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We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems., (© 2023. The Author(s).)

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Trophoblastic differentiation of endometrial carcinoma is extremely rare, till date 18 cases reports are there in the literature. A 68-year-old postmenopausal female presented with abnormal vaginal bleeding. Histopathologically, there were areas of serous carcinoma with trophoblastic differentiation (~90%). On immunohistochemistry, the trophoblastic component was positive for β-human chorionic gonadotropin (hCG), HPL and EMA. IHC confirmed the diagnosis of serous carcinoma with trophoblastic differentiation. The clinicopathological features of 18 previously reported cases of trophoblastic differentiation in the uterine tumor were analyzed in addition to the present case., Competing Interests: There is no conflict of interest

Tumors of trophoblastic derivation other than choriocarcinoma are very rare in the testis but have been reported on occasion in association with other germ cell tumors. Their morphologic spectrum is analogous to the trophoblastic tumors of the female genital tract including epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT). Herein we report our experience with 8 cases of trophoblastic tumors of testicular origin that lacked the features of choriocarcinoma; these included 4 ETTs, 1 PSTT, 1 unclassified trophoblastic tumor (UTT), 1 partially regressed choriocarcinoma with a monophasic morphology, and 1 hybrid tumor showing a mixture of adenocarcinoma and a UTT. All tumors occurred in young men 19 to 43 years old. Five arose de novo within the testis (2 ETTs, 1 UTT, 1 regressing choriocarcinoma, and the hybrid tumor) as a component of mixed germ cell tumors, and 3 (2 ETTs and 1 PSTT) were found in metastatic sites after chemotherapy. The trophoblastic component was minor (5% to 10%) in 6 tumors but was 95% of 1 metastatic tumor (ETT) and 50% of the hybrid tumor. Other germ cell tumor elements were identified in all cases, most commonly teratoma. The ETTs consisted of nodules and nests of squamoid trophoblast cells showing abundant eosinophilic cytoplasm, frequent apoptotic cells, extracellular fibrinoid material, and positivity for p63 and negativity for human placental lactogen (HPL). The PSTT showed sheets of discohesive, pleomorphic, mononucleated trophoblast cells that invaded blood vessels with fibrinoid change and were p63 negative and HPL positive. The UTT showed a spectrum of small and large trophoblast cells, some multinucleated but lacking distinct syncytiotrophoblasts, and was patchily positive for both p63 and HPL. The hybrid tumor had ETT-like and adenocarcinomatous areas that coexpressed inhibin and GATA3 but were negative for p63 and HPL, leading to classification of the trophoblastic component as UTT. Seven of the patients were alive and well on follow-up (8 to 96 mo; median, 39 mo), whereas the patient with the hybrid tumor died of liver metastases at 2 years. Our study verifies that trophoblastic neoplasms often having the features of nonchoriocarcinomatous gestational trophoblastic tumors may arise from the testis, occur either in the untreated primary tumor or in metastases after chemotherapy, and should be distinguished from choriocarcinoma given what appears to be a less aggressive clinical course.

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

Immunohistochemical expression of GATA-3 is seen predominantly in non-neoplastic bladder and breast epithelium and their respective carcinomas; however, data on expression in normal and lesional trophoblastic tissues are limited. Immunohistochemical staining for GATA-3 was assessed in a range of normal/lesional trophoblastic tissues and tumors in the differential diagnosis (n=445), including nonmolar products of conceptions/second and third trimester placentas/ectopic pregnancies, hydatidiform moles, placental site nodules, normal/exaggerated implantation sites, choriocarcinomas, epithelioid trophoblastic tumors, placental site trophoblastic tumors, atypical smooth muscle tumors (including leiomyosarcoma), and cervical and pulmonary squamous cell carcinomas. The extent of expression (0 to 4+) and intensity (weak to strong) were recorded. All cases with developing trophoblast/non-neoplastic trophoblastic proliferation and 81% of trophoblastic neoplasms were positive. Of all non-neoplastic trophoblast cell types, expression was observed in cytotrophoblast in 89% of cases, syncytiotrophoblast in 50%, intermediate trophoblast in 100%, and villous trophoblastic columns in 100%. Increasing gestational age was associated with a decrease in extent/intensity of expression in non-neoplastic cytotrophoblast and syncytiotrophoblast, whereas intermediate trophoblast maintained diffuse and strong expression from early to late gestation (P<0.0001). Eighty-nine percent of normal/exaggerated implantation sites showed 3+ or 4+ expression, whereas staining in 55% of placental site nodules was 1+ or 2+. Staining for GATA-3 was present in 78% of choriocarcinomas, 95% of epithelioid trophoblastic tumors, and 71% of placental site trophoblastic tumors. Although the number of choriocarcinomas and placental site trophoblastic tumors that showed a spectrum of expression ranging from negative to diffuse was relatively evenly distributed, 81% of epithelioid trophoblastic tumors had 3+ or 4+ staining. None of the atypical smooth muscle tumors and 3% of squamous cell carcinomas were positive, all of which exhibited weak staining. We conclude that GATA-3 is frequently expressed in normal and lesional trophoblastic tissues. It is also differentially expressed in intermediate trophoblast and cytotrophoblast/syncytiotrophoblast, which varies according to time during pregnancy. This study expands the spectrum of neoplasms known to express GATA-3. Thus, recognition of expression in trophoblastic tumors is important, because it can present a diagnostic pitfall in the assessment of suspected metastatic bladder or breast carcinomas involving the gynecologic tract. In the evaluation of diagnostically problematic tumors for which trophoblastic neoplasms are in the differential diagnosis, such as leiomyosarcoma and squamous cell carcinoma, GATA-3 can be included as part of an immunohistochemical panel particularly when other trophoblastic markers are either not available or yield ambiguous results.

Pulmonary extrauterine epithelioid trophoblastic tumors (ETTs) are extremely rare. A 26-year-old nonsmoking woman with a history of a suspected subclinical miscarriage presented with a large mass in the right lower lobe that was confirmed to be a pulmonary extrauterine ETT using immunohistochemical stains. When a nonsmoking fertile woman presents with a pulmonary mass and an elevated serum β-human chorionic gonadotrophin in the absence of gynecologic disease, pulmonary extrauterine ETT should be considered., (Georg Thieme Verlag KG Stuttgart · New York.)

Our objective was to describe the clinicopathologic features of epithelioid trophoblastic tumors (ETTs) in a series of patients who presented with elevated beta-human chorionic gonadotrophin (hCG) levels and extrauterine lesions resembling primary lung carcinomas. Clinical and pathologic materials were reviewed and Shih and Kurman's diagnostic criteria were applied. Three parous women (38, 49, and 34 y of age) with elevated beta-hCG levels had nondiagnostic gynecologic evaluations, including negative dilation and curettage specimens. Imaging revealed isolated pulmonary lesions, 2 to 8.5 cm in size, resembling primary lung carcinomas. Two patients received multiagent chemotherapy consisting of etoposide, methotrexate, dactinomycin, alternating with cisplatin and etoposide, and all underwent pulmonary resection. Histologically, the cytologic features, epithelioid growth pattern, and hyaline-like material simulated the appearance of nonsmall cell lung carcinoma, but overall, the histologic features along with the immunophenotype supported classification as ETT. Follow-up hysterectomy specimens were histologically normal. All 3 patients are alive and well. The rarity of ETT and its resemblance to squamous and pleomorphic carcinomas of lung have led to diagnostic difficulties. When reproductive-age women present with elevated beta-hCG levels, a pulmonary lesion, and no apparent intrauterine disease, primary pulmonary ETT should be considered. Correlating clinical indices with specific morphologic and immunohistochemical features can ensure diagnostic accuracy and appropriate treatment for favorable outcomes.

Background & Objective: High expression of replication factor C (RFC) mRNA in hydatidiform mole and choriocarcinoma were detected previously with DNA microarray. Replication factor C subunit 2 (RFC2) was reported to be associated with DNA duplication, DNA repair, and the function of cellular checkpoint. The aim of current study was to investigate the expression levels of RFC2 and proliferating cell nuclear antigen (PCNA) in gestational trophoblastic diseases (GTD) and to explore the relationship of expressions of two proteins with GTD., Methods: The expression of RFC2 and PCNA were detected with immunohistochemical method in 15 cases of normal villi, 38 cases of hydatidiform moles (HM), 42 cases of invasive moles (IM), and 18 cases of choriocarcinomas (CC)., Results: The expression of RFC2 and PCNA were significantly increased in HM, IM, and CC than in normal villi (P=0.000 for RFC2,P=0.004 for PCNA). There was no significant difference of the expression of RFC2 among HM, IM, and CC. The PCNA expression was significantly higher in CC than in HM (P=0.037). PCNA expression was significantly higher in the patients with malignantly transformed molar pregnancy than in the patients without malignantly transformed molar pregnancy (P=0.039). RFC2 expression in no preoperative chemotherapeutic group of gestational trophoblastic tumors (GTT) including IM and CC was significantly higher than that in the group with the chemotherapy of more than 3 cycles (P=0.028). Compared with patients at stageI, patients at stage III (WHO) had significantly increased expression of RFC2 (P=0.01). The level of RFC2 was higher in the patients with high risk in WHO prognostic scoring system than that in the patients with low risk (P=0.018). The levels of PCNA were significantly higher in the patients with high risk and middle risk than that in the patients with low risk (P=0.036 and P=0.048, respectively). The expression of PCNA protein was not associated with the preoperative chemotherapy and WHO stage of GTT. The RFC2 expression was positively correlated with the PCNA expression (P=0.000)., Conclusion: The over-expression of RFC2 and PCNA in GTD may be associated with the malignant transformation of HM and the behavior of trophoblastic tumor.

A case of epithelioid trophoblastic tumour (ETT), occurring in a fallopian tube of a 39-year-old woman, is reported. The patient presented with a positive pregnancy test, but continued to have 'periods'. A palpable right adnexal mass was noted that was confirmed on ultrasound. The mass was removed together with the uterus, omentum and associated ovary. Careful examination of the uterus revealed no evidence of either an antecedent tumour or intra-uterine pregnancy. Histologically, the tubal mass displayed sheets and islands of large, relatively uniform, mitotically active polyhedral cells, with surrounding necrosis. The immunoprofile of the tumour was atypical in that alpha-inhibin and epidermal growth factor were weakly positive, but other results were consistent with the diagnosis of ETT. The patient received a foreshortened course of standard EMACO (etoposide, actinomycin-D, methotrexate, vincristine, and cyclophosphamide) combination chemotherapy for high-risk gestational trophoblastic disease. Serum beta-hCG fell from a pre-operative level of 52 000 U/mL to non-pregnant levels within two courses and she remains well and disease-free 12 months post-diagnosis.

SALL1 was originally identified on the basis of its DNA sequence homology to the region-specific homeotic gene Sal, in Drosophila melanogaster, which acts as a downstream target of hedgehog/tumor growth factor-beta-like decapentaplegic signals. The SALL1 gene has been associated with the Townes-Brocks Syndrome (TBS), a disorder characterized by multiorgan dysgenesis including renal and genital malformations. In this study, SALL1 message production was evaluated in association with the tissue localization of the protein product of SALL1, p140. SALL1 protein expression was observed in various adult and fetal tissues which elaborate reproductive endocrine hormones. The p140 was localized in specific microanatomic sites of the pituitary, adrenal cortex and the placenta. In the human pituitary, SALL1 protein expression was limited to the adenohypophysis, where it colocalized to those cells producing GH and the gonadotropins, LH and FSH. SALL1 expression was also found in most of the fetal and adult adrenal cortex in addition to the trophoblastic cells of the placenta. This pattern of expression complements prior studies demonstrating p140 in testicular fetal Leydig cells, adult Leydig and Sertoli cells, and granulosa cells of the ovary. The SALL1 protein was also shown here to be highly expressed in trophoblast tumors, which overproduce sex hormones. The expression patterns of SALL1 at multiple levels of the reproductive endocrine axis and the phenotypic effects associated with TBS suggest that SALL1 may have an important role in the interaction of the pituitary-adrenal/gonadal axis during reproduction.

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.

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.

Recent years have seen the publication of many articles investigating the value of antibodies against inhibin in diagnostic surgical pathology. This review concentrates on the uses of inhibin staining in gynecological pathology. alpha-inhibin is diagnostically the most useful antibody and is a sensitive immunohistochemical marker of most ovarian sex cord-stromal tumors and, as such, is of value in the diagnosis of this heterogeneous group of neoplasms that can be confused morphologically with a wide range of other tumors. Because the antibody is not entirely specific for ovarian sex cord-stromal tumors, it should always be used as part of a larger panel. alpha-inhibin staining may also be of value in confirming late recurrence or metastasis of an ovarian sex cord-stromal tumor, especially a granulosa cell tumor. Sex cord-like elements within uterine tumors resembling ovarian sex cord tumors are also commonly immunoreactive with alpha-inhibin, perhaps indicating true sex cord differentiation. alpha-inhibin staining may also be of value in cytological preparations in confirming a functional cyst and excluding a cyst or cystadenoma of epithelial origin. Syncytiotrophoblastic cells are also immunoreactive, as are most trophoblastic tumors. Thus, positive staining may be of value in confirming an intrauterine gestation or in the diagnosis of a trophoblastic neoplasm. Another gynecological neoplasm that is commonly positive with alpha-inhibin is the so-called female adnexal tumor of probable wolffian origin, and, therefore, the antibody is of no value in the distinction of this neoplasm from a sex cord-stromal tumor, tumors that are often in the differential diagnosis.

The aim of the present study was to investigate the expression of nm23-H1 in human placenta, hydatidiform mole and choriocarcinoma cells. Nm23-H1 protein was localized in the cytotrophoblast, but not in the syncytiotrophoblast. In the hydatidiform mole cases with subsequent spontaneous remission, nm23-H1 mRNA levels were significantly lower than those in first-trimester placentas. However, its levels were elevated in the hydatidiform mole cases that progressed to persistent gestational trophoblastic disease and were comparable to those of first-trimester placentas, and they were further elevated in choriocarcinoma cells. The present data suggest an association of nm23-H1 for the proliferation activity of trophoblast, and its increased expression may influence the development of persistent trophoblastic disease., (Copyright 2001 S. Karger AG, Basel)

We describe an epithelioid trophoblastic tumor (ETT) metastatic to the vagina in a 30-year-old Japanese woman. A polypoid tumor in the vaginal orifice was composed of nests of intermediate trophoblastic cells that showed a striking epithelioid appearance. In the hysterectomy specimen, a tumor infiltrated through the myometrium and showed histologic findings similar to those of the vaginal tumor. The tumor cells were positive for cytokeratin, inhibin-alpha, and melanoma cell adhesion molecule (Mel-CAM, CD146) but were only focally positive for human placental lactogen. Electron microscopic examination revealed bundles of well-developed, intermediate-type filaments surrounding the nuclei.

Objective: Our purpose was to investigate the expression of matrix metalloproteinases (MMPs) in gestational trophoblastic diseases and normal first-trimester placenta., Methods: Paraffin sections of 16 partial moles, 25 complete moles, 10 gestational choriocarcinomas, and 11 normal first-trimester placentas were studied immunohistochemically for expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and tissue inhibitor of metalloproteinase-1 (TIMP-1)., Results: Nine (90.0%) of the choriocarcinoma cases showed strong intensity of staining for MMP-1. Choriocarcinoma exhibited significantly stronger staining for MMP-1 than syncytiotrophoblast in normal placenta (P < 0.01), partial mole (P < 0.01), and complete mole (P < 0.01). Choriocarcinoma also showed significantly stronger staining for MMP-1 than the extravillous trophoblast in placenta (P < 0.05). MMP-2 was expressed only in syncytio- and extravillous trophoblasts in normal placenta, partial mole, and complete mole. Choriocarcinoma and the extravillous trophoblast in partial mole and complete mole had significantly stronger staining for MMP-2 than the extravillous trophoblast in placenta (P < 0.05, P < 0.01, P < 0.01, respectively). Choriocarcinoma also exhibited significantly stronger staining for MMP-2 than syncytiotrophoblasts in placenta (P < 0.01), partial mole (P = 0.05), and complete mole (P < 0.01). The expression of MMP-3, MMP-9, and MMP-13 was similar in all four tissues with the predominance of syncytiotrophoblast for MMP-3 and MMP-13 and cytotrophoblast for MMP-9. While 8 (73.0%) placentas, 14 (87.5%) partial moles, and 19 (76.0%) complete moles showed strong immunoreactivity for TIMP-1 in syncytiotrophoblasts, no strong staining was found in choriocarcinomas (P < 0.01, P < 0.01, P < 0.01, respectively)., Conclusion: The extravillous trophoblast of first-trimester placenta has significantly less expression of MMP-1 than choriocarcinoma and significantly less expression of MMP-2 than choriocarcinoma and extravillous trophoblast of partial and complete mole. The expression of TIMP-1 was significantly less in choriocarcinoma than the syncytiotrophoblast of normal placenta, partial mole, and complete mole. MMPs and their inhibitors may play a role in the pathogenesis of gestational trophoblastic diseases., (Copyright 1999 Academic Press.)

Background: Placental site trophoblastic tumor (PSTT) is a rare form of trophoblastic neoplasm. Approximately 100 cases of PSTT have been reported, but we found no report on its cytodiagnosis., Cases: Case 1, a 39-year-old female, came to the hospital because of abnormal genital bleeding. Case 2, a 36-year-old female came because of amenorrhea for a year. In both cases, endometrial smear and intrauterine curettage suggested trophoblastic disease, and hysterectomy was performed. Laboratory data revealed a mild increase in human chorionic gonadotropin (hCG) and beta-hCG but normal human placental lactogen (hPL). In the cytologic examination, the background contained some hemorrhagic and fibrinous areas but no necrosis. Most tumor cells stained light green, were round or polygonal, and contained abundant cytoplasm. Some were palely stained and had vacuoles. Some cells showed hyperchromatism, an irregular nucleus, fine-to-coarse chromatin granules and markedly different sizes. Most of the cells were hPL positive, and a few were hCG positive., Conclusion: Both cases were considered benign because of rare mitoses despite cellular pleomorphism. However, careful follow-up is required. The differential diagnosis of PSTT is difficult from cytologic and biopsy specimens alone but may be achieved with additional magnetic resonance imaging findings and positive staining of hPL and hCG.

We report two unusual forms of testicular trophoblastic tumor. One was a mixed germ cell tumor in a 19-year-old man that had a predominant component of nodules of cytotrophoblast cells with only rare syncytiotrophoblast cells. These nodules of "monophasic" choriocarcinoma were diffusely positive for human chorionic gonadotropin (hCG), which stained the syncytiotrophoblast cells more intensely; stains for human placental lactogen (HPL) highlighted only the latter cells. The second tumor occurred in a 16-month-old boy. It consisted of a pure proliferation of intermediate trophoblast cells and was identical to the placental site trophoblastic tumor of the uterus. The tumor cells showed diffuse immunoreactivity for HPL and patchy staining for hCG. Despite the occurrence of vascular wall invasion, the patient was alive and well at 8 years follow-up with no treatment other than orchiectomy. These cases show that trophoblastic tumors other than classic choriocarcinoma occur rarely in the testis. The differential diagnosis of the "monophasic" choriocarcinoma included seminoma and the solid variant of yolk sac tumor, but the tumor had larger, more irregular nuclei than those of seminoma and was not associated with distinctive yolk sac tumor patterns. The placental site trophoblastic tumor may be confused with Leydig cell tumor or choriocarcinoma, but awareness of its occurrence in the testis and the immunohistochemical findings should permit its recognition.

The placental site nodule (PSN), a recently described benign lesion of intermediate trophoblast, is usually an incidental finding in younger women. It is a well-circumscribed, round to oval lesion that is extensively hyalinized and immunohistochemically stains for cytokeratin, placental alkaline phosphatase (PLAP), human placental lactogen (HPL) and, focally, for human chorionic gonadotropin (HCG) and epithelial membrane antigen (EMA). Thus far, the cases reported have been found in endometrial curettage or hysterectomy specimens. The pathogenesis of PSN is yet to be ascertained; however, there is wide acceptance of the fact that it represents a remnant of the placental implantation site. If this is indeed the case, it should not be surprising to find PSN occurring at sites of ectopic gestation. We describe herewith a case in which PSN was found in a fallopian tube segment resected in a postpartum tubal ligation.

This is the first report on the ATP cell viability assay as a chemosensitivity test system for gestational trophoblastic neoplasms (GTN). We obtained chemosensitivity profiles in two established trophoblastic cell lines and four fresh tumors. Ten drugs were tested in vitro in the two cell lines JAR and JEG-3. The IC50 values of the 10 chemotherapeutic agents tested were very similar for both cell lines. The three most active drugs in these cell lines were VP-16, paclitaxel and vincristine. This is the first report on the activity of paclitaxel in trophoblastic cell lines. We furthermore evaluated this assay for chemosensitivity testing in four fresh malignant GTN tumors: one placental site trophoblastic tumor, one chorocarcinoma and two invasive moles. The placental site trophoblastic tumor specimen revealed to be rather chemoresistant in vitro whereas the other three tumors were chemosensitive. From our cell line data we conclude that the ATP cell viability assay is a practicable assay for chemosensitivity testing of GTN cell lines and gives repeatable results. However, the value of this assay for fresh GTN chemosensitivity testing needs to be defined.

This report describes the clinical, histological, and immunohistochemical features of 38 cases of placental site nodule (PSN), a recently described lesion of intermediate trophoblast (IT). The patients ranged in age from 20 to 47 years (mean, 31.1 years). PSNs were diagnosed in endometrial (30 cases), endocervical (seven cases), and both endometrial and endocervical specimens (one case). The majority of biopsies were prompted by an abnormal Pap smear (13 cases) or complaints of menorrhagia (21 cases). All PSNs were microscopically detected, lobulated nodules composed of acellular, hyalinized material admixed with IT. Mitotic activity was noted in seven cases. Immunohistochemically, the IT expressed human placental lactogen (hPL) in 78% of cases and human chorionic gonadotropin (hCG) in 42% of cases, but their expression was weak and focal in contrast to uniform, strong staining for placental alkaline phosphatase (PLAP) (100%), cytokeratins (96%), and epithelial membrane antigen (EMA) (84%). Type IV collagen outlined the IT and stained the extracellular material in the cellular areas. Vimentin-positive cells within the lesions were fewer in number and in a different distribution than those expressing PLAP, CK, and EMA. Two consecutive PSNs occurred in one patient, but no patient developed gestational trophoblastic disease or a significant gynecologic neoplasm.

Objective: Much debate exists on the initiation of chemotherapy for women at risk for persistent gestational trophoblastic disease. This is a result of a lack of early predictors for the development of persistent gestational trophoblastic disease after evacuation of a complete hydatidiform mole, because the only current reliable method of detection and diagnosis lies in persistent or rising postmolar beta-human chorionic gonadotropin values. We used immunocytochemical techniques to retrospectively study the expression of the c-erb B-2 oncogene product in formalin-fixed, paraffin-embedded trophoblastic tissues as a potential indicator of the development of persistent gestational trophoblastic disease., Study Design: In this retrospective study 56 trophoblastic tumors were examined by means of immunocytochemical techniques to stain for the oncogene product for evidence of c-erb B-2 expression. Our 56 cases included original tissue from 20 cases of complete mole that progressed to persistent gestational trophoblastic disease, seven cases of choriocarcinoma after term pregnancy or abortion, and 29 cases of hydatidiform mole representing postevacuation, spontaneously regressing disease (including one partial mole). We also studied 11 cases of first-trimester trophoblast and 15 cases of term placenta as additional controls., Results: Our results showed positive immunostaining for c-erb B-2 gene product in one case of persistent gestational trophoblastic disease, with negative staining in all other cases in the study groups and controls., Conclusion: Analysis for the significance of c-erb B-2 expression in persistent gestational trophoblastic disease showed that this correlation between c-erb B-2 expression and persistent gestational trophoblastic disease is not significant, suggesting that future efforts should be directed at the involvement of different oncoproteins.

We performed an immunohistochemical and flow cytometric study of the formalin-fixed, paraffin-embedded tissues of eight recent gestational choriocarcinomas (CCs) and three placental-site trophoblastic tumors (PSTTs). The follow-up period ranged from 1 to 144 months (mean, 74.3 months). In the CCs, which consisted predominantly of cytotrophoblasts and syncytiotrophoblasts intermingled with small amounts of intermediate trophoblasts, cytotrophoblasts were occasionally positive for beta-subunit human chorionic gonadotropin (HCG) and syncytiotrophoblasts contained abundant HCG. Some intermediate trophoblasts were positive for HCG and many were positive for human placental lactogen. In the three PSTTs, which were characterized by a monomorphic proliferation of intermediate trophoblasts, the tumor cells were positive for human placental lactogen and placental alkaline phosphatase. The tumors of two patients, including one fatal case, contained more human placental lactogen-positive cells than HCG-positive cells, while the tumor of the remaining patient, who had high serum HCG levels, showed a reversed staining pattern resembling that of CC; this patient has been alive without disease for 9 years. One CC patient and one PSTT patient died of multiple lung metastases, despite hysterectomy and multiagent chemotherapy. All CCs and PSTTs had an exclusively diploid DNA content, and there was no correlation among histopathologic and immunohistochemical features, DNA ploidy, S-phase fraction, and clinical outcome for patients with these tumors. These results suggest that there is a PSTT that immunohistochemically resembles CC and that flow cytometric and immunohistochemical analysis may not be effective tools to predict the biologic behavior of malignant trophoblastic tumors.

An immunohistochemical and flow cytometric DNA study of two cases of metastasizing placental site trophoblastic tumor are presented. One patient aged 29 died rapidly of widespread metastases despite hysterectomy and multiagent chemotherapy. The patient had a low level of serum HCG. The course was complicated by the presence of a nephrotic syndrome. The other patient aged 34 had a vaginal metastasis and high levels of serum HCG, and was alive without disease for 9 years after hysterectomy and chemotherapy. Histologically, these tumors were characterized by a monomorphic trophoblastic cell population, probably derived from intermediate trophoblast in the placental site. The mitotic rate in these tumors was 2-4/10 high-power fields. Immunohistochemically, many tumor cells contained human placental lactogen and placental alkaline phosphatase. Beta-unit chorionic gonadotropin was present in many cells of the second patient, and only focally in the first. All specimens including the curettaged and metastatic lesions revealed a diploid DNA content in both cases. Neither DNA ploidy nor S-phase fraction was associated with survival of patient. Since predicting the biologic behavior of placental site trophoblastic tumor is very difficult, making a correct diagnosis on endometrial curettings, hysterectomy, and monitoring serum HCG level is essential in patients with this tumor.

Preliminary observation on immunocytochemical localization of anti-HCG and anti-HPL in 49 patients with gestational trophoblastic neoplasms was studied. The findings were; (1) staining patterns to the two antibodies were different in cytotrophoblasts (CT), intermediate trophoblasts (IT), and syncytiotrophoblasts (ST) of the different types of trophoblastic tumor, (2)STs in tumors of all patients except one, showed positive staining of anti-HCG, and ITs in 17 cases of HM, 10 cases of IM and 1 case of GC were stained positively for anti-HCG; (3)STs in all of the 29 cases of HM, 14 cases of IM and 1 case of GC were positive for anti-HPL, ITs in 22 cases of HM, 11 cases of IM and 2 cases of GC were stained positively for anti-HPL. CTs in all tumors of the 49 patients were devoid of HCG and HPL. The results indicated that the production of HPL was found in well-differentiated cells and HCG in undifferentiated cells. The prognostic value of immunocytochemical localization of the two antibodies in trophoblastic tumors needs to be further clarified.

Flow cytometric analysis of nuclear DNA is a quick and accurate method of determining nuclear ploidy. This technique allows a clear distinction to be made between diploid and triploid hydatidiform moles. Additional ploidy aberrations, such as tetraploidy and aneuploidy, have also been reported in flow cytometric studies of hydatidiform moles. Recent investigations have suggested that aneuploidy in complete hydatidiform moles is associated with a high risk of persistent gestational trophoblastic disease. In addition to DNA ploidy analysis, cell cycle activity may be calculated from analysis of the DNA histogram. No significant correlation between clinical course and cell cycle kinetics has been demonstrated to date. By providing valuable DNA ploidy data, flow cytometric studies of hydatidiform moles may be helpful in the identification of patients at high risk of postmolar trophoblastic sequelae.