Placental site trophoblastic tumor (PSTT): a case report and review of the literature.

Placental site trophoblastic tumor (PSTT), also known as atypical choriocarcinoma, syncytioma, chorioepitheliosis or trophoblastic pseudotumor, is a rare gestational trophoblastic disease (0.25-5% of all trophoblastic tumors) and it is composed by neoplastic proliferation of intermediate trophoblasts at placental implantation site. It consists of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells with a characteristic vascular and myometrial invasion. Main differential diagnoses are gestational choriocarcinoma (GC) and epitelioid trophoblastic tumor (ETT). We present a case of PSTT in a 25-year-old woman. Neoplastic cells showed moderate/high nuclear pleomorphism, abundant amphophilic, eosinophilic and clear cytoplasm, numerous mitotic figures (10 mitoses/10 HPF), and myometrial invasion. Other features are necrosis, vascular invasion with replacement of myometrial vessels by tumor cells and hemorrhage. The patient showed typical low serum ß-hCG levels and high serum humane placental lactogen (hPL) levels.

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.

Exaggerated placental site gestational trophoblastic disease: A case report / Philippine Journal of Obstetrics and Gynecology

@#Gestational trophoblastic diseases (GTDs) represent a unique group of lesions with an abnormal proliferation of trophoblasts. GTD can be divided into molar lesions and nonmolar lesions. Partial and complete hydatidiform moles and invasive moles are under molar lesions, whereas non‑molar lesions include choriocarcinomas and lesions that are derived from intermediate trophoblasts (ITs). These IT can be from the implantation site (exaggerated placental site [EPS] and placental site trophoblastic tumor) or from the chorionic type (placental site nodule and epithelioid trophoblastic tumor). EPS is a relatively uncommon form of GTD. It is a challenging condition for clinicians to diagnose because of the limited number of reported cases. From 1990 to April 2022, there were only 25 case reports published internationally, and this is the first local case report. Implantation site ITs (ISITs) are difficult to distinguish histologically. Immunohistochemical staining such as Ki‑67 can improve diagnostic accuracy by differentiating ISIT. Ki 67 will show staining of <1% in EPS. This is the case of a 25‑year‑old patient, G6P5 (5005), who experienced vaginal bleeding associated with pelvic and hypogastric pain after 13 weeks of missed menses. She was diagnosed with a molar pregnancy and underwent an emergency total abdominal hysterectomy with bilateral salpingectomy due to severe uterine bleeding. Histopathologic studies in this case showed diffuse and infiltrative growth of atypical monomorphic ITs arranged in sheets and cords, infiltrating and separating myometrial fibers. The uterine blood vessel wall was replaced with fibrinoid deposition, with areas of hemorrhages and necrosis. There were also chorionic villi. The histopathological findings revealed GTD arising from ITs, specifically EPS. This article describes the clinical presentation, diagnostic procedure, and management, together with histopathological observations and a review of related literature, of this rare GTD.

Nódulo del lecho placentario: una entidad benigna poco frecuente / Placental bed nodule: a rare benign entity

Antecedentes: El nódulo del lecho placentario es una lesión rara del trofoblasto intermedio que repre-senta una involución incompleta del sitio de implantación pla-centaria.Caso Clínico: Presentamos el caso de una mujer de 26 años que consultó por sangrado intermestrual y coitorragia, tras legrado uterino evacuador seis meses antes. Se realizó una biopsia por aspirado endometrial cuyo resultado fue de nódu-lo del lecho placentario. Se realizó histeroscopia en la que se visualizó un pólipo de 2 cm que fue resecado, siendo confirmada la histología tras la polipectomía.Conclusión: El diagnóstico de nódulo de sitio placentario es histológico y debe ser minucioso para poder diferenciar esta entidad de otras potenciales neoplasias tro-foblásticas gestacionales. Por lo que respecta a los factores de riesgo tanto la cesá-rea como el legrado uterino evacuador constituyen procedimientos que predispo-nen al desarrollo de esta entidad. (AU)

Background:The placental bed nodule is a rare lesion of the intermediate tro-phoblast that represents an incomplete involution of the placental implantation site. Clinical Case: We present the case of a 26-year-old woman who consulted for in-termestrual bleeding and coitorrhagia, after evacuating uterine curettage six months earlier. An endometrial aspirate biopsy was performed, the result of which was a nodule in the placental bed. Hysteroscopy was performed in which a 2-cm polyp was visualized, which was resected, and the histology was confirmed after polypec-tomy.Conclusion:The diagnosis of placental site nodule is histological and must be thorough in order to differentiate this entity from other potential gestational tro-phoblastic neoplasms. With regard to risk factors, both cesarean section and eva-cuating uterine curettage are procedures that predispose to the development of this entity. (AU)

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.

Placental site nodule: a clinicopathological study of 20 cases / 临床与实验病理学杂志

Purpose To investigate the clinical manifesta-tions and morphologic features of placental site nodules (PSNs), and its clinical significance. Methods Twenty patients diag-nosed as PSNs were collected, then a retrospective analysis was conducted, and the characteristics of clinical data and follow-up results were analyzed,including of clinical manifestations, ultra-sonographic evaluation, morphologic and immunohistochemical features. Results The age of patients ranged from 25 to 41 years (32. 48 ± 4. 77 years in average). Three fifths of patients had pregnancy history for at least two times and the interval time to the last pregnancy ranged from 5 to 37 months (15. 33 ± 8. 05 months on average). 15 (75% ) patients went to the hospital because of abnormal vaginal bleeding. In our study, most of the samples showed a membrane-like structure without definite nod-ule. Microscopically, single or multiple, well-circumscribed and oval small nodules were found in endometrial tissue. In most ca- ses, the hyalinization was generally uniform in the center of the nodules, more or less intermediate trophoblasts appeared on the edge of the nodules. Immunohistochemically, the strong diffuse expressed CK (AE1/AE3), CAM5. 2, EMA, GATA-3, Cyclin E and p63 were detected in most of all cases, and PLAP showed strong focal expression, α-inhibin and hPL showed faint focal expression, Ki-67 staining for proliferative index was less than 4% . Conclusion PSN is a benign lesion of the intermediate trophoblast at the chorionic leave. Some diseases including hya-linized decidua, epithelioid trophoblastic tumor, and squamous cell carcinoma with hyalinization need to be identified. Some im-munohistochemical markers may be certain helpful in distinguis-hing as necessary.

Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor.

OPINION STATEMENT: Placental site trophoblastic tumor (PSTT) is the least common and the most ambiguous gestational trophoblastic tumor. Presentation of PSTT may occur in the course of gestation or from 1 week to 14 years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion). The indicators of aggressive behavior for this tumor are not well established. Due to the rarity of this disease that usually affects women of childbearing potential, we aimed to review the current literature, to identify risk factors and the best conservative therapeutic choices among the cases described. We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. Based on selective inclusion/exclusion criteria, we considered eight papers eligible for the review. Five were case reports and three were retrospective studies. We extracted and organized data into three different categories depending on the main treatment used. A total of 12 cases were treated with laparotomy; in 5 cases, the treatment was not curative. Therefore, a total abdominal hysterectomy was needed. Five cases were treated successfully with a minimally invasive approach, 2 with uterine evacuation, 2 with hysteroscopic resection, and 1 with a combined hysteroscopic/laparoscopic resection. Only 1 case treated with exclusive chemotherapy proved curative for the patient. Preservation of fertility in PSTT patients of childbearing age should be considered and as showed by the abovementioned studies, is a possible and safe therapeutic choice. Laparotomy for local uterine resection with the modified Strassman approach could be offered in patients at clinical stage 1 that are very motivated to retain fertility, extensively informing the patient of the risks and benefits related to this choice.

Clinicopathological study of eight cases of atypical placental site nodule / 临床与实验病理学杂志

Purpose To investigate clinical and pathological features,diagnosis and differential diagnosis,treatment and prognosis of the atypical placental site nodules (APSN).Methods 8 cases of APSN were analyzed retrospectively.Their gross and microscopic features and immune phenotypes were observed,and the clinical histories and followed up were also reviewed.Results The patients were 26 to 42 years old (mean 32.8 years old).Clinical symptoms included occupation disease in uterine cavity,irregular vaginal bleeding,etc.Some patients were checked by hysteroscope and showed pale-yellow space-occupying lesions.Microscopically,the lesions consisted of single to multiple nodules or plaques of hyalinized extracelluar matrix,in which chorionic-type intermediate trophoblasts with mild atypia were haphasardly distributed.All the lesions were without myometrial invasion.Chorionic-type intermediate trophoblasts of the 3 cases expressed CK (AEI/AE3),p63,HLA-G,β-catenin,GATA-3 and the Ki-67 labelling index was 8％ ～ 15％.One of the 8 patients had a hysterectomy.Other seven patients were managed by lesionectomy under the hysteroscopy.8 patients were followed up with ultrasonography,curetting endometrium and endocervical mucosa and all of the patients were alive without the progress of the lesion.Conclusion APSN is easily misdiagnosed as squamous cell carcinoma,epithelioid leiomyosarcoma and other gestational trophoblastic diseases.It is important to understand the pathological features of APSN and we can avoid misdiagnosing for other benign or malignant tumours.Misdiagnosis will influence the clinical treatment.

Downregulation of miR-29a/b/c in placenta accreta inhibits apoptosis of implantation site intermediate trophoblast cells by targeting MCL1.

OBJECTIVE: Placenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. METHODS: Expression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction. Western blotting was used to analyze expression of the MCL1 protein in HTR8/SVneo trophoblast cells with altered expression of miR-29a/b/c. To determine their role in apoptosis, miR-29a/b/c were overexpressed in HTR-8/SVneo cells, and levels of apoptosis were analyzed by flow cytometry. Luciferase activity assays were used to determine whether MCL1 is a target gene of miR-29a/b/c. RESULTS: Expression of miR-29a/b/c was significantly lower in creta sites compared to noncreta sites (p = 0.018, 0.041, and 0.022, respectively), but expression of MCL1 was upregulated in creta sites (p = 0.039). MCL1 expression was significantly downregulated in HTR-8/SVneo cells overexpressing miR-29a/b/c (p = 0.002, 0.008, and 0.013, respectively). Luciferase activity assays revealed that miR-29a/b/c directly target the 3' untranslated region of MCL1 in 293T cells. Over-expression of miR-29a/b/c induced apoptosis in the HTR-8/SVneo trophoblast cell line. Moreover, histopathological evaluation revealed that the number of implantation site intermediate trophoblast (ISIT) cells was increased in creta sites and that these cells were positive for MCL1. CONCLUSIONS: Our results demonstrate that in placenta accreta, miR-29a/b/c inhibits apoptosis of ISIT cells by targeting MCL1. These findings provide new insights into the pathogenesis of placenta accreta.

Intermediate trophoblast--A distinctive, unique and often unrecognized population of trophoblastic cells.

The trophoblast forms an outer layer of the blastocyst in the developing placenta and fetal membrane chorion. It is composed of different types of cells. Two main cell types are cytotrophoblasts and syncytiotrophoblasts. The third type of trophoblastic cells, often "forgotten" in most of histological and embryological textbooks, is morphologically and functionally between the first and second one, therefore, it is called the intermediate trophoblast. There is no mention of it in the internationally accepted Terminologia Embryologica. This term is not universally used by pathologists as some of them prefer the name extravillous trophoblast. This review provides an overview of morphology, localization, function and immunohistochemistry of different types of intermediate trophoblast cells. An indisputable reason for categorizing these cells as a distinct group is the fact that they are a source of various forms of gestational trophoblastic disease.

Placental site trophoblastic tumor: A case report and literature review.

Here, we report a case of a placental site trophoblastic tumor (PSTT) in a 36-year-old Chinese woman 10 months after a normal pregnancy. Two months postpartum, the woman presented with abnormal vaginal discharge and her condition was overlooked by her local hospital. The woman did not receive further attention until a mass with a heterogeneous echo was found in an ultrasound examination eight months postpartum. The final diagnosis was confirmed by histological examinations in conjunction with immunohistochemical studies. Since the patient had potential risk factors, she was successfully treated with a hysterectomy and peri- and post-operative chemotherapy. The latest follow-up (16 months after diagnosis) was uneventful, and the patient exhibited no signs of recurrence or metastasis.

Placental Site Nodules & Plaques: A clinicopathologic analysis of 14 cases

Placental site nodules and plaques have been recently described to designated single or multiple, well-circumscribed, rounded lesions at the placental site, composed of viable or degenerating intermediate trophoblastic cells and extensive hyalinization between the cells. We described clinicopathologic findings of 14 cases of placental site nodules and plaques. The age of 14 patients ranged from 25 to 39(average 33) years and all of them had been pregnant in the past. Ten of them presented with vaginal spotting, which was preceded by recent pregnancy in only 3 cases. Three patients presented with secondary infertility and one with secondary infertility and vaginal spotting. Urine pregnancy tests were negative in all 14 cases at the time of presentation. Ultrasonographic examination disclosed abnormalities in only 3 cases and the remaining cases were normal. Hysterosalpingography was performed in 3 patients who presented with 2 degrees infertility and revealed moderate to severe intrauterine adhesions. Microscopically, chronic endometritis of varying degrees evidenced by plasma cells and eosinophiles were present in all cases and these were more prominent in the vicinity of the lesions. It is presumed that the placental site nodules and plaques are not sloughed at the time of menstruation and it may cause chronic endometritis or intrauterine adhesions at any time after previous delivery.

THE HISTOLOGICAL AND IMMUNOCYTOCHEMICAL OBSERVATION OF THE INTERMEDIATE TROPHOBLAST OF THE HUMAN DECIDUA AT THE IMPLANTATION SITE / 解剖学报

This report presents microscopic observation on morphological and immuno- cytochemical characteristics of the trophoblast cells of the human decidua at the implantation site in the first trimester pregnancy .The infiltration of a unique type of large cells different from cytotrophoblast (CT) and syncytotrophoblast (ST) was found in the decidua at the implantation site. These unique cells are termed inter- mediate trophoblast (IT). They are typically mononucleate, but may be binucleate or multinucleate. The mononucleate cells vary in shape from round, polyhedral spindle shaped. Their cytoplasm is typically abundant and eosinophilic or amphophilic. The nuclei may vary in size and shape. These cells usually distribute around the spiral arterioles, differse blood vessel wall, penetrate into the lumen, and even replace the blood vessel wall totally. Immunocytochemically, both these cells and ST are stained positive for HCG and HPL. However, the HCG-stained Cell population of IT.is much lower than that of ST,while the of HPL stained cell population of IT is significantly higher than that of ST.On the other hand,neither HCG nor HPL are positive in CT. The results of SP-1 ?-HCG usually go with those of HCG.in CT, ST and IT.The PAPP-A gives non specific staining result. It is believed that IT,with its distinct morphological and immunocytochemical feats,is regarded as a transitional form in the shift from CT to ST.

Proliferation of Mel-CAM defined IT in first-trimester villi and hydatidiform mole / 西安交通大学学报(医学版)

Objective To explore the relationship between Mel-CAM and adherence and invasion of trophoblastic cells and proliferation of Mel-CAM defined intermediate trophoblast.Methods Double immunohistochemical staining technique was used to detect the expression of Ki-67 in Mel-CAM defined intermediate trophoblast in human villi during the first trimester and hydatidiform mole.Results In this study there was a significantly stronger expression of Mel-CAM in hydatidiform mole than that in first-trimester villi (P