Pathology of Gestational Trophoblastic Lesions

Selected References

  • Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol, 20:31-47, 2001.
    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.

  • Shih IM, Kurman RJ. Molecular basis of gestational trophoblastic diseases. Curr Mol Medicine, 2:1-12, 2002.
    Gestational trophoblastic disease (GTD) encompasses a diverse group of lesions with specific pathogenesis, morphological characteristics and clinical features. The modified World Health Organization-classification of GTD includes complete and partial hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor, exaggerated placental site, and placental site nodule. The various forms of gestational trophoblastic disease can be defined and related to discrete pathologic aberrations occurring at different stages of trophoblastic differentiation. Some of these lesions are true neoplasms, whereas others represent abnormally formed placentas with a predisposition for neoplastic transformation of the trophoblast. Except hydatidiform moles in which the cytogenetic studies have been extensively reported, the pathogenesis of other trophoblastic lesions is poorly understood. Recent studies have shed light on the molecular mechanisms of trophoblastic function, especially as it relates to trophoblastic disease. This review will focus on these advances with special emphasis on the pathogenesis of each specific form of GTD. In addition, the morphology and clinical behavior of each of these entities will be briefly discussed.

  • Shih IM, Kurman RJ. Placental site trophoblastic tumor- past as prologue. Gynecol Oncol, 82:413-414, 2001.
    (No abstract available)

  • Shih IM, Seidman JD, Kurman RJ. Placental site nodule and characterization of distinctive types of intermediate trophoblast. Hum Pathol, 30:687-694, 1999.
    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.

  • Shih IM, Kurman RJ. Epithelioid trophoblastic tumor --- a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol, 22:1393-1403, 1998.
    This report describes the clinicopathologic and immunohistochemical features of 14 cases of epithelioid trophoblastic tumor (ETT), a distinctive but rare gestational trophoblastic tumor. The patients with this neoplasm were in the reproductive age group and presented with abnormal vaginal bleeding. Although diagnosis was usually associated with a gestational event, the latter was sometimes remote. Two of the 14 patients presented with extrauterine ETT without evidence of prior gestational trophoblastic disease in the uterus. Serum human chorionic gonadotropin levels were elevated in eight of nine patients in whom this information was available. In the uterus, ETT presented as a discrete, hemorrhagic, solid and cystic lesion that was located either in the fundus, lower uterine segment, or endocervix. Microscopically, the tumor was composed of a relatively uniform population of mononucleate intermediate trophoblastic cells forming nests and solid masses. The cells resemble the trophoblastic cells in the chorion laeve, and we have therefore designated them "chorionic-type intermediate trophoblast." Typically, islands of trophoblastic cells were surrounded by extensive necrosis and were associated with a hyaline-like matrix creating a "geographic" pattern that is quite characteristic of this lesion. The mean mitotic count was two mitoses per 10 high-power fields, and the average Ki-67 nuclear labeling index was 18%. Immunohistochemically, all cases were diffusely positive for inhibin-alpha, cytokeratin (AE1/AE3), epithelial membrane antigen, E-cadherin, prolyl 4-hydroxylase, and epidermal growth factor receptor but were only focally immunoreactive for human placental lactogen, human chorionic gonadotropin, PlAP, and Mel-CAM. The monomorphic growth pattern of ETT resembles placental site trophoblastic tumor to a much greater degree than choriocarcinoma which is characterized by a dimorphic population of trophoblast. In contrast to placental site trophoblastic tumor, the cells of ETT are smaller and display less nuclear pleomorphism. In addition, ETT grows in a nodular fashion compared with the infiltrative pattern of placental site trophoblastic tumor. In some of the cases, the trophoblastic cells in ETT replaced the endocervical surface epithelium, giving the appearance that the tumor was derived from the cervix. Moreover, because the associated hyaline-like material in ETT resembles keratin, the tumor can be misinterpreted as a keratinizing squamous cell carcinoma of the cervix. Ten patients underwent total hysterectomy and two had an endometrial curettage only. The two patients who presented with extrauterine ETT underwent small bowel resection and lung resection. Two of 12 patients with ETT in the uterus developed metastasis in the lungs and bone. One of these patients is alive with disease at 43 months and one patient was lost to follow-up after 2 months. One of the two patients who had extrauterine disease died of widespread tumor 36 months after diagnosis. The remainder of the patients are alive and well from 1 to 120 months. In summary, ETT is a rare trophoblastic tumor that simulates carcinoma and can behave in a malignant fashion. It appears to be less aggressive than choriocarcinoma, more closely resembling the behavior of placental site trophoblastic tumor. Based on the morphologic and immunohistochemical features, it appears that ETT develops from neoplastic transformation of chorionic-type intermediate trophoblast.

  • Markers in trophoblastic lesions and differential diagnosis Shih IM and Kurman RJ. p63 expression is useful in the distinction of epithelioid trophoblastic tumors and placental site trophoblastic tumor by profiling trophoblastic subpopulations. Am J Surg Pathol, 28:1177-1183, 2004.
    Human trophoblast is composed of a heterogeneous population of cells which give rise to a variety of trophoblastic tumors and tumor-like lesions. In this report, we analyzed the expression pattern of the p63 gene, a transcription factor belonging to the p53 family, in different trophoblastic subpopulations and in trophoblastic lesions. p63 has various isoforms that are classified into two groups designated TA and Np63 isoforms. The TA isoforms have a p53-like suppressor function whereas the Np63 isoforms exert an oncogenic effect. Based on immunohistochemistry and RT-PCR, it appears that cytotrophoblast expresses the Np63 isoform whereas chorionic-type intermediate trophoblast in the fetal membranes, placental site nodules and epithelioid trophoblastic tumors expresses the TAp63 isoform. Intermediate trophoblast in the implantation site and placental site trophoblastic tumors does not express p63. Based on the expression patterns of p63 and the previously described expression patterns of other trophoblastic markers including HLA-G, cytokeratin 18, hPL and Ki-67, we developed an immunohistochemical algorithm to diagnose trophoblastic lesions. A validation set of 22 trophoblastic lesions and 34 non-trophoblastic tumors were classified correctly using this algorithm. In conclusion, the findings in this study demonstrate that different trophoblastic subpopulations and their related trophoblastic lesions are characterized by distinctive patterns of p63 expression. Recognizing these distinctive expression patterns helps to further elucidate the biology of trophoblast and can also provides a useful tool for the differential diagnosis of trophoblastic lesions.

  • Shih IM, Kurman RJ. Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies. Hum Pathol, 29:27-33, 1998.
    The diagnosis of placental site trophoblastic lesions, particularly the distinction of a placental site trophoblastic tumor from an exaggerated placental site, can be difficult. Mel-CAM (also known as CD146 and MUC18) is a recently recognized cell adhesion molecule belonging to the immunoglobin gene superfamily that specifically identifies intermediate trophoblast (IT). In this study, we evaluated immunohistochemical staining of Ki-67 (using Mib-1 antibody) in Mel-CAM defined IT as an aid in the differential diagnosis of these lesions. Formalin-fixed tissue samples from 24 normal implantation sites, 19 exaggerated placental sites, five molar implantation sites, 16 placental site trophoblastic tumors, and 12 choriocarcinomas were stained with a Mel-CAM-specific polyclonal antibody and a Ki-67 antibody using streptavidin-biotin immunoperoxidase with two different chromagens. No Ki-67 nuclear labeling was seen in IT of normal implantation sites. The Ki-67 index (mean +/- standard deviation) in IT of exaggerated placental site was near zero, but in the molar implantation sites the Ki-67 index was 5.2% +/- 4.0%. In contrast, the Ki-67 index in IT of placental site trophoblastic tumor was 14% +/- 6.9% and in choriocarcinoma was 69% +/- 20%. The differences in the Ki-67 labeling index were statistically significant (P < .001) between exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma. In conclusion, a double-staining technique using MIB-1 antibody to determine the Ki-67 proliferative index in Mel-CAM defined IT is a useful technique in the differential diagnosis of exaggerated placental site versus placental site trophoblastic tumor and placental site trophoblastic tumor versus choriocarcinoma.

  • Singer G, Kurman RJ, McMaster MT, Shih IM. HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis. Am J Surg Pathol, 26:914-920, 2002.
    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.

  • Shih IM, Kurman RJ. Immunohistochemical localization of inhibin-alpha in the human placenta and gestational trophoblastic lesions. Int J Gynecol Pathol, 18:144-150, 1999.
    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.

  • Shih IM, Kurman RJ. Expression of melanoma cell adhesion molecule in intermediate trophoblast. Lab Invest, 75: 377-388, 1996.
    Melanoma cell adhesion molecule (Mel-CAM), also known as MUC18, is a cell adhesion molecule belonging to the immunoglobulin supergene family. Because of the importance of cell adhesion molecules in trophoblastic function and development, we studied the immunohistochemical distribution of Mel-CAM in trophoblastic cells in the implantation site and the normal placenta and compared it with a variety of gestational trophoblastic lesions. Formalin-fixed paraffin-embedded tissues from 44 normal placentas, 54 implantation sites (37 normal and 17 exaggerated), 13 hydatidiform moles, 13 placental site trophoblastic tumors (PSTT), and 16 choriocarcinomas were evaluated for Mel-CAM expression in trophoblast using a Mel-CAM-specific polyclonal antibody and an immunoperoxidase method. Mel-CAM was demonstrated in intermediate trophoblastic (IT) cells in all normal placentas, implantation sites, and exaggerated placental sites. Mel-CAM staining was also found in all the multinucleated IT cells in the placental site. In contrast, Mel-CAM was not detected in either cytotrophoblast (CT) or syncytiotrophoblast (ST). Similarly, in hydatidiform moles, Mel-CAM was confined to IT. In trophoblastic neoplasms, Mel-CAM was expressed in all 13 placental site trophoblastic tumors, and in 14 of 16 (88%) choriocarcinomas. Mel-CAM staining was localized to IT in both placental site trophoblastic tumors and in choriocarcinomas. In conclusion, Mel-CAM is a specific and sensitive marker for IT differentiation in normal placentas, implantation sites, and in gestational trophoblastic lesions. The differential staining pattern of Mel-CAM provides support for a dual pathway of trophoblastic differentiation in the normal placenta and in gestational trophoblastic lesions in which CT differentiates directly into ST on the villous surface, compared with the differentiation of CT to IT and then into multinucleated IT cells in extravillous sites. In view of the difficulty in distinguishing IT from CT by conventional light microscopy, it is proposed that IT cells be defined on the basis of both their morphologic features and immunophenotype as a mononucleate trophoblastic cell that expresses Mel-CAM.

  • Oldt R J, Kurman RJ, Shih IM. Molecular genetic analysis of placental site trophoblastic tumors and epithelioid trophoblastic tumors confirms their trophoblastic origin. Am J Pathol, 161:1033-1038, 2002.
    Trophoblastic tumors represent a unique group of human neoplasms because they are derived from fetal tissue. Except for choriocarcinoma, the neoplasms that develop from human trophoblast are poorly characterized. Placental site trophoblastic tumors and epithelioid trophoblastic tumors are thought to arise from intermediate (extravillous) trophoblasts based on histopathological studies, but direct molecular evidence of a trophoblastic origin has not been established. In this study, we performed molecular analysis in an attempt to confirm their presumable trophoblastic origin. We demonstrated that such tumors contain a Y-chromosomal locus and/or new (paternal) alleles not present in adjacent normal uterine tissue in all 31 informative cases. Loss of heterozygosity was found in 60% of tumors and all 42 tumors assessed contained wild-type K-ras. All of the trophoblastic tumors were heterozygous in at least 1 of 10 single-nucleotide polymorphism markers studied in contrast to homozygosity in all 10 single-nucleotide polymorphism markers in most complete hydatidiform moles indicating that these tumors are not related to complete hydatidiform moles. This study provides the first molecular evidence that placental site trophoblastic tumors and epithelioid trophoblastic tumors are of fetal (trophoblastic) origin.

  • Shih IM, Hsu M-Y, Oldt RJ III, Herlyn M, Gearhart JD, Kurman RJ. The role of E-cadherin in the motility and invasion of implantation site intermediate trophoblast. Placenta, 23:706-715, 2002.
    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.

  • Shih IM, Wang T-L, Wu T-C, Kurman RJ, Gearhart JD. Expression of Mel-CAM in implantation site intermediate trophoblastic cell line, IST-1, limits its migration on uterine smooth muscle cells. J Cell Sci, 111: 2655-2664, 1998.
    An immortalized implantation site intermediate trophoblastic cell line, IST-1, was established from a human placenta of 7 weeks gestation. IST-1 cells phenotypically resembled the implantation site intermediate trophoblastic cells in situ and expressed Mel-CAM (MUC 18 or CD146). Mel-CAM is a cell adhesion molecule belonging to the immunoglobulin gene superfamily. It is involved in heterophilic cell-cell adhesion and plays a role in several biological processes including tumor progression. We have previously shown that Mel-CAM was highly expressed in the intermediate (extravillous) trophoblast in the human implantation site. In this study we determined the function of Mel-CAM in the interaction of trophoblast and uterine smooth muscle in the implantation site. IST-1 cells failed to adhere to immobilized recombinant Mel-CAM in solid phase whereas the uterine smooth muscle cells did. The presence of the putative Mel-CAM ligand in smooth muscle cells was further supported by the finding that Mel-CAM-transfected but not the mock-transfected U937 leukemia cells bind to the confluent monolayer of uterine smooth muscle cells. IST-1 cells attached efficiently to the monolayer of the uterine smooth muscle cells and acquired a spindle-shaped morphology simulating smooth muscle cells. The cell binding was only marginally affected by Mel-CAM blocking antibodies. However, Mel-CAM blocking antibodies and recombinant Mel-CAM promoted cell migration from IST-1 cell spheroids on the smooth muscle monolayer. Taken together, our results suggest that IST-1 cells express Mel-CAM but not the putative Mel-CAM ligand. In contrast, the uterine smooth muscle cells express the putative Mel-CAM ligand which binds to Mel-CAM on the surface of the IST-1 cells. The interaction between Mel-CAM and its putative ligand confers a stationary phenotype for trophoblastic cells. These observations are consistent with an important role for Mel-CAM in limiting trophoblastic migration within the myometrium in the implantation site.