Implantation Site Intermediate Trophoblast Research Articles

Downregulation of MicroRNA-125a in Placenta Accreta Spectrum Disorders Contributes Antiapoptosis of Implantation Site Intermediate Trophoblasts by Targeting MCL1.

The typical hallmark of placenta accreta spectrum (PAS) disorders is increased implantation site intermediate trophoblast (ISIT) cell numbers. However, the extent of trophoblast proliferation and apoptosis have not been found to differ from those of normal placentation. MicroRNA-125a (miR-125a) induces apoptosis in colon cancer cell by targeting myeloid cell leukemia-1 gene (MCL1). We aimed to investigate the influence of miR-125a on ISIT cells in PAS disorders in 15 patients (self-paired trials) with placenta previa and PAS disorders. Expression of miR-125a and MCL1 were measured in villous trophoblasts and basal plate myometrial fibers from creta site and adjacent noncreta tissues by real-time quantitative polymerase chain reaction, and expression of the MCL1 protein was assayed by Western blotting. Flow-cytometry was used to examine the effect of miR-125a overexpression on apoptosis in vitro in HTR-8/SVneo cells, and luciferase activity assays was used to confirm miR-125a targeting of MCL1. In vivo, the expression levels of miR-125a was significantly lower in creta versus noncreta tissues, and the expression of MCL1 was upregulated; moreover, immunohistochemistry showed that the increased ISIT cells in the creta were positive for MCL1 protein. MCL1 was downregulated in the miR-125a-overexpressing HTR-8/SVneo cells in vitro, and overexpression of miR-125a-induced apoptosis in the HTR-8/SVneo trophoblast line. Finally, luciferase activity assays confirmed that miR-125a directly target the 3' untranslated region of MCL1 in the 293T cell line. In conclusion, downregulation of MCL1-targeting miR-125a exerts an antiapoptotic effect on ISIT cells in PAS disorders.

Histopathology of Placenta Creta: Chorionic Villi Intrusion into Myometrial Vascular Spaces and Extravillous Trophoblast Proliferation are Frequent and Specific Findings With Implications for Diagnosis and Pathogenesis.

Placenta creta is characterized by invasion of placental villi into the myometrium in the setting of a dysfunctional or absent decidua. Histopathologic diagnosis of placenta creta is important, particularly in cases of hysterectomy because of unanticipated intractable postpartum hemorrhage. Previous studies have documented a higher amount and depth of myometrial infiltration by the implantation site intermediate trophoblast compared with controls. In addition, we have anecdotally observed chorionic villi in myometrial vascular spaces in specimens with placenta creta. The aim of this study was to explore the prevalence and specificity of these features. Sixty-one postpartum hysterectomies, 44 with placenta creta and 17 without were reviewed. Villous intrusion into vascular spaces was recorded. Using immunohistochemistry for GATA3, the amount of intermediate trophoblast (number of positive cells in five 40× fields) and depth of trophoblast myometrial infiltration were assessed. Mean gestational ages of the creta group (34.4 yr; range, 20-43 yr) and control group (35 yr; range, 25-51 yr) were comparable. Presence of chorionic villi in myometrial vascular spaces was frequent in placenta creta: 31/44 versus 1/17 controls (70.4% vs. 5.8%, P<0.0001). This finding was more common in the percreta (87.5%) and increta (84%) than in the accreta (27.2%, P=0.0008). Mean depth of trophoblast myometrial invasion was greater in cretas (47.9%) than in controls (14.5%, P=0.004). Likewise, mean distance of deepest trophoblast to serosa was shorter in the cretas (7.3 mm) than in controls (23.8 mm, P<0.0001). These differences were, however, attributable to placentas increta and percreta. When only accretas and controls were compared, the myometrial depth of trophoblast was similar. The mean intermediate trophoblast cell count in the placental bed was greater in cretas (664) than in controls (288, P<0.0001). Such difference was seen in all creta cases despite the type (accreta 639, increta 676, percreta 661). A trophoblast count of ≥100 cells/high-power field was seen in 75.8% of cretas and 11.1% of controls (P=0.0009). For the first time, we document the finding of chorionic villi intrusion into myometrial vascular spaces, which is highly specific of placenta creta. In addition, assessment of the amount of intermediate trophoblast using GATA3 immunohistochemistry can assist in the diagnosis. We hypothesize that placental invasion in placenta creta is due, at least partially, to transformation of low-resistance myometrial vessels leading to subsequent protrusion of villi into their lumens, in the context of absent decidua.

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

ObjectivePlacenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. MethodsExpression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction. Western blotting was used to analyze expression of the MCL1 protein in HTR8/SVneo trophoblast cells with altered expression of miR-29a/b/c. To determine their role in apoptosis, miR-29a/b/c were overexpressed in HTR-8/SVneo cells, and levels of apoptosis were analyzed by flow cytometry. Luciferase activity assays were used to determine whether MCL1 is a target gene of miR-29a/b/c. ResultsExpression of miR-29a/b/c was significantly lower in creta sites compared to noncreta sites (p = 0.018, 0.041, and 0.022, respectively), but expression of MCL1 was upregulated in creta sites (p = 0.039). MCL1 expression was significantly downregulated in HTR-8/SVneo cells overexpressing miR-29a/b/c (p = 0.002, 0.008, and 0.013, respectively). Luciferase activity assays revealed that miR-29a/b/c directly target the 3′ untranslated region of MCL1 in 293T cells. Over-expression of miR-29a/b/c induced apoptosis in the HTR-8/SVneo trophoblast cell line. Moreover, histopathological evaluation revealed that the number of implantation site intermediate trophoblast (ISIT) cells was increased in creta sites and that these cells were positive for MCL1. ConclusionsOur results demonstrate that in placenta accreta, miR-29a/b/c inhibits apoptosis of ISIT cells by targeting MCL1. These findings provide new insights into the pathogenesis of placenta accreta.

Exaggerated placental site/placental site trophoblastic tumor: an underestimated risk factor for emergency peripartum hysterectomy

Objective: To assess the indications and possible underlying causes of emergency peripartum hysterectomy (EPH) at the present hospital during the 2001-2011 period. Materials and Methods: A revision of the charts and pathology reports corresponding to 42,728 parturients. Results: During the study period, 25 peripartum hysterectomies were performed (0.61/1.000), of which 23 were EPHs (0.54/1.000) and two were planned cesarean hysterectomies. The indication for EPH was acute postpartum hemorrhage in 22 of 23 instances (95.7%). Roughly two-thirds of the operated uteri (16/25, 64%) showed placental site anomalies, half corresponding to different degrees of placental accretism and half to anomalies derived from the implantation site intermediate trophoblast. In five cases (31%), the anomaly was an exaggerated placental site and three cases corresponded to placental site trophoblastic tumors. Of the 16 cases showing placental site anomalies, ten (62.5%) were associated with one or more previous cesarean sections. Conclusions: Roughly one-third of EPHs performed at the present center during the last ten years were associated with placental site anomalies originating in the implantation site intermediate trophoblast (exaggerated placental site and placental site trophoblastic tumor). This association has not been described before, and should be taken into consideration when facing acute peripartum hemorrhage predisposing to EPH.

Transformation of a post-cesarean section placental site nodule into a coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor: a case report

Placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs) respectively represent non-neoplastic and neoplastic lesions of chorionic-type intermediate trophoblasts (ITs). Many patients with a PSN have a history of a cesarean section (CS) or therapeutic abortion. Recent evidence shows that a PSN may progress to an ETT. Herein, we describe a coexisting ETT and placental site trophoblastic tumor (PSTT) intimately associated with PSNs in the post-cesarean lower uterine segment of a 41-year-old woman. The patient presented with abnormal vaginal bleeding 1 year after a cesarean delivery for her most recent pregnancy. We speculated that the neoplasms had transformed from PSNs, the formation of which was related to faulty expulsion of the placental tissue or abnormal colonization of chorionic-type ITs during the CS. Neoplastic trophoblastic cells derived from PSNs displayed differentiation plasticity toward chorionic-type ITs and implantation site ITs that were respectively constituted of an ETT and PSTT.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1597949195882123

The Expression and Diagnostic Utility of p63 in the Female Genital Tract

p63 plays a key role in epithelial development in various organs, being expressed in myoepithelial cells and in basal cells of stratified epithelia. In the female genital tract, p63 is expressed in the basal and parabasal cells of mature cervical, vaginal and vulval squamous epithelium, and also in cervical reserve cells at the transformation zone and in immature metaplastic and atrophic cervical squamous epithelium. In this review, the diagnostic utility of p63 immunohistochemical staining in various pathologic scenarios within the female genital tract is discussed. Cervical microglandular hyperplasia is p63 positive with a characteristic subcolumnar location due to expression in reserve cells. There is increased expression in cervical intraepithelial neoplasia, in accordance with the degree of dysplasia. One of the most useful applications of p63 is in the evaluation of problematic cervical carcinomas; most squamous carcinomas exhibit diffuse nuclear immunoreactivity whereas most adenocarcinomas and neuroendocrine carcinomas are negative or focally positive. In conjunction with neuroendocrine markers, p63 is useful in distinguishing between a squamous carcinoma and a small cell or large cell neuroendocrine carcinoma. In the normal endometrium, a population of p63-positive cells is present which may act as a stem cell population and which is increased in various forms of metaplasia. Placental site nodule and epithelioid trophoblastic tumor (lesions derived from chorionic-type intermediate trophoblast) are usually p63 positive whereas placental site reaction and placental site trophoblastic tumor (lesions derived from implantation site intermediate trophoblast) are usually negative; thus, p63 may be useful in the diagnostic algorithm of trophoblastic lesions. p63 positivity in ovarian epithelial tumors is uncommon and largely restricted to squamous and transitional neoplasms, including benign and borderline Brenner tumor. p63 is also positive in cervical transitional metaplasia, Walthard rests, vulval Paget disease secondary to an underlying urothelial malignancy, tubulosquamous polyp of the vagina, and ectopic prostatic tissue in the cervix.

Immunohistochemistry of Choriocarcinoma

Choriocarcinoma is traditionally described as being composed of cytotrophoblast and syncytiotrophoblast. Microscopically, these 2 types of cells are intimately associated with each other, forming a characteristic biphasic plexiform pattern, however, the nature of these 2 types of trophoblastic cells is not well understood. In this study, we used immunohistochemistry for several trophoblastic markers to analyze the trophoblastic subpopulations in 36 gestational choriocarcinomas. Eighty-one specimens including placenta, complete mole, placental site nodule, epithelioid trophoblastic tumor, and placental site trophoblastic tumor were analyzed. The antibodies included Mel-CAM, HLA-G, MUC-4, and beta-catenin. A semiquantitative assessment of positive cells and the cellular localization of these markers were recorded. We found diffuse strong membranous and cytoplasmic staining for MUC-4 in mononucleate cells in all 36 cases (100%) and a similar pattern of localization in 28 cases (78%) for HLA-G. This distribution was similar to that in normal placentas, where MUC-4 and HLA-G are expressed in the trophoblastic cells of the trophoblastic columns and implantation site. In choriocarcinoma, mononucleate trophoblastic cells showed moderate immunoreactivity for Mel-CAM, a specific marker for implantation site intermediate trophoblast, in 78% of the cases. The MUC-4, HLA-G, and Mel-CAM-positive trophoblastic cells were larger than cytotrophoblastic cells, with more abundant cytoplasm, consistent with the morphology of intermediate trophoblast. In contrast, 31% of the choriocarcinomas contained a very small proportion (<5%) of mononucleate trophoblastic cells compatible with cytotrophoblast that was positive for nuclear beta-catenin, a cytotrophoblast-associated marker. These results suggest that choriocarcinoma is composed predominantly of a mixture of syncytiotrophoblast and intermediate trophoblast with only a small proportion of cytotrophoblast. The presence of nuclear beta-catenin staining in the cytotrophoblast of choriocarcinoma is consistent with the view that choriocarcinoma develops from transformed cytotrophoblastic cells which are presumably the cancer stem cells that differentiate into either intermediate trophoblast or syncytiotrophoblast.

Occult Placenta Accreta: The Missing Link in the Diagnosis of Abnormal Placentation

Placenta creta (accreta, increta, or percreta) is a clinically symptomatic condition, usually diagnosed histologically on hysterectomy specimens. At a minimum, focal absence of decidua is the histological finding for this condition; however, excessive amounts of extravillous trophoblasts were recently documented on hysterectomy specimens. The histological finding of basal plate myometrial fibers (BPMF) without intervening decidua in spontaneously delivered placentas, which we term occult placenta accreta (OPA), is not infrequent, even in clinically asymptomatic cases. To prove that OPA is a missing link between normal placental implantation and clinical placenta accreta, CD146 immunohistochemical stains were performed on 25 sections of OPA (study group) and 25 placental sections without BPMF (control group). Implantation-site intermediate trophoblast (ISIT) cell number, thickness, and density were compared between the study and control groups. The ISIT micrometry thickness and cell number at BPMF sites were statistically significantly higher in OPA than in control group and same OPA placentas away from BPMF. There were no statistically significant differences in ISIT density. Therefore, although asymptomatic, OPA features the same histopathology as clinical placenta accreta and may share same pathogenesis, which may include decidual deficiency, abnormal trophoblast/decidua interaction, and/or hypoxia.

Villotrophoblastic Pulmonary Nodule With Implantation Site Intermediate Trophoblasts After Induced Abortion

We describe a case of villotrophoblastic pulmonary nodule with a hitherto unrecognized implantation site intermediate trophoblasts (ISITs) in an asymptomatic 19-year-old woman, who had an induced abortion 1 month before the discovery of a pulmonary nodule. This 8-mm-sized nodule was incidentally identified on chest computed tomography during routine postoperative follow-up for osteosarcoma, for which she was treated with surgery and chemotherapy 3 years previously. The nodule was located in the subpleural lung parenchyma and was composed histologically of a few chorionic villi and trophoblasts surrounded by fibrinoid materials, with individually scattered intermediate trophoblasts at the periphery of the nodule. The intermediate trophoblasts were strongly immunopositive for cytokeratin, human placental lactogen, and Mel-CAM (CD146), but immunonegative for human chorionic gonadotropin and p63, characteristic features of ISITs. Our case indicates that villotrophoblastic pulmonary emboli have the potential to implant after migration from their original sites through the invasive property of ISITs.

Placental site trophoblastic tumor: report of four cases and review of literature

Placental site trophoblastic tumor (PSTT) is a rare variant of gestational trophoblastic disease that originates from the implantation site intermediate trophoblast. We report four patients with PSTT and review pertinent literature. Three patients presented with disease confined to the uterus and one patient with disease extension beyond the uterus. Antecedent pregnancy was full-term pregnancy in three patients and termination of a 21-week pregnancy in one patient. Interval from the antecedent pregnancy was <1 year in three patients and 13 years in one patient. Primary treatment was simple hysterectomy in three patients and radical hysterectomy in one patient. Overall, three patients received chemotherapy; one had EP/EMA as adjuvant chemotherapy, one had EMA/CO for rising levels of serum beta-hCG and one had BEP then VIP for recurrent disease. The three patients with disease confined to the uterus have remained after treatment alive and with no evidence of disease, whereas the one patient with disease extension beyond the uterus died of disease despite surgery and aggressive chemotherapy. It is concluded that disease extension beyond the uterus is the most important adverse prognostic factor. Other adverse prognostic factors are interval from antecedent pregnancy >2 years, age >40 years, and mitotic count >5 mitotic figures/10 high-power fields. Because of the relative insensitivity to chemotherapy, hysterectomy is the mainstay of treatment. EP/EMA seems to be the most effective first-line chemotherapy available to date for metastatic and relapsing PSTT.

Clinicopathologic study of tumors of intermediate trophoblasts

To study the clinicopathologic features and immunophenotype of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). During the period from 1959 to 2005, a total of 1012 cases of gestational trophoblastic disease were diagnosed in Beijing Obstetrics and Gynecology Hospital. Six cases of PSTT and a case of ETT were retrieved from the archives of Beijing Obstetrics and Gynecology Hospital. Immunohistochemical study for cytokeratin 18, human chorionic gonadotropin (hCG), human placental lactogen (hPL), Mel-CAM (CD146), placental-like alkaline phosphatase (PLAP), epithelial membrane antigen (EMA), inhibin-alpha and proliferative cell nuclear antigen (PCNA) were performed. The morphologic features and immunohistochemical findings were compared with those of the controlled group which consisted of 20 cases of early gestational villi with decidua basalis and 20 cases of hydatidiform moles with implantation site. The mean age of patients with PSTT was 32.4, while the age of patients with ETT was 36. Major clinical findings included irregular vaginal bleeding and amenorrhea. Preoperative serum hCG level varied from normal to moderately elevated. Serum testosterone level was raised in 1 case. Uterine curettage could achieve an accurate pathologic diagnosis in 60% of cases. ETT involved mainly the lower uterine segment and endocervix. Histologically, PSTT cells permeated between the myometrial fibers and vessels either individually or connecting in cords or sheets in a manner reminiscent of the implantation site reaction. ETT composed of a relatively uniform population of mononuclear trophoblastic cells, clumping together in nests as the cell islets associating with eosinophilic, fibrillary and hyaline material and necrotic debris, forming a "geographic map" like pattern. Immunohistochemical study for hPL, hCG, Mel-CAM (CD146) and PLAP was most helpful for the differential diagnosis. The duration of follow-up varied from 14 months to 19 years. One case of PSTT developed metastasis in pancreas, 5 months after the operation. The remaining patients survived without tumor recurrence. PSTT is a tumor of implantation site intermediate trophoblasts while ETT differentiates towards chorionic-type intermediate trophoblasts. The different pathologic features and immunophenotype observed were closely related with the difference in tumor cell differentiation. An accurate pathologic diagnosis of the uterine curettage material is important for the clinical management. According to the limited follow-up data available, the clinical behavior of ETT is seemed similar to that of PSTT.

Id helix‐loop‐helix proteins are differentially expressed in gestational trophoblastic disease

To assess the expression of Id proteins in trophoblastic tissues and to correlate this with clinical parameters, proliferative and apoptotic indices as well as to related oncogene expression. Immunohistochemistry for Id1, Id2, Id3 and Id4 was performed on 83 trophoblastic tissues including 17 normal first-trimester placentas, seven term placentas, 47 hydatidiform moles (HM), and 12 spontaneous miscarriages. The four Id proteins were predominantly expressed in the villous and implantation site intermediate trophoblast. Expression of Id1 in HM was significantly higher than that in normal placenta (P = 0.0006) and spontaneous miscarriage (P = 0.0001) but did not correlate with subsequent development of gestational trophoblastic neoplasia (GTN). Id1 expression correlated with the proliferation index as assessed by MCM7 (P = 0.003) and Ki67 (P = 0.017) and with the apoptotic activity assessed by TUNEL (P = 0.001) and M30 CytoDeath antibody (P = 0.013). Moreover, the expression of Id1 correlated with the expression of p53 (P = 0.004), p21(WAF1) (/CIP1) (P = 0.003) but not with p16 (P = 0.107). Id proteins may play a role in the regulation of proliferative and apoptotic activity in trophoblastic tissue and are potentially useful in differentiating molar and non-molar gestation, but are not helpful in predicting GTN.

Implantation site intermediate trophoblasts in placenta cretas

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas. To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300±1200 μm) than noncretas (1500±1200 μm, P<0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P<0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly. These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.

The Role of E-cadherin in the Motility and Invasion of Implantation Site Intermediate Trophoblast.

During early pregnancy, intermediate (extravillous) trophoblast infiltrates the basal plate and invades the spiral arteries, a physiological process required to establish the maternal-fetal circulation. Immunostaining studies have shown that differentiation of trophoblast into this invasive subpopulation is associated with down-regulation of E-cadherin expression. To study the function of E-cadherin in trophoblast in vitro, we restored E-cadherin expression in an E-cadherin negative human implantation site intermediate trophoblastic cell line, IST-1, using a recombinant adenovirus, E-cad/Ad5 which constitutively expresses E-cadherin. In contrast to the control IST-1 cells which were individual and pleomorphic in shape, E-cad/Ad5 transduced cells were cohesive, uniform, and round. The motility and invasiveness of E-cad/Ad5 transduced IST-1 cells, as compared with the control cells, was significantly reduced. These effects were contact-dependent and were attenuated by a function-perturbing anti-E-cadherin antibody. In conclusion, our results indicate that expression of E-cadherin in IST-1 cells results in a contact-mediated inhibition of motility and invasion and suggest an important role for E-cadherin down-regulation in the intermediate trophoblast during implantation.

The Role of E-cadherin in the Motility and Invasion of Implantation Site Intermediate Trophoblast

During early pregnancy, intermediate (extravillous) trophoblast infiltrates the basal plate and invades the spiral arteries, a physiological process required to establish the maternal–fetal circulation. Immunostaining studies have shown that differentiation of trophoblast into this invasive subpopulation is associated with down-regulation of E-cadherin expression. To study the function of E-cadherin in trophoblast in vitro, we restored E-cadherin expression in an E-cadherin negative human implantation site intermediate trophoblastic cell line, IST-1, using a recombinant adenovirus, E-cad/Ad5 which constitutively expresses E-cadherin. In contrast to the control IST-1 cells which were individual and pleomorphic in shape, E-cad/Ad5 transduced cells were cohesive, uniform, and round. The motility and invasiveness of E-cad/Ad5 transduced IST-1 cells, as compared with the control cells, was significantly reduced. These effects were contact-dependent and were attenuated by a function-perturbing anti-E-cadherin antibody. In conclusion, our results indicate that expression of E-cadherin in IST-1 cells results in a contact-mediated inhibition of motility and invasion and suggest an important role for E-cadherin down-regulation in the intermediate trophoblast during implantation.

HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis.

HLA-G is a nonclassical MHC class I antigen that has been shown to be a specific marker for normal intermediate trophoblast (IT). In this study HLA-G immunoreactivity assessed with an HLA-G specific antibody (4H84) was detected in all 14 cases of choriocarcinoma, 14 placental site trophoblastic tumors, 13 epithelioid trophoblastic tumors, 16 placental site nodules, and nine exaggerated placental sites. In contrast, HLA-G immunoreactivity was not detected in 34 nontrophoblastic uterine neoplasms. HLA-G immunoreactivity was present in all the IT cells of exaggerated placental sites and placental site trophoblastic tumors and in 70-100% of IT cells in placental site nodules and epithelioid trophoblastic tumors. The pattern of distribution of HLA-G in different subpopulations of IT confirms the relationship of various trophoblastic lesions to different types of IT (exaggerated placental site and placental site trophoblastic tumor to implantation site IT and placental site nodule and epithelioid trophoblastic tumor to chorionic-type IT) and suggests that choriocarcinoma is related to villous-type IT because the majority of mononucleate cells in this neoplasm were HLA-G immunoreactive. In conclusion, HLA-G immunoreactivity appears to be specific for IT in gestational trophoblastic disease and can serve as a useful marker in the differential diagnosis of these 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.

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-α 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.

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.

Dignity and death: a reply.

Some form of utilitarian approach can be discerned as underlying much current medical ethical decision-making. Criticisms of the practical effects of such an approach are not parried by asserting the fundamental strengths of utilitarianism as theory.