotrophoblastic shell developed a different pattern of staining, such that only cells located nearer to the intervillous space or near the tips of the anchoring villi were positive. CONCLUSIONS: We conclude that NCAM is one of a group of cell adhesion molecules that participates in trophoblast cell adhesion during migration within maternal arteries. NCAM appears to be active in trophoblast-trophoblast cell interactions. It may also contribute to binding trophoblast cells to the surfaces of arterial endothelium as well as extracellular matrix molecules of the arterial wall. After secondary invasion into the arterial walls NCAM is down-regulated, possibly in response to the appearance of extracellular matrix capsules, where other cell adhesion molecules may appear.

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