Gestational Trophoblastic Lesions Research Articles

LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth.

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

Histomorphological Study of Gestational Trophoblastic Lesions in a Tertiary Medical Centre: A Prospective Study

Background: Gestational trophoblastic diseases(GTDs) consists of pregnancy related disorders ranging from benign Hydatidiform mole, Invasive mole to neoplastic conditions including Choriocarcinoma, Placental site trophoblastic tumor and Epitheloid trophoblastic tumor with varying potential for local invasion and metastasis. GTDs mimic growth pattern encountered in early normal placental development, nonmolar abortions and variety of nontrophoblastic lesions. Therefore an appreciation of different types of GTDs with its histomorphological manifestations are important for the confirmation of diagnosis. Thus the study was undertaken. Materials & methods: The material for the study comprised of products of conception specimens received in the Department of Pathology, J.J.M. Medical college, Davangere, India during the period of 2 years. Detailed gross examination was done before fixation and subsequent microscopic analysis was done. Results: 65 cases of GTDs were diagnosed in 495 cases of products of conception. 37 cases of complete mole, 27 cases of partial mole and one case of Invasive mole were diagnosed. Diffuse hydropic swelling of the villi, round smooth villous outline, circumferential trophoblastic proliferation and focal hydropic swelling of the villi, irregular scalloping outline of the enlarged villi, focal trophoblastic cell proliferation were characteristic features of complete & partial mole respectively. Histomorphological features were analysed in all the cases and compared with studies done by others. Conclusion: The classification and histomorphological analysis of GTDs are important elements for better understanding of the disease. Studies are needed to look for ancillary markers in distinguishing different types of GTDs and for predicting the prognosis. DOI: 10.21276/APALM.1193

Vaginal bleeding in the first trimester

Causes of vaginal bleeding in early pregnancy include: miscarriage, ectopic pregnancy, gestational trophoblastic disease and lesions in the lower genital tract. Miscarriage is the most common pregnancy disorder and can be classified as threatened, complete, incomplete or early embryonic/fetal demise. Ectopic pregnancy should be suspected in any pregnant woman presenting with lower abdominal pain and/or vaginal bleeding in the first trimester. Patients with gestational trophoblastic disease need to be followed up due to the potential risk of choriocarcinoma. Cervical polyps, cervical ectropion, and carcinoma, can give rise to vaginal bleeding, but one should conclude that these are the sole causes only after exclusion of all the other causes. All units should provide a dedicated outpatient early pregnancy assessment service so that women receive efficient care of high quality. In view of the psychological sequelae associated with pregnancy loss, a system must be in place for informing all relevant primary care professionals.

Expression Pattern of the Activating Protein-1 Family of Transcription Factors in Gestational Trophoblastic Lesions

The human placenta is an endocrine tissue with a unique capacity for rapid, but tightly controlled, proliferation and invasion. Gestational trophoblastic diseases (GTDs) are placental pathologies with endocrine activity and partially malignant potential and include hydatidiform moles, placental site nodules, and tumors such as placental site trophoblastic tumor and choriocarcinomas. The activating protein-1 (AP-1) family of transcription factors is composed of the cellular homologs of the Jun and Fos oncoproteins, which are immediately involved in cellular proliferation, differentiation, and invasion processes and in the regulation of endocrine genes. The expression pattern of the AP-1 family in the normal human placenta has been recently described, where most of the factors were found in the extravillous (invasive) trophoblast. Their systematic expression in GTD has not been studied thus far. For this reason in this study, we investigated the expression pattern of the AP-1 family in GTDs and compared it with the expression in normal placenta using immunohistochemistry with specific polyclonal antibodies against all members of the AP-1 family (JunB, JunD, c-Jun, c-Fos, FosB, Fra-1, Fra-2). Immunohistochemistry was performed on normal human placentas (positive control) and on 28 cases of GTD including 7 choriocarcinomas and 21 hydatidiform moles. In the normal placenta and in hydatidiform molar samples, most AP-1 factors (especially c-Jun, JunD, and Fra2) were expressed in the intermediate (extravillous) trophoblast. In addition, in molar lesions, strong expression was found in trophoblasts proliferating from the surface of villi. There was only a weak expression of JunB and Fra2 in small fractions of villous cyto- and syncytiotrophoblast nuclei. In choriocarcinomas, there was a strong expression for c-Jun, JunD, Fra1, and Fra2. The specific localization to extravillous trophoblasts and their expression pattern in GTDs indicate that the AP-1 family of transcription factors might be implicated in regulating proliferation and invasion of trophoblasts and play a role in the pathogenesis of GTDs.

Expression of inhibin-alpha by granular cell tumors of the gallbladder and extrahepatic bile ducts.

This is the first report of inhibin-alpha expression in granular cell tumors. A Medline search of the literature revealed no case reports of granular cell tumors in any location of the body being tested for inhibin-alpha immunohistochemically, by enzyme-linked immunosorbent assay, by radioimmunoassay, or by immunoprecipitation. Seventeen cases of previously diagnosed granular cell tumors of the gallbladder and extrahepatic bile ducts with hematoxylin and eosin-stained sections, and S-100 protein immunostain were retrieved from the archives of the Armed Forces Institute of Pathology. All cases were reviewed for diagnostic accuracy and then immunostained for inhibin-alpha (with endogenous biotin blocking). All 17 (100%) cases were diffusely positive for inhibin-alpha immunostain. Previous studies of inhibin-alpha-positive lesions reported in the literature include sex cord stromal tumors (granulosa cell tumors, luteinized thecomas, Leydig cell tumors), placental and gestational trophoblastic lesions, and adrenal cortical tumors. This study adds the granular cell tumor to the list of inhibin-positive lesions and should prove helpful in differential diagnosis of these lesions.

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.

The role of CD146 (Mel-CAM) in biology and pathology.

CD146, also known as Mel-CAM, MUC18, A32 antigen, and S-Endo-1, is a membrane glycoprotein which functions as a Ca(2+)-independent cell adhesion molecule involved in heterophilic cell-cell interactions. Based on homology of the nucleotide sequence, CD146 is classified as a member of the immunoglobulin gene superfamily, since it contains the characteristic V-V-C2-C2-C2 immunoglobulin-like domain structure. Using immunohistochemistry with CD146-specific antibodies, CD146 expression has been demonstrated in a relatively limited spectrum of normal human tissues and malignant neoplasms. The lineage-specific expression pattern of CD146 can be useful in the differential diagnosis of certain lesions including melanomas and various types of gestational trophoblastic lesions. Although the biological role of CD146 in normal tissue and malignant tumours remains unclear, CD146 has been suggested to play an important role in tumour progression, implantation and placentation. CD146 expression can promote tumour progression in human melanoma, possibly through enhanced interaction between melanoma cells and endothelial cells. In contrast, CD146 may act as a tumour suppressor in breast carcinoma. CD146 expression is frequently lost in breast carcinomas and overexpression of CD146 in breast carcinoma cells results in a more cohesive cell growth and the formation of smaller tumours in nude mice. During implantation and placentation, CD146 expressed by the intermediate trophoblast in the placental site binds to its putative receptor in uterine smooth muscle cells and limits trophoblastic invasion in the myometrium. In conclusion, CD146 is a recently identified novel cell adhesion molecule and its biological functions and role as a diagnostic marker in pathology are now being recognized. Identification of the receptor for CD146 and the development of experimental models that can account for the complex interactions between CD146-expressing cells and their microenvironment are needed to investigate further the functions of this molecule in biology and in pathological states.

Immunohistochemical localization of inhibin-alpha in the placenta and gestational trophoblastic lesions.

The immunohistochemical distribution of inhibin-alpha in formalin-fixed, paraffin-embedded tissues was evaluated in placentas (2 to 40 weeks of gestation), implantation sites, and a variety of trophoblastic lesions. In the first trimester placenta, inhibin-alpha was strongly and diffusely expressed in syncytiotrophoblast. Implantation site intermediate trophoblast in normal and exaggerated placental sites was either negative or only weakly and focally positive for inhibin-alpha. With increasing gestational age, the staining intensity and distribution of inhibin-alpha decreased in syncytiotrophoblast but increased in the implantation site intermediate trophoblast. Chorionic-type intermediate trophoblast, present in the chorion laeve of the term placenta, was weakly but diffusely positive for inhibin-alpha. Cytotrophoblast remained negative for inhibin-alpha throughout gestation. In trophoblastic lesions, inhibin-alpha immunoreactivity was detected in all 17 hydatidiform moles (7 complete and 10 partial), 32 placental site nodules, 23 placental site trophoblastic tumors, 15 epithelioid trophoblastic tumors, and 16 choriocarcinomas. Inhibin-alpha immunoreactivity was confined to the syncytiotrophoblast in hydatidiform moles and choriocarcinoma. As with the normal placenta, inhibin-alpha was not detected in cytotrophoblast. To evaluate the utility of inhibin-alpha in the differential diagnosis of gestational trophoblastic lesions, we tested 32 squamous cell carcinoma of the cervix, 11 low-grade endometrial stromal sarcomas, 12 endometrial (7 well differentiated and 5 moderately differentiated) carcinomas, 7 epithelioid leiomyomas, and 10 leiomyosarcomas for the expression of inhibin-alpha. None of these lesions was positive. These data indicate that inhibin-alpha is expressed by all populations of trophoblast except cytotrophoblast and in all gestational trophoblastic lesions. Accordingly, immunohistochemical detection of inhibin-alpha is useful in the differential diagnosis of gestational trophoblastic lesions.

Human endogenous retrovirus (HERV)-K transcripts in germ cell and trophoblastic tumours.

Prompted by the observation of retroviral particle formation in teratocarcinoma cell lines and the consistent finding of antibodies against Gag and Env proteins encoded by human endogenous retrovirus (HERV)-K genomes in the sera of patients with classical seminoma, we studied ovarian and testicular germ cell tumours, their precursor lesions, dysgenetic gonads, and trophoblast lesions for expression of HERV-K sequences by in situ hybridization using radioactive and non-radioactive probes. HERV-K transcripts were detected in all testicular and ovarian germ cell tumours with the exception of teratomas and spermatocytic seminomas. HERV-K expression was also common to testicular carcinoma in situ as well as gonocytes of dysgenetic gonads. Among gestational trophoblastic lesions, HERV-K expression was regularly found in choriocarcinomas, but not in molar lesions. The patterns of HERV-K expression suggest a common molecular pathogenesis of most germ cell tumour entities and malignant gestational trophoblastic disease. They furthermore support the concept of carcinoma in situ as a precursor lesion common to most testicular germ cell neoplasms. The detection of HERV-K gene products in body fluids and tissues may aid diagnosis and monitoring of germ cell tumours and related lesions.