Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT.Copyright © 2016 Elsevier Inc. All rights reserved.

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

This study aims to estimate the population-based incidence of gestational trophoblastic diseases (GTDs) and to identify the characteristics of gestational trophoblastic neoplasia (GTN) in Japan.The annual number of GTD and live births from 1974 to 2018 were used to estimate the incidence of GTD. The data of 1,574 GTN cases from 1999 to 2018 were analyzed to identify the characteristics of low-risk GTN, high-risk GTN, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT).The incidence of hydatidiform mole was 2.02 per 1,000 live births on average which decreased from 1974 to 2008 and increased from 2009 to 2018. The incidence of low-risk GTN, high-risk GTN, PSTT, and ETT was 15.3, 3.4, 0.3, and 0.07 per 100,000 live births, respectively. The estimated incidence of post-molar GTN was 9.8% of molar patients. High-risk GTN was diagnosed more pathologically, had more various kinds of antecedent pregnancies, and had longer intervals after the antecedent pregnancy compared to low-risk GTN. Furthermore, 8.2% of high-risk GTN occurred after the subsequent non-molar pregnancy of hydatidiform mole. The cumulative percentage of developing high-risk GTN after hydatidiform mole reached 89.3% at the 60th month.The incidence of hydatidiform mole, low-risk GTN, high-risk GTN was 2.02 per 1,000 live births, 15.3 per 100,000 live births, and 3.4 per 100,000 live births, respectively. High-risk GTN was diagnosed more pathologically and later after the antecedent pregnancy than low-risk GTN. Following molar patients for five years is needed to improve the mortality of malignant GTN.Copyright © 2022. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.

Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT.A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records.Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104months. All patients with an interval >4years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy.This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4years following the antecedent pregnancy suggesting that surgery remains critical in disease control.Copyright © 2015 Elsevier Inc. All rights reserved.

Epithelioid trophoblastic tumor (ETT) is very rare; and therefore, a substantially increased data set is unlikely to be obtained in the near future. This analysis aimed to assess the effects of current management on clinical outcomes and to identify potential prognostic indicators in ETT.We applied a literature search using PubMed to analyze the clinical data of 78 published cases of ETT.Women with ETT present at reproductive age (mean ± SD, 37.1 ± 8.7 years) and have a slightly to moderately elevated serum β-human chorionic gonadotropin (median, 665 IU/L). Epithelioid trophoblastic tumor is frequently present in the lower uterine segment/cervix (26/58 cases) and can be misdiagnosed as squamous cell carcinoma (6/26). Lung is the most common extrauterine site of ETT (5/11 with uterine ETT and 10/20 without uterine ETT). Kaplan-Meier analysis indicates that chemotherapy (surgery with postoperative chemotherapy vs surgery alone) is associated with increased ETT relapse (P = 0.005), even after stratification by International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.008); but FIGO stage remains the only significant prognostic indicator for ETT (P = 0.015).This analysis confirms the hypothetical chemotherapy resistance and prognostic value of FIGO staging in ETT. These findings remain tentative given the small data set available for analysis and the reporting bias from these published cases; however, they may confer a risk-adapted therapy. Finally, both gynecologists and pathologists should be alert to the potential misdiagnosis of squamous cell carcinoma when ETT is present in the lower uterine segment/cervix.

Epithelioid trophoblastic tumor is a rare gestational trophoblastic neoplasm usually presenting in women of reproductive age, with a history of a prior gestational event. Its presentation in postmenopausal women is extremely rare. Immunohistochemical staining is a helpful aid to distinguish epithelioid trophoblastic tumor from other gestational trophoblastic neoplasms. Correct diagnosis is crucial for clinical management that can vary according to the type of gestational trophoblastic neoplasm.We report the case of a 63-year-old postmenopausal woman 33 years after her last full-term pregnancy and another case of a 57-year-old postmenopausal woman who had had a first-trimester abortion 30 years previously as her last gestational event, both presenting cervical epithelioid trophoblastic tumors. In both cases, immunohistochemistry played an important role in differentiating this entity from other gestational trophoblastic neoplasms. Surgery was the primary treatment in both cases. The first patient remained disease-free and died 5 years later due to a rectal adenocarcinoma, and the second patient remains disease-free at publication.In both cases, the hysterectomy specimen confirmed the presence of two large epithelioid trophoblastic tumors arising in the endocervix and lower uterine segment with no extrauterine disease. Nuclear positivity for p63 allowed differentiation from a placental site trophoblastic tumor. The Ki67 proliferative index was 20% and 35%, respectively.Epithelioid trophoblastic tumors may occur a long time after a prior gestational event and should even be excluded in postmenopausal women with uterine masses. Immunohistochemical staining is helpful to make the differential diagnosis with other gestational trophoblastic neoplasms.

An intermediate trophoblast is a distinctive trophoblastic cell population from which four trophoblastic lesions are thought to arise: exaggerated placental site (EPS), placental site nodule (PSN), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). EPSs and PSTTs are related to the differentiation of the intermediate trophoblast in the implantation site (implantation site intermediate trophoblast), whereas PSNs and ETTs are related to the intermediate trophoblast of the chorion laeve (chorionic-type intermediate trophoblast). EPSs and PSNs are nonneoplastic lesions, whereas PSTTs and ETTs are neoplasms with a potential for local invasion and metastasis. Microscopically, intermediate trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors, but an appreciation of the morphologic features and immunophenotype allows their diagnosis to be relatively straightforward in most instances. Correct diagnosis is important because each of these lesions may require different therapeutic approaches.

The WHO Classification of Gestational Trophoblastic Tumors classifies placental site nodule (PSN) as a benign tumor-like trophoblastic neoplasm. Cases of PSN with atypical features were described [atypical placental site nodule (APSN)] and we started registering APSN in our unit in 2005. The aim of this study is to present our initial experience with these lesions. The Trophoblastic Disease Unit database was searched to identify all patients who were either referred with, or on review were diagnosed with, APSN from September 2005 to May 2013. Case notes and the pathology findings for these patients were retrieved and reviewed. A total of 21 cases of APSN were included, 3 of which were associated with gestational trophoblastic neoplasm on follow-up or review. Malignant gestational trophoblastic disease was associated with 3/21 (14%) cases of APSN, either concurrently or developing/manifesting within 16 mo of APSN diagnosis. None of these patients had raised serum hCG levels either at presentation or follow-up. Presence of APSN should indicate a thorough clinical and radiologic investigation and follow-up if diagnosed on curettage specimens. With increased recognition of this entity and corresponding larger series with longer follow-up, more accurate patient counseling will be possible.

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

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.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.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.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.Copyright © 2019 Elsevier Inc. All rights reserved.

Epithelioid trophoblastic tumour (ETT) is a rare condition with a paucity of cases reported in the literature.We present two unusual cases of ETT. Both patients presented with markedly elevated hCG levels; one case presented with a mass in the gallbladder, the other with extensive metastases; and both patients died from disease.To gain a greater understanding of the nature and progression of this disease, reporting of cases in the literature should be thorough and contain detailed information on patient clinicopathological characteristics and treatment. To enable identification of prognostic factors, long-term follow up must also be reported because recurrence can be both late and complex.

Placental site trophoblastic tumor [PSTT] and epithelioid trophoblastic tumor [ETT] are the rarest gestational trophoblastic neoplasias, developing from intermediate trophoblast of the implantation site and chorion leave, respectively. PSTT and ETT share some clinical-pathological features, such as slow growth rates, early stage at presentation, relatively low βhCG levels and poor response to chemotherapy. The mortality rate ranges from 6.5% to 27% for PSTT and from 10% to 24.2% for ETT. Advanced stage, long interval between antecedent pregnancy and diagnosis, and presence of clear cells are the independent prognostic variables for PSTT, and they may be similar for ETT. Hysterectomy can represent the only therapy for early disease, whereas adjuvant chemotherapy should be reserved to patients with poor risk factors, such as an interval from the antecedent pregnancy >4 years, deep myometrial invasion or serosal involvement. Few cases of fertility-sparing treatment in young women have been reported. An individualized multidisciplinary approach, including chemotherapy and debulking surgery with abdominal and/or extra-abdominal procedures, is warranted for advanced disease. EP/EMA and TP/TE are the preferred regimens in this setting. Immunohistochemistry has sometimes shown expression of EGFR, VEGF, MAPK, PDGF-R and PD-L1, and therefore investigational studies on biological agents targeting these molecules are strongly warranted for chemotherapy resistant-disease.Copyright © 2019 Elsevier Inc. All rights reserved.

Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT.Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS).Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively).Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN.Copyright © 2018 Elsevier Inc. All rights reserved.

To investigate the clinicopathological characteristics, diagnoses, treatments, and outcomes of a special type of gestational trophoblastic neoplasia (GTN) which only has extrauterine metastases without uterine primary lesions.

To elucidate the clinicopathological characteristics and oncological outcomes of a special group of patients with gestational trophoblastic neoplasia (GTN) initially presenting with isolated lung lesions, elevated human chorionic gonadotropin (hCG) levels, and unobserved pelvic lesions.Overall, 2358 patients with GTN treated at our hospital between 2000 and 2023 were retrospectively reviewed, and 40 patients were evaluated. The demographic characteristics, clinicopathological features, treatment data, and follow-up information of each patient were collected. The primary outcome was progression free survival. Kaplan-Meier analysis and univariate and multivariate Cox proportional hazard analyses were used to identify the risk factors.Among the 40 patients, 95.0 % had solitary lung lesions, with a median size of 1.9 cm. Moreover, 72.5 % of patients were pathologically confirmed as epithelioid trophoblastic tumors (ETT). During a median follow-up period of 53.5 months (range, 2-143), 11 patients experienced recurrence, including all patients who received chemotherapy alone as the initial treatment, and no death was observed. Relapse treatment involved lung segmentectomy and lobectomy combined with chemotherapy and immunotherapy. Univariate and multivariate Cox analyses identified comparing with surgery±chemotherapy, chemotherapy alone as the initial treatment (hazard ratio [HR] =7.738, 95 % confidence interval [CI] 1.698-35.269, P = 0.008) as independent risk factor for recurrence.In patients with a history of pregnancy exhibiting isolated pulmonary lesions, elevated hCG levels (mostly <1000 mIU/mL), and unobserved pelvic lesions, ETT should be considered first. Surgical resection of lung lesion is crucial for optimal management. When chemotherapy is considered, multidrug regimen is recommended.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

While epithelioid trophoblastic tumour (ETT) primarily arises from the uterus, cases have been increasingly documented at extrauterine sites, originating from an ectopic gestation or presenting as a metastatic tumour, leading to the major differential diagnosis of somatic carcinoma with trophoblastic differentiation. The precise separation of a gestational trophoblastic tumour from its somatic carcinoma mimics is highly relevant and crucial for patient management and prognosis.

Gestational trophoblastic disease (GTD) is a heterogeneous group of disorders characterised by abnormal proliferation of trophoblastic tissue. Since GTD and its malignant sequel gestational trophoblastic neoplasia (GTN) are rare diseases, little evidence is available from randomised controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centres within countries. One of the goals of the 'European Organisation for Treatment of Trophoblastic Diseases' (EOTTD) is to harmonise treatment in Europe. To provide a basis for European standardisation of definitions, treatment and follow-up protocols in GTD, we composed a set of guidelines for minimal requirements and optimal management of GTD.Members from each EOTTD country attended multiple workshops during annual EOTTD meetings. Clinical guidelines were formulated by consensus and evidence where available. The following guidelines were discussed: diagnostics of GTD and GTN, treatment of low-risk GTN, high-risk GTN, ultra-high-risk GTN, placental site and epithelioid trophoblastic tumours and follow-up.Between 40 and 65 EOTTD members from 17 European countries and 7 non-European countries attended the clinical workshops held on 6 occasions. Flow diagrams for patient management were composed to display minimum and best practice for most treatment situations. New agreed definitions of recurrence and chemotherapy resistance were formulated.Despite the many differences between and within the participating countries, an important step in uniform treatment of GTD and GTN within Europe was made by the Clinical Working Party of the EOTTD. This is an example on how guidelines and harmonisation can be achieved within international networks.Copyright © 2020 Elsevier Ltd. All rights reserved.

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.

Gestational trophoblastic disease (GTD) is subclassified into hydatidiform mole (HM), gestational trophoblastic tumours (GTT) and non-neoplastic trophoblastic lesions. HM, partial and complete, originate from villous trophoblast and are considered as preneoplastic conditions. The risk for the development of persistent GTD, mostly as invasive HM, ranges from 0.5% to 20%, which depends on the type of molar pregnancy. The risk of development of trophoblastic tumour after PHM is <0.5% and 2%-3% after CHM. GTT represent a spectrum of neoplasms that originates from the intermediate, largely extravillous, trophoblast and these include choriocarcinoma (CC), placental site trophoblastic tumour (PSTT), epithelioid trophoblastic tumour (ETT) and mixed trophoblastic tumour. Among tumour like conditions, exaggerated placental site reaction (EPSR) and placental site nodule (PSN) (s)/plaque (s) are included. The morphological appearances of HM can be mimicked by abnormal (non-molar) villous lesions, and similarly, GTT can be mimicked both by non-malignant tumour-like conditions and non-gestational tumours with trophoblastic differentiation, which add to the diagnostic dilemma of these rare conditions. GTT have a favourable prognosis and better response to specific chemotherapeutic regimens when compared with non-gestational malignant genital tract neoplasms. The correct diagnosis and classification of these rare conditions are therefore important. This article focusses on the morphological appearances, immunocytochemistry as an aid in the diagnosis and the changes in current WHO classification of GTDs (WHO 2020).Copyright © 2021. Published by Elsevier Ltd.

Mixed gestational trophoblastic neoplasia (GTN) is a rare occurrence that refers to the coexistence of choriocarcinoma and/or placental site trophoblastic tumor and/or epithelioid trophoblastic tumor. The diagnosis and management of mixed GTN are challenging. We investigated the clinicopathological characteristics, diagnoses, treatments, and outcomes of patients with mixed GTN. The medical records and pathological sections of 16 patients with mixed GTN who were treated at Peking Union Medical College Hospital and The Second Xiangya Hospital of Central South University between January 2012 and December 2018 were reviewed. Pretreatment serum human chorionic gonadotropin (hCG) levels ranged from 180 to 625,024 IU/L, and were >10,000 IU/L in 14 of the 16 patients, none of whom were diagnosed correctly at initial presentation. Two patients were diagnosed with choriocarcinoma coexisting with intermediate trophoblastic tumor (ITT) through dilation and curettage (D&C) before treatment. Another 5 patients were histologically confirmed to have placental site trophoblastic tumor (PSTT) by D&C but final pathological findings showed mixed PSTT and choriocarcinoma at subsequent hysterectomy. Seven post-chemotherapy patients with an initial clinical diagnosis of choriocarcinoma underwent surgery because of chemoresistance and their pathological findings revealed coexisting ITT. The remaining 2 patients were found to have choriocarcinoma coexisting with ITT following cervical biopsy and pulmonary lobectomy. All patients received chemotherapy: 14 underwent surgery combined with chemotherapy and 2 received chemotherapy alone to preserve fertility. Other than 1 patient who died of disease progression, 15 patients (93.8%) achieved complete remission (CR) after treatment, although 5 (33.3%) relapsed. Of these 5 patients with relapse, 3 achieved CR after additional treatment, 1 was receiving an immune checkpoint inhibitor, and 1 was lost to follow-up after refusing further therapy. Mixed GTN is difficult to diagnose on initial presentation. Overlap of the ITT component should be considered in refractory chemoresistant choriocarcinoma. Coexistence of choriocarcinoma should be suspected in ITT patients with high hCG levels. Surgery combined with chemotherapy is optimal treatment for choriocarcinoma mixed with ITT.Copyright © 2019 Kong, Tao, Zong, Yang, Wan, Wang and Xiang.

Gestational trophoblastic disease (GTD) is a spectrum of both benign and malignant gestational tumors, including hydatidiform mole (complete and partial), invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The latter four entities are referred to as gestational trophoblastic neoplasia (GTN). These conditions are aggressive with a propensity to widely metastasize. GTN can result in significant morbidity and mortality if left untreated. Early diagnosis of GTD is essential for prompt and successful management while preserving fertility. Initial diagnosis of GTD is based on a multifactorial approach consisting of clinical features, serial quantitative human chorionic gonadotropin (β-hCG) titers, and imaging findings. Ultrasonography (US) is the modality of choice for initial diagnosis of complete hydatidiform mole and can provide an invaluable means of local surveillance after treatment. The performance of US in diagnosing all molar pregnancies is surprisingly poor, predominantly due to the difficulty in differentiating partial hydatidiform mole from nonmolar abortion and retained products of conception. While GTN after a molar pregnancy is usually diagnosed with serial β-hCG titers, imaging plays an important role in evaluation of local extent of disease and systemic surveillance. Imaging also plays a crucial role in detection and management of complications, such as uterine and pulmonary arteriovenous fistulas. Familiarity with the pathogenesis, classification, imaging features, and treatment of these tumors can aid in radiologic diagnosis and guide appropriate management. RSNA, 2017.

There is no consensus for the management of epithelioid trophoblastic tumor (ETT) up to date.

This study aimed to investigate the clinicopathologic features and prognostic factor in patients with epithelioid trophoblastic tumor (ETT).From January 2002 to June 2010, the clinicopathologic characteristics, treatments, outcomes, and prognosis of 9 patients with ETT were analyzed retrospectively in our institution.Of 9 patients, 8 (88.9%) had metastases. The histopathologic results of 7 patients (77.8%) with poor outcomes showed diffuse multifocal disease within the uterus, full-thickness myometrial invasion, uterine serosal involvement, and extensive necrosis. The size of the uterus exceeded 8 weeks of gestation in 7 patients. Two of them had poorly differentiated carcinoma. All patients were treated with multimodality treatment that combined with surgery and chemotherapy. After the initial treatments, 5 patients with International Federation of Gynecology and Obstetrics stage I achieved complete remission (CR), 1 patient achieved partial remission, and 3 patients (33.3%) had no response to treatments and died of progressive disease. After following up for 6 to 107 months (mean, 24 months), 4 (44.4%) of the 5 patients with initial CR had relapse: 3 of them achieved a second CR and the other 1 was under treatment.Epithelioid trophoblastic tumor is a rare and special type of intermediate trophoblastic tumor with a high degree of malignancy and poor prognosis. Multifocal lesions in bulky uterus, combined with full-thickness myometrial invasion and uterine serosal involvement, could be related to poor outcomes in patients with ETT. The prognosis of ETT could be improved by increasing diagnostic accuracy, identifying prognostic factor at an early stage, and providing early intensive multimodality treatment to patients with poor prognostic factors.

Placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT) are the rarest subtypes of gestational trophoblastic disease (GTD). Their diagnosis is complicated and lacks specific and sensitive tumour markers. They are slow-growing tumours and can occur months to years after any type of antecedent pregnancy. The primary treatment for localised disease is hysterectomy. However, extra-uterine invasion and/or metastasis occur in about one-third of cases and still cause death in a small number. Most patients are young; hence, fertility preservation is a consideration. The major obstacle for prognosis is chemotherapy resistance. The current understanding of these tumours remains elusive and no randomized controlled trials have been done. Even those centres treating a large number of patients with GTD will infrequently manage PSTT/ETT. In this review, we assess progress in the understanding of the disease and discuss four main clinical challenges - establishing conformity of practice, devising a risk-adapted approach to clinical management, establishing long-term follow-up data and evaluating therapies for poor prognosis and multi drug-resistant patients.Copyright © 2020. Published by Elsevier Ltd.

This study aimed to systematically review the existing literature on epithelioid trophoblastic tumors (ETTs), the rarest type of gestational trophoblastic neoplasia.

To review the clinicopathologic features of five patients with epithelioid trophoblastic tumor (ETT).Characteristics of patients diagnosed with ETT in 2000 to 2012 were reviewed.Among 190 patients with gestational trophoblastic neoplasia (GTN), two had pure ETT and three had mixed ETT and choriocarcinoma. The median age was 32.5 years. All the patients had localized disease in the uterus. One patient with pure ETT had a recurrence in the ureter 6 years after the initial treatment. Another patient with pure ETT had two full-term deliveries after fertility-sparing surgery. The three patients with mixed tumors had chemotherapy for GTN before their diseases were completely treated by hysterectomy. At a median follow-up of 102 months, all patients survived.ETT is indolent. Recurrence can happen, but the risk factors are not clear. When patients with GTN fail to respond to chemotherapy, the possibility of mixed GTN should be considered.

The objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs).Databases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS).HDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred.Despite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy.Copyright © 2019 Elsevier Ltd. All rights reserved.

The B7 family check‐point molecules are potential therapeutic targets in cancer immunotherapy. However, their expression status in human gestational trophoblastic neoplasia (GTN) remains unknown. We investigated the expression profiles of the B7 family check‐point proteins PD‐L1, PD‐L2, B7‐H3, B7‐H4, VISTA and B7‐H6 in GTN and their clinical significance.

Epithelioid trophoblastic tumours are rare neoplasms showing differentiation towards the chorion leave-type intermediate cytotrophoblast, with only a handful of cases being reported in the literature. These tumours are slow-growing and are typically confined to the uterus for extended periods of time. While the pathogenesis is unclear, they are thought to arise from a remnant intermediate trophoblast originating from prior normal pregnancies or, less frequently, gestational trophoblastic tumours. A protracted time period between the gestational event and tumour development is typical. This case describes a 49-year-old previously healthy female who presented with a completely asymptomatic uterine mass, discovered incidentally during a routine gynaecological assessment. The pathological analysis of the hysterectomy specimen confirmed an epithelioid trophoblastic tumour, involving the uterus and cervix. This is a rare gynaecological tumour. A comparative short tandem repeat analysis revealed genetic similarities to a previous healthy gestation seventeen years prior. She was successful treated with adjuvant pembrolizumab, with no evidence of disease recurrence to date.

The aim is to analyze the clinical characteristics of intermediate trophoblastic tumor (ITT).12 cases diagnosed at Qilu Hospital of Shandong University from January 2005 to December 2016 were investigated. Additionally, 50 cases were selected from MEDLINE and CBM databases between January 2010 and December 2016. The clinical data extracted from those aforementioned 62 cases were analyzed.There were 42 cases with placental site trophoblastic tumor (PSTT), 19 cases with epithelioid trophoblastic tumor (ETT), and 1 case with mixed type (PSTT and ETT). No significant differences were found between PSTT and ETT in terms of age, type of antecedent pregnancy, main complaints, serum β-hCG peak, FIGO stage or prognosis. However, the interval between antecedent pregnancy and the onset was longer in ETT than in PSTT (P = 0.01). FIGO stage was irrelevant to serum β-hCG (P = 0.263). All 62 cases underwent surgeries and seven cases preserved fertility. Fifteen cases with high risk factors were not treated with adjuvant chemotherapy. Univariate analysis results showed that age ≧ 40 years, serum β-hCG peak ≧ 1000 IU/L and nonstandard treatment were associated with poor survival, but only age remained significant on multivariate analysis for ITT (P = 0.018).PSTT and ETT have similar clinical characteristics generally. Serum β-hCG can not reflect the progress of ITT. Age ≧ 40 years is the independent high risk factor for ITT.

Epithelioid trophoblastic tumor (ETT) is the rarest gestational trophoblastic tumor, with poor response to chemotherapy. Hysterectomy, as the cornerstone therapy for early ETT, is particularly challenging in reproductive-age women who often have a strong desire for fertility preservation. The management of extra-uterine ETT could be even more complicated and inconsistent. Here we reported a case of isolated ETT lesions in lungs managed with thoracic surgery without hysterectomy.