Expression profiling of lncRNAs and mRNAs in placental site trophoblastic tumor (PSTT) by microarray.

As a rare type of gestational trophoblastic disease, placental site trophoblastic tumor (PSTT) is originated from intermediate trophoblast cells. Long noncoding RNAs (lncRNAs) regulate numerous biological process. However, the role of lncRNAs in PSTT remains poorly understood. In the present study, expression levels of lncRNAs and mRNAs in four human PSTT tissues and four normal placental villi were investigated. The results of microarray were validated by the reverse transcription and quantitative real-time polymerase reaction (RT-qPCR) and immunohistochemistry analyses. Furthermore, GO and KEGG pathway analyses were performed to identify the underlying biological processes and signaling pathways of aberrantly expressed lncRNAs and mRNAs. We also conducted the coding-non-coding gene co-expression (CNC) network to explore the interaction of altered lncRNAs and mRNAs. In total, we identified 1247 up-regulated lncRNAs and 1013 down-regulated lncRNAs as well as 828 up-regulated mRNAs and 1393 down-regulated mRNAs in PSTT tissues compared to normal villi (fold change ≥ 2.0, p < 0.05). GO analysis showed that mitochondrion was the most significantly down-regulated GO term, and immune response was the most significantly up-regulated term. A CNC network profile based on six confirmed lncRNAs (NONHSAT114519, NR_103711, NONHSAT003875, NONHSAT136587, NONHSAT134431, NONHSAT102500) as well as 354 mRNAs was composed of 497 edges. GO and KEGG analyses indicated that interacted mRNAs were enriched in the signal-recognition particle (SRP)-dependent cotranslational protein targeting to membrane and Ribosome pathway. It contributes to expand the understanding of the aberrant lncRNAs and mRNAs profiles of PSTT, which may be helpful for the exploration of new diagnosis and treatment of PSTT.

Whole transcriptome analysis of gestational trophoblastic neoplasms reveals altered PI3K signaling pathway in epithelioid trophoblastic tumor.

OBJECTIVE: Genomic characteristics of gestational trophoblastic neoplasm (GTN) are mostly unknown. This study reveals the molecular features of malignant GTN, including choriocarcinoma (CC), epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT), by whole transcriptome sequencing analysis. METHODS: Data obtained from the total RNA sequencing of 2 CC, 4 ETT, and 4 PSTT were evaluated for differential gene expression, pathway alteration, fusion gene, infiltrating immune cell type, PD-L1 and PTEN expression level, and mutation analysis was performed. RESULTS: The transcriptome data were correlated with known biomarkers, including HDS3B1, p63, hCG, and hPL for all tumor types. ETT and PSTT were more closely clustered compared with CC in clustering analysis using gene expression; however, ETT showed various altered signaling pathways, including PI3K-Akt-mTOR, with frequent loss of PTEN protein expression. This finding was both well correlated with PIK3CA c.3140A > G pathogenic mutation, detected in 1 ETT, and further confirmed using the MassARRAY method. PSTT showed an overexpressed gene cluster associated with muscle contraction and G protein-coupled receptor activity. No significant fusion gene was seen in all 10 cases. In tumor-infiltrating immune cell profiles, CD4 memory T cell and macrophage signature were relatively high in ETT and PSTT. PD-L1 mRNA expression level was high in all cases, which was significantly correlated with the PD-L1 level by immunohistochemistry (p = 0.03) with positivity in all 10 cases. CONCLUSIONS: ETT and PSTT were similar at the transcriptome level, with a high level of PD-L1 expression in all tumor types; however, specific pathways, such as PI3K signaling, were altered in ETT.

lnc003875/miR-363/EGR1 regulatory network in the carcinoma -associated fibroblasts controls the angiogenesis of human placental site trophoblastic tumor (PSTT).

The rare gestational trophoblastic neoplasia placental site trophoblastic tumor (PSTT) frequently demonstrates a high degree of vascularization, which may facilitate the tumor metastasis. However, the underlying mechanisms remain largely unknown. In the present study, we found that early growth response 1 (EGR1) was highly expressed in the carcinoma-associated fibroblasts (CAFs) of PSTT tissues. Further data showed that miR-363 down-regulated EGR1 expression whereas long non-coding RNA NONHSAT003875 (lnc003875) up-regulated EGR1 expression in PSTT derived CAFs. lnc003875 exerted no effect on miR-363 expression, but it recovered the decrease of EGR1 caused by miR-363 mimic. The conditioned media from PSTT CAFs treated with miR-363 mimic abrogated the tube formation capacity of human umbilical vein endothelial cells (HUVECs), which can be partially restored by lnc003875 over-expression. Moreover, over-expression of EGR1 promoted the secretion of Angiopoietin-1 (Ang-1) in PSTT derived CAFs and improved the tube formation of HUVECs, which could be effectively abrogated by Ang-1 siRNAs. In vivo vasculogenesis assay demonstrated that lnc003875/EGR1 in PSTT derived CAFs promoted the vasculogenesis of HUVECs in C57BL/6 mice. Collectively, these findings indicated that lnc003875/miR-363/EGR1/Ang-1 in CAFs may be crucial for the angiogenesis of PSTT.

Ovarian Intermediate Trophoblastic Tumors: Genotyping Defines a Distinct Category of Nongestational Tumors of Germ Cell Type.

Trophoblastic neoplasms involving the ovary are uncommon and include gestational tumors, which are either metastatic from the uterus or ectopic and nongestational tumors, which include those of germ cell type/origin and somatic tumors with trophoblastic differentiation; in all these types, most are pure choriocarcinoma. Intermediate trophoblastic tumors, which include placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), are rare in the ovary, with most assumed to be gestational; this is the only category formally recognized in 2014 World Health Organization (WHO) classification, likely due to few well-documented nongestational examples. We report the clinicopathologic features of 6 ovarian intermediate trophoblastic tumors, including 3 PSTTs, 2 ETTs, and 1 ETT with choriocarcinomatous differentiation. DNA-based short tandem repeat genotyping identified 4 of these as nongestational (3 PSTTs and 1 ETT), as evidenced by sharing of alleles between tumor and normal tissue at all informative loci. Interestingly, all 3 of the nongestational PSTTs coexisted with mature cystic teratoma. The remaining 2 tumors (1 ETT and 1 ETT with some choriocarcinomatous differentiation) were gestational (likely ectopic due to lack of evidence of a uterine tumor), as evidenced by the presence of both maternal and novel/nonmaternal alleles at informative loci in tumor compared with normal tissue. It is important to recognize a distinct category of primary ovarian nongestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, in classification systems to guide clinical management, as gestational and nongestational tumors have different genetic origins and may require different therapy. Genotyping is useful for classification as nongestational versus gestational, particularly as traditional clinicopathologic findings cannot always predict the nature of a trophoblastic tumor.

Molecular genotyping of placental site and epithelioid trophoblastic tumours; female predominance.

OBJECTIVE: To investigate a large series of placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) and determine the relationship between their development and the type and sex of both the immediately antecedent and causative pregnancies. METHODS: The antecedent pregnancy was determined from patient records in 92 cases with a confirmed diagnosis of PSTT, ETT or mixed PSTT/ETT. In a subset of 57 cases, type and sex of the causative pregnancy was established by molecular genotyping of tumour tissue microdissected from formalin-fixed, paraffin-embedded blocks. RESULTS: The antecedent pregnancy was a normal live birth in 59 (64%) cases, a hydatidiform mole in 19 (21%) and other pregnancy loss in 14 (15%). Where the sex was recorded, 36 (78%) of 46 antecedent normal pregnancies were female, a significantly greater proportion than expected (p<0.0001). Genotyping of 57 cases found 15 (26%) to derive from hydatidiform moles while 42 (74%) arose in non-molar pregnancies. Where the causative pregnancy was non-molar, 38 (91%) tumours arose in female conceptions, significantly greater than expected (p<0.0001). Analysis of short tandem repeats on the X chromosome in three tumours with an XY chromosomal constitution confirmed that the X chromosome was maternal in origin. CONCLUSIONS: PSTT and ETT predominantly arise in female pregnancies but can develop in male pregnancies. A male derived X chromosome is not required for the development of these tumours. While these tumours are predominantly female it is not because most originate in complete hydatidiform moles.

Extragestational ßHCG secretion due to an isolated lung epithelioid trophoblastic tumor: microsatellite genotyping of tumoral cells confirmed their placental origin and oriented specific chemotherapy.

CONTEXT: Persistent secretion of ß-human chorionic gonadotropin (ßHCG) in the absence of an ongoing or recent pregnancy and without persistent uterine gestational disease is a rare but challenging situation that requires locating the extrauterine secreting tumor and distinguishing between extragestational choriocarcinoma and gestational trophoblastic neoplasms. CASE PRESENTATION: An unexplained, persistent extragestational ßHCG secretion occurring in a 29-year-old, nonsmoking woman with abnormal uterine bleeding 4 years after a normal pregnancy and without persistent gestational disease led to the discovery by whole-body computed tomography/positron emission tomography of an isolated pulmonary tumor. OBJECTIVE: Characterization of paternal alleles in tumoral cells in order to establish their fetal origin, which may be helpful for the diagnosis and treatment of such tumors. METHODS AND RESULTS: After the surgical procedure, clinical, histological, and immunocytochemical analysis ruled out primary or metastatic bronchopulmonary carcinoma or choriocarcinoma and supported the diagnosis of an isolated, primary, epithelioid trophoblastic tumor. Microsatellite genotyping of tumoral cells identifying paternal alleles confirmed their placental origin and their migration to the lungs, with likely secondary malignant transformation, and guided the choice of postsurgical chemotherapy needed to completely eradicate ßHCG secretion. CONCLUSION: Persistent extragestational secretion of ßHCG in a young nonsmoking woman with a precedent pregnancy and an isolated lung tumor suggests the diagnosis of epithelioid trophoblastic tumor, a very rare malignant tumor for which placental origin needs to be confirmed, especially when occurring several years after the patient's last pregnancy. Simple microsatellite genotyping of tumoral cells will allow this confirmation of diagnosis and help in personalizing chemotherapy.

Lack of genetic association between exaggerated placental site reaction and placental site trophoblastic tumor.

Exaggerated placental site (EPS) reaction is a reactive or an exuberant physiologic process involving intermediate trophoblasts infiltrating the underlying endomyometrium at the implantation site. Sharing similar cytological and immunohistochemical features with the tumor cells of placental site trophoblastic tumor, a biological link between the 2 lesions can be speculated. Because placental site trophoblastic tumor has a unique sex chromosomal requirement in its genome that requires a paternal X chromosome (i.e. a female antecedent gestation), we investigated whether EPS carries the similar genetic profile by DNA genotypic analysis. Twenty cases of EPS were reviewed and analyzed by AmpFlSTR Identifiler polymerase chain reaction amplification system (Applied Biosystems, Inc., Foster City, CA). The genetic profile of all cases demonstrated unique paternal alleles to that of the paired maternal tissue, confirming the trophoblastic origin of EPS. The presence of an XY genome (male) was identified in 11 cases (55%), and an XX genome (female) was seen in the rest of 9 cases (45%). Therefore, EPS is a trophoblastic lesion that can arise from either male or female gestations. The assignment of sex chromosomes in our study (XY, 55% and XX, 45%) does not support a neoplastic association between placental site trophoblastic tumor and EPS.

Activated Stat3 expression in gestational trophoblastic disease: correlation with clinicopathological parameters and apoptotic indices.

AIMS: To assess the expression profile of the activated form of signal transducer and activator of transcription (Stat)3 in gestational trophoblastic disease (GTD) and correlate the findings with clinicopathological parameters. METHODS AND RESULTS: By immunohistochemistry, both cytoplasmic and nuclear expression of p-Stat3-Ser(727) was demonstrated in 88 trophoblastic tissues, including placentas and GTD. Nuclear immunoreactivity of p-Stat3-Ser(727) was significantly higher in hydatidiform mole (HM) (P < 0.001) and choriocarcinoma (P = 0.009) when compared with normal placentas. Placental site trophoblastic tumours (PSTT) and epithelioid trophoblastic tumours (ETT) also demonstrated higher nuclear p-Stat3-Ser(727) expression than their normal trophoblast counterparts. Higher p-Stat3-Ser(727) expression was confirmed in choriocarcinoma cell lines, JEG-3 and JAR, than in a normal trophoblast cell line, with both nuclear and cytoplasmic fractions demonstrated by immunoblotting. Spontaneously regressed HM showed significantly increased nuclear and cytoplasmic p-Stat3-Ser(727) immunoreactivity over those that developed gestational trophoblastic neoplasia (GTN) (P = 0.013, P = 0.039). There was a significant positive and inverse correlation between nuclear p-Stat3-Ser(727) immunoreactivity and apoptotic indices [terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling and M30 CytoDeath antibody] (P = 0.001, P < 0.001, Spearman's rho test) and Bcl-2 expression (P = 0.034), respectively. CONCLUSIONS: p-Stat3-Ser(727) plays a role in the pathogenesis of GTD, probably through the regulation of apoptosis. p-Stat3-Ser(727) immunoreactivity is a potential marker in predicting GTN in HM.

p57(KIP2) immunohistochemical staining of gestational trophoblastic tumours does not identify the type of the causative pregnancy.

AIM: To determine whether immunohistochemical staining for p57(KIP2), the product of the maternally expressed gene CDKN1C, can be used to differentiate between gestational trophoblastic tumours arising from a complete hydatidiform mole and those originating from non-molar pregnancies. METHODS: The immunohistochemical expression of p57(KIP2) was investigated in 23 cases of choriocarcinoma and 17 placental site trophoblastic tumours. Fourteen of the tumours examined were shown by DNA analysis to have arisen from complete hydatidiform moles and 26 from non-molar pregnancies. RESULTS: Five of 11 (45%) post-complete hydatidiform mole choriocarcinomas and two of three (67%) post-complete hydatidiform mole placental site trophoblastic tumours were found to be p57(KIP2)+ and showed similar immunostaining characteristics to tumours that developed from non-molar pregnancies. Although there was a statistically significant reduction in the proportion of cases showing positive p57(KIP2) staining in post-complete hydatidiform mole tumours compared with those originating in non-molar pregnancies [proportion difference 0.35 [95% confidence interval (CI) 0.05, 0.61], P = 0.02], immunostaining did not provide diagnostically useful information to differentiate between these tumours in clinical practice. There was no significant difference between the extent of staining in choriocarcinoma versus placental site trophoblastic tumours [proportion difference 0.17 (95% CI - 12, 42), P = 0.19]. The majority of both types of gestational trophoblastic tumour were positive for the presence of the p57(KIP2) protein irrespective of their genetic origin. CONCLUSION: Immunostaining for p57(KIP2) fails to discriminate between gestational trophoblastic tumours that have arisen from complete hydatidiform moles and those that have originated from other types of pregnancy.

Comparative genomic hybridization study of placental site trophoblastic tumour: a report of four cases.

Placental site trophoblastic tumour (PSTT) is a neoplastic proliferation of the implantation intermediate trophoblast. Although clinicopathological studies are not uncommon in case reports or small series, molecular and genetic studies are quite limited. Four archived cases of PSTT were successfully analysed by comparative genomic hybridization (CGH) in this study. Regional chromosomal gains were observed in two cases. One case showed chromosomal gains in the regions of 19p13.2, 21q11-21 and 22q12. The second case demonstrated a single regional chromosomal gain involving 21q21. No chromosomal loss is observed. The remaining two cases showed a balanced CGH profile without detectable chromosomal gain or loss. In summary, although chromosomal alterations detectable by CGH are not common, rare chromosomal gains do occur in PSTT. The recurrent chromosomal gain involving chromosomal 21q observed in two of our cases deserves additional studies to ascertain whether it carries any pathobiological significance.

Placental site trophoblastic tumour.

Placental site trophoblastic tumour (PSTT) is a very rare and unique form of gestational trophoblastic disease (GTD). This tumour represents a neoplastic transformation of intermediate trophoblastic cells that normally play a critical role in implantation. PSTT can occur after a normal pregnancy, abortion, term delivery, ectopic pregnancy or molar pregnancy. It displays a wide clinical spectrum, and when metastatic, can be difficult to control even with surgery and chemotherapy. Unlike other forms of GTD, PSTT is characterized by low beta-hCG levels because it is a neoplastic proliferation of intermediate trophoblastic cells. Expression, however, of human placental lactogen (hPL) is increased on histologic section as well as in the serum. The most common presenting symptoms of PSTT are vaginal bleeding and amenorrhoea. Diagnosis is confirmed by dilatation and curettage (D and E) and hysterectomy but meticulous evaluation of metastasis is mandatory. Most cases are confined to the uterus but pelvic involvement, lung and other organ metastasis has been reported. Unlike other forms of GTD, the WHO prognostic score is of little help. For the PSTT patient, surgery is the primary treatment of choice. For patients desiring future childbearing, D and C and adjuvant chemotherapy is an option. Because these tumours tend to be less sensitive than other types of GTD to chemotherapy, the most successful regimen to date has been with EMA/CO or EMA/EP. Good prognosis is anticipated in cases localized to the uterus, and when the interval between antecedent pregnancy and treatment is less than 2 years. In cases with distant metastasis or delayed treatment, the outcome is dismal. Advances in chemotherapeutic regimens have improved clinical reponse in metastatic disease.

Placental site trophoblastic tumor: p53 gene analysis.

BACKGROUND: Placental site trophoblastic tumor (PSTT) is the rarest type of trophoblastic neoplasm. Because of its rarity, the clinical behavior and pathogenesis of PSTT are still unclear. CASE: A 20-year-old woman presented with secondary amenorrhea and irregular vaginal bleeding. Examination of the patient revealed elevated serum hCG and a uterine mass. The specimen obtained by curettage was diagnosed as possible PSTT. The patient was treated with two cycles of EMA/CO, but her uterine mass increased in size. Subsequently, she underwent total abdominal hysterectomy. Microscopic observation revealed a PSTT. To estimate the status of expression of p53 protein and to determine whether p53 gene mutation was present in this PSTT, we carried out immunohistochemical staining for p53 and PCR-SSCP analysis. Immunohistochemical staining for p53 revealed intense nuclear labeling, but no p53 gene mutation was detected in exons 5-8. CONCLUSION: Analysis of the p53 gene may aid understanding of the pathogenesis of PSTT.

Malignant placental site trophoblastic tumor: a cytogenetic study using comparative genomic hybridization and chromosome in situ hybridization.

BACKGROUND: Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasm composed predominantly of intermediate trophoblast. Most showed benign behavior whereas 10-15% of PSTTs were clinically malignant with later recurrence and metastasis. Currently, there are no reliable means to predict clinical outcome, and cytogenetic information is scanty. METHODS: The clinicopathologic features of two cases of malignant PSTT were analyzed. Cytogenetic analysis was performed by comparative genomic hybridization (CGH) and chromosome in situ hybridization (CISH) using frozen tissue and paraffin embedded sections, respectively. RESULTS: Both patients were 32 years old at time of diagnosis. One patient with PSTT presented with menorrhagia, and the other presented with symptoms of missed abortion. Elevated serum human chorionic gonadotropin (HCG) was detected in both patients. Histologic examination showed the typical features of PSTT with high mitotic count (> 5/10 high-power fields). Ovarian and lung metastasis occurred in both patients. Immunohistochemical staining revealed an equal distribution of HCG and human placental lactogen. Cytogenetic studies by CISH showed that karyotypes of these two malignant PSTTs were diploid. Analysis of the tumor tissue by CGH did not show any changes in DNA copy numbers. CONCLUSIONS: The authors' study indicated that the two metastasizing PSTTs had balanced diploid karyotype. The malignant behavior of PSTTs may be not related to the DNA copy number changes. Such cytogenetic study may be useful in distinguishing metastatic PSTT from choriocarcinoma.

Current understandings of the molecular genetics of gestational trophoblastic diseases.

Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases characterized by abnormally proliferating trophoblastic tissues. This includes partial and complete hydatidiform moles, invasive mole, choriocarcinoma and placental site trophoblastic tumour. Cytogenetic studies revealed that hydatidiform moles contain either solely (as in complete moles) or an excess (as in partial moles) of paternal contribution to the genome. Genomic imprinting is believed to play a pivotal role in the pathogenesis of hydatidiform moles. However its precise role and mechanism remains poorly understood. Hydatidiform mole carries a potential of malignant transformation. Similar to other human cancers, malignant transformation in gestational trophoblastic tumours is likely a multistep process and involves multiple genetic alterations including activation of oncogenes and inactivation of tumour suppressor genes. In addition, expression of telomerase activity, altered expression of cell--cell adhesion molecules and abnormal expression of matrix metalloproteinases have also been reported in GTD. These represent disruption of the delicate balance and regulation of cellular processes including proliferation, differentiation, apoptosis and invasion. The significance of these alterations in the pathogenesis and malignant transformation of gestational trophoblastic diseases is reviewed in this paper.

Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor.

OBJECTIVE: The goal of this work was to study the expression of epidermal growth factor receptor (EGFR) and c-erbB-3 and c-erbB-4 oncogenes in gestational trophoblastic diseases and normal first-trimester placenta. STUDY DESIGN: Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma, and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-3, and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. RESULTS: Staining for EGFR was detected immunohistochemically in all cell types in gestational trophoblastic diseases and normal placenta. In situ hybridization for EGFR mRNA correlated with immunostaining for EGFR in all tissues studied. All 10 cases of choriocarcinoma exhibited strong immunoreactivity for EGFR. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (P < 0.01, P < 0.01). Expression of c-erbB-3 did not significantly differ among placental and gestational trophoblastic disease tissues and trophoblastic cell types except for significantly increased expression in choriocarcinoma as compared with cytotrophoblasts of partial mole (P = 0.02). The placenta, complete and partial mole, and choriocarcinoma tissues demonstrated similar immunoreactivity for c-erbB-4. Strong immunostaining for EGFR (P = 0.02) and c-erbB-3 (P < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. CONCLUSION: The EGFR-related family of oncogenes may be important in the pathogenesis of gestational trophoblastic diseases. The increased expression of EGFR and c-erbB-3 in complete mole may also influence the development of persistent gestational trophoblastic tumor.

Apoptosis in gestational trophoblastic disease is correlated with clinical outcome and Bcl-2 expression but not Bax expression.

Apoptosis has been found to play a crucial role in the pathogenesis and prognosis of many human diseases. The pathogenesis of gestational trophoblastic disease (GTD), which encompasses hydatidiform moles (HMs) and choriocarcinomas (CCAs), is not fully understood. Prognostic indicators of HM have also been scanty. In this study, we investigated apoptotic activity and the expression of two apoptosis regulatory genes, Bcl-2 and Bax, in an attempt to determine the role of apoptosis in GTD. Formalin-fixed paraffin-embedded tissue of 33 normal placentas, 14 spontaneous abortions, 14 partial moles, 34 complete moles, and eight CCAs were examined. Apoptotic activity was assessed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Quantitative assessment of apoptotic index (AI) was calculated as a percentage of TUNEL-positive nuclei. Expression of Bcl-2 and Bax were assessed immunohistochemically. Extensive apoptosis was located in syncytiotrophoblasts, cytotrophoblasts, and villous stromal cells in all HM cases. Apoptosis was detected at a much lower level in spontaneous abortions and normal placentas. Moreover, in normal placentas, TUNEL positive nuclei were exclusively found in syncytiotrophoblasts. AIs were significantly different among various categories of trophoblastic lesions (P < .001) in an ascending order: normal placentas less than spontaneous abortions less than CCAs less than HMs. Furthermore, AIs of those cases that spontaneously regressed was statistically higher than those that developed persistent trophoblastic disease requiring chemotherapy. AIs of trophoblastic lesions in general inversely correlated with Bcl-2 expression (P < .001), but no significant correlation was found between AI and Bax expression (P > .5). We conclude that AI may be a useful prognostic marker for clinical progress of HMs. Bcl-2 expression is probably regulating apoptosis in normal placentas and GTD, whereas Bax expression is not. The difference in AI and Bcl-2 expression between non-molar placentas and HMs offers a potential adjunctive diagnostic tool to distinguish the two entities.

Recent advances in gestational trophoblastic disease.

Advances in the last 20 years have led to a better understanding of the process of gestational trophoblastic disease (GTD), and consequently, to improved diagnosis, management, and prognosis. Patients with GTD should be registered at a trophoblastic disease center for follow-up, and those with persistent disease should receive chemotherapy, methotrexate, and folinic acid for low-risk disease, and EMACO (etoposide, actinomycin-D, methotrexate, vincristine, and cyclophosphamide) for high-risk disease, without loss of fertility. Most patients with relapsing or resistant disease can be treated effectively with surgery and/or cisplatin in EP/EMA (etoposide, platinum-etoposide, methotrexate, actinomycin-D) combination.

Studies of non-disjunction in trisomies 2, 7, 15, and 22: does the parental origin of trisomy influence placental morphology?

Recently, there have been several molecular studies of trisomic fetuses and liveborns which have examined the parent and meiotic stage of origin of nondisjunction. However, little is known about the possible phenotypic effects of the origin of trisomy. For trisomic spontaneous abortions, no distinct phenotype has been described, although some have been reported to have features, such as trophoblastic hyperplasia, similar to hydatidiform moles. In the present report, we describe molecular and histological studies of spontaneous abortions with trisomies 2, 7, 15, or 22, conditions occasionally linked to trophoblastic hyperplasia. Our results provide strong evidence for chromosome specific mechanisms of nondisjunction, with trisomy 2 having a high frequency of paternally derived cases and trisomy 7 typically originating postzygotically. In studies correlating parental origin of trisomy with phenotype, we found no difference in the proportion of cases with trophoblastic hyperplasia, fetal tissue, nucleated red blood cells, or hydropic villi among paternally or maternally derived trisomies 2, 7, 15, or 22. However, paternally derived trisomies tended to abort earlier than maternally derived trisomies. This suggests that parental origin might affect the developmental stage at which abortion occurs but not other features of placental phenotype.

Management of placental site trophoblastic tumors.

OBJECTIVE: To analyze the genetic background of tumors in patients with placental site trophoblastic tumors (PSTTs) and clinical outcome in patients treated for this rare variant of trophoblastic disease at a single center. STUDY DESIGN: Analysis of all patients with PSTTs treated at the Charing Cross Hospital between 1975 and 1995. RESULTS: We studied the molecular genetics of a group of PSTTs using polymerase chain reaction allelotyping and GeneScan software. We were able to show, in the seven cases in which detailed molecular analysis was successful, that four of these PSTTs were from diploid, bi-parental pregnancies and three were androgenetic tumors following monospermic complete hydatidiform moles. For patients with PSTT localized to the uterus, the treatment of choice is hysterectomy. The sensitivity of PSTT to current cytotoxic chemotherapy is variable. Several patients have been cured using the etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine schedule, but clinical impressions suggest that cisplatinum probably should be introduced into the chemotherapy schedule from the outset in a schedule such as etoposide, cisplatin/etoposide, methotrexate, actinomycin D. CONCLUSION: PSTT is a very rare variant of gestational trophoblastic tumor, and its biologic behavior is clearly heterogeneous. The treatment of choice for patients whose disease is limited to the uterus is hysterectomy; for patients with more extensive or metastatic disease, chemotherapy is indicated, but the clinical outcome is variable. A long interval from the antecedent pregnancy to clinical presentation is a major adverse prognostic variable, and the outcome in patients whose last known pregnancy was > 2 years prior to presentation with PSTT is poor.