Expression pattern of the CCAAT/enhancer-binding protein C/EBP-beta in gestational trophoblastic disease.

The CCAAT/enhancer-binding protein (C/EBP) family consists of several factors that are important regulators of intracellular processes and hormone action. C/EBP-beta, the most important member of the C/EBP family, was shown recently to be expressed in the normal human placenta where it is localized in villous syncytiotrophoblast and in the extravillous (intermediate) trophoblast but not the villous cytotrophoblast. The purpose of this study was to investigate the expression pattern of C/EBP-beta in gestational trophoblastic disease (GTD) which has not been studied so far. We used immunohistochemistry on a total of 15 cases of GTD including nine complete hydatidiform moles, one placental site nodule (PSN), one placental site trophoblastic tumor (PSTT), and four choriocarcinomas. All our tested specimens showed positivity for C/EBP-beta. The strongest C/EBP-beta expression could be observed in villous syncytiotrophoblast and in the trophoblast proliferations on the villous surface of hydatidiform moles; villous cytotrophoblast was negative. The PSN also showed positive nuclear staining but the expression was not as strong as it was in the hydatidiform moles and the total amount of stained cells was the lowest of all GTD. The PSTT also showed immunoreactivity but with a weaker and more heterogeneous staining than in the choriocarcinomas. The specific expression pattern of C/EBP-beta in GTD indicate that C/EBP-beta could potentially be an additional marker of such lesions.     

The pathology of intermediate trophoblastic tumors and tumor-like lesions.

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.     

Ancillary Techniques to Refine Diagnosis of GTD

Gestational trophoblastic disease (GTD) consists of hyperplastic and neoplastic disorders of placental trophoblast; i.e., hydatidiform moles and gestational trophoblastic tumors, respectively. While the histological diagnosis of well-developed complete hydatidiform mole and gestational choriocarcinoma is generally accurate, significant diagnostic challenges persist in the routine evaluation of early complete hydatidiform mole, partial hydatidiform mole, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Recently, the applications of new immunohistochemical markers and molecular techniques have significantly enhanced the diagnostic accuracy of various GTDs. P57 immunohistochemistry is a highly useful marker in confirming complete hydatidiform mole, including its early forms. PCR-based short tandem repeat DNA genotyping has emerged as a powerful diagnostic measure to precisely classify both complete and partial hydatidiform moles. With highly desired sensitivity and specificity, these powerful ancillary studies should be advocated and integrated into the routine diagnostic algorithm of GTD.     

Pathology of gestational trophoblastic diseases

Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases. This used to include partial and complete hydatidiform moles, invasive mole, choriocarcinoma and placental site trophoblastic tumour. In recent years, new entities, including epithelioid trophoblastic tumour, have been added to this family. Non-neoplastic and neoplastic lesions derived from implantation site and chorion intermediate trophoblast have been gaining attention in the literature. New markers for trophoblasts have been identified facilitating histological diagnosis in cases with unusual clinical or pathological features. It is worth noting that histological distinction between hydropic abortion and partial mole and between complete and partial moles, especially at early gestational age, may be difficult. It may not be possible to predict progress of the heterogeneous group of GTD from histopathological features, except probably in placental site trophoblastic tumour. Alternative biological markers may be explored for better patient management.     

Expression pattern of the adhesion molecule CEACAM1 (C-CAM, CD66a, BGP) in gestational trophoblastic lesions.

CEACAM1 (CD66a, BGP, C-CAM) is an adhesion molecule of the carcinoembryonic antigen (CEA) family which has been shown to be normally expressed at the apical pole of epithelial cells and to show a dysregulated expression pattern in tumors derived from the latter. The purpose of the present study was to investigate the expression pattern of CEACAM1 in gestational trophoblastic lesions and to compare this expression with the one observed in the normal trophoblast. For this purpose, we performed immunohistochemistry using the 4D1/C2 monoclonal antibody which specifically recognizes CEACAM1 and does not interact with other members of the CEA family. Immunohistochemistry was performed on a total of 20 cases of gestational trophoblastic lesions including complete hydatidiform moles, one placental site trophoblastic nodule (PSN), one placental site trophoblastic tumor (PSTT), and three choriocarcinomas. Immunostaining for cytokeratin, hPL, hCG, and Ki-67 was also performed. Normal placental samples served as a control. CEACAM1 was absent from villous cyto- and syncytiotrophoblast in both normal placenta and hydatidiform molar samples. It was present in the benign extravillous trophoblast, with stronger expression in the proximal extravillous trophoblast of anchoring villi, but was also observed in interstitial and endovascular intermediate trophoblast and chorionic intermediate-like trophoblast. Partial expression was observed in the trophoblast proliferating from the surface of molar villi. In choriocarcinomas, areas of weak expression could be observed along with large areas without CEACAM1 expression. In the PSN and especially in the PSTT, CEACAM1 expression was stronger and more diffuse. The specific localization to extravillous trophoblast and its expression pattern in gestational trophoblastic lesions indicate that CEACAM1 can potentially be a helpful additional diagnostic marker in the differential diagnosis of such lesions.     

妊娠滋养细胞疾病的影像学特征及意义

妊娠滋养细胞疾病（gestational trophoblasticdisease,GTD）是一组以滋养细胞组织异常增殖为特征的异质性疾病,是一种罕见疾病,包括良性和恶性两种形式,后者统称为妊娠滋养细胞肿瘤（gestational trophoblastic neoplasia,GTN）。影像检查在GTD早期诊断必不可少,尤其在GTD良恶性的鉴别、肿瘤的分期及风险评估方面起着至关重要的作用,能对GTD患者的病变定位和估测范围,为治疗方案的选择和判断预后提供依据,且能动态观察化疗效果及复发情况,对滋养细胞疾病的诊断有很高的临床应用价值。使用双功能多普勒的经腹和经阴道超声评估通常在上述任何一种情况下和治疗后监测中都是合适的辅助检查方法。更广泛成像技术的应用取决于GTN的诊断和其他因素。     

c-mos immunoreactivity aids in the diagnosis of gestational trophoblastic lesions.

C-mos is an important proto-oncogene involved in the mitogen-activating protein kinase pathway. This study was designed to explore c-mos immunoreactivity in gestational trophoblastic lesions and compare it with immunoreactivity in normal placentas as well as other gynecological lesions and germ cell tumors using antibody P-19. The immunohistochemical distribution of c-mos in 159 cases of gynecological lesions and 26 germ cell tumors using formalin-fixed, paraffin-embedded tissues was evaluated. The lesions included 45 (32 complete and 13 partial) hydatidiform moles, 17 choriocarcinomas, 5 placental site trophoblastic tumors, 18 squamous cell carcinomas and 5 adenocarcinomas of the cervix, 11 endometrial carcinomas, 9 ovarian carcinomas, 4 primary peritoneal papillary serous carcinomas, 9 low-grade endometrial stromal sarcomas, 4 epithelioid leiomyomas, 6 leiomyosarcomas, and 26 gem cell tumors (3 embryonal carcinomas, 5 yolk sac tumors, 6 immature teratomas, and 3 mature teratomas from the ovary; 9 testicular seminomas). Twenty-six normal placentas also were included for comparison. Among cases of gestational trophoblastic diseases, c-mos immunoreactivity was found in all hydatidiform moles and choriocarcinomas, but in none of the placental site trophoblastic tumors. The c-mos staining pattern was similar in trophoblastic diseases and normal placentas with strong expression in syncytiotrophoblast, moderate expression in villous intermediate trophoblast, and predominantly negative expression in implantation site intermediate trophoblast, chorionic-type intermediate trophoblast, and villous cytotrophoblast. All the nontrophoblastic tumors, including carcinomas, sarcomas, and germ cell tumors, were negative for c-mos expression. Immunohistochemical detection of c-mos is useful in differentiating choriocarcinoma from placental site trophoblastic tumor and nontrophoblastic tumors of the female genital tract that may sometimes cause problems in differential diagnosis.     

Placental site trophoblastic tumor: with features between an exaggerated placental site reaction and a placental site trophoblastic tumor

Chorionic villi, whose presence in cases of trophoblastic disease is normally used to exclude both a choriocarcinoma and placental site trophoblastic tumor (PSTT), were present in the initial uterine curettage specimen of a trophoblastic tumor. The lesion shared morphologic features of both an exaggerated placental site reaction and a PSTT. There was infiltration of the posterior wall of the uterus by small clusters and isolated cells which had a prominent affinity for vessels and resembled a usual placental bed reaction. There was, however, deep involvement of myometrium with extension to the cervix, and the condition persisted for 5 months after uterine evacuation. Because different treatment is entailed, identification of this lesion as a tumor of nonvillous trophoblast is also of great importance in a region where the more usual forms of trophoblastic disease represent a declining but not infrequent event. When products of gestation are examined, the possibility of a PSTT should be considered and the clinician alerted if there is a suggestion of excessive intermediate trophoblastic activity, regardless of the presence of chorionic villi. While this may result in the unnecessary followup of some cases, it would permit, with the aid of serial beta-hCG and HPL levels, the earlier detection of PSTTs.     

Current understandings of the molecular genetics of gestational trophoblastic diseases

Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases characterized by abnormally proliferating trophoblastic tissues. This includes partial and complete hydatidiform moles, invasive mole, choriocarcinoma and placental site trophoblastic tumour. Cytogenetic studies revealed that hydatidiform moles contain either solely (as in complete moles) or an excess (as in partial moles) of paternal contribution to the genome. Genomic imprinting is believed to play a pivotal role in the pathogenesis of hydatidiform moles. However its precise role and mechanism remains poorly understood. Hydatidiform mole carries a potential of malignant transformation. Similar to other human cancers, malignant transformation in gestational trophoblastic tumours is likely a multistep process and involves multiple genetic alterations including activation of oncogenes and inactivation of tumour suppressor genes. In addition, expression of telomerase activity, altered expression of cell--cell adhesion molecules and abnormal expression of matrix metalloproteinases have also been reported in GTD. These represent disruption of the delicate balance and regulation of cellular processes including proliferation, differentiation, apoptosis and invasion. The significance of these alterations in the pathogenesis and malignant transformation of gestational trophoblastic diseases is reviewed in this paper.     

Pathology of gestational trophoblastic tumors

Gestational trophoblastic tumours result from an abnormal proliferation of different types of trophoblasts. The morphological pattern, together with the immunohistochemical aspect, the cytogenetic data and the clinical profile, helps identify each pathological entity. Hydatiform moles represent malformed placentas caused by genetic aberrations of the villous trophoblast. A complete hydatiform mole displays an hydropic degeneration of all the chorionic villi with a more or less marked proliferation of trophoblasts. A partial hydatiform mole is made up of molar vesicles interspersed with normal chorionic villi. In an invasive hydatiform mole or chorioma destruens, molar vesicles penetrate the myometrium giving rise to a mass distorting the uterine wall. A choriocarcinoma is a malignant proliferation of atypical villous trophoblasts without villi formation. Necrosis, haemorrhage, vascular invasion and distant metastases strongly compromise its outcome. A trophoblastic implantation site tumor, clearly less frequent, results from a proliferation of extravillous trophoblasts, particular for their secretion of human placental lactogen hormone (hPL). This tumour, exceptionally malignant, should be differentiated from the exaggerated placental site and its variants. Except for the placental site trophoblastic tumour, and whatever the outcome (benign or malignant), all gestational trophoblastic tumours secrete the beta-subunit of the chorionic gonadotropic hormone (beta-hCG) more or less abundantly. The serum or urinary level of this unit is proportional to the tumour volume and represents a fundamental basis for the follow-up of these tumours. Multidisciplinary care of high-risk cases allows us to cure the disease, and helps the patient recover her reproductive uterine function.     

Exaggerated placental site mimicking placental site trophoblastic tumor: case report and literature review

Exaggerated placental site is defined as a non-neoplastic trophoblastic lesion featuring exuberant infiltration into the endometrium and myometrium by intermediate trophoblasts and syncytiotrophoblasts. Exaggerated placental site can occur following normal or ectopic pregnancy, abortion, or hydatidiform mole. We encountered a case of reactive exaggerated placental site seven months following normal pregnancy that clinically mimicked placental site trophoblastic tumor. Few reports have described the clinical course, histopathology and differential diagnosis of exaggerated placental site; we present our patient's case together with histopathological observations and review of related literature.     

Immunohistochemical expression analysis of inhibin-alpha and -beta subunits in partial and complete moles, trophoblastic tumors, and endometrial decidua.

The expression of inhibin-alpha subunit has been described in normal placentas, hydatidiform moles, and trophoblastic tumors. We performed a double immunohistochemical expression analysis of inhibin-alpha and inhibin-beta subunits in a cytogenetically well characterized series of 21 complete and 22 partial hydatidiform moles, 2 placental site trophoblastic tumors, and one choriocarcinoma. Syncytiotrophoblastic cells were consistently inhibin-alpha and inhibin-beta positive in all hydatidiform moles and in the one choriocarcinoma. Cytotrophoblast was negative for both subunits in all trophoblastic lesions studied. While villous intermediate trophoblastic cells were consistently inhibin-alpha negative in all hydatidiform moles, focal inhibin-beta immunoreactivity was detected in villous intermediate trophoblast in approximately one third of complete and partial hydatidiform moles. Decidual stromal cells in 40 hydatidiform moles were inhibin-alpha and inhibin-beta positive in approximately one third of cases. Both placental site trophoblastic tumors were inhibin-alpha positive but inhibin-beta negative. Our findings indicate that inhibin-alpha and -beta subunits are consistently coexpressed in syncytiotrophoblast in complete and partial moles. Immunohistochemical detection of inhibin subunits may be useful in the differential diagnosis of trophoblastic lesions.     

超常胎盘部位反应的病理学与临床特点

研究超常胎盘部位反应的病理与临床特点,提出诊断标准及鉴别诊断要点。方法 对１３例经病理检查诊断为ＥＰＳ的病人,采用免疫组化标记法,进行病理学特征,临床表现及预后分析。结果 ＥＰＳ组织学特征为以中间型为主的滋细胞向蜕膜及平滑肌层当润,不破坏原有组织结构,并保留部分胎盘特点。     

Human chorionic gonadotropin free beta-subunit measurement as a marker of placental site trophoblastic tumors

OBJECTIVE: To evaluate the utility of free human chorionic gonadotropin beta-subunit (hCGbeta) proportion of total hCG measurement to distinguish placental site trophoblastic tumor (PSTT) from more common forms of gestational trophoblastic disease (GTD). STUDY DESIGN: Serum samples collected from PSTT, persistent trophoblastic disease (PTD) and choriocarcinoma patients were used for retrospective analysis of free hCGbeta-subunit. Results were reported as a percentage of total hCG using our in-house competitive radioimmunoassay. RESULTS: The percentage of free hCGbeta was significantly greater in serum from 18 PSTT patients, yielding a median value of 45.5% than in a combined GTD group of 49 PTD and 12 choriocarcinoma patients. Receiver operating characteristic analysis confirms that the percentage free hCGbeta distinguishes PSTT from GTD patients. Choriocarcinoma patients had significantly higher hCGbeta measurements than PTD patients and were not well distinguished from PSTT patients. CONCLUSION: Our findings show that an elevated proportion of free hCGbeta-subunit is a helpful but not definitive test to discriminate PSTT from other forms of GTD.     

Expression pattern of the cell cycle promoter cyclin e in benign extravillous trophoblast and gestational trophoblastic lesions: correlation with expression of Ki-67.

In this study, a specific monoclonal antibody was used to immunohistochemically investigate correlated expression of the cell cycle promoter cyclin E and the proliferation marker Ki-67 in benign extravillous trophoblast and gestational trophoblastic lesions. Our data show that cyclin E is expressed in the normal extravillous trophoblast, with strongest levels of expression in the cell columns of anchoring villi. Differences could be observed in expression of Ki-67 in both normal extravillous trophoblast and gestational trophoblastic lesions. In the extravillous trophoblast of the cell columns, expression of cyclin E started more distal compared with Ki-67 and was maintained (with less intensity) into the deeper layers of interstitial trophoblast. In the benign trophoblastic lesions (exaggerated placental site [EPS] and placental site nodule [PSN]) and in the trophoblast proliferations on the surface of hydropic villi of hydatidiform moles (HM), the percentage of cells expressing cyclin E was higher than of those expressing Ki-67. The same observation could be made for a case of placental site trophoblastic tumor (PSTT). In contrast, choriocarcinomas (N=8), which are definitely malignant tumors, showed an opposite pattern, with a much higher percentage of strongly Ki-67-positive cells compared with cyclin E-positive cells. We conclude that cyclin E is expressed in benign extravillous trophoblast and gestational trophoblastic lesions, where a ratio cyclin E/Ki-67<1 characterizes choriocarcinomas, whereas PSTT and the benign lesions (HM, EPS, PSN) show expression of cyclin E in a higher percentage of cells than Ki-67 (cyclin E/Ki-67 ratio >1).     

妊娠滋养细胞疾病的组织病理学和分子病理学研究现状

妊娠滋养细胞疾病包括非肿瘤性的水泡状胎块和肿瘤性的绒癌、胎盘部位滋养细胞肿瘤和上皮样滋养细胞肿瘤。通过对发病机制的深入研究,陆续发现了一些新的疾病亚型,如家族性复发性水泡状胎块、双胎一胎为完全性水泡状胎块等;同时拓展了与临床诊治密切相关的分子诊断方法,如p57免疫组化染色和微卫星位点（short tandom repeat,STR）分子分型等,使病理诊断较既往的形态学诊断更为精确,并更能反映肿瘤发生的深层机制。文章结合最新的文献和世界卫生组织（WHO）女性生殖道肿瘤分类对该类疾病的病理特征和分子检测进行综述。     

Placental-site chorioma. The neoplasm of the implantation-site trophoblast

The unusual lesion of gestational trophoblast, variously termed "placental site tumor" and "placental site trophoblastic tumor," may complicate or follow seemingly normal pregnancy, abortion or hydatidiform mole. Posing indeterminate risks of malignant behavior, those lesions must be differentiated from the banal processes of implantation-site reaction, on the one hand, and from choriocarcinoma and other poorly differentiated uterine neoplasms, on the other. A history of antecedent pregnancy, serum assay of chorionic gonadotropin and human placental lactogen, and immunohistochemical studies of tumor tissue lead to a correct diagnosis. Assessment of the degree of malignancy may be problematic in individual cases, and treatment is not always successful. With an origin in the chorionic epithelium at the implantation site, this condition may be termed "placental-site chorioma." Refined diagnostic criteria may then provide a basis for designating some lesions benign chorioma and others malignant--i.e., placental-site choriocarcinoma.     

Management of gestational trophoblastic disease and other cases with low serum levels of human chorionic gonadotropin

Recent publications show that the measurements of particular human chorionic gonadotropin (hCG) variants are extremely beneficial in the diagnosis, monitoring and treatment of gestational trophoblastic disease (GTD). Here we review the possible sources of hCG and the use of commercial tests in the optimal management of GTD, quiescent GTD,false positive hCG results, placental site trophoblastic tumor (PSTT) detection, nontrophoblastic neoplasms and pituitary hCG. Hyperglycosylated hCG (hCG-H) measurements are ideal for discriminating active (invasive) from inactive (quiescent or benign) disease. hCG-H testing is also more sensitive than regular hCG in detecting recurrent or persistent disease. After excluding false positive hCG results, and in the absence of any radiographic evidence of tumor, hCG-H should be measured before starting chemotherapy or surgery in women presenting with low hCG (<1,000 mIU/mL) with or without a history of GTD. The hCG free beta assay is an invaluable test in discriminating PSTT from other GTDs, thereby aiding the determination of appropriate treatment options.     

Immunocytochemical localization of chorionic gonadotropin, placental lactogen, and placental alkaline phosphatase in the diagnosis of complete and partial hydatidiform moles

Complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) represent different clinicopathologic entities with characteristic morphologic and cytogenetic findings. In the absence of cytogenetic data, the histologic distinction between these lesions and abortuses showing hydropic swelling (AHS) may be difficult. An immunocytochemical study analyzing the distribution of human chorionic gonadotropin (hCG), human placental lactogen (hPL), and placental alkaline phosphatase (PlAP) in CHMs, PHMs, and AHS was undertaken to determine whether the expression of these trophoblastic proteins might assist in the differential diagnosis. A total of 24 CHMs, 22 PHMs, and 13 AHS were selected on the basis of established morphologic criteria. Thirty-four specimens of abortuses without hydropic swelling and normal placentas, ranging from 6 to 24 weeks gestational age, were similarly analyzed. The immunocytochemical localization of the three trophoblastic proteins, predominantly in syncytiotrophoblast (ST), was scored using a semiquantitative scoring system. In CHMs hCG is widely distributed and PlAP is patchily distributed in ST regardless of the gestational age, whereas hPL tends to increase with increasing gestational age. In contrast, in PHMs hPL is more widely distributed in ST compared with CHMs regardless of gestational age, while PlAP increases with increasing gestational age; in PHMs the distribution of hCG is markedly less than in CHMs except early in the first trimester when the staining patterns are similar. The different patterns of distribution of hCG, hPL, and PlAP may reflect differences in the pathobiology of trophoblast in CHMs and PHMs and appear to be useful in the differential diagnosis of these conditions.