Gestational trophoblastic neoplasia (GTN) is a group of rare tumors characterized by abnormal trophoblastic proliferation following pregnancy including invasive moles, choriocarcinomas, and intermediate trophoblastic tumors (ITT). Although the treatment and follow-up of GTN has been heterogeneous, globally the emergence of expert networks has helped to harmonize its management.
We provide an overview of the current knowledge, diagnosis, and management strategies in GTN and discuss innovative therapeutic options under investigation. While chemotherapy has been the historical backbone of GTN treatment, promising drugs such as immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway and anti-angiogenic tyrosine kinase inhibitors are currently being investigated remodeling the therapeutical landscape of trophoblastic tumors.
Chemotherapy regimens for GTN have potential long-term effects on fertility and quality of life, making innovative and less toxic therapeutic approaches necessary. Immune checkpoint inhibitors have shown promise in reversing immune tolerance in GTN and have been evaluated in several trials. However, immunotherapy is associated with rare but life-threatening adverse events and evidence of immune-related infertility in mice, highlighting the need for further research and careful consideration of its use. Innovative biomarkers could help personalize GTN treatments and reduce chemotherapy burden in some patients.

BACKGROUND: Mixed gestational trophoblastic neoplasms are extremely rare and comprise a group of fetal trophoblastic tumors including choriocarcinomas, epithelioid trophoblastic tumors, and placental site trophoblastic tumors. We present a case of a patient with extrauterine mixed gestational trophoblastic neoplasm adjacent to the abdominal wall cesarean scar. On the basis of a literature review, this type of case has never been reported before due to the unique lesion location and low incidence.
METHODS: Our patient was a 39-year-old Chinese woman who had a history of two cesarean sections and one miscarriage. She had a recurrent anterior abdominal wall mass around her cesarean scar, and the mass was initially suspected of being choriocarcinoma of unknown origin. The patient had concomitant negative or mildly increased serum β-human chorionic gonadotropin at follow-up and no abnormal vaginal bleeding or abdominal pain. However, she underwent local excision twice and had two courses of chemotherapy with an etoposide and cisplatin regimen. She finally opted for exploratory laparotomy with abdominal wall lesion removal, subtotal hysterectomy, bilateral salpingectomy, and left ovarian cyst resection, which showed the abdominal wall lesion, whose components were revealed by microscopy and immunohistochemical staining to be approximately 90% epithelioid trophoblastic tumors and 10% choriocarcinomas from a solely extrauterine mixed gestational trophoblastic neoplasm around an abdominal wall cesarean scar.
CONCLUSIONS: It is worth noting whether epithelioid trophoblastic tumor exists in the setting of persistent positive low-level β-human chorionic gonadotropin. More studies are required to provide mechanistic insights into these mixed gestational trophoblastic neoplasms.

OBJECTIVE: Epithelioid trophoblastic tumor (ETT) is very rare and few cases have been published in the English literature. Hysterectomy is the recommended treatment, due to the high rate of recurrence and mortality. The objective of this article is to present a rare case of ETT with fertility-preserving treatment and review published similar cases.
METHODS: We report the case of ETT in a 19-year-old Chinese woman, who had a strong desire of fertility preservation. She presented with vaginal spotting and hysteroscopy showed an isolated solid mass (2.0 × 1.5 × 1.5 cm) at the right corner of the uterine cavity. Serum β-human chorionic gonadotropin (β-HCG) persisted at low level elevation about 100 IU/L. We treated her with a lesionectomy and 3 cycles EP-EMA (etoposide, cisplatin/etoposide, methotrexate and actinomycin) chemotherapy regimen. The patient is now in stable condition, without any signs of recurrence during 20 months of follow-up.
CONCLUSIONS: Fertility-preserving surgery would probably be a feasible and safe strategy for the patients whose lesions can be completely removed.

Epithelioid trophoblastic tumor is a rare gestational trophoblastic neoplasm arising from the intermediate trophoblasts. Although usually seen in the reproductive period, it may be encountered during the postmenopausal period. A 56-year-old woman who had given her last birth 21 years ago presented to the hospital with a complaint of postmenopausal bleeding. She had a history of eight live pregnancies and had been in menopause for 4 years. With the help of typical histopathologic and immunohistochemical findings, a diagnosis of \"epithelioid trophoblastic tumor\" was made. The diagnosis was made at an advanced age and the case had extraordinary features such as high mitotic activity and Ki-67 proliferation index (70%). Gestational trophoblastic neoplasms are rare causes of postmenopausal bleeding which may cause differential diagnosis problem. They should be kept in mind even if the patient age does not comply with because of the differences in treatment.

Objective: Mixed gestational trophoblastic neoplasia (GTN) is a rare occurrence that refers to the coexistence of choriocarcinoma and/or placental site trophoblastic tumor and/or epithelioid trophoblastic tumor. The diagnosis and management of mixed GTN are challenging. We investigated the clinicopathological characteristics, diagnoses, treatments, and outcomes of patients with mixed GTN. Materials and Methods: The medical records and pathological sections of 16 patients with mixed GTN who were treated at Peking Union Medical College Hospital and The Second Xiangya Hospital of Central South University between January 2012 and December 2018 were reviewed. Results: Pretreatment serum human chorionic gonadotropin (hCG) levels ranged from 180 to 625,024 IU/L, and were >10,000 IU/L in 14 of the 16 patients, none of whom were diagnosed correctly at initial presentation. Two patients were diagnosed with choriocarcinoma coexisting with intermediate trophoblastic tumor (ITT) through dilation and curettage (D&C) before treatment. Another 5 patients were histologically confirmed to have placental site trophoblastic tumor (PSTT) by D&C but final pathological findings showed mixed PSTT and choriocarcinoma at subsequent hysterectomy. Seven post-chemotherapy patients with an initial clinical diagnosis of choriocarcinoma underwent surgery because of chemoresistance and their pathological findings revealed coexisting ITT. The remaining 2 patients were found to have choriocarcinoma coexisting with ITT following cervical biopsy and pulmonary lobectomy. All patients received chemotherapy: 14 underwent surgery combined with chemotherapy and 2 received chemotherapy alone to preserve fertility. Other than 1 patient who died of disease progression, 15 patients (93.8%) achieved complete remission (CR) after treatment, although 5 (33.3%) relapsed. Of these 5 patients with relapse, 3 achieved CR after additional treatment, 1 was receiving an immune checkpoint inhibitor, and 1 was lost to follow-up after refusing further therapy. Conclusion: Mixed GTN is difficult to diagnose on initial presentation. Overlap of the ITT component should be considered in refractory chemoresistant choriocarcinoma. Coexistence of choriocarcinoma should be suspected in ITT patients with high hCG levels. Surgery combined with chemotherapy is optimal treatment for choriocarcinoma mixed with ITT.

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

Epithelioid trophoblastic tumor (ETT) is a rare trophoblastic tumor originating from chorionic-type intermediate trophoblasts (ITs). It is usually associated with a prior gestational event. We present a 44-year-old woman who had unusual pregnancy related history. The patient received her second spontaneous abortion at the age of 25 years and had suffered from choriocarcinoma in left board ligament at the age of 29 years. She admitted no more treatment after 3 courses of multiagent chemotherapy when serum β-hCG returned to normal. Then she had Full-term delivery, induced abortion at the ages of 32, 33 years. The patient had high serum levels of beta-human chorionic gonadotropin (6587 IU/L). Microscopically, the tumor was composed of mainly mononuclear tumor cells, grew in cords, nests, and sheets within which were aggregates of hyaline material. Most were with distinct cell borders, eosinophilic cytoplasm. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CK18), P63, focal reactivity for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The Ki-67 index was 77%. The histological and immunohistochemical features were characteristic of epithelioid trophoblastic tumor. This is the first reported case of these two gestational trophoblastic tumor happened on one person with the intervening normal pregnancy.