Trophoblastic tumors: ultrastructural comparison of choriocarcinoma and placental-site trophoblastic tumor

Ten trophoblastic tumors, including seven classical choriocarcinomas, two choriocarcinomas with atypical histology, and one placental-site trophoblastic tumor (PSTT), were studied to compare their fine structural features. Ultrastructurally, the classical choriocarcinomas showed well-defined cytotrophoblasts and syncytiotrophoblasts. The cytotrophoblasts were primitive epithelial cells, while the syncytiotrophoblasts were complex cells with multiple nuclei and dense cytoplasm containing dilated endoplasmic reticulum, lysosomes, vesicles, and tonofilaments. The syncytiotrophoblast cell membranes often contained numerous microvilli. In the choriocarcinomas, scattered intermediate trophoblasts showed features transitional between the cytotrophoblasts and the syncytiotrophoblasts, with moderately complex cytoplasm containing some of the organelles found in the syncytiotrophoblasts. Histologically, the atypical choriocarcinomas showed a predominance of mononucleate and binucleate cells and indistinct syncytiotrophoblasts. Ultrastructurally, these atypical tumors were composed largely of intermediate trophoblasts, yet contained scattered syncytiotrophoblasts with microvilli in compressed aggregates. The PSTT was composed primarily of intermediate trophoblasts that contained prominent paranuclear filaments not seen in the intermediate trophoblasts of the choriocarcinomas. Rare cells resembling syncytiotrophoblasts were found in the PSTT, but no cytotrophoblasts were observed. Immunoreactivity for human chorionic gonadotropin and human placental lactogen was found in the intermediate trophoblasts and syncytiotrophoblasts of both the choriocarcinomas and the PSTT, demonstrating functional homology between these tumors despite some ultrastructural differences. These results demonstrate ultrastructural features of trophoblastic cells that correlate with the morphologic diversity seen in these tumors by light microscopy. Furthermore, the comparisons suggest that the PSTT is composed of a distinct form of intermediate trophoblast that appears to reflect its origin from the extravillous trophoblast.     

Gestationsbedingte Trophoblasterkrankungen

The non-villous forms of gestational trophoblastic disease (GTD) include a wide range of morphologic different lesions and cover a wide range of differential diagnosis. Choriocarcinomas (CCA) represent the most malignant form displaying a dimorphic pattern with proliferation of syncytio- and zytotrophoblast. An early start of chemotherapy is of great prognostic impact. Placental site nodule (PSN) and exaggerated placental site (EPS) are non-neoplastic lesions of the intermediate trophoblast without tumorous appearance, whereas placental site trophoblastic tumor (PSTT) and epitheloid trophoblastic tumor (ETT) represent tumorous neoplasms with a potential for local invasion and metastases. PSNs are incidental findings of highly polymorphic cells. In EPS chorionic villi are almost present, endometrial glands and spiral arteries are completely engulfed by intermediate trophoblastic cells without necroses. In PSTT the monomorphic, occasional multinucleated giant cells separating individual muscle fibers and charactersitically blood vessel walls are extensively replaced by trophoblastic cells and fibrinoid material. The ETT consists large necrotic areas with hyalinisation. Typically small blood vessels with preserved walls are located within the center of glycogen-rich monomorphous proliferation of trophoblastic cells.     

中间型滋养细胞肿瘤的临床病理分析

目的探讨中间型滋养细胞（IT）源性肿瘤即胎盘部位滋养叶细胞肿瘤（PSTT）及上皮样滋养细胞肿瘤（ETT）临床病理特征及免疫表型表达特点、诊断与预后。方法北京妇产医院1959-2005年中,因恶性滋养叶疾病住院治疗患者共1012例,从中筛选6例PSTT及1例ETT,对其临床特征、病理诊断要点及免疫组织化学（SP法）结果进行分析,抗体包括CK18、胎盘催乳素（hPL）、人绒毛膜促性腺激素（hCG）、Mel—CAM（CDl46）及胎盘碱性磷酸酶（PLAP）。对照组为20例附有底蜕膜的早期绒毛及20例见有着床部位反应的葡萄胎。结果平均年龄PSTT为32．4岁,ETT为36岁;症状主要为阴道不规则出血和闭经;术前检查hCG呈正常→轻度→中度增高趋势,1例睾酮明显增高。5例PSTT术前行刮宫及宫腔镜切取标本之确诊率为3／5。镜下PSTT瘤细胞呈单个、条索状或片状浸润于肌纤维间,将单个或一束肌纤维分离;ETT则显示岛屿状细胞群位于玻璃样物及坏死物中,呈地图样结构。治疗手段以子宫切除术或术后辅以化疗为主。随访时间14个月至19年,其中1例PSTT术后5个月发生胰腺转移,单纯化疗PSTT患者疗效尚不能肯定,其余均无复发。结论PSTT与ETT分别为发生于着床部位IT及绒毛膜类型IT,二者有不同病理形态学,免疫组织化学特征性表达可辅助诊断和鉴别诊断;术前诊断性刮宫病理诊断具有重要临床意义;PSTT与ETT显示相同的生物学行为和预后。     

Placental Site Trophoblastic Tumor of the Uterus: An Ultrastructural and Immunohistochemical Study and Immunohistochemical Study

Ultrastructural and immunohistochemical studies in a case of placental site trophoblastic tumor (PSTT) of the uterus were carried out in order to define the nature of the abnormal tissue. By electron microscopy, the large cells, whether mononuclear or syncytial, showed numerous ribosomes, prominent Golgi elements, and abundant rough endoplasmic reticulum (RER) filled with granular material. Pseudopods and microvilli were found on the cell surfaces. By immunofluorescence, the well-developed filamentous cyto-skeleton proved to be actin-rich. (3-HCG (human chorionic gonadotropin) and SP, (0,-specific pregnancy glycoprotein) were detected in only a few tumor cells, whereas most of them stained for HPL (human placental lactogen). The present results show the secretory nature of most of the tumor cells, which resemble the intermediate trophoblast of the placental bed. Together with previous studies, they suggest that a varying spectrum of syncytiotrophoblastic differentiation exists in PSTT. Decidual, myometrial, or histiocytic cells do not seem involved in the histogenesis of the tumor tissue.     

Placental site nodule and characterization of distinctive types of intermediate trophoblast.

Both placental site nodule and exaggerated placental site are described as being composed of intermediate trophoblast (IT), yet their morphological features and clinical presentation differ significantly. This study was undertaken to evaluate the morphological and immunohistochemical features of trophoblastic cells in placental site nodules and compare them with the trophoblastic cells in exaggerated placental sites as well as in different anatomic locations in the developing placenta to evaluate these differences. Forty-two placental site nodules, 20 abortus specimens ranging from 3 to 13 weeks, 8 second- and 10 third-trimester placentas, and 12 exaggerated placental sites were studied by conventional light microscopy and immunohistochemistry. This analysis showed that the trophoblastic cells in the placental site nodule closely resemble those in the chorion laeve. We have designated these cells "chorionic-type IT cells." They are composed of two populations of cells, one with eosinophilic and the other with clear (glycogen-rich) cytoplasm. The eosinophilic cells tended to be larger with more pleomorphic nuclei, whereas the clear cells were smaller with more uniform nuclei. Chorionic-type IT cells in the chorion laeve and placental site nodule were diffusely positive for placental alkaline phosphatase but were only focally positive or negative for human placental lactogen (hPL), Mel-CAM (CD146), and oncofetal fibronectin. In contrast, hPL, Mel-CAM, and oncofetal fibronectin were diffusely expressed in IT cells in the placental site, both normal and exaggerated. The chorionic-type IT cells in placental site nodule and chorion laeve showed mild proliferative activity as indicated by an increased Ki-67 labeling index (3% to 10%). In contrast, the Ki-67 labeling index in normal and exaggerated implantation sites was zero. The morphological and immunohistochemical features of chorionic-type IT cells contrast with the IT cells in the implantation site that we have designated "implantation site IT cells." Both types of IT cells develop from a population of trophoblastic cells in the trophoblastic columns that we have tentatively termed "villous IT cells." Four of 42 placental site nodules were larger (>5 mm) than the remainder and showed transitional features between a typical placental site nodule and an epithelioid trophoblastic tumor, a recently described distinctive gestational trophoblastic tumor. There were no recurrences among the placental site nodules regardless of size. All placental site nodules were immunoreactive for inhibin-alpha and cytokeratin 18, whereas 33 squamous cell carcinomas of the cervix, which can at times be confused with placental site nodules, were negative. In conclusion, there appear to be three subpopulations of IT cells with distinctive morphological and immunohistochemical features. Different subpopulations can be related to different trophoblastic lesions: implantation site IT cells to an exaggerated placental site and its neoplastic counterpart, placental site trophoblastic tumor and chorionic-type IT cells to a placental site nodule and its neoplastic counterpart, epithelioid trophoblastic tumor.     

胎盘部位滋养细胞肿瘤的临床病理特点及鉴别诊断

目的了解胎盘部位滋养细胞肿瘤（ＰＳＴＴ）的临床病理特点及其鉴别诊断要点。方法对５例ＰＳＴＴ进行临床,光镜,电镜及免疫组化研究,并同时对比观察１０例绒癌及２例过度的胎盘部位反应（ＥＰＳ）。结果ＰＳＴＴ见于育龄妇女,前次妊娠多为足月产,常见症状为闭经及／或阴道出血。血清绒毛膜促性腺激素（ｈＣＧ）可有轻～中度升高。光镜下瘤细胞组成单一,仅见中间型滋养细胞,成片状,条索状穿插浸润于子宫平滑肌束间。血管浸润明显,却少有出血或坏死。分裂相少见。电镜下瘤细胞核周有丰富的中间丝。免疫组化表现为胎盘催乳素（ｈＰＬ）阳性而ｈＣＧ多为阴性。结论ＰＳＴＴ为一少见的滋养细胞肿瘤,具有独特的光镜,电镜及免疫组化特点,这些特点可与其它滋养细胞疾病鉴别     

Expression of merosin, a tissue-specific basement membrane protein, in the intermediate trophoblast cells of choriocarcinoma and placenta

Merosin is a novel tissue-specific basement membrane-associated protein found in basement membranes of trophoblast, striated muscle and Schwann cells. In placental extracts, the immuno-reactivity for merosin was detected in a protein band of 80 kilodaltons, and a 65 kilodalton polypeptide fragment of merosin could be isolated from proteolytic digests of placenta. In the present study, we describe the expression of merosin in human choriocarcinomas and normal placentas using immunoperoxidase staining of paraffin-embedded tissues. All five choriocarcinomas studied show immunoreactivity for merosin. Tumor cells, exhibiting the morphology typical of the intermediate trophoblast, stained distinctly for merosin. The cytotrophoblast and syncytiotrophoblast cells in these tumors showed negligible or no staining. In second and third trimester human placentas, merosin immunoreactivity was found in large extravillar mononuclear trophoblast cells of the basal plate as well as in the trophoblast basement membranes of the chorionic villi. The results indicate that merosin is mainly expressed in the intermediate trophoblast cells of both neoplastic and normal origin, whereas almost no expression is seen in cytotrophoblast and syncytiotrophoblast. Consequently, it is suggested that the intermediate trophoblast may represent a third, independently differentiated trophoblastic cell type.     

Promyelocytic leukaemia (PML) protein expression in human placenta and choriocarcinoma

Promyelocytic leukaemia (PML) protein, the product of the pml gene, is heterogeneously expressed in various normal and neoplastic tissues, and the fusion of the pml gene with retinoic acid receptor-alpha is believed to be a central mechanism in acute PML tumourigenesis. As PML is important for controlling major cellular processes, such as growth and differentiation, it is believed that it plays an important role during human gestation. The human placenta is a critical organ for the maintenance of gestation, but the expression pattern and functional significance of PML in the placenta have not been documented. The present study has therefore investigated the expression of PML in the human placenta and in choriocarcinoma, and has observed the biological effects following the overexpression of PML in choriocarcinoma cell lines (BeWo and JEG-3). In the human placenta, PML expression was readily found in villous stromal fibroblasts, capillary endothelial cells, Hofbauer cells, and occasionally in amnion cells. Moreover, immunoblotting of placental lysates demonstrated increased PML expression with increasing gestation. Interestingly, PML expression was confined to intermediate trophoblasts and syncytiotrophoblastic giant cells at the placental site (placental site giant cells) in the trophoblastic cell population. Intermediate trophoblasts at non-placental sites, and villous cytotrophoblasts and syncytiotrophoblasts consistently did not express PML. Further screening of PML expression in hydatidiform moles (n = 4) and choriocarcinomas (n = 7) also revealed selective PML expression in intermediate trophoblastic cells and syncytiotrophoblastic cells, but not in the cytotrophoblastic populations, which corresponds well with observations in the placental bed. Adenoviral transduction of PML resulted in a marked reduction in cell growth in both choriocarcinoma cell lines, which was associated with increased apoptosis. The findings of the present study strongly suggest that PML plays an important role in human placental development and growth, and in the pathobiology of trophoblasts and trophoblastic neoplasia.     

Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells

We recently identified two novel aminopeptidases, placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP). Enzymatically, P-LAP degrades oxytocin, vasopressin, and angiotensin III, while A-LAP degrades angiotensin II and kallidin. In this study we investigated the expression and localization of P-LAP and A-LAP in human trophoblastic cells in the normal placenta (n = 26), gestational choriocarcinoma (n = 8), and placental site trophoblastic tumor (n = 3). On immunoblot analysis both P-LAP and A-LAP proteins were detected in normal placenta and five choriocarcinoma tissues, as well as in two choriocarcinoma cell lines. Immunohistochemical staining of normal placental tissues demonstrated that P-LAP was not only localized in villous syncytiotrophoblasts but also highly expressed in extravillous trophoblasts (EVTs) invading the decidua or maternal spiral arteries. The expression level of P-LAP on these invasive EVTs reached a maximum during the late first to second trimesters of pregnancy, and it decreased in the third trimester. Similarly, A-LAP was strongly expressed in EVTs invading the decidua or spiral arteries in the second trimester of pregnancy, while it was weakly or moderately expressed in villous cytotrophoblasts or EVTs located in the cell columns. These two aminopeptidases were more strongly expressed in all eight choriocarcinomas and three placental site trophoblastic tumors and mainly localized to the intermediate-type trophoblastic tumor cells invading the uterine myometrium or stromal vessels. In summary P-LAP and A-LAP were predominantly expressed in the invasive phenotype of EVTs during placentation, as well as in the invasive tumor cells of trophoblastic neoplasms. These results suggest the involvement of these aminopeptidases in invasiveness of both normal and malignant intermediate-type trophoblasts possibly through degradation of specific peptide substrates.     

PLAGENTAL-SITE TROPHOBLASTIC TUMOR OF THE UTERUS: Clinicopathological and Immunohlstochemical Observations of a Case

The clinicopathological features of a 28-y-ear-old woman with placental-site trophoblastic tumor (PSTT) are described. The patient presented with severe proteinuria and was found to have a cystic uterine tumor. The serum β- human chorionic gonadotropin (hCG) level was only slightly elevated. The tumor extended to the serosa without gross metastasis, and was resected. The specimen was composed of active intermediate trophoblasts (IT) and degenerative or inactive ITs. The former component had round to oval and vesicular nuclei, and abundant amphophilic or lightly eosinophilic cytoplasm. The latter component had irregular-shaped pyknotic nuclei and deeply eosinophilic cytoplasm. However, the tumor lacked the bilaminar (cyto- and syncytio-trophoblastic) structure that is a characteristic feature of choriocarcinoma. Immunohistochemical evaluation with human placental lactogen (hPL) and hCG antisera revealed that most of the tumor cells contained abundant hPL, whereas only a small number of cells contained hCG. This method seemed to be most helpful for the differential diagnosis of PSTT from other trophoblastic tumors or non-trophoblastic uterine tumors, and also to be useful for determining the prognostic behavior of PSTT.     

A case of a placental site trophoblastic tumor

A rare placental site trophoblastic tumor (PSTT) in a 39-year-old female was studied. This tumor, protruding into the uterine cavity, was histologically similar to tumors in previously reported cases of PSTT. Ultrastructurally, the characteristic finding was the presence of perinuclear filaments. Also, the tumor cells were strongly positive for hPL by immunohistochemical method. These findings suggest that this was a tumor caused by neoplastic proliferation of the extravillous intermediate trophoblast.     

Activation of mitogen-activated protein kinase is required for migration and invasion of placental site trophoblastic tumor

Placental site trophoblastic tumor (PSTT) is a gestational neoplasm derived from the extravillous (intermediate) trophoblast of the implantation site. PSTT is characterized by a highly invasive phenotype, but the molecular mechanisms are poorly understood. In this report, we demonstrate that PSTTs expressed the activated (phosphorylated) form of mitogen-activated protein kinase (MAPK) in 84% of cases, whereas the normal extravillous trophoblastic cells did not. To characterize the role of MAPK activation in PSTT, we established the first PSTT cell culture, IST-2, from a surgically resected PSTT. IST-2 cells expressed HLA-G and Mel-CAM but not E-cadherin, an immunophenotype characteristic of PSTT. IST-2 cells were highly motile and invasive in culture as compared to choriocarcinoma JEG-3 cells and normal extravillous trophoblastic cells. Based on wound assay, time-lapse videomicroscopy for cell tracking, and invasion chamber assays, we found that the motility and invasion of IST-2 cells were significantly reduced (P<0.01) after treatment with the MEK inhibitors CI-1040 and PD 59089, which prevent activation of MAPK. In contrast, neither compound had any effect on normal extravillous trophoblastic cells or JEG-3 cells. In conclusion, our findings demonstrate a functional role of MAPK activation in the motility and invasion of PSTT.     

Gestational trophoblastic disease: histopathological diagnosis in the molecular era

Gestational trophoblastic disease is a heterogeneous group of proliferative disorders of the placental trophoblasts, often with challenging morphology, posing diagnostic problems for the general, even specialty pathologists. In this review we discuss characteristic histological features of complete- and partial hydatidiform moles, with special focus on the diagnosis of hydatidiform moles evacuated at early stage and their mimics. The diagnostic criteria and potential pitfalls in the diagnosis of gestational choriocarcinoma and two rare, unique neoplasms of the intermediate trophoblast – placental site trophoblastic tumour and epithelioid trophoblastic tumour – are presented, along with their differential diagnoses from two tumour-like conditions including exaggerated placental site and placental site nodule. We also review the current practice of immunohistochemistry, ploidy analysis and molecular genotyping in the diagnosis of gestational trophoblastic disease. Finally, how molecular testing may change the future diagnostic algorithm of gestational trophoblastic diseases is discussed.     

Coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor of the uterus following a term pregnancy: report of a case and review of literature

Gestational trophoblastic neoplasms are a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs). Mixed gestational trophoblastic neoplasms are extremely rare. The existence of mixed gestational trophoblastic neoplasms that were composed of choriocarcinoma and/or PSTT and/or ETT was also reported. Herein, we present a case of uterine mixed gestational trophoblastic neoplasm which is ETT admixed with PSTT, and reviewed 9 cases of mixed gestational trophoblastic neoplasms reported in English literature available. The most common combination was a choriocarcinoma admixed with an ETT and/or PSTT. Mixed gestational trophoblastic neoplasms present in women of reproductive age and rare in postmenopausal, Abnormal vaginal bleeding is the most common presenting symptom, serum β-HCG levels are elevated, mostly below 2500 mIU/ml, the tumor was limited to uterus in 7 cases, the rest of 3 with pulmonary metastases at the time of diagnosis. Mixed gestational trophoblastic neoplasms have more similar clinical features with intermediate trophoblastic tumors (ITTs). Total hysterectomy with lymph node dissection is recommended treatment for mixed gestational trophoblastic neoplasms, and chemotherapy should be used in patients with metastatic disease and with nonmetastatic disease who have adverse prognostic factors.     

Proliferations and tumors of intermediate trophoblast of the placental site

The clinical and pathologic features of proliferations and tumors of intermediate trophoblast of the placental site are reviewed. These lesions include the exaggerated placental site reaction, which is a florid form of the process that occurs normally at the placental site; a hitherto undescribed variant of this lesion, which we have designated placental site nodule, and the neoplasm of intermediate trophoblast that has been termed placental site trophoblastic tumor. Problems encountered in distinguishing these lesions from one another and from nontrophoblastic lesions, particularly in endometrial biopsy specimens and curettings, are discussed.     

Placental site trophoblastic tumour: a case report

Placental site trophoblastic tumour (PSTT) is a rare form of trophoblastic disease accounting for < 2% of all gestational trophoblastic neoplasms. Most of the cases follow a normal pregnancy and a small number have a preceeding molar pregnancy or spontaneous abortion. It can occur as early as several weeks or as late as 15 years after normal delivery, molar pregnancy or abortion. Excessive intermediate trophoblastic activity is the most important diagnostic criterion of this tumour originating from non villous trophoblast. But the possibility of a PSTT should be considered when there is excessive intermediate trophoblastic activity despite the presence of chorionic villi as in the present case. This case report highlights the unusual features like rarity of the tumour (< 2%), occurrence following spontaneous abortion which happens only in a minority of cases, and presence of chorionic villi in the tumour despite the fact that the tumour is of non villous trophoblastic origin.     

Decreased expression of Ras GTPase activating protein in human trophoblastic tumors.

The normally developing placenta undergoes extensive but regulated noninvasive cellular proliferation. Various proto-oncogenes and growth factors have been associated with the regulation of trophoblastic placental growth. Activation of some oncogenes and altered expression of growth factors have been demonstrated in trophoblastic tumors (hydatidiform mole and choriocarcinoma). The ras proto-oncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types. Ras GTPase activating protein (RasGAP), a major down-regulator of ras activity, is present at high levels in placenta. To assess the role that Ras-GAP plays in the development of trophoblastic tumors, we performed immunohistochemical analyses with anti RasGAP antibodies of normal placentas, hydatidiform moles, invasive moles, and malignant choriocarcinomas. Normal placentas and noninvasive hydatidiform mole displayed intense positive staining confined to trophoblasts, whereas no staining was observed in the trophoblasts of invasive moles or choriocarcinomas. Thus, there was an inverse correlation between expression levels of RasGAP protein and the invasive potential and malignant phenotype in human trophoblastic tumors. The data indicate that RasGAP may play a regulatory role in trophoblast proliferation and that abolishing its activity may be associated with malignant transformation of these cells.     

Pathogenesis of placental site trophoblastic tumor may require the presence of a paternally derived X chromosome

Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of intermediate trophoblasts that invades the myometrium at the placental site after a pregnancy. Less than 100 cases have been reported. Information of the sex assignment of the antecedent gestation is available in 21 cases: 18 of these were female. To explore this interesting phenomenon, we have determined the sex chromosome composition of the tumor tissue preserved in paraffin blocks for five new cases of this condition. The last documented gestational event included a normal vaginal delivery of female infants in three cases, normal vaginal delivery of an infant of unknown sex in one case and a molar gestation in one case. Using the X-linked human androgen receptor (AR) gene as a polymorphic marker, we showed that in all five cases the tumor had a likely XX chromosomal composition; and in four cases it was possible to determine that one of the X chromosomes was of paternal origin. In one case, the paternal X chromosome showed no polymorphism to either maternal X chromosomes. In addition, sensitive semi-nested PCR failed to show a human Y chromosome element in any of the five cases of PSTT. Overall, of 21 cases from the literature and 5 cases of ours, 89% (23 of 26) showed an XX genomic composition in PSTT, either by history or genetic analysis. These results suggest that most PSTT were derived from the antecedent female conceptus and were likely to have possessed a functional paternal X chromosome. Methylation status analysis at the AR locus was performed in the three PSTT in which the paternal X chromosome was identifiable. In two cases, the paternal AR locus was hypomethylated while the corresponding maternal locus was hypermethylated. The methylation status of other loci was not investigated. Collectively, sex chromosome analysis of five cases of PSTT with literature support suggests a unique genetic basis for the development of PSTT that involves the paternal X chromosome. Although largely speculative, an active paternal X chromosome may be of importance in the pathogenesis of PSTT.     

Epithelioid trophoblastic tumor after induced abortion with previous broad choriocarcinoma: a case report and review of literature

Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum β-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy.     

The expression and localization of neutral endopeptidase 24.11/CD10 in human gestational trophoblastic diseases

Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that hydrolyzes various bioactive peptides. NEP is distributed in both normal and neoplastic cells and plays a functional role by modulating cellular responses to peptide substrates. Recently, NEP has been shown to be expressed in normal placental trophoblasts, suggesting its physiological role during pregnancy. In the present study, we investigated the expression of NEP in hyperplastic and anaplastic trophoblasts in gestational trophoblastic diseases (GTDs). Flow cytometric analysis demonstrated that NEP was expressed in all choriocarcinoma cell lines examined. The NEP enzyme activity in these cell lines correlated with cell-surface protein levels and was abolished by the NEP inhibitor phosphoramidon. On immunoblot analysis, NEP protein was detected in both hydatidiform mole and choriocarcinoma tissues as a double band of 95 and 100 kDa similar to that of the normal placental tissues. Immunohistochemical analysis revealed that NEP was present on syncytiotrophoblasts, while no or very faint NEP immunoreactivity was observed on cytotrophoblasts in the normal placenta. Similarly, NEP in hydatidiform mole and invasive mole was localized on the membrane of syncytiotrophoblasts, but not on hyperplastic cytotrophoblasts. In contrast, in choriocarcinoma, NEP was highly expressed not only on syncytiotrophoblastic cells but also on invading anaplastic cytotrophoblasts. In addition, NEP was also expressed on intermediate trophoblasts in placental site trophoblastic tumors. In summary, this is the first study demonstrating the expression of NEP/CD10 in GTDs. The differential localization of NEP among various trophoblastic tumors suggests that NEP may play a functional role in the regulation of trophoblast transformation and human chorionic gonadotropin secretion.