Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.

BACKGROUND: Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors. METHODS: The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976-2006) were compared to our new modern cohort (2007-2014), when intensified treatments were introduced. RESULTS: Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8-87.6%) and 75% (95% CI 66.3-84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61-23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17-50.96, p < 0.001) were most significant on multivariable analysis. No significant differences in prognostic factors were seen between the old and new patient cohort. However, the new cohort received significantly more cisplatin-based and high-dose chemotherapy, and patients with an interval ≥48 months demonstrated an improved median overall survival (8.3 years, 95% CI 1.53-15.1, versus 2.6 years, 95% CI 0.73-4.44, p = 0.·005). CONCLUSION: PSTT/ETT with advanced FIGO stage or an interval ≥48 months from their last known pregnancy have poorer outcomes. Platinum-based and high-dose chemotherapy may help to improve survival in poor-prognosis patients.

Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database.

OBJECTIVE: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT. METHODS: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS). RESULTS: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively). CONCLUSIONS: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN.

Diagnosing and treating rare lesions in a low resource setting: lessons from ahybrid epithelioid trophoblastic tumor and choriocarcinoma.

OBJECTIVE: To raise awareness of the existence of a rare type of malignant trophoblastic tumor and discuss the diagnostic challenges and management of this lesion in a low resource setting. CASE REPORT AND INTERVENTION: A 35 -year -old G6P3 woman was referred to our facility on account of persistent vaginal bleeding due to a suspected incomplete miscarriage with a cervical mass. Her serum ß-HCG was elevated (36,900 mIU/ml) and examination showed a bleeding cervical mass. An initial histopathological diagnosis of moderately differentiated squamous cell carcinoma was reviewed to epithelioid trophoblastic tumor resulting in an extra-fascial hysterectomy. A final histopathological diagnosis of hybrid Epithelioid Trophoblastic Tumor and Choriocarcinoma (ETT/CC) was made after external review and immunohistochemistry. She received subsequent chemotherapy. CONCLUSION: Epithelioid trophoblastic tumor and its hybrids are difficult to diagnose. They may be diagnosed as moderately differentiated squamous cell carcinoma especially in low resource settings where cervical squamous cell carcinoma is relatively more common. A high index of suspicion, a serum ß HCG test and close collaboration between clinicians and pathologists can help make the diagnosis. FUNDING: None.

[Clinical and radiological features of gestational trophoblastic tumors]. / Tumeurs trophoblastiques gestationnelles: aspects cliniques et radiologiques.

Gestational trophoblastic disease incorporates a group of diseases which differ from each other by their regressive evolution, their evolution to metastasis and to recurrence. It is a severe disease that affects women of childbearing age. Gestational trophoblastic tumors (GTT) are the malignant forms of gestational trophoblastic diseases. They are always a result of pregnancy, more often molar pregnancy (hydatidiform mole). The most common type of gestational trophoblastic tumors (GTT) is the invasive mole because, in most cases, the diagnosis is made when cancer is still confined to the uterus. Choriocarcinoma is a more rare type of tumor, often developing distant metastases. When there is a progression to a trophoblastic tumor, the assessment of locoregional extension and distant metastases is essential to establish an appropriate treatment protocol. We here report three clinical cases of GTT by describing their clinical presentations and the use of imaging techniques in the diagnosis and management of these disorders.

Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms.

The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms.

Epithelioid trophoblastic tumor: a case report and literature review.

Epithelioid trophoblastic tumor (ETT) is a very rare case of malignant trophoblastic tumor, which can occur particularly during the fertile age of women with a long history of abortion and delivery. ETT originates from the intermediate trophoblastic cells of chorion laeve. The main features of this tumor include lack of vessels within the tumor, nuclear hyperchromasia and pleomorphism and a large zone of necrosis and hyalinization. The clinical features of ETT are specific to each case and often consist of vaginal bleeding or amenorrhea in the absence of other complains. The beta-human chorionic gonadotropin (ß-hCG) serum level cannot be an absolute criterion useful in defining diagnosis. The right diagnosis can only be established by a histopathological examination of the tissue picked-up via intrauterine curettage. This paper describes the case of a 35-year-old woman who required gynecological investigation for amenorrhea. The diagnosis established by biopsic curettage and the clinical evolution have influenced the physician's decision to perform hysterectomy. The only method to differentiate between the microscopic diagnosis of ETT and choriocarcinoma was the immunohistochemical staining of trophoblastic cells for cytokeratin AE1÷AE3, p63, Ki67. Despite the diagnosis of malignity, this tumor does not usually require a recommendation for chemotherapy and does not seem to have a bad prognostic. However, these data do not rule out that clinical behavior is sometimes difficult to predict. We analyzed the clinical and histology criteria in line with the data published in literature.

Trophoblastic disease review for diagnosis and management: a joint report from the International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup.

OBJECTIVE: The objective of this study was to provide a consensus review on gestational trophoblastic disease diagnosis and management from the combined International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup. METHODS: A joint committee representing various groups reviewed the literature obtained from PubMed searches. RESULTS AND CONCLUSIONS: Guidelines were constructed on the basis of literature review. After initial diagnosis in local centers, centralization of pathology review and ongoing care is recommended to achieve the best outcomes.

[Hydatidiform mole and malignant trophoblastic tumors initiated by hydatidiform mole. Standards and innovation of diagnosis and treatment].

Malignant trophoblastic tumors are hormone and hormone-dependent allografts initiated by, in the most cases, hydatidiform mole. The absence of methodological principles for monitoring of women after evacuation of hydatidiform mole often leads to late detection of the disease, inadequate chemotherapy conducted in clinics with no experience of treatment, followed by the development of drug-resistant tumors and worse prognosis. This paper analyzes the problem at the moment.

Epithelioid trophoblastic tumor: an outcome-based literature review of 78 reported cases.

OBJECTIVES: Epithelioid trophoblastic tumor (ETT) is very rare; and therefore, a substantially increased data set is unlikely to be obtained in the near future. This analysis aimed to assess the effects of current management on clinical outcomes and to identify potential prognostic indicators in ETT. METHODS: We applied a literature search using PubMed to analyze the clinical data of 78 published cases of ETT. RESULTS: Women with ETT present at reproductive age (mean ± SD, 37.1 ± 8.7 years) and have a slightly to moderately elevated serum ß-human chorionic gonadotropin (median, 665 IU/L). Epithelioid trophoblastic tumor is frequently present in the lower uterine segment/cervix (26/58 cases) and can be misdiagnosed as squamous cell carcinoma (6/26). Lung is the most common extrauterine site of ETT (5/11 with uterine ETT and 10/20 without uterine ETT). Kaplan-Meier analysis indicates that chemotherapy (surgery with postoperative chemotherapy vs surgery alone) is associated with increased ETT relapse (P = 0.005), even after stratification by International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.008); but FIGO stage remains the only significant prognostic indicator for ETT (P = 0.015). CONCLUSIONS: This analysis confirms the hypothetical chemotherapy resistance and prognostic value of FIGO staging in ETT. These findings remain tentative given the small data set available for analysis and the reporting bias from these published cases; however, they may confer a risk-adapted therapy. Finally, both gynecologists and pathologists should be alert to the potential misdiagnosis of squamous cell carcinoma when ETT is present in the lower uterine segment/cervix.

Analysis of clinicopathologic prognostic factors in 9 patients with epithelioid trophoblastic tumor.

OBJECTIVE: This study aimed to investigate the clinicopathologic features and prognostic factor in patients with epithelioid trophoblastic tumor (ETT). METHODS: From January 2002 to June 2010, the clinicopathologic characteristics, treatments, outcomes, and prognosis of 9 patients with ETT were analyzed retrospectively in our institution. RESULTS: Of 9 patients, 8 (88.9%) had metastases. The histopathologic results of 7 patients (77.8%) with poor outcomes showed diffuse multifocal disease within the uterus, full-thickness myometrial invasion, uterine serosal involvement, and extensive necrosis. The size of the uterus exceeded 8 weeks of gestation in 7 patients. Two of them had poorly differentiated carcinoma. All patients were treated with multimodality treatment that combined with surgery and chemotherapy. After the initial treatments, 5 patients with International Federation of Gynecology and Obstetrics stage I achieved complete remission (CR), 1 patient achieved partial remission, and 3 patients (33.3%) had no response to treatments and died of progressive disease. After following up for 6 to 107 months (mean, 24 months), 4 (44.4%) of the 5 patients with initial CR had relapse: 3 of them achieved a second CR and the other 1 was under treatment. CONCLUSIONS: Epithelioid trophoblastic tumor is a rare and special type of intermediate trophoblastic tumor with a high degree of malignancy and poor prognosis. Multifocal lesions in bulky uterus, combined with full-thickness myometrial invasion and uterine serosal involvement, could be related to poor outcomes in patients with ETT. The prognosis of ETT could be improved by increasing diagnostic accuracy, identifying prognostic factor at an early stage, and providing early intensive multimodality treatment to patients with poor prognostic factors.

Psychologic impact of follow-up after low-risk gestational trophoblastic disease.

OBJECTIVE: To investigate the psychological consequences of hCG measurements during follow-up in patients with low-risk gestational trophoblastic disease. The length of follow-up of patients with molar pregnancy and spontaneous normalization of the hCG level is currently discussed, in consideration of the low incidence of recurrent disease. STUDY DESIGN: Patients registered in the Dutch Central Registry of Hydatidiform Mole between January 2006 and December 2007 were eligible for this study. Patients received a questionnaire containing questions about follow-up and anxiety and stress during this period. RESULTS: Seventy-six patients were eligible for the study. An inverted correlation (r = -0.35, p = 0.003) was found between the age of patients and the level of anxiety. Anxious patients scored higher for fear of recurrence (r = 0.49, p < 0.0001), of infertility (r = 0.40, p = 0.001) and of conceiving again (r = 0.30, p = 0.01). They experienced the measurements as a burden (r = 0.35, p = 0.003). Fewer patients (24%) were insecure before the monthly hCG measurement, compared to 51% during weekly measurements. The majority of women (80%) completed the follow-up and confirmed that they would come for weekly and monthly hCG measurements if it were optional. CONCLUSION: Follow-up after low-risk GTD has psychologic consequences but provides reassurance as well. Therefore, women tend to accept the offered surveillance and refrain from pregnancy. Women with GTD should be counseled about the minor risk of recurrence and the consequences of follow-up.

A case of uterine pseudoaneurysm combined with gestational trophoblastic disease in a 30-year-old woman.

Uterine artery pseudoaneurysm is a rare disease and it can be diagnosed using conventional doppler ultrasongraphy. Damaged uterine arteries from cesarean section, myomectomy, dilatation & curettage, etc. are known as causes of the disease. Massive bleeding in the rupture can cause fatal result. We observed an increase in ß-hCG and uterine artery pseudoaneurysm a year after the performance of dilatation & curettage for hydatidiform mole and treated it with arterial embolization and chemotherapy. We report the case and give a brief review of the literature.

What do women with gestational trophoblastic disease understand about the condition?

INTRODUCTION: Little is known about patients' understanding of the causes, treatments, and implications of gestational trophoblastic disease (GTD). Clinical observation suggests that such health literacy is limited. We report on the perceptions of causes and treatment of GTD and its impact on fertility and reproductive outcomes. METHODS: Cross-sectional analysis of 176 Australian women previously diagnosed with GTD (no longer receiving follow-up/treatment) recruited from a state-wide registry. Participants comprised 149 (85%) women with GTD who did not require chemotherapy and 27 (15%) women who required chemotherapy for malignancy or persistent molar disease. Data were collected from medical records and via self-report questionnaire. RESULTS: Participants were 94 women (53%) with partial mole, 75 (43%) with complete mole, 4 (2%) with choriocarcinoma, and 3 (2%) with hydatidiform mole not otherwise specified. Mean (SD) age at diagnosis and time since diagnosis were 32.1 (6.3) and 4.7 (3.3) years, respectively. Chance/bad luck was the most endorsed cause (n = 146, 83%); 23 (13%) thought GTD was hereditary and 10 (6%) identified a chromosomal etiology. Between 24% and 32% were unsure of the role of alcohol/drugs, venereal diseases, smoking, pollution, contraceptives, and lowered immunity. Surgical/medical procedure (n = 127, 72%) and healthy diet (n = 53, 30%) were the most endorsed treatments. Between 18% and 23% were unsure of the treatment effectiveness of diet, vitamins, exercise, complementary therapy, and contraception. All women treated with chemotherapy understood the rationale thereof; 23 (85%) perceived chemotherapy to be successful, and 19 (70%) could name the agent. Few women perceived a negative impact on their fertility (n = 28, 16%); 52 (30%) were reluctant to conceive again and 100 (57%) questioned their ability to have healthy children. After diagnosis, 111 (63%) had at least 1 live birth. CONCLUSIONS: Notwithstanding limitations, this study is the largest of its type to date. These descriptive data enhance our understanding of patients' experience on GTD, highlight the scope of GTD health literacy, and may be useful for clinicians to adjust the content of their patient education.

Fertility-preserving surgical procedures for patients with gynecologic malignancies.

Gynecologic malignancies often affect young women who are at the peak of their reproductive potential. The treatment for gynecologic malignancies often consists of removal of the ovaries or uterus, affecting the future fertility of these patients. Advances in surgical management have allowed patients to undergo more conservative treatment with preservation of their fertility. This review summarizes fertility-sparing surgical procedures for patients with gynecologic malignancies evaluating the role of radical trachelectomy and ovarian transposition in cervical cancer, hormonal therapy and hysteroscopic resection in endometrial cancer, and conservative surgery in ovarian cancer.

Metastatic epithelioid trophoblastic tumor involving the spine.

STUDY DESIGN: This is a single case-based report. OBJECTIVE: We report the first case of epithelioid trophoblastic tumor (ETT) presenting as primary metastasis to the spine. SUMMARY OF BACKGROUND DATA: ETT is an extremely rare form of gestational trophoblastic neoplasm with less than 100 cases reported in the literature. A 36-year-old, postpartum woman presented with severe low back pain and was found to have a contrast-enhancing lesion in lower thoracic spine subsequently confirmed as ETT. METHODS: The patient data, history, clinical examination findings, laboratory, and histopathology data and imaging studies were retrospectively reviewed and findings reported. A literature search using Pubmed and Cochrane database was conducted. RESULT: We described the first case of an ETT to present as a primary metastasis to the spine. CONCLUSION: This first report of metastasis of ETT to the spine adds significant new information to the growing literature of this rare and newly identified tumor. It also alerts the neurosurgeon into considering the diagnosis with appropriate clinical presentation. As more number of cases of nervous system involvement with this tumor are reported, crucial information on prognostic factors and treatment regimens will emerge.

Extrauterine epithelioid trophoblastic tumors presenting as primary lung carcinomas: morphologic and immunohistochemical features to resolve a diagnostic dilemma.

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.

[Case report and literature review of epithelioid trophoblastic tumor].

OBJECTIVE: To evaluate the clinical characteristics of epithelioid trophoblastic tumor (ETT). METHODS: Six cases of ETT treated in Women's Hospital, School of Medicine, Zhejiang University from 2005 to 2007 were retrospectively analyzed, together with a literature review. RESULTS: Six cases of ETT were diagnosed pathologically after surgery. The age of patients ranged from 27 to 46 years. The most common presentation was abnormal vaginal bleeding (5/6). The preceding gestational events were hydatidiform mole in 1 case, abortion in 2 cases, and term delivery in 3 cases. The interval between the preceding gestation and the diagnosis of ETT ranged from 15-48 months. The serum human chorionic gonadotropin (hCG) level was 46-121.47 IU/L. Four cases presented with metastasis, including lung metastasis in all of the 4 cases, liver metastasis in 1 case, and pancreas metastasis in another 1 case. The main therapies were surgery combined with chemotherapy. All of the 6 cases received total abdominal hysterectomy, and 1 case also had lung lobectomy. One case had a recurrence but refused any treatment again, and was lost to follow up; the therapy of 1 case unfinished; another 4 cases were without evidence of disease 9 to 19 months after surgery. CONCLUSIONS: The confirmation of ETT diagnosis is difficult before surgery. Surgical management is mostly recommended in ETT. The role of chemotherapy in ETT is not clear yet.