Our goal was to assess the outcomes and explore the prognostic factors for patients with placental-site trophoblastic tumor (PSTT) through this retrospective analysis.
2043 patients with gestational trophoblastic neoplasia (GTN) were registered at two tertiary hospitals between January 2003 and March 2021, of whom 58 (2.8%) were diagnosed with PSTT. We retrospectively analyzed the clinico-pathological characteristics, treatments, outcomes and prognostic factors.
Only 4 patients died and 5 patients experienced a recurrence. Patients (n = 49) with stage I disease had a favorable prognosis, surgery with (n = 21) or without (n = 28) chemotherapy made no significant difference in overall survival (OS) (p = 0.251) or disease-free survival (DFS) (p = 0.425). 3 patients with stage I had fertility preserving surgery and successful pregnancy was achieved in 2 of them. The outcome of patients with advanced disease was poor. Univariate analysis revealed serum β-hCG levels at diagnosis, FIGO stage IV and metastatic disease were significant predictors of both overall survival and disease-free survival. However, multivariate analysis indicated stage IV was the only significant independent predictor of adverse OS, while metastatic disease was the only significant independent predictor of adverse DFS.
Surgery alone is sufficient for patients with stage I disease without high-risk factors. The prognosis of patients with advanced stage disease remains poor. Stage IV and metastatic disease were the most critical risk factors.

The management of hydatidiform mole (HM) and the incidence of post-molar gestational trophoblastic neoplasia (GTN) in Vietnam has not been reported to date. This study aimed to study the incidence of HM and post-molar GTN and identify factors associated with post-molar GTN at a tertiary hospital in Vietnam. Five hundred and eighty-four patients who were treated for HM at Tu Du Hospital between January and December 2010 were included in this study. The mean age and gestational age at the first evacuation were 28.8 years old and 11.0 weeks, respectively. After the initial evacuation and pathological examination, 87 patients who were older than 40 or did not wish to have children underwent a hysterectomy, while the others underwent second curettage. All 472 patients who had human chorionic gonadotropin (hCG) ≥ 100,000 IU/L before treatment received one cycle of methotrexate with folinic acid as prophylactic chemotherapy. The incidence of HM was 11.1 per 1,000 deliveries; 47 patients (8.0%) developed post-molar GTN. Gestational week, hCG level at one week after the first evacuation, and pathological remnants were significantly associated with the development of post-molar GTN. The results of this study suggest that prophylactic chemotherapy and hysterectomy may be useful for high-risk HM patients to reduce post-molar GTN in settings in which the risk of post-molar GTN and loss to follow-up after HM are greater and hCG measurements and appropriate GTN treatments are unavailable. However, future studies on the long-term outcomes and side effects of prophylactic therapies on HM are required.

There are limited data on ultrasound morphologic features of gestational trophoblastic neoplasia. A predictive model to determine predictors of response to therapy would be ideal in the management of patients with this rare disease.
TITANIUM is a prospective, multicenter, observational study aiming to describe ultrasound features of gestational trophoblastic neoplasia and to investigate the role of ultrasound in identifying patients at high risk of resistance to single-drug therapy. The study hypothesis is that ultrasound could improve the International Federation of Gynecology and Obstetrics (FIGO) scoring system for early identification of patients predisposed to single-drug resistance.
Patients eligible have a diagnosis of gestational trophoblastic neoplasia according to FIGO or the criteria set by Charing Cross Hospital, London, UK. At diagnosis, patients are classified as low-risk (score 0-6) or high-risk (score >6) according to the FIGO risk scoring system, and a baseline ultrasound scan is performed. Patients receive treatment according to local protocol at each institution. Follow-up ultrasound examinations are performed at 1, 4, 10, 16, and 22 months after start of chemotherapy, and at each scan, serum human chorionic gonadotropin (hCG) level, and chemotherapy treatment, if any, are recorded.
Our aims are to define ultrasound features of gestational trophoblastic neoplasia and to develop a predictive model of resistance to single-drug therapy in low-risk patients.
The sample size was calculated assuming that 70% of patients with gestational trophoblastic neoplasia are at low risk, and estimating the rate of resistance to single-drug therapy in this group to be 40%. Assuming a dropout rate of 10%, we should recruit at least 120 patients. With this sample size, we can attempt to create a mathematical model with three variables (either two ultrasound parameters in addition to the risk score or three ultrasound variables statistically significant at univariate analysis) to predict resistance to single-drug therapy in low-risk patients.
The accrual started in February 2019. Additional referral centers for gestational trophoblastic disease, with similar ultrasound expertise, are welcome to participate in the study. Enrollment should be completed by December 2021, and analysis will be conducted in December 2023.
The study received the Ethical Committee approval of the Coordinator Center (Rome) in January 2019 (Protocol No. 0004668/19).

BACKGROUND: Placental-site trophoblastic tumours are a rare form of gestational trophoblastic disease and consequently information about optimum management or prognostic factors is restricted. We aimed to assess the long-term outcome of stage-adapted management by surgery, chemotherapy, or both for patients with the disorder.
METHODS: 35 550 women were registered with gestational trophoblastic disease in the UK (1976-2006), of whom 62 were diagnosed with placental-site trophoblastic tumours and included, retrospectively, in the study. Patients were treated by surgery, chemotherapy, or both. We estimated the probabilities of overall survival and survival without recurrence of disease 5 and 10 years after the date of first treatment, and calculated the association of these endpoints with prognostic factors, including time since antecedent pregnancy, serum concentration of beta-human chorionic gonadotropin, and stage of disease, with both univariate and multivariate analyses.
RESULTS: Probabilities of overall and recurrence-free survival 10 years after first treatment were 70% (95% CI 54-82) and 73% (54-85), respectively. Patients with stage I disease had a 10-year probability of overall survival of 90% (77-100) and did not benefit from postoperative chemotherapy. By contrast, patients with stage II, III, and IV disease required combined treatment with surgery and chemotherapy; probability of overall survival at 10 years was 52% (3-100) for patients with stage II disease and 49% (26-72) for stage III or IV disease. Outcome for patients who had recurrent or refractory disease was poor: only four (22%) patients achieved long-term survival beyond 60 months. Multivariate analysis showed that the only significant independent predictor of overall and recurrence-free survival was time since antecedent pregnancy. A cutoff point of 48 months since antecedent pregnancy could differentiate between patients\' probability of survival (<48 months) or death (>/=48 months) with 93% specificity and 100% sensitivity, and with a positive predictive value of 100% and a negative predictive value of 98%.
CONCLUSIONS: Stage-adapted management with surgery for stage I disease, and combined surgery and chemotherapy for stage II, III, and IV disease could improve the effectiveness of treatment for placental-site trophoblastic tumours. Use of 48 months since antecedent pregnancy as a prognostic indicator of survival could help select patients for risk-adapted treatment.
BACKGROUND: National Commissioning Group.

OBJECTIVE: To identify an indicator that can predict tumor cell spread beyond the uterine corpus.
METHODS: We studied clinicopathology and immunohistochemistry of 12 cases of PSTT. Two cases of epithelioid trophoblastic tumor (ETT) were included as reference cases. For immunohistochemistry, antibodies against Ki-67, p53, human chorionic gonadotropin (hCG), human placental lactogen (hPL), carcinoembryonic antigen (CEA, polyclonal antibodies; pCEA), carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), and bcl-2 were used. PSTT cases were divided as confined and non-confined groups (CG and NCG, respectively). CG consisted of stage I cases with no evidence of recurrence during the follow-up, while NCG consisted of either advanced (stage II or higher) or recurrent stage I lesions.
RESULTS: Age, the interval from the latest pregnancy, serum hCG/hPL levels, tumor size, mitotic figures, Ki-67 labeling indices, and bcl-2 did not discriminate NCG from CG. CEACAM1 and CEA-related antigens as determined by polyclonal anti-CEA antibodies were specifically stained in PSTT cells, but they could not discriminate groups. p53 was positive in PSTT cells in NCG (6/6, 100%), while it was positive in only one case of CG (1/6, 16.7%), indicating a possible usefulness of p53 immunostaining in predicting an invasive or recurrent propensity of PSTT cells (p=0.015).
CONCLUSIONS: This finding also suggests the importance of p53 function in the biology of PSTT cells.

OBJECTIVE: To study the clinicopathologic features and immunophenotype of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT).
METHODS: During the period from 1959 to 2005, a total of 1012 cases of gestational trophoblastic disease were diagnosed in Beijing Obstetrics and Gynecology Hospital. Six cases of PSTT and a case of ETT were retrieved from the archives of Beijing Obstetrics and Gynecology Hospital. Immunohistochemical study for cytokeratin 18, human chorionic gonadotropin (hCG), human placental lactogen (hPL), Mel-CAM (CD146), placental-like alkaline phosphatase (PLAP), epithelial membrane antigen (EMA), inhibin-alpha and proliferative cell nuclear antigen (PCNA) were performed. The morphologic features and immunohistochemical findings were compared with those of the controlled group which consisted of 20 cases of early gestational villi with decidua basalis and 20 cases of hydatidiform moles with implantation site.
RESULTS: The mean age of patients with PSTT was 32.4, while the age of patients with ETT was 36. Major clinical findings included irregular vaginal bleeding and amenorrhea. Preoperative serum hCG level varied from normal to moderately elevated. Serum testosterone level was raised in 1 case. Uterine curettage could achieve an accurate pathologic diagnosis in 60% of cases. ETT involved mainly the lower uterine segment and endocervix. Histologically, PSTT cells permeated between the myometrial fibers and vessels either individually or connecting in cords or sheets in a manner reminiscent of the implantation site reaction. ETT composed of a relatively uniform population of mononuclear trophoblastic cells, clumping together in nests as the cell islets associating with eosinophilic, fibrillary and hyaline material and necrotic debris, forming a \"geographic map\" like pattern. Immunohistochemical study for hPL, hCG, Mel-CAM (CD146) and PLAP was most helpful for the differential diagnosis. The duration of follow-up varied from 14 months to 19 years. One case of PSTT developed metastasis in pancreas, 5 months after the operation. The remaining patients survived without tumor recurrence.
CONCLUSIONS: PSTT is a tumor of implantation site intermediate trophoblasts while ETT differentiates towards chorionic-type intermediate trophoblasts. The different pathologic features and immunophenotype observed were closely related with the difference in tumor cell differentiation. An accurate pathologic diagnosis of the uterine curettage material is important for the clinical management. According to the limited follow-up data available, the clinical behavior of ETT is seemed similar to that of PSTT.

OBJECTIVE: The placental site trophoblastic tumor is a rare form of gestational trophoblastic disease. Fifteen percent of reported cases have been fatal, but predicting behavior in individual patients has been challenging.
METHODS: The clinical, gross and histopathological features of 55 cases and 180 cases in the literature were analyzed for their effect on survival and in relation to tumor stage.
RESULTS: The 55 patients in our series were 20 to 62 (average 32) years of age. The tumors occurred on an average of 34 months after the last known gestation. 84% were stage I, 2% stage II, 5% stage III, and 9% stage IV. Serum levels of human chorionic gonadotropin (hCG) were elevated (average 691 mIU/ml) in 77% of the cases. The tumors were on average 5 cm in greatest dimension and were composed microscopically of infiltrative sheets of intermediate (extravillous) trophoblastic cells. The mitotic rate ranged from 0 to 20 (average 5.0) per 10 high power fields. The follow-up interval averaged 4.6 years. Eight patients (15%) died from metastatic tumor, and nine additional patients had metastases or a recurrence but were alive at last contact. The most common metastatic sites were the lungs, liver, and vagina.
CONCLUSIONS: Significant factors associated with adverse survival in the present series were age over 35 years (P = 0.025), interval since the last pregnancy of over 2 years (P = 0.014), deep myometrial invasion (P = 0.006), stage III or IV (P < 0.0005), maximum hCG level > 1000 mIU/ml (P = 0.034), extensive coagulative necrosis (P = 0.024), high mitotic rate (P = 0.005), and the presence of cells with clear cytoplasm (P < 0.0005). Only stage and clear cytoplasm were independent predictors of overall survival, while stage and age were the only independent predictors of time to recurrence or disease-free survival. In the literature, factors associated with survival were stage (P < 0.005), interval from preceding pregnancy of over 2 years (P = 0.029), previous term pregnancy (P = 0.046), high mitotic rate (P < 0.0005), and high hCG level (P = 0.037).

OBJECTIVE: To investigate the clinicopathological features of intermediate trophoblastic non-tumor lesions, and to evaluate the position of immunohistochemistry in differential diagnoses.
METHODS: Clinical presentation and morphological study of 15 cases of exaggerated placental site (EPS) and 4 cases of placental site nodule or plaque (PSNP) were reviewed. Immunohistochemical stains for hCG, hPL, inhibin-alpha, PLAP, CK18 and Ki-67 were performed.
RESULTS: The age of patients ranged from 25 to 40 years with an average of 31.5 years for EPS and 26 to 39 years with an average of 34.3 years for PSNP. Microscopically, EPS was characterized by cords and small sheets of implantation site intermediate trophoblasts infiltrating the endometrium, myometrium and arterial walls. The general histological structures of the endometrium and myometrium were preserved. PSNP was characterized by multiple circumscribed nodular lesions consisting of so-called chorionic-type intermediate trophoblasts and hyaline-like matrix present in the endometrium. Immunohistochemical stainings for hPL and CK18 were positive in the 15 EPS cases. Immunoreactivity for CK18, Inhibin-alpha and PLAP was detected in 4 PSNP cases. The Ki-67 labeling index in 15 EPS cases was low (< or = 5%), while Ki-67 index in 4 PSNP cases was close to 0.
CONCLUSIONS: The clinical presentation and pathological features of EPS and PSNP differ from those of trophoblastic tumors (placental site trophoblastic tumor, epithelioid trophoblastic tumor and choriocarcinoma). Immunochemical staining is of great value in their differential diagnoses.

Placental site trophoblastic tumour (PSTT) is a neoplastic proliferation of the implantation intermediate trophoblast. Although clinicopathological studies are not uncommon in case reports or small series, molecular and genetic studies are quite limited. Four archived cases of PSTT were successfully analysed by comparative genomic hybridization (CGH) in this study. Regional chromosomal gains were observed in two cases. One case showed chromosomal gains in the regions of 19p13.2, 21q11-21 and 22q12. The second case demonstrated a single regional chromosomal gain involving 21q21. No chromosomal loss is observed. The remaining two cases showed a balanced CGH profile without detectable chromosomal gain or loss. In summary, although chromosomal alterations detectable by CGH are not common, rare chromosomal gains do occur in PSTT. The recurrent chromosomal gain involving chromosomal 21q observed in two of our cases deserves additional studies to ascertain whether it carries any pathobiological significance.

BACKGROUND: Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasm composed predominantly of intermediate trophoblast. Most showed benign behavior whereas 10-15% of PSTTs were clinically malignant with later recurrence and metastasis. Currently, there are no reliable means to predict clinical outcome, and cytogenetic information is scanty.
METHODS: The clinicopathologic features of two cases of malignant PSTT were analyzed. Cytogenetic analysis was performed by comparative genomic hybridization (CGH) and chromosome in situ hybridization (CISH) using frozen tissue and paraffin embedded sections, respectively.
RESULTS: Both patients were 32 years old at time of diagnosis. One patient with PSTT presented with menorrhagia, and the other presented with symptoms of missed abortion. Elevated serum human chorionic gonadotropin (HCG) was detected in both patients. Histologic examination showed the typical features of PSTT with high mitotic count (> 5/10 high-power fields). Ovarian and lung metastasis occurred in both patients. Immunohistochemical staining revealed an equal distribution of HCG and human placental lactogen. Cytogenetic studies by CISH showed that karyotypes of these two malignant PSTTs were diploid. Analysis of the tumor tissue by CGH did not show any changes in DNA copy numbers.
CONCLUSIONS: The authors\' study indicated that the two metastasizing PSTTs had balanced diploid karyotype. The malignant behavior of PSTTs may be not related to the DNA copy number changes. Such cytogenetic study may be useful in distinguishing metastatic PSTT from choriocarcinoma.