Recurrent Metastatic Choriocarcinoma Responsive to Etoposide and Cisplatin with Etoposide, Methotrexate, and Dactinomycin: A Case Report.

Choriocarcinoma is a malignant trophoblastic tumour usually of placental origin. It is characterized by early metastasis to the brain and lungs. With early detection, it has a better prognosis with treatment. We report a case of 18 years female at 26 weeks of gestation in her third pregnancy who had a history of treatment for metastatic gestational trophoblastic neoplasm with chemotherapy and radiotherapy two years back. Therefore, she was managed as a case of recurrent choriocarcinoma with brain metastasis with chemotherapy (etoposide and cisplatin with etoposide, methotrexate, and dactinomycin) and was responsive. Her symptoms resolved and ß-human chorionic gonadotropin dropped to normal value (<2.39 mIU/ml) which has shown that timely diagnosis and management can be vital for the successful treatment of brain metastasis. Keywords: chemotherapy; choriocarcinoma; metastasis; recurrence.

Recommendations for the surgical management of gynecological cancers during the COVID-19 pandemic - FRANCOGYN group for the CNGOF.

INTRODUCTION: In the context of the COVID-19 pandemic, specific recommendations are required for the management of patients with gynecologic cancer. MATERIALS AND METHOD: The FRANCOGYN group of the National College of French Gynecologists and Obstetricians (CNGOF) convened to develop recommendations based on the consensus conference model. RESULTS: If a patient with a gynecologic cancer presents with COVID-19, surgical management should be postponed for at least 15 days. For cervical cancer, radiotherapy and concomitant radiochemotherapy could replace surgery as first-line treatment and the value of lymph node staging should be reviewed on a case-by-case basis. For advanced ovarian cancers, neoadjuvant chemotherapy should be preferred over primary cytoreduction surgery. It is legitimate not to perform hyperthermic intraperitoneal chemotherapy during the COVID-19 pandemic. For patients who are scheduled to undergo interval surgery, chemotherapy can be continued and surgery performed after 6 cycles. For patients with early stage endometrial cancer of low and intermediate preoperative ESMO risk, hysterectomy with bilateral adnexectomy combined with a sentinel lymph node procedure is recommended. Surgery can be postponed for 1-2 months in low-risk endometrial cancers (FIGO Ia stage on MRI and grade 1-2 endometrioid cancer on endometrial biopsy). For patients of high ESMO risk, the MSKCC algorithm (combining PET-CT and sentinel lymph node biopsy) should be applied to avoid pelvic and lumbar-aortic lymphadenectomy. CONCLUSION: During the COVID-19 pandemic, management of a patient with cancer should be adapted to limit the risks associated with the virus without incurring loss of chance.

BRCA1 promoter hypermethylation in human placenta: a hidden link with ß-hCG expression.

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of 'ß-hCG' with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates ß-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- ß-hCG relationship and unraveling etio-pathology of GTD. BRCA1 level in GTD is down-regulated due to the over-expression of DNMT3b and subsequent promoter hypermethylation, when compared to the normal placentae accompanied with its shift in localization. There is an inverse correlation of serum ß-hCG levels with BRCA1 mRNA expression. The effects of methotrexate (MTX), which is the first-line chemotherapeutic used for GTD treatment, when analyzed in comparison with plumbagin (PB) revealed that PB alone is efficient than MTX alone or MTX-PB in combination, in showing selective cytotoxicity against GTD. Interestingly, PB increases BRCA1 levels post-treatment, altering DNMT3b levels and resultant BRCA1 promoter methylation. Also, cohort study analyzed the incidence of GTD at Sree Avittom Thirunal (SAT) Hospital, Thiruvananthapuram, which points out that 11.5% of gestational trophoblastic neoplasia (GTN) cases were referred to Regional Cancer Centre, Thiruvananthapuram, for examination of breast lumps. This has lend clues to supervene the risk of GTD patients towards BRCA1-associated diseases and unveil novel therapeutic for GTD, a plant-derived naphthoquinone, PB, already reported as selectively cytotoxic against BRCA1 defective tumors.

Effects of Phytoestrogen Extracts Isolated from Elder Flower on Hormone Production and Receptor Expression of Trophoblast Tumor Cells JEG-3 and BeWo, as well as MCF7 Breast Cancer Cells.

Hereinwe investigated the effect of elderflower extracts (EFE) and of enterolactone/enterodiol on hormone production and proliferation of trophoblast tumor cell lines JEG-3 and BeWo, as well as MCF7 breast cancer cells. The EFE was analyzed by mass spectrometry. Cells were incubated with various concentrations of EFE. Untreated cells served as controls. Supernatants were tested for estradiol production with an ELISA method. Furthermore, the effect of the EFE on ER/ER/PR expression was assessed by immunocytochemistry. EFE contains a substantial amount of lignans. Estradiol production was inhibited in all cells in a concentration-dependent manner. EFE upregulated ER in JEG-3 cell lines. In MCF7 cells, a significant ER downregulation and PR upregulation were observed. The control substances enterolactone and enterodiol in contrast inhibited the expression of both ER and of PR in MCF7 cells. In addition, the production of estradiol was upregulated in BeWo and MCF7 cells in a concentration dependent manner. The downregulating effect of EFE on ER expression and the upregulation of the PR expression in MFC-7 cells are promising results. Therefore, additional unknown substances might be responsible for ER downregulation and PR upregulation. These findings suggest potential use of EFE in breast cancer prevention and/or treatment and warrant further investigation.

Nonchoriocarcinomatous Trophoblastic Tumors of the Testis: The Widening Spectrum of Trophoblastic Neoplasia.

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.

Robotic-assisted Laparoscopic Management of Chemoresistant Myoinvasive Complete Molar Pregnancy.

Postmolar malignant conditions are rare after evacuation of a complete molar pregnancy. Both medical and surgical management have a role in the treatment of persistent gestational trophoblastic neoplasia. Treatment decisions must account for the natural history of the disease, previous therapies, site of disease, and the patient's desire for uterine preservation. We report on a woman who presented with chemotherapy-refractory persistent gestational trophoblastic disease (GTD). She was found to have isolated, persistent trophoblastic tissue within the uterine myometrium. She underwent a robotic-assisted laparoscopic hysterectomy with curative results. Minimally invasive surgical management may be an option for treatment of women with isolated myoinvasive GTD.

Fatal methotrexate toxicity: could it have been avoided?

Methotrexate is used judiciously, only when specifically indicated. However, in this case the patient had a fatal outcome after only three doses. A young nulliparous woman diagnosed as having high-risk persistent trophoblastic disease was considered for multidrug chemotherapy. However, because of persistent low-grade fever it was decided to give only single agent, methotrexate. She developed severe toxicity which proved fatal, even before the first course could be completed. Analysing causes of this rare, unexpected outcome of methotrexate administration, suggested that estimation of serum levels can be a useful tool in monitoring patients showing hypersensitivity but this facility is rarely available especially in low-resource countries. Pharmacogenetical analysis of blood/tissue sample may be useful to help in identifying patients likely to show hypersensitivity reaction.

Targeted nanoparticle delivery of doxorubicin into placental tissues to treat ectopic pregnancies.

Abnormal trophoblast growth can cause life-threatening disorders such as ectopic pregnancy, choriocarcinoma, and placenta accreta. EnGeneIC Delivery Vehicles (EDVs) are nanocells that can promote tissue-specific delivery of drugs and may be useful to medically treat such disorders. The objective of this study was to determine whether EDVs loaded with the chemotherapeutic doxorubicin and targeting the epidermal growth factor receptor (EGFR, very highly expressed on the placental surface) can regress placental cells in vitro, ex vivo, and in vivo. In female SCID mice, EGFR-targeted EDVs induced greater inhibition of JEG-3 (choriocarcinoma cells) tumor xenografts, compared with EDVs targeting an irrelevant antigen (nontargeted EDVs) or naked doxorubicin. EGFR-targeted EDVs were more readily taken up by human placental explants ex vivo and induced increased apoptosis (M30 antibody) compared with nontargeted EDVs. In vitro, EGFR-targeted EDVs administered to JEG-3 cells resulted in a dose-dependent inhibition of cell viability, proliferation, and increased apoptosis, a finding confirmed by continuous monitoring by xCELLigence. In conclusion, EGFR-targeted EDVs loaded with doxorubicin significantly inhibited trophoblastic tumor cell growth in vivo and in vitro and induced significant cell death ex vivo, potentially mediated by increasing apoptosis and decreasing proliferation. EDVs may be a novel nanoparticle treatment for ectopic pregnancy and other disorders of trophoblast growth.

Ovarian involvement of epithelioid trophoblastic tumor: a case report.

Epithelioid trophoblastic tumor (ETT) is an uncommon type of gestational trophoblastic neoplasia originating from the chorionic-type intermediate trophoblast. To our knowledge, ovarian involvement of ETT with initial presentation as an ovarian tumor has not been reported. A 32-year-old woman presented with a 9-cm left ovarian mass. No clinical evidence of uterine involvement was identified at diagnosis or follow-up. The patient had a previous history of hydatidiform mole treated with suctional curettage 5 years before. Ovarian involvement of ETT can be challenging to pathologists and may be potentially confused with ovarian epithelial carcinoma, particularly of clear cell differentiation.

Salpingotomy or salpingectomy in tubal ectopic pregnancy: what do women prefer?

There is an ongoing debate whether tubal ectopic pregnancy should be treated by salpingotomy or salpingectomy. It is unknown which treatment women prefer in view of the potentially better fertility outcome but disadvantages of salpingotomy. This study investigated women surgically treated for tubal ectopic pregnancy and subfertile women desiring pregnancy and their preferences for salpingotomy relative to salpingectomy by means of a web-based discrete choice experiment consisting of 16 choice sets. Scenarios representing salpingotomy differed in three attributes: intrauterine pregnancy (IUP) chance, risk of persistent trophoblast and risk of repeat ectopic pregnancy. An 'opt out' alternative, representing salpingectomy, was similar for every choice set. A multinomial logistic regression model was used to analyse relative importance of the attributes. This study showed that the negative effect of repeat ectopic pregnancy was 1.6 times stronger on the preference of women compared with the positive effect of the spontaneous IUP rate. For all women, the risk of persistent trophoblast was acceptable if compensated by a small rise in the spontaneous IUP rate. The conclusion was that women preferred avoiding a repeat ectopic pregnancy to a higher probability of a spontaneous IUP in the surgical treatment of tubal ectopic pregnancy. An ectopic pregnancy occurs when a fertilized egg gets stuck inside the Fallopian tube where it starts growing instead of passing on to the uterus. This may lead to serious problems, such as internal bleeding and pain. Therefore, in the majority of women, it is necessary to remove the ectopic pregnancy by means of an operation. Two types of surgery are being used in removing the ectopic pregnancy. A conservative approach, salpingotomy, preserves the tube but bears the risk of incomplete removal of the pregnancy tissue (persistent trophoblast), which then needs additional treatment, and of a repeat ectopic pregnancy in the same tube in the future. A radical approach, salpingectomy, bears no risk of persistent trophoblast and limits the risk of repeat tubal pregnancy, but leaves only one tube for reproductive capacity. It is unknown which type of operation is better, especially for future fertility. We investigated women's preferences between these two treatments for ectopic pregnancy, i.e. does a better fertility prognosis outweigh the potential disadvantages of persistent trophoblast and an increased risk for ectopic pregnancy in the future? The study results show in the surgical treatment of tubal ectopic pregnancy that women preferred avoiding a repeat ectopic pregnancy to gaining a higher chance of a spontaneous intrauterine pregnancy. The risk of additional treatment in the case of persistent trophoblast after salpingotomy was acceptable if compensated by a small rise in intrauterine pregnancy rate.

External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease.

Van Trommel et al have previously shown that serum human chorionic gonadotropin (hCG) cutoff levels can provide early prediction of resistance to first-line methotrexate (MTX) in patients with persistent trophoblastic disease (PTD). In this study, we validate this approach of prediction of resistance to single-agent chemotherapy in an independent and larger cohort of PTD patients using a different hCG assay. Receiver operating characteristics (ROC) curves were constructed to determine hCG cutoff levels and sensitivity between patients cured on single-agent chemotherapy (control group) and patients requiring change to combination chemotherapy (study group). Receiver operating characteristics analysis identified an hCG cutoff value of 737 IU l(-1) that enabled us to predict the subsequent development of single-agent chemotherapy resistance in 52% of patients before their fourth MTX course at 97.5% specificity. This would have enabled an earlier switch to combination chemotherapy reducing the MTX exposure by an average of 2.5 courses. The present findings confirm that serum hCG cutoff levels predict resistance to single-agent therapy earlier than traditional methods. Change to combination chemotherapy should be considered for patients whose serum hCG levels exceed these hCG cutoff values. For patients not exceeding the hCG cutoff levels, static or rising hCG levels should still be included in the criteria for change of chemotherapy.

[Clinicopathologic analysis of uterine epithelioid trophoblastic tumor].

OBJECTIVE: To study the clinicopathologic features, immunophenotype, differential diagnosis and prognosis of uterine epithelioid trophoblastic tumor(ETT). METHODS: From 2000 to 2007, 5 ETTs cases were diagnosed in the affiliated Women's Hospital, School of Medicine, Zhejiang University. The pathologic characteristics and immunophenotype of the tumors were analyzed by histological examination and immunohistochemistry of CK18, p63, inhibin-alpha, HCG, HPL, PLAP and Ki-67. The clinical prognostic factors were evaluated based on a following-up data with a period of 11 - 50 months. RESULTS: The overall prevalence of ETT was 0.48% among all the gestational trophoblastic diseases patients received in the same period. Five ETT patients were in the reproductive ages with a median of 33 years. Histologically, the tumor showed an invasive, nodular growth consisting of uniform mononuclear trophoblastic cells. There were zones of hyaline material in the tumour nests. Necrosis was commonly seen with a characteristic geographic pattern. Immunohistochemically, all cases displayed a diffuse CK18 and p63 positivity, to be either positive focally or negative for HCG, HPL and PLAP staining. Inhibin-alpha staining was positive or negative either in the 5 cases. Two patients died of the tumour relapse: one died after 1 year with the tumor having a high mitotic activity (averagely 15 mitotic figures per 10 high-power fields), and the other died of lung metastasis 2 years after the diagnosis. CONCLUSIONS: ETT is a rare trophoblastic disease with distinct clinicopathological features and immunostaining patterns. A high mitotic index and lung metastasis are indicators for an unfavorable prognosis.

Methotrexate monotherapy for high-risk gestational trophoblastic neoplasia after therapy with etoposide, methotrexate, and dactinomycin: a case report.

We present a case of high-risk metastatic gestational trophoblastic neoplasia treated successfully with methotrexate monotherapy after severe toxicity from the combination chemotherapy: etoposide, dactinomycin, methotrexate, vincristine, and cyclophosphamide.

Gestational trophoblastic neoplasia: an update.

Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, and placental site trophoblastic tumors. The overall cure rate in treating these tumors currently exceeds 90%. Thorough evaluation and staging allow selection of appropriate therapy that maximizes chances for cure while minimizing toxicity. Nonmetastatic (stage I) and low-risk metastatic (stages II and III, World Health Organization score < 7) GTN can be treated with single-agent chemotherapy, resulting in a survival rate approaching 100%. High-risk metastatic GTN (stage IV, WHO score > or = 7) requires initial multiagent chemotherapy with or without adjuvant radiation and surgery to achieve a survival rate of 80% to 90%.

[Trophoblastic pregnancy persistant disease with a menopausal woman: ultrasonography-Doppler benefits]. / Maladie trophoblastique persistante chez une patiente ménopausée: apport de l'échographie-Doppler.

We present the case of a 53-year-old menopaused woman who developed an invasive persistent trophoblastic uterine disease with several lung metastasis. Patient case was listed in a highly risked group in the WHO classification. As the patient refused primary hysterectomy she received polychemotherapy alone. Monitoring of the treatment and vascularity evolution of the tumor was followed through pelvic endovaginal ultrasound using 3D and contrast enhancement as well as HCG decrease in the context of uterus conservation that was wished by the patient.

Epithelioid trophoblastic tumor of paracervix and parametrium.

Epithelioid trophoblastic tumor (ETT) is an unusual variant of gestational trophoblastic tumor that is closely related to choriocarcinoma and placental site trophoblastic tumor but shows different morphologic and immunohistochemical features. We report an ETT discovered in paracervix, parametrium, and periadnexal soft tissue of a 44-year-old woman. She underwent laparoscopic surgery and four courses of chemotherapy with a regimen of etoposide, methotrexate, and dactinomycin. ETT has a distinctive growth pattern and immunohistochemical profile. The difficulties and clues in distinguishing ETT from nontrophoblastic lesions are discussed.

Successful salvage of a relapsed high risk gestational trophoblastic neoplasia patient using capecitabine.

BACKGROUND: Although most patients at high risk of Gestational Trophoblastic Neoplasia (GTN) respond to standard treatments, there is a group of patients that will die because of it. The use of new single or combination drugs in this population has become a priority. CASE REPORT: We present the case of a relapsed high risk choriocarcinoma patient who did not respond to several chemotherapy treatments nor to PET guided salvage surgery. Because of treatment toxicity, the patient was started on Capecitabine, with which she achieved total remission, still present after 15 months of starting treatment. CONCLUSIONS: The use of Capecitabine and the multidisciplinary management of this population should be taken into account for patients at high risk of relapsing to EP/EMA because of its efficacy and little toxicity.

Tratamento da neoplasia trofoblástica gestacional resistente ao metotrexate / Treatment of gestational trophoblastic neoplasia resistant to methotrexate

O presente estudo tem como objetivo revisar o tratamento da neoplasia trofoblástica gestacional resistente à quimioterapia primária de acordo com as proposições dos centros de referência relatadas na literatura, e também o consenso da FIGO (2003). Neoplasia trofoblástica gestacional é extremamente responsiva à quimioterapia apropriada, no entanto o fenômeno da quimiorresistência é observado em 10 a 30 porcento dos casos. Constatada a resistência ao metotrexate, deve ser feito o reestadiamento da paciente segundo padronização da FIGO 2000, e sendo de baixo risco, o tratamento recomendado é agente único alternativo, actinomicina-D. Se houver resistência à segunda linha de agente único de quimioterapia, indica-se tratamento com quimioterapia combinada, de acordo com o protocolo de cada serviço. A histerectomia é opção oferecida à paciente com neoplasia trofoblástica e quimiorresistência, entretanto é necessária cuidadosa investigação de metástases antes da cirurgia. O encaminhamento antecipado para centros de referência otimiza o tratamento das pacientes, possibilitando abordagem multidisciplinar, identificação precoce de resistência e mudança rápida para novo protocolo de quimioterapia.