Molecular Analyses of Chorionic-Type Intermediate Trophoblastic Lesions: Atypical Placental Site Nodules are Closer to Placental Site Nodules Than Epithelioid Trophoblastic Tumors.

Gestational trophoblastic diseases derived from the chorionic-type intermediate trophoblast include benign placental site nodule (PSN) and malignant epithelioid trophoblastic tumor (ETT). Among PSNs, the World Health Organization classification introduced a new entity named atypical placental site nodule (APSN), corresponding to an ETT precursor, for which diagnostic criteria remain unclear, leading to a risk of overdiagnosis and difficulties in patient management. We retrospectively studied 8 PSNs, 7 APSNs, and 8 ETTs to better characterize this new entity and performed immunohistochemical analysis (p63, human placental lactogen, Cyclin E, and Ki67), transcriptional analysis using the NanoString method to quantify the expression of 760 genes involved in the main tumorigenesis pathways, and RNA sequencing to identify fusion transcripts. The immunohistochemical analysis did not reveal any significant difference in Cyclin E expression among the 3 groups (P = .476), whereas the Ki67 index was significantly (P < .001) higher in ETT samples than in APSN and PSN samples. None of the APSN samples harbored the LPCAT1::TERT fusion transcripts, in contrast to 1 of 6 ETT samples, as previously described in 2 of 3 ETT samples. The transcriptomic analysis allowed robust clustering of ETTs distinct from the APSN/PSN group but failed to differentiate APSNs from PSNs. Indeed, only 7 genes were differentially expressed between PSN and APSN samples; CCL19 upregulation and EPCAM downregulation were the most distinguishing features of APSNs. In contrast, 80 genes differentiated ETTs from APSNs, establishing a molecular signature for ETT. Gene set analysis identified significant enrichments in the DNA damage repair, immortality and stemness, and cell cycle signaling pathways when comparing ETTs and APSNs. These results suggested that APSN might not represent a distinct entity but rather a transitional stage between PSN and ETT. RNA sequencing and the transcriptional signature of ETT described herein could serve as triage for APSN from curettage or biopsy material, enabling the identification of cases that need further clinical investigations.

Gestational trophoblastic neoplasia: Novelties and challenges.

Gestational trophoblastic diseases are a group of pregnancy-related disorders, originated from trophoblast cells. They include benign and aggressive tumors, such as the invasive mole, the choriocarcinoma, the placental site trophoblastic tumor (PSTT), and the epithelioid trophoblastic tumor (ETT). These malignancies are characterized as gestational trophoblastic neoplasm (GTN), rarer, although more dangerous. The diagnosis of GTN is made in most cases by monitoring serum chorionic gonadotropin (hCG) with histological confirmation. The use of specific tissue biomarkers has been increasingly employed as a differential diagnosis, leading to more accurate results and different therapy protocols and prognosis for each GTN. The treatment is based on the International Federation of Gynecology and Obstetrics anatomical staging system and the World Health Organization prognostic score system. If an accurate diagnosis is made and the guidelines followed, the cure for choriocarcinoma and invasive mole cases can reach 98%, whereas PSTT and ETT still present mild success rates. The improved knowledge about GTN and its peculiarities allows physicians to efficiently achieve the differential diagnosis and choose the best available therapy protocol, thus increasing the overall survival of affected women. Nevertheless, obtaining epidemiological data and improving knowledge through basic and translational research are essential to answer open questions on GTN physiopathology, their causes, and cellular behavior.

Placental site trophoblastic disease.

A case study of a 38-year-old woman with a diagnosis of placental site trophoblastic tumor is presented. The patient had a 22-month history of amenorrhea since her last pregnancy, and a dilation and curettage procedure was performed after a 3.1×2.4×2.8 cm endometrial echogenic lesion was visualized on a pelvic ultrasound. When the diagnosis of placental site trophoblastic tumor was made by histopathologic and immunohistochemical analysis, complementary examinations including including pelvic magnetic resonance imaging (MRI) and a chest computed tomography (CT) were done. There was no evidence of disease outside the uterus, and a laparoscopic hysterectomy with bilateral salpingectomy was performed. After a surveillance period of 12 months, no disease recurrence was identified. Best imaging studies, treatment options, and proper surveillance for these type of tumors are discussed alongside the case study.

Extrauterine Placental Site Trophoblastic Tumor Involving the Vagina.

Very few cases of placental site trophoblastic tumor (PSTT) primarily involving extrauterine sites have been reported to date. We report a case of a 29-year-old female who presented with a vaginal nodule 9 months after delivery at an outside hospital which was initially diagnosed as a poorly differentiated squamous cell carcinoma. Subsequently she was referred to our institute, and on the basis of histology, mildly elevated serum ß-HCG level, and immunohistochemistry, PSTT was diagnosed. After the completion of chemotherapy, the vaginal nodule completely regressed and serum ß-hCG returned to baseline. Her follow-up has been unremarkable. This case highlights the importance of the fact that PSTT can be easily misdiagnosed at extrauterine sites in the absence of proper clinical, histologic, and immunohistochemical correlation.

Massive perivillous fibrin deposition in the placenta and uterine metastasis of gastric adenocarcinoma during pregnancy.

The prognosis of gastric cancer during pregnancy is unfavorable because of delayed diagnosis and advanced stage. We present a case of gastric carcinoma metastasized to the placenta and uterus during pregnancy. Pathological examination revealed a poorly differentiated adenocarcinoma of the stomach with lymph node metastasis. After counseling, the patient decided to terminate the pregnancy and begin immediate treatment for gastric cancer. Hysterectomy and subtotal hysterectomy were performed because medical termination of the pregnancy was unsuccessful. Pathological examination of the placenta and uterus revealed metastases of gastric adenocarcinoma. All the uterine vessels were packed with tumor cells and the myometrium showed extensive coagulative necrosis. Moreover, microscopic findings of the placenta were consistent with massive perivillous fibrin deposition. Our case clearly suggests that massive perivillous fibrin deposition in the placenta can be associated with malignancy during pregnancy and that uterine metastasis of maternal malignancy may result in myometrial dysfunction unresponsive to uterotonics.

The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration.

INTRODUCTION: Gastrokine-1 (GKN1) is a secreted auto-/paracrine protein, described to be expressed in the gastric mucosa. In gastric cancers GKN1 expression is commonly down-regulated. While current research focusses on the exploration of tumor-suppressive properties of GKN1 with regard to its potential clinical use in the treatment of gastroenterologic tumor disease, nothing is known about GKN1 expression and function in other organ systems. We investigated GKN1 expression in placental tissue and cells. MATERIALS AND METHODS: GKN1 was localized using immunohistochemistry in first and third trimester placental tissue, hydatidiform moles and various gestational trophoblastic neoplasias. We determined the expression of GKN1 in immunomagnetic bead-separated term placental cells and in choriocarcinoma cell lines. The role of GKN1 for JEG-3 migration was studied using live cell imaging. E-cadherin, MMP-2 and -9, TIMP-1 and -2, as well as urokinase (uPA) expression levels were determined. RESULTS: GKN1 is expressed in healthy third trimester placentas. Its expression is specifically limited to the extravillous trophoblast (EVT). GKN1 expression is significantly reduced in choriocarcinoma cell lines and gestational trophoblastic neoplasias. GKN1 attenuates the migration of JEG-3 choriocarcinoma cells in vitro, possibly via AKT-mediated induction of E-cadherin. GKN1 treatment reduced MMP-9 expression in JEG-3. DISCUSSION: Besides its role in gastric physiology our results clearly indicate regulatory functions of GKN1 in the EVT at the feto-maternal interface during pregnancy. Based on our findings in the JEG-3 choriocarcinoma cell line, an auto-/paracrine role of GKN1 for EVT motility and villous anchorage at the basal plate is conceivable. Thus, the tumor suppressor GKN1 is expressed in placental EVT and might contribute to the regulation of EVT migration/invasion.

Placental site trophoblastic tumor: lymphatic spread and possible target markers.

OBJECTIVES: The behaviors of placental site trophoblastic tumor (PSTT), especially lymphatic spread, have not been completely understood. We aimed to investigate the nature of lymphatic spread in PSTT as well as the expression of several molecules on tumor. METHODS: The clinical data of 5 cases with PSTT were reviewed retrospectively. The expression of EGFR, VEGF, HER2/neu, and CD117 was analyzed by immunohistochemical staining. A MEDLINE search was performed to identify patients with PSTT. RESULTS: There were several special aspects in our 5 cases. One patient was postmenopausal and had a 33-year long interval from antecedent pregnancy; two patients had lymph node and ovarian involvement each; the postmenopausal patient had 4 relapses and survived 57 months after the first recurrence. Tumor cells in all cases were strongly positive for EGFR and VEGF and negative for HER2/neu and CD117. A total of 286 cases (281 from the literature and 5 from our data) were analyzed for lymphatic spread. Of them, 17 (5.9%) had lymph node metastases, including pelvic in 5 patients, para-aortic in 7, retroperitoneal but not specified in 2, and other sites in 6. CONCLUSIONS: Lymph node metastasis is one way of spread in PSTT. Retroperitoneal node, especially para-aortic node, is the most common site of lymphatic spread. EGFR and VEGF may be commonly expressed in PSTT tumors.

The expression and diagnostic utility of p63 in the female genital tract.

p63 plays a key role in epithelial development in various organs, being expressed in myoepithelial cells and in basal cells of stratified epithelia. In the female genital tract, p63 is expressed in the basal and parabasal cells of mature cervical, vaginal and vulval squamous epithelium, and also in cervical reserve cells at the transformation zone and in immature metaplastic and atrophic cervical squamous epithelium. In this review, the diagnostic utility of p63 immunohistochemical staining in various pathologic scenarios within the female genital tract is discussed. Cervical microglandular hyperplasia is p63 positive with a characteristic subcolumnar location due to expression in reserve cells. There is increased expression in cervical intraepithelial neoplasia, in accordance with the degree of dysplasia. One of the most useful applications of p63 is in the evaluation of problematic cervical carcinomas; most squamous carcinomas exhibit diffuse nuclear immunoreactivity whereas most adenocarcinomas and neuroendocrine carcinomas are negative or focally positive. In conjunction with neuroendocrine markers, p63 is useful in distinguishing between a squamous carcinoma and a small cell or large cell neuroendocrine carcinoma. In the normal endometrium, a population of p63-positive cells is present which may act as a stem cell population and which is increased in various forms of metaplasia. Placental site nodule and epithelioid trophoblastic tumor (lesions derived from chorionic-type intermediate trophoblast) are usually p63 positive whereas placental site reaction and placental site trophoblastic tumor (lesions derived from implantation site intermediate trophoblast) are usually negative; thus, p63 may be useful in the diagnostic algorithm of trophoblastic lesions. p63 positivity in ovarian epithelial tumors is uncommon and largely restricted to squamous and transitional neoplasms, including benign and borderline Brenner tumor. p63 is also positive in cervical transitional metaplasia, Walthard rests, vulval Paget disease secondary to an underlying urothelial malignancy, tubulosquamous polyp of the vagina, and ectopic prostatic tissue in the cervix.

Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study.

BACKGROUND: Placental-site trophoblastic tumours are a rare form of gestational trophoblastic disease and consequently information about optimum management or prognostic factors is restricted. We aimed to assess the long-term outcome of stage-adapted management by surgery, chemotherapy, or both for patients with the disorder. METHODS: 35 550 women were registered with gestational trophoblastic disease in the UK (1976-2006), of whom 62 were diagnosed with placental-site trophoblastic tumours and included, retrospectively, in the study. Patients were treated by surgery, chemotherapy, or both. We estimated the probabilities of overall survival and survival without recurrence of disease 5 and 10 years after the date of first treatment, and calculated the association of these endpoints with prognostic factors, including time since antecedent pregnancy, serum concentration of beta-human chorionic gonadotropin, and stage of disease, with both univariate and multivariate analyses. FINDINGS: Probabilities of overall and recurrence-free survival 10 years after first treatment were 70% (95% CI 54-82) and 73% (54-85), respectively. Patients with stage I disease had a 10-year probability of overall survival of 90% (77-100) and did not benefit from postoperative chemotherapy. By contrast, patients with stage II, III, and IV disease required combined treatment with surgery and chemotherapy; probability of overall survival at 10 years was 52% (3-100) for patients with stage II disease and 49% (26-72) for stage III or IV disease. Outcome for patients who had recurrent or refractory disease was poor: only four (22%) patients achieved long-term survival beyond 60 months. Multivariate analysis showed that the only significant independent predictor of overall and recurrence-free survival was time since antecedent pregnancy. A cutoff point of 48 months since antecedent pregnancy could differentiate between patients' probability of survival (<48 months) or death (>/=48 months) with 93% specificity and 100% sensitivity, and with a positive predictive value of 100% and a negative predictive value of 98%. INTERPRETATION: Stage-adapted management with surgery for stage I disease, and combined surgery and chemotherapy for stage II, III, and IV disease could improve the effectiveness of treatment for placental-site trophoblastic tumours. Use of 48 months since antecedent pregnancy as a prognostic indicator of survival could help select patients for risk-adapted treatment. FUNDING: National Commissioning Group.

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.

Decreased breast cancer rates among women with choriocarcinoma.

OBJECTIVE: We hypothesized that exposure to high levels of hCG in women diagnosed with choriocarcinoma would decrease future breast cancer risk. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) registry limited-use database (1973-2004) to search for placenta tumors (ICD-10 C58), i.e. choriocarcinoma (CC). Demographics were obtained including patient ID, primary site, year of diagnosis, sex, race, DOB, age group and survival months. Patients with initial choriocarcinoma were searched for subsequent breast cancers. The cohort diagnosis with CC and subsequent breast cancers were compared to general population-based rates of breast cancer. RESULTS: A query for CC yielded 646 women between the ages 15 and 54 years. Of the 646 women, 422 were white, 129 African-American, and 95 "other". Total women-years of observation were 7165.3 with two CC patients developing breast cancer yielding a breast cancer incidence rate of 27.9/100,000 women-years. The incidence rate ratio(IRR) of the CC cohort to the general population was 0.21 (95% CI(0.145-0.327); P<0.01). In women with CC under the age of 35 years the breast cancer rate was 34.1/100,000, IRR 0.27 (95% CI(0.182-0.386); P<0.01). Controlling for race, breast cancer rates in whites were 49.3/100,000 (IRR 0.37, P<0.01); in African-American 1.3/100,000 (IRR 0.01, P<0.001); and 2.6/100,000 (IRR 0.03, P<0.001) in "others" compared to the general population. CONCLUSION: Women with prior CC had a 79% reduction in breast cancer risk compared to the general population regardless of age and race. Given the high level of hCG and decreased rate of breast cancer among women with CC, the hypothesis that hCG is protective against breast cancer seems plausible.

[Clinicopathologic study of tumors of intermediate trophoblasts].

OBJECTIVE: To study the clinicopathologic features and immunophenotype of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). METHODS: During the period from 1959 to 2005, a total of 1012 cases of gestational trophoblastic disease were diagnosed in Beijing Obstetrics and Gynecology Hospital. Six cases of PSTT and a case of ETT were retrieved from the archives of Beijing Obstetrics and Gynecology Hospital. Immunohistochemical study for cytokeratin 18, human chorionic gonadotropin (hCG), human placental lactogen (hPL), Mel-CAM (CD146), placental-like alkaline phosphatase (PLAP), epithelial membrane antigen (EMA), inhibin-alpha and proliferative cell nuclear antigen (PCNA) were performed. The morphologic features and immunohistochemical findings were compared with those of the controlled group which consisted of 20 cases of early gestational villi with decidua basalis and 20 cases of hydatidiform moles with implantation site. RESULTS: The mean age of patients with PSTT was 32.4, while the age of patients with ETT was 36. Major clinical findings included irregular vaginal bleeding and amenorrhea. Preoperative serum hCG level varied from normal to moderately elevated. Serum testosterone level was raised in 1 case. Uterine curettage could achieve an accurate pathologic diagnosis in 60% of cases. ETT involved mainly the lower uterine segment and endocervix. Histologically, PSTT cells permeated between the myometrial fibers and vessels either individually or connecting in cords or sheets in a manner reminiscent of the implantation site reaction. ETT composed of a relatively uniform population of mononuclear trophoblastic cells, clumping together in nests as the cell islets associating with eosinophilic, fibrillary and hyaline material and necrotic debris, forming a "geographic map" like pattern. Immunohistochemical study for hPL, hCG, Mel-CAM (CD146) and PLAP was most helpful for the differential diagnosis. The duration of follow-up varied from 14 months to 19 years. One case of PSTT developed metastasis in pancreas, 5 months after the operation. The remaining patients survived without tumor recurrence. CONCLUSIONS: PSTT is a tumor of implantation site intermediate trophoblasts while ETT differentiates towards chorionic-type intermediate trophoblasts. The different pathologic features and immunophenotype observed were closely related with the difference in tumor cell differentiation. An accurate pathologic diagnosis of the uterine curettage material is important for the clinical management. According to the limited follow-up data available, the clinical behavior of ETT is seemed similar to that of PSTT.

Placental site trophoblastic tumor of the mediastinum.

Choriocarcinoma has been described as the most frequent subtype of mediastinal germ cell tumors showing trophoblastic differentiation. We report a unique case of a placental site trophoblastic tumor, which developed in the mediastinum of a 14-year-old boy 2 years after the resection of a mature teratoma. The recurrent tumor was composed of a grossly hemorrhagic and necrotic mass. Histologically, diffusely infiltrating large polygonal cells with focal nodular growth and a teratomatous part containing mature intestinal, respiratory, and squamous epithelium with adjacent cutaneous adnexal structures were found. The typical morphologic features included vessel wall infiltration by the neoplastic cells with fibrinoid deposits and geographic necroses within the tumor masses. Characteristic diffuse positivity for melanoma cell adhesion molecule and human leucocyte antigen G was found on immunohistochemical investigation, confirming the diagnosis of placental site trophoblastic tumor. The patient died 1 year later after polychemotherapy. The outcome of this rare tumor is similar to the reported poor clinical outcome in patients with mediastinal choriocarcinomas.

Galectin-1 and galectin-3 in the trophoblast of the gestational trophoblastic disease.

While the presence and distribution of galectin-1 and galectin-3 in different normal trophoblast cell populations is known, no information is available regarding their occurrence in malignant trophoblast of gestational trophoblastic disease (GTD). Galectins-1 and -3 have, however, been implicated in malignancies of other tissues. Immunoreactivity for these galectins in the transformed trophoblast of invasive mole (n = 8), choriocarcinoma (n = 7) and one case of placental site trophoblastic tumor (PSTT) was compared to that of the invasive trophoblast of the normal first trimester of pregnancy implantation sites (n = 9). A large proportion of the transformed trophoblast cells of all GTD studied were positive for galectin-1 and galectin-3. Immunoreactivity was scored semiquantitatively to include both the prevalence among the trophoblast cells and the intensity of staining. Immunoreactivity for both galectin-1 and galectin-3 in gestational trophoblastic disease is increased (significant differences at p < 0.05, Mann-Whitney Rank Sum Test). This finding may suggest a possible implication of galectins-1 and -3 in the invasiveness of the transformed trophoblastic cell, although the exact physiological significance of this finding remains to be determined.

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.

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.

Implantation site intermediate trophoblasts in placenta cretas.

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas. To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300+/-1200 mum) than noncretas (1500+/-1200 microm, P<0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P<0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly. These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.

Placental site trophoblastic tumor presenting with a pneumothorax during pregnancy.

BACKGROUND: Placental site trophoblastic tumor is a rare form of gestational trophoblastic disease that commonly presents with vaginal bleeding and amenorrhea after pregnancy. CASE: A women with a normal gestation at 37 weeks presented with a pneumothorax. The patient underwent placement of a chest tube and a subsequent thoracoscopic pulmonary bullous resection for persistence of the pneumothorax. Histological examination of the specimen revealed a metastatic placental site trophoblastic tumor. CONCLUSION: Gestational trophoblastic disease must be considered in the differential diagnosis of pneumothorax during pregnancy.