Intermediate Trophoblast Research Articles

Epithelioid Trophoblastic Tumor Predominant Mixed Germ Cell Tumor of the Testis: A Case Report and Review of the Literature.

An epithelioid trophoblastic tumor is a rare form of gestational trophoblastic neoplasia that mostly affects the uterus and endocervix in female patients of the reproductive age group. The tumor is believed to arise from chorion leave-type intermediate trophoblast. The epithelioid trophoblastic tumor in men is extremely rare and mostly described in association with mixed germ cell tumors of the testis. It is more commonly identified at the metastatic sites than in the testis. The epithelioid trophoblastic tumor should be differentiated from placental site trophoblastic tumor and squamous cell carcinoma. The distinctive morphology and characteristic immunohistochemical staining pattern help differentiate epithelioid trophoblastic tumors from other neoplasms. Only 7 male patients with epithelioid trophoblastic tumors have been described to date. Of these 7 patients, 4 were in metastatic sites, 2 in the testis, and 1 in the lung without the involvement of the testis or retroperitoneum. The proportion of epithelioid trophoblastic tumors was only 5% in the 2 patients with testis involvement. Here, we report the third patient with a primary testicular epithelioid trophoblastic tumor in a young man. Further, this is the first report to document epithelioid trophoblastic tumor as dominant histology in a testicular germ cell tumor.

A Rare Placental Site Nodule Involving the Ovary.

Placental site nodule (PSN) is a benign lesion representing a nodular aggregate of intermediate trophoblast, embedded in a hyalinized stroma, thought to arise from noninvoluted placental site remaining from a past gestation. Uterus is the most common site of PSN. Occurrence in extrauterine sites is rare, with most examples being reported in the fallopian tubes. Here we report an example of PSN in the ovary. A 35-year-old woman, gravida 4, para 1, with history of adnexal ectopic pregnancy treated with methotrexate, at 39 weeks and 1 day of a subsequent pregnancy, underwent a scheduled C-section. The surgery was successful, and a healthy female infant was delivered. Intraoperative adnexal inspection revealed a small pedunculated mass on the right ovary, which was excised and sent for pathological examination. Gross inspection showed a soft, tan-white tissue fragment measuring 2.0 × 1.0 × 0.2 cm. Microscopic examination showed epithelioid cells with hyperchromatic, mildly atypical nuclei and abundant eosinophilic cytoplasm, embedded in a hyalinized stroma, forming a nodule. A diagnosis of placental site nodule was made. Immunohistochemical stains for keratin AE1/AE3, vimentin, and inhibin were strongly positive in the epithelioid cells, and immunostain for p63 was focally positive, supporting the diagnosis. PSN of the ovary is extremely rare. To our knowledge, there has been only one reported patient in the literature so far. Extrauterine PSNs are thought to arise from ectopic pregnancies. Our patient's ovarian PSN is most likely a consequence of her previous adnexal ectopic pregnancy, which was treated medically.

Villous Capillary Malformation and Intermediate Trophoblast Invasiveness: Histopathologic Findings From Fetomaternal Hemorrhage with Gestational Choriocarcinoma

Villous Capillary Malformation and Intermediate Trophoblast Invasiveness: Histopathologic Findings From Fetomaternal Hemorrhage with Gestational Choriocarcinoma

Diagnostic Utility of TSSC3 and RB1 Immunohistochemistry in Hydatidiform Mole.

The general notion of complete hydatidiform moles is that most of them consist entirely of paternal DNA; hence, they do not express p57, a paternally imprinted gene. This forms the basis for the diagnosis of hydatidiform moles. There are about 38 paternally imprinted genes. The aim of this study is to determine whether other paternally imprinted genes could also assist in the diagnostic approach of hydatidiform moles. This study comprised of 29 complete moles, 15 partial moles and 17 non-molar abortuses. Immunohistochemical study using the antibodies of paternal-imprinted (RB1, TSSC3 and DOG1) and maternal-imprinted (DNMT1 and GATA3) genes were performed. The antibodies' immunoreactivity was evaluated on various placental cell types, namely cytotrophoblasts, syncytiotrophoblasts, villous stromal cells, extravillous intermediate trophoblasts and decidual cells. TSSC3 and RB1 expression were observed in all cases of partial moles and non-molar abortuses. In contrast, their expression in complete moles was identified in 31% (TSSC3) and 10.3% (RB1), respectively (p < 0.0001). DOG1 was consistently negative in all cell types in all cases. The expressions of maternally imprinted genes were seen in all cases, except for one case of complete mole where GATA3 was negative. Both TSSC3 and RB1 could serve as a useful adjunct to p57 for the discrimination of complete moles from partial moles and non-molar abortuses, especially in laboratories that lack comprehensive molecular service and in cases where p57 staining is equivocal.

Gestational trophoblastic neoplasia of intermediate trophoblasts: Epithelioid trophoblastic tumor and placental site trophoblastic tumor, a study of morphologic, immunohistochemical, and next generation sequencing.

Gestational trophoblastic tumors are very rare neoplasms. We determined the distinctive morphological, immunohistochemical, and clinical features of placental site trophoblastic tumors (PSTT) and epithelioid trophoblastic tumors (ETT) in our cohort. Nine cases of PSTT and four cases of ETT were retrieved from the archives. Histomorphologic, immunohistochemical, and clinical features were noted. A molecular study was performed on one PSTT and one ETT case using next-generation sequencing. While the nodular pattern, geographic necrosis, and extracellular eosinophilic globules were peculiar to ETTs, vessel wall affinity, marked pleomorphism, intranuclear pseudoinclusion, spindle tumor cell, and vacuolar degeneration were more specific for PSTTs in our series. An immunohistochemical panel of p63, hPL, and CD146 were helpful for the exact typing of the tumor. p63 positivity supports the ETT and diffuse staining of hPL and CD146 supports the PSTT diagnosis. Three of the patients with metastatic disease (lung and brain metastasis) except one have a high mitotic count (12 and 8) and a long interval between (8 and 10 years) antecedent pregnancy and diagnosis. While KIT and TP53 mutations were observed only in PSTT, amino acid changes in KDR, APC, and SMAD4 genes were detected both in the ETT and PSTT cases. In the prediction of metastasis, the long intervals between antecedent pregnancy and diagnosis, deep myometrial invasion, mitotic count, and Ki67 proliferation index were involved rather than other histomorphological parameters, but none of the parameters is an absolute predictor of the metastasis.

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.

Uterine choriocarcinoma arising from serous carcinoma in a postmenopausal woman: an analysis of next-generation sequencing and PD-L1 immunochemistry

BackgroundUterine somatic choriocarcinoma is a rare, clinically aggressive malignant tumor. They frequently concur with other cancer. However, the molecular pathogenesis between somatic choriocarcinoma and the concurrent carcinoma has rarely been addressed to date.Case presentationWe report a 68-years old Chinese woman with a uterine choriocarcinoma arising from serous carcinoma. The patient underwent radical surgery including total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy and pelvic lymph node resection. She received 10 courses of post-operative chemotherapy. She died of disease 13 months after her surgery. Microscopically, the tumor showed a biphasic pattern of choriocarcinoma and serous carcinoma. The choriocarcinomatous component showed a combination of cytotrophoblast, intermediate trophoblast and syncytiotrophoblast with hemorrhage and necrosis. The component of serous carcinoma was characterized by solid sheets of small cells with marked nuclear atypia and occasional glandular and papillary formation. PD-L1 was exclusively expressed in the choriocarcinomatous component. Next-generation sequencing revealed that the genetic abnormalities were overlapping between the two components.

The mysterious extravillous trophoblast

Extravilluos Trophoblast (EVT) is a truly special cell. It has a temporary character and tumor-like behavior and tumor-like appearance, all of which seem to belong to the malignancy field [1,2]. It is also known as intermediate trophoblast, derived from cytotrophoblast [3-5], having formed between the latter and the syncytiotrophoblast. EVT is capable of reaching the decidua through trophoblast cell columns that connect the anchoring villi to the basal plate in early gestation.

PLACENTAL SITE TROPHOBLASTIC TUMOUR: A CASE REPORT

Placental site trophoblastic tumour (PSTT) is a rarest type of gestational trophoblastic disease (GTD) with an incidence of 1/50,000–100,000 of all pregnancies. In contrary to other variants of GTD, it arises from the intermediate trophoblast at placental site, secretes minimal beta-hCG and very less sensitivity for chemotherapeutic agents. Patient presents with amenorrhoea and abnormal bleeding. Imaging modalities like ultrasonography and MRI helps in making the diagnosis but is conrmed after histological evaluation and immunohistochemistry (IHC) studies. Patients mostly present with tumour limited to the uterine body. The mainstay of treatment is total hysterectomy. The prognosis of patients with tumour limited to the uterus is good

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.

Uterine Epithelioid Trophoblastic Tumor

A woman in her early 60s presented with postmenopausal bleeding. Pelvic ultrasound examination identified a large uterine mass. The patient underwent total hysterectomy to remove this uterine mass. Which of the following is a malignant trophoblastic neoplasm that can develop many years after pregnancy?a.Placental site noduleb.Exaggerated implantation sitec.Epithelioid trophoblastic tumord.Endometrial stromal sarcoma Answer: c. Epithelioid trophoblastic tumor Epithelioid trophoblastic tumor is a rare malignant neoplasm of chorionic-type intermediate trophoblast.1WHO Classification of Tumors5th ed. Female Genital Tumors. Vol 4. International Agency for Research on Cancer, Lyon2020Google Scholar Epithelioid trophoblastic tumor is generally not associated with specific symptoms, but vaginal bleeding or menometrorrhagia is often noted, as is low elevation of serum β-human chorionic gonadotropin.1WHO Classification of Tumors5th ed. Female Genital Tumors. Vol 4. International Agency for Research on Cancer, Lyon2020Google Scholar Epithelioid trophoblastic tumor can develop within a year of and up to 2 decades after an antecedent gestation and thus can be seen in postmenopausal patients. Epithelioid trophoblastic tumor forms a solid to cystic mass most commonly in the cervix or lower uterine segment with varying amounts of necrosis and hemorrhage. On microscopic examination, the tumor shows infiltrative mononuclear epithelioid cytologically atypical intermediate trophoblastic cells, often forming nests with hyalinization or necrosis centrally.2Fadare O. Parkash V. Carcangiu M.L. Hui P. Epithelioid trophoblastic tumor: clinicopathological features with an emphasis on uterine cervical involvement.Mod Pathol. 2006; 19: 75-82Crossref PubMed Scopus (76) Google Scholar

Extrauterine Epithelioid Trophoblastic Tumor (ETT) Arising from an Antecedent Undiagnosed Molar Pregnancy Presenting as an Adnexal mass: A Case Report

Abstract Introduction/Objective Epithelioid trophoblastic tumor (ETT) is an extremely rare neoplasm derived from chorionic type intermediate trophoblast. ETT usually follows an antecedent term pregnancy but can also follow spontaneous abortions or molar pregnancy. ETT most often arises from the endometrium, followed by the cervix. Extrauterine ETT are extremely rare, with few cases reported in literature. Methods/Case Report A 41-year-old woman with three term pregnancies presented with abdominal pain, ten years after her last pregnancy. Imaging findings of a 3.5 cm adnexal mass coupled with an elevated serum β-hCG (~ 900 mIU/ml), led to the suspicion of an ectopic pregnancy. Hysterectomy with salpingectomy revealed a 4.7 cm, tan- yellow, necrotic mass in the adnexal region abutting but distinct from the uterine serosa. Histologic evaluation showed a well- circumscribed tumor with pushing borders. The tumor cells were epithelioid with well-defined eosinophilic cytoplasm, monomorphic nuclei, frequent mitosis, and abundant geographic necrosis. The tumor cells were positive for β-hCG, GATA-3, PLAP and inhibin, with focal weak staining squamous markers p63 and p40. DNA fingerprinting analysis, performed to confirm the diagnosis of ETT, revealed a homozygous tumor with two copies of non-maternal genes indicating that the antecedent index gestation giving rise to the tumor was an undiagnosed hydatidiform mole. Following surgery, serum β-hCG levels were normal and the patient is currently on surveillance. Results (if a Case Study enter NA) NA Conclusion We present an extremely rare case of extrauterine ETT arising from a previously undetected molar pregnancy. The diagnosis should be suspected when a mass is observed at extrauterine sites with elevated β-hCG levels in patients with or without vaginal bleeding. Histologic differential of squamous cell carcinoma needs to be ruled out with immunostains. Due to its rarity and highly variable presentation, this entity remains a diagnostic challenge. DNA fingerprinting analysis demonstrating non-maternal genes can help confirm the diagnosis of ETT.

Objective Histologic Characterization of Trophoblastic Proliferations

Abstract Introduction/Objective Placental site nodules (PSNs) are rare intermediate trophoblastic lesions characterized by hyalinized cellular aggregates that are small, well-circumscribed, non-necrotic, and paucicellular. PSNs are generally incidental in gynecologic specimens. ETTs are malignant proliferations of intermediate trophoblasts and are generally larger, with nuclear atypia, and higher mitotic rate. Atypical placental site nodules (APSNs) are histologically intermediate between PSN and ETT and not well characterized in the literature to date. There exists room for more objective characterization of PSN and APSN. We use objective measurements to characterize trophoblastic proliferations based on size, location, mitotic rate, number of trophoblasts per high-power field (t-HPF), ki-67 index, beta-hCG, time since last pregnancy, presence of calcification or necrosis, and clinical follow-up. Methods The surgical pathology database of a single large academic institution was searched for cases of “placental site nodule,” “atypical placental site nodule,” “epithelioid trophoblastic tumor,” and “placental site trophoblastic tumor”. Clinical and morphologic data were recorded for each case. Ki-67/cytokeratin AE1/AE3 dual immunohistochemical stains were performed to assess the proliferative index of the trophoblastic cells. Results 70 cases of trophoblastic lesions (53 PSN, 4 APSN, 5 ETT, 8 PSTT) were identified. Results include: PSNs were on average 3.2 mm, 56.5 t-HPF, and 2.6% ki-67. APSNs 4.3 mm, 97.8 t-HPF, and 6.4% ki-67. ETTs 16.5 mm, 161.8 t-HPF, and 12.2% ki-67. Conclusion Objective measurements of trophoblastic lesions, as well as correlation with clinical data, may be useful for more accurate classification of these lesions, especially by those who encounter them rarely. To date, the clinical risk, optimal management, and risk for progression of APSNs are not well characterized and thus are worthy of additional study and description. For example, in our data, 14 cases originally signed out at PSN were at least 4 mm, which may re-classify them as APSN.

Abstract 2988: PLAC8 confers the chemoresistance of placental site trophoblastic tumor and choriocarcinoma to etoposide in an autophagy-dependent manner

Abstract Chemotherapy is commonly used to treat gestational trophoblastic neoplasia (GTN), but placental site trophoblastic tumor (PSTT) and a small proportion of choriocarcinoma demonstrate chemotherapy resistance, which becomes the major obstacle for the treatment. However, the underlying mechanism remains elusive. In the present study, we found that PLAC8 expression in PSTT tissues was higher than that in placental site intermediate trophoblast cells. In addition, PLAC8 was also highly expressed in human choriocarcinoma tissues compared with normal placental villi. Over-expression of PLAC8 inhibited p53 protein stability and induced the autophagic flux in HTR-8 and JAR cells. PLAC8-induced autophagic activity could be partially recovered by p53 re-expression. Further, PLAC8 over-expression conferred chemoresistance of trophoblast cells to etoposide, which can be effectively abrogated by autophagic inhibitors 3-methyladenine (3-MA) or chloroquine (CQ). In conclusion, over-expression of PLAC8 in PSTT and choriocarcinoma tissues may endow the trophoblast cells with enhanced chemoresistance via inducing autophagy activity. Therefore, PLAC8 may serve as a potential therapeutic target for the treatment of PSTT and choriocarcinoma. Citation Format: Xuan Feng, Huandi Yu, Xiang Tao, Yan Du, Jing Wu, Yinhua Yu, Congjian Xu, Hongbo Zhao. PLAC8 confers the chemoresistance of placental site trophoblastic tumor and choriocarcinoma to etoposide in an autophagy-dependent manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2988.

Identification of miR-210-5p in human placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction, and its potential role in the pregnancy complications.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are pregnancy complications resulting from abnormal placental development. As epigenetic regulators, microRNAs can regulate placental development and contribute to the disease pathophysiology by influencing the expression of genes involved in placental development or disease. Our previous study revealed an increase in miR-210-5p expression in placentae from patients with early-onset pregnancy complications and identified candidate gene targets for miR-210-5p. The purpose of this study was to: (i) validate candidate gene targets predicted for miR-210-5p from microRNA-RNA expression data, and (ii) overexpress miR-210-5p in a trophoblast cell line (HTR-8/SVneo) to assess impact on trophoblast cell functions. Integration of the miRNA and RNA sequencing expression data revealed 8 candidate gene targets for miR-210-5p in patients with PE only or PE+IUGR. Luciferase reporter assays identified two gene targets for miR-210-5p, CSF1 and ITGAM. Real-time PCR confirmed the decreased expression of CSF1 and ITGAM in patients with PE+IUGR. Immunohistochemistry of placentae from late second trimester identified CSF1 and ITGAM in intermediate trophoblast cells in the decidua. Expression levels of CSF1 and ITGAM were reduced in HTR-8/SVneo cells following increased miR-210-5p expression. Concomitantly, HTR-8/SVneo cells demonstrate an average 45% reduction in cell migration. These findings suggest that miR-210-5p may contribute to dysfunction of intermediate trophoblasts and potentially contribute to the disease process of these pregnancy complications.

Downregulation of MicroRNA-125a in Placenta Accreta Spectrum Disorders Contributes Antiapoptosis of Implantation Site Intermediate Trophoblasts by Targeting MCL1.

The typical hallmark of placenta accreta spectrum (PAS) disorders is increased implantation site intermediate trophoblast (ISIT) cell numbers. However, the extent of trophoblast proliferation and apoptosis have not been found to differ from those of normal placentation. MicroRNA-125a (miR-125a) induces apoptosis in colon cancer cell by targeting myeloid cell leukemia-1 gene (MCL1). We aimed to investigate the influence of miR-125a on ISIT cells in PAS disorders in 15 patients (self-paired trials) with placenta previa and PAS disorders. Expression of miR-125a and MCL1 were measured in villous trophoblasts and basal plate myometrial fibers from creta site and adjacent noncreta tissues by real-time quantitative polymerase chain reaction, and expression of the MCL1 protein was assayed by Western blotting. Flow-cytometry was used to examine the effect of miR-125a overexpression on apoptosis in vitro in HTR-8/SVneo cells, and luciferase activity assays was used to confirm miR-125a targeting of MCL1. In vivo, the expression levels of miR-125a was significantly lower in creta versus noncreta tissues, and the expression of MCL1 was upregulated; moreover, immunohistochemistry showed that the increased ISIT cells in the creta were positive for MCL1 protein. MCL1 was downregulated in the miR-125a-overexpressing HTR-8/SVneo cells in vitro, and overexpression of miR-125a-induced apoptosis in the HTR-8/SVneo trophoblast line. Finally, luciferase activity assays confirmed that miR-125a directly target the 3' untranslated region of MCL1 in the 293T cell line. In conclusion, downregulation of MCL1-targeting miR-125a exerts an antiapoptotic effect on ISIT cells in PAS disorders.

A Review on the Pathogenesis and Clinical Management of Placental Site Trophoblastic Tumors.

Placental site trophoblastic tumor (PSTT) is a rare type of gestational trophoblastic disease originating from the intermediate trophoblast. Compared with hydatidiform mole, invasive hydatidiform mole and choriocarcinoma, the diagnosis of PSTT is more complicated and lacks specific and sensitive tumor markers. Most PSTT patients demonstrate malignant potential, and the primary treatment of PSTT is hysterectomy. However, metastasis occasionally occurs and even causes death in a small number of PSTT patients. Most PSTT patients are young women hence fertility preservation is an important consideration. The major obstacle for PSTT patient prognosis is chemotherapy resistance. However, the current understanding of the pathogenesis of PSTT and clinical treatment remains elusive. In this review, we summarized the research progress of PSTT in recent years from three aspects: mechanism, clinical presentation, and treatment and prognosis. Well-conducted multi-center studies with sufficient sample sizes are of great importance to better examine the pathological progress and evaluate the prognosis of PSTT patients, so as to develop prevention and early detection programs, as well as novel treatment strategies, and finally improve prognosis for PSTT patients.

P57 in Hydatidiform Moles: Evaluation of Antibodies and Expression in Various Cell Types.

The protein p57 is encoded by CDKN1C. This gene is known to be paternally imprinted and maternally expressed in cytotrophoblasts and villous stromal cells. We present a method for evaluating p57 antibodies (Abs) in hydatidiform mole (HM) and demonstrate the results for 4 p57 Abs in various cell types. Five cases of complete HM, diploid with 2 paternal genome sets (CHM;PP), 5 cases of partial HM, triploid with 2 paternal and 1 maternal genome sets (PHM;PPM), and 5 cases of non-HM, with diploid biparental genomes (non-HM;PM) were stained with p57 Abs: 57P06, EP183, KP10, and KP39. Assessment of the fraction of nuclei stained, and the intensity of staining of the nuclei and cytoplasm was performed. For evaluation of the Abs, the observations in cytotrophoblasts, villous stromal cells, maternal decidual cells, and intermediate trophoblasts were scored. The fraction of stained nuclei in cytotrophoblasts and villous stromal cells and the staining of cytoplasm showed to be important parameters in the evaluation of the Abs. 57P06 was evaluated as optimal. KP10 showed moderate cytoplasmatic staining in maternal decidual cells and intermediate trophoblasts, and was evaluated as good. EP183 was evaluated as poor, primarily due to nuclear staining in ≥10% of the villous stromal cells in CHM;PP. KP39 was evaluated as poor, primarily due to strong cytoplasmatic staining in some cytotrophoblasts and villous stromal cells. A structured testing of p57 for diagnosing HM is recommended. No nuclear staining was observed in syncytiotrophoblasts of CHM;PP, indicating that in syncytiotrophoblasts also, CDKN1C is paternally imprinted.

Clinical characteristics and outcomes of extrauterine epithelioid trophoblastic tumors.

Epithelioid trophoblastic tumor (ETT) derived from intermediate trophoblasts is one type of gestational trophoblastic neoplasia (GTN), and it accounts for less than 2% of all gestational trophoblastic diseases (GTD). Extrauterine ETT is extremely rare, and there is currently no consistent strategy for its treatment and management. Therefore, the aim of the study is to analyze and summarize the clinicopathologic features of extrauterine ETT with or without metastasis. The Web of Knowledge, Google Scholar, EMbase, congress of library, and PubMed were searched for extrauterine ETT without primary uterine lesions. All available data were extracted from published case reports or serial case reports, and then, the clinical and pathological characteristics were analyzed. Twenty-two clinical studies consisting of 27 patients diagnosed with extrauterine ETT, according to the given inclusion and exclusion criteria, were included in the study. A total of 27 cases of extrauterine ETT were identified. Of these cases, four (14.81%) were located in the lungs, three (11.11%) in the ovaries, two (7.41%) in the vagina, and eight (29.63%) patients had other primary lesions. The patients originated from different continents, with 59% located in Asia and 26% in North America. Among 23 patients, the antecedent pregnancy prior to the diagnosis was full-term in 12 cases, abortion in 6 cases, hydatidiform mole in 3 cases, and invasive mole in 1 case. From the available antecedent information on pregnancy, the median interval from pregnancy to diagnosis of extrauterine ETT was 4years. Additionally, the median gravidity and para of the patients was three times and two times, respectively. The median hCG titer was 14,374mIU/mL in 5 patients, and the mean β-HCG titer was 3,724,805mIU/mL in 14 patients. For all patients, the disease was confined to extrauterine ETT at diagnosis. From the available information, 20 cases were successfully treated by extraction of local lesions, and 12 cases received chemotherapy. Diagnosis was confirmed by histological tests. The Ki-67 staining ranged from 8.7 to 80%, and tumors were positive for hCG, PLAP, EMA, and p63. In this study, we observed that abnormal levels of serum hCG titers and the local presentation of lesions with varying intervals after antecedent term pregnancy were the most common presenting features of extrauterine ETT. In addition, we found that the extraction of extrauterine lesions was needed for the treatment of extrauterine ETT. Of course, the follow-up was also important.

PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua.

Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23. We also show that the intermediate extravillous trophoblast (iEVT) expresses high levels of the PD-1-ligand PD-L1, suggesting that PD-1/PD-L1 interaction may regulate ILC3 function at the feto-maternal interface. Our present data provide the first evidence that human decidual ILC3 express a functional PD-1. It is possible that an altered expression or function of PD-1 may break the immune-tolerance resulting in pregnancy failure.