A Review of Current Management of Placental Site Trophoblastic Tumor and Epithelioid Trophoblastic Tumor.

IMPORTANCE: Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are rare forms of gestational trophoblastic neoplasia (GTN). These tumors differ from choriocarcinoma as they are monophasic, have slower growth rates, have lower ß-hCG concentrations, and are more chemoresistant. Placental site trophoblastic tumor and ETT can be misdiagnosed, leading to inappropriate management.. OBJECTIVE: The aim of this study was to review the pathogenesis, presentation, pathologic findings, and treatment for PSTT and ETT. EVIDENCE ACQUISITION: A comprehensive literature review was performed identifying relevant research and review articles. Relevant textbook chapters and guidelines were also reviewed. RESULTS: Placental site trophoblastic tumor and ETT can present months to years after any antecedent pregnancy event with abnormal uterine bleeding and an elevated ß-hCG. Tumors are typically confined to the uterus and secrete lower levels of ß-hCG compared with other GTNs. The International Federation of Gynecology and Obstetrics prognostic scoring system does not correlate well with prognosis. These lesions can be misdiagnosed as smooth muscle tumors, metastatic melanoma, and cervical squamous cell carcinoma. However, they can be distinguished by their unique histologic and immunophenotypic features. CONCLUSIONS: Surgery is the mainstay of treatment for early-stage PSTT and ETT. For patients with advanced disease or for those with poor prognostic indicators, such as an antecedent pregnancy interval of greater than 48 months, a multimodal treatment paradigm of surgery and chemotherapy using a high-risk GTN platinum-etoposide containing regimen is recommended. RELEVANCE: Placental site trophoblastic tumor and ETT should be considered in the differential diagnosis in a reproductive age patient presenting with abnormal uterine bleeding and an elevated ß-hCG after any antecedent pregnancy event.

Gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in a retrospective cohort of 7761 patients in France.

BACKGROUND: The risk of malignant transformation of molar pregnancies after human chorionic gonadotropin levels return to normal is low, roughly 0.4%, but may justify an adaptation of monitoring strategies for certain patients. OBJECTIVE: This study aimed to determine the risk of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in women with molar pregnancy and identify risk factors for this type of malignant transformation to optimize follow-up protocols after human chorionic gonadotropin normalization. STUDY DESIGN: This was a retrospective observational national cohort study based at the French National Center for Trophoblastic Diseases of 7761 patients, treated between 1999 and 2020 for gestational trophoblastic disease, whose human chorionic gonadotropin levels returned spontaneously to normal. RESULTS: Among 7761 patients whose human chorionic gonadotropin levels returned to normal, 20 (0.26%) developed gestational trophoblastic neoplasia. The risk of malignant transformation varied with the type of mole, from 0% (0 of 2592 cases) for histologically proven partial mole to 0.36% for complete mole (18 of 5045) and 2.1% (2 of 95) for twin molar pregnancy. The median time to diagnosis of malignant transformation after human chorionic gonadotropin normalization was 11.4 months (range, 1-34 months). At diagnosis, 16 of 20 patients (80%) had the International Federation of Gynecology and Obstetrics stage I tumor, and 10 of 20 patients (50%) had a tumor classified as low risk in terms of the International Federation of Gynecology and Obstetrics score. In 9 of 20 patients (45%), the most common first-line treatment was combination chemotherapy. A quarter of these tumors (5 of 20) were histologically proven placental site or epithelioid trophoblastic tumors. In univariate analysis, the factors significantly associated with a higher risk of developing gestational trophoblastic neoplasia after the end of the normal human chorionic gonadotropin monitoring period were age of ≥45 years (odds ratio, 8.3; 95% confidence interval, 2.0-32.7; P=.004) and time to human chorionic gonadotropin normalization of ≥8 weeks (odds ratio, 7.7; 95% confidence interval, 1.1-335; P=.03). The risk was even higher for human chorionic gonadotropin normalization times of ≥17 weeks (odds ratio, 19.5; 95% confidence interval, 3.3-206; P<.001). CONCLUSION: In this group of patients with gestational trophoblastic disease, none of the those with pathologically verified partial mole had malignant transformation, supporting the current recommendation of stopping human chorionic gonadotropin monitoring after 3 successive negative tests. In cases of complete mole or twin molar pregnancy, we proposed to extend the monitoring period with quarterly human chorionic gonadotropin measurements for an additional 30 months in patients with the identified risk factors for late malignant transformation (age, ≥45 years; time to human chorionic gonadotropin normalization, ≥8 weeks).

Placental site trophoblastic tumour: five challenges of patient clinical management.

Placental site trophoblastic tumour is a rare form of gestational trophoblastic disease accounting for about 1%-2% of all trophoblastic tumours. Diagnosis and management of placental site trophoblastic tumour can be difficult.We report a case of a 30-year-old woman diagnosed with a placental site trophoblastic tumour and identify the challenges in diagnosis and treatment of this rare situation. The presenting sign was abnormal vaginal bleeding that started 3 months after delivery. Image exams revealed an enlarged uterus with a heterogeneous mass, with vesicular pattern, and the increased vascularisation serum human chorionic gonadotropin level was above normal range. The histological diagnosis was achieved through hysteroscopic biopsy. Staging exams revealed pulmonary micronodules. The patient was successfully treated with hysterectomy and chemotherapy. The latest follow-up (37 months after diagnosis) was uneventful, and the patient exhibited no signs of recurrence or metastasis.

Placental site trophoblastic tumor and epithelioid trophoblastic tumor: Clinical and pathological features, prognostic variables and treatment strategy.

Placental site trophoblastic tumor [PSTT] and epithelioid trophoblastic tumor [ETT] are the rarest gestational trophoblastic neoplasias, developing from intermediate trophoblast of the implantation site and chorion leave, respectively. PSTT and ETT share some clinical-pathological features, such as slow growth rates, early stage at presentation, relatively low ßhCG levels and poor response to chemotherapy. The mortality rate ranges from 6.5% to 27% for PSTT and from 10% to 24.2% for ETT. Advanced stage, long interval between antecedent pregnancy and diagnosis, and presence of clear cells are the independent prognostic variables for PSTT, and they may be similar for ETT. Hysterectomy can represent the only therapy for early disease, whereas adjuvant chemotherapy should be reserved to patients with poor risk factors, such as an interval from the antecedent pregnancy >4 years, deep myometrial invasion or serosal involvement. Few cases of fertility-sparing treatment in young women have been reported. An individualized multidisciplinary approach, including chemotherapy and debulking surgery with abdominal and/or extra-abdominal procedures, is warranted for advanced disease. EP/EMA and TP/TE are the preferred regimens in this setting. Immunohistochemistry has sometimes shown expression of EGFR, VEGF, MAPK, PDGF-R and PD-L1, and therefore investigational studies on biological agents targeting these molecules are strongly warranted for chemotherapy resistant-disease.

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.

Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor.

OPINION STATEMENT: Placental site trophoblastic tumor (PSTT) is the least common and the most ambiguous gestational trophoblastic tumor. Presentation of PSTT may occur in the course of gestation or from 1 week to 14 years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion). The indicators of aggressive behavior for this tumor are not well established. Due to the rarity of this disease that usually affects women of childbearing potential, we aimed to review the current literature, to identify risk factors and the best conservative therapeutic choices among the cases described. We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. Based on selective inclusion/exclusion criteria, we considered eight papers eligible for the review. Five were case reports and three were retrospective studies. We extracted and organized data into three different categories depending on the main treatment used. A total of 12 cases were treated with laparotomy; in 5 cases, the treatment was not curative. Therefore, a total abdominal hysterectomy was needed. Five cases were treated successfully with a minimally invasive approach, 2 with uterine evacuation, 2 with hysteroscopic resection, and 1 with a combined hysteroscopic/laparoscopic resection. Only 1 case treated with exclusive chemotherapy proved curative for the patient. Preservation of fertility in PSTT patients of childbearing age should be considered and as showed by the abovementioned studies, is a possible and safe therapeutic choice. Laparotomy for local uterine resection with the modified Strassman approach could be offered in patients at clinical stage 1 that are very motivated to retain fertility, extensively informing the patient of the risks and benefits related to this choice.

Placental site trophoblastic tumors and epithelioid trophoblastic tumors: Biology, natural history, and treatment modalities.

Placental site (PSTT) and epithelioid trophoblastic tumor (ETT) are rare types of gestational trophoblastic neoplasia (GTN) that arise from intermediate trophoblast. Given that this cell of origin is different from other forms of GTN, it is not surprising that the clinical presentation, tumor marker profile, and treatment paradigm for PSTT and ETT are quite different as well. The mainstay for therapy for stage I PSTT and ETT is hysterectomy with adjuvant chemotherapy reserved for those presenting greater than four years from the antecedent pregnancy. Surgery is also important for metastatic disease. There is no standardized chemotherapy regimen for advanced stage disease but often consists of a platinum-containing combination therapy, usually EMA-EP or TE/TP. Despite its rarity, PSTT and ETT account for a disproportionate percentage of mortality from GTN likely resulting from their relative chemotherapy resistance. Novel therapeutic modalities therefore are needed to improve the outcomes of women with advanced stage or resistant PSTT and ETT.

[Placental site trophoblastic tumor: When do we suspect it and which treatment shall we decide?] / Tumeur du site d'implantation trophoblastique : quand la suspecter et quel traitement décider ?

Tumors of trophoblast implantation site TTSI are rare gestational tumors. This case highlights the diagnostic difficulties and treatment of tumors of trophoblastic implantation site early. Patient of 28 years with no medical history, G1P1 who gave birth 11 months ago presented bleeding with an HCG level of 73IU that led to the diagnosis of early miscarriage. Treatment of miscarriage by hysteroscopy and curettage is complicated leading to the realization of an abdominopelvic CT and pelvic ultrasound that show an atypical uterine vascularity and an intracavitary heterogeneous mass. The pelvic MRI performed evokes a TTSI stage I. A hysterectomy with bilateral salpingectomy and ovarian conservation is achieved. Despite the standard treatment with surgery the HCG levels do not normalize before seven months after surgery. This indicates an adjuvant chemotherapy, the patient refuses. The presented case illustrates the diagnostic difficulties of the disease. He noted the importance of the second reading network proposed by the specialized center in Lyon. It also raises the question of adjuvant chemotherapy in some cases of early stage TTSI. The challenge is to define cases requiring adjuvant therapy. Predictors of chemotherapy in early stages could be tumor size, degree of infiltration of the myometrium and mutation p53. Amenorrhea, bleeding associated with uterine atypical vascularization, and atypical development of HCG<1000IU and/or unusual complications of treatment of miscarriage should evoke a tumor site trophoblastic implantation. Hysterectomy is the first treatment in early stages. Tumor size, degree of infiltration of the myometrium and mutation p53 are predictors to assess in multicentre studies to define the indications of postoperative chemotherapy.

Evolution of a Teenage and Young Adult Service, in Sheffield, U.K., for Patients with Gestational Trophoblastic Neoplasia.

OBJECTIVE: To describe the evolution of a teenage and young adult (TYA) service for patients with gestational trophoblastic neoplasia (GTN). BACKGROUND: Since its opening in 2002 the TYA unit has demonstrated its effectiveness and ability to care for GTN patients, offering additional emotional assessment and meeting the specific needs that many young GTN patients have. Patients using the TYA unit were identified from the Centre's databases, and individual records were scrutinized for demographics, clinical presentation, barriers to care, compliance, and specific needs. RESULTS: Of the 121 GTN patients who have utilized the facilities, there were 94 complete moles, 11 choriocarcinomas, 3 placental site trophoblastic tumors, 1 twin molar pregnancy, and 4 with persistent unexplained hCG elevation. Presenting with a complicated social background was identified as a barrier to care in 8 patients. In addition to patients, 40 relatives and 12 infants have also utilized the facilities. A total of 33% of patients and carers had social work input and/or refer-ral to psychology services. CONCLUSION: The bespoke service and care offered to TYA patients is appropriate and should be considered the gold standard for young patients, enabling them to cope with their unique challenges during diagnosis and treatment.

Placental site trophoblastic tumor: A review of 108 cases and their implications for prognosis and treatment.

OBJECTIVE: To identify important prognostic factors and optimized treatment strategies through the analysis of the clinical and pathological characteristics of placental site trophoblastic tumor. METHODS: 108 patients with PSTT registered in two GTD centers or in six tertiary hospitals in China were analyzed retrospectively between the years 1998 and 2013. The computerized database of clinical and pathological reports was reviewed on this patient group. The data were subsequently analyzed retrospectively using SPSS software. RESULTS: Among 3581 patients with GTNs treated in GTD centers or in the tertiary hospitals between 1998 and 2013, 108 cases were histologically confirmed PSTT (3%). Only seven deaths and eleven relapse cases were observed. All seven of the deaths were disease related, due to chemotherapy-resistant or relapsed. 23 patients who received fertility preservation treatment did not experience poor outcome or high risk of relapse. In 71 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I disease, the use of adjuvant chemotherapy following surgery (n=49) or not (n=22) made no significant difference in relapse rate (P=0.303) or survival (P=0.782). Univariate analysis revealed the interval between antecedent pregnancy and onset of PSTT, stage, prognosis score, and necrosis as significant predictors of poor survival but only stage remained significant on multivariate analysis. CONCLUSIONS: Patients with FIGO stage IV disease demonstrate the most critical risk indicator of PSTT in the current study. Preservation of fertility is considered in highly-selected patients with localized tumor; and surgery without chemotherapy is recommended as first line treatment for patients with stage I who are at low-risk.

Management of gestational trophoblastic disease: a survey of New Zealand O&G practice.

AIM: The aim of the study was to obtain information on pathways for diagnosis and management of molar pregnancy/gestational trophoblastic disease (GTD) across New Zealand, the protocols used, and, in addition, to consider the view of O&G Specialists on a national GTD reference centre. METHOD: An electronic survey approved by the RANZCOG Continues Professional Development Committee was distributed amongst registered O&G Specialists currently working in New Zealand. Data were analysed using Microsoft Excel 2011. Frequency distributions were used to determine the percentage of participants responding to the listed alternatives for each question. RESULTS: There were 234 potential responders, but only 68 complete questionnaires were received and available for analysis. The diagnosis of GTD requires histopathological analysis of pregnancy tissue, however only 79.7% of participants request this test routinely. Sixty-five percent of Fellows thought that a number of molar pregnancies can be missed with increasing proportion of medically-managed miscarriages, reliance on ultrasound and appearance of the tissue being contributing factors. Sixty-six percent of specialists were directly involved in the management of patients with GTD to various degrees. Follow-up responsibilities were divided between designated O&G specialists (52.3%), specialised gynaecology clinics (29.2%), acute assessment units (13.8%), nurse specialists (12%), O&G registrars (10.8%), GPs (6.2%), and others (6.2%). NZGCG guidelines were used by the majority of responders (54.8%), followed by local (29%) and RCOG (27.4%) guidelines. Seventy-two percent of specialists felt that some form of centralisation in the management of GTD is needed. CONCLUSION: In spite of the low response rate, our research demonstrates existing practice heterogeneity at every level of care. It also confirms that there is a desire for some form of centralisation in diagnosis and management of GTD, and a definite need for data collection in the form of a national register.

Retrospective analysis of the clinicopathologic and prognostic characteristics of stage I placental site trophoblastic tumor in China.

OBJECTIVE: To investigate clinicopathologic features and identify prognostic factors of placental site trophoblastic tumor (PSTT). METHODS: In a retrospective study, data were analyzed from patients with stage I PSTT treated at a tertiary hospital in Shanghai, China, from January 2007 to May 2013. Univariate log-rank tests were used to examine the association between clinicopathologic characteristics and overall survival and disease-free survival (DFS). RESULTS: In total, seven patients had stage I PSTT. Mean age was 31.6 years (range 22-42). Four patients had term delivery as the outcome of their antecedent pregnancy. Six had a ß-human chorionic gonadotropin (ß-hCG) serum concentration of less than 10 000 mIU/mL. Among five patients who underwent hysterectomy combined with chemotherapy, one had recurrent disease. One patient received fertility-preserving therapy and achieved complete remission. The mean 5-year overall survival and DFS were 100% and 86%, respectively. Maximum ß-HCG concentration of at least 10 000 mIU/mL and a mitotic index of more than 5 mitotic counts per 10 high-power fields were associated with disease recurrence (both P=0.014). CONCLUSION: Pretreatment ß-hCG concentration and mitotic index might be predictors of recurrence among patients with PSTT. Fertility-preserving therapy might be practical in some patients.

Epidemiological report on the treatment of patients with gestational trophoblastic disease in 10 Brazilian referral centers: results after 12 years since International FIGO 2000 Consensus.

OBJECTIVE: To evaluate treatment of Brazilian patients with gestational trophoblastic disease (GTD). STUDY DESIGN: A retrospective cohort study with analysis of medical reports performed in 10 Brazilian referral centers from January 2000 to December 2011. RESULTS: Of 5,250 patients 3 died (0.06%) at the time of uterine evacuation. Spontaneous remission of GTD (group G1) was observed in 4,103 cases, and 1,144 (21.8%) progressed to gestational trophoblastic neoplasia (GTN) (G2). In G1 2,716 (66.2%) had complete hydatidiform mole (HM) and 1,210, partial HM (29.5%); 3,772 patients (92.7%) recovered as noted in December 2012. In G2, of 1,118 patients treated, initial histopathological results of previous gestation were complete HM (77.5% [n = 886]), partial HM (8.8% [n = 100]), and choriocarcinoma (8.0% [n = 92]); 930 (81.3%) were low-risk, 200 (17.5%) were high-risk GTN, and 14 had placental site trophoblastic tumor (PSTT) (1.2%); cure was achieved in 1,078 cases (96.4%), but 26 patients (2.3%) died (4 low-risk [0.4%], 19 high-risk [9.5%], and 3 PSTT [21.4%]). CONCLUSION: The highest death rates were due to high-risk GTN and PSTT. Patients with molar pregnancy should be referred to a referral center for an early diagnosis and prompt treatment of GTN in order to reduce the morbidity and mortality found in advanced stages.

Multicenter analysis of gestational trophoblastic neoplasia in Turkey.

BACKGROUND: To evaluate the incidence, diagnosis and management of GTN among 28 centers in Turkey. MATERIALS AND METHODS: A retrospective study was designed to include GTN patients attending 28 centers in the 10-year period between January 2003 and May 2013. Demographical characteristics of the patients, histopathological diagnosis, the International Federation of Gynecology and Obstetrics (FIGO) anatomical and prognostic scores, use of single-agent and multi-agent chemotherapy, surgical interventions and prognosis were evaluated. RESULTS: From 2003-2013, there were 1,173,235 deliveries and 456 GTN cases at the 28 centers. The incidence was calculated to be 0.38 per 1,000 deliveries. According to the evaluated data of 364 patients, the median age at diagnosis was 31 years (range, 15-59 years). A histopathological diagnosis was present for 45.1% of the patients, and invasive mole, choriocarcinoma and PSTTs were diagnosed in 22.3% (n=81), 18.1% (n=66) and 4.7% (n=17) of the patients, respectively. Regarding final prognosis, 352 (96.7%) of the patients had remission, and 7 (1.9%) had persistence, whereas the disease was mortal for 5 (1.4%) of the patients. CONCLUSIONS: Because of the differences between countries, it is important to provide national registration systems and special clinics for the accurate diagnosis and treatment of GTN.

Worldwide survey of the results of treating gestational trophoblastic disease.

OBJECTIVE: To determine factors influencing outcome for patients with gestational trophoblastic disease (GTD) from throughout the world. STUDY DESIGN: Physicians known to treat GTD were sent a questionnaire. RESULTS: There were 32 responses from 17 countries, totaling 26,153 patients. Of 14,093 patients with complete mole 20.6% developed trophoblastic neoplasia, and 5.7% died. There were 10,230 patients with partial mole, of whom 6.5% received therapy for neoplasia. There were 548 patients with post-term pregnancy choriocarcinoma, of whom 13.4% died. Of 137 patients with placental site trophoblastic tumor 16.1% died. The remaining 1,165 patients did not fit into a designated diagnostic category. The mortality rate for 2,818 patients with GTD primarily treated at a trophoblast center was 2.1%, as compared with 8% among 1,854 patients referred after failure of primary treatment (p < 0.01). CONCLUSION: Patients treated by physicians experienced in the management of trophoblastic disease have better results and survival.

Diagnosis and treatment of placental site trophoblastic tumor.

Here we report a case of a placental site trophoblastic tumor in a 36 year old Chinese woman, 31 months following a prior normal pregnancy. Her clinical presentation and ultrasound findings were uncharacteristic; and the final definitive diagnosis was established based on histological examination in conjunction with immunohistochemistry studies and a normal beta human chorionic gonadotropin level. The tumor exhibited high grade histological features with tumor necrosis, nuclear atypia and high mitosis. The patient was successfully treated with hysterectomy with pre- and post-operative chemotherapy.

Placental site trophoblastic tumor: analysis of presentation, treatment, and outcome.

OBJECTIVE: Placental-site trophoblastic tumor (PSTT) is the rarest form of gestational trophoblastic disease (GTD). A risk-adapted treatment approach has been advocated, but controversy exists as to the most important prognostic markers for this disease. Our goal was to determine the prognostic markers for patients with PSTT seen at our center. METHODS: We conducted a retrospective analysis of patients with PSTT seen at a single tertiary care center between 1996 and 2011. The association of FIGO stage, interval from antecedent pregnancy, antecedent pregnancy outcome, human chorionic gonadotropin (hCG) level, and age to overall survival was examined using univariate log-rank tests. Presentation, treatment, and outcome were summarized using descriptive statistics. RESULTS: Data from 17 patients were analyzed. Eight (47%) had Stage I/II disease and 9 (53%) had Stage III/IV disease. Median overall survival for the entire cohort was 86 months (range, 2-101 months). Median duration of follow-up for surviving patients was 56 months. Increasing FIGO stage (I-III versus IV) was associated with a worse overall survival (p=0.009). Interval from antecedent pregnancy (≥12months), antecedent pregnancy outcome (full-term), hCG (≥1000 IU/L), and age (≥40) were not associated with worse survival. CONCLUSION: FIGO stage, specifically Stage IV disease, was the most important predictor of overall survival in our cohort of PSTT patients.