Evolution of Treatment Strategies for Gestational Trophoblastic Neoplasia: Chemotherapy, Immunotherapy, and Molecular Targeted Therapy.

OPINION STATEMENT: In addressing Gestational Trophoblastic Neoplasia (GTN), it is imperative to acknowledge the evolving landscape of treatment options, especially in light of the challenges posed by traditional methods. While historically, surgical interventions, radiation therapy, and chemotherapeutic agents have been the mainstays, the emergence of resistance and high-risk scenarios necessitates a reevaluation of our therapeutic approaches. Our review highlights the promising advancements in immunotherapy and molecular targeted therapy as viable alternatives for GTN management. The introduction of immune checkpoint inhibitors and kinase inhibitors offers a paradigm shift, particularly for patients resistant to conventional chemotherapy regimens. These novel therapies not only exhibit efficacy but also demonstrate manageable toxicity profiles, particularly in high-risk cases. However, integrating these innovative treatments into established international guidelines presents a formidable task. As we move forward, it is imperative that future research not only prioritizes fertility preservation but also rigorously evaluates long-term toxicity implications. International collaboration becomes pivotal in addressing the nuances of this rare and complex disease. In conclusion, our review underscores the need for a nuanced approach to GTN treatment, one that prioritizes reduced toxicity and improved quality of life. By embracing the advancements in immunotherapy and molecular targeted therapy, we can pave the way for more effective and patient-centered care in the management of GTN.

Retrospective evaluation of gestational trophoblastic disease - experience with ultrasounds.

OBJECTIVE: Our study aims to determine the frequency and types of GTD (Gestational Trophoblastic Disease) in our clinic, to evaluate its relationship with clinical parameters, and the consistency of clinical prediagnosis and pathological definitive diagnosis. PATIENTS AND METHODS: In the present study, hospital records of 120 patients with gestational trophoblastic disease between January 2019 and August 2022 were obtained and evaluated retrospectively. Demographic, hematological, biochemical, and clinical data were collected in detail, and the data were analyzed statistically. RESULTS: Our study included a total of 120 female patients, with an average age of 31.16±9.70. The average number of patients was 3. The average time for women to receive the diagnosis was 9.80±2.45 weeks, with the most frequent complaint on our part being bleeding (85.8%). When the pathology outcomes of the patients we included in our study were examined, it was found that the number of patients diagnosed with incomplete abortion was 34, the number of patients diagnosed with complete abortion was 82, the number of invasive moles diagnosed was 3, and the number of patient diagnosed with choriocarcinoma was 1. Kappa ratio was calculated as 0.419 (p<0.001) when the compliance of the clinical diagnosis was assessed. This value was consistent with median level alignment. In a study that examined the three years of our calism in our bulk, 1.8 per 1,000 births were followed frequently. CONCLUSIONS: We should inform patients in detail about gestational trophoblastic diseases and warn patients not to delay their consequences. We should recommend that pregnancy be avoided for 12 months for low-risk patients and 18 months for high-risk patients after GTD.

Contraceptive strategies for reducing the risk of reproductive cancers.

Reproductive cancers, encompassing various malignancies like endometrial, ovarian, cervical cancer, and gestational trophoblastic neoplasia, pose a significant global health burden. Understanding their patterns is vital for effective prevention and management. Contraceptives show a protective effect against some of these cancers. This clinical guidance document aims to elucidate the disease burden of reproductive cancers and the evidence supporting contraceptive methods in prevention and management. Regional disparities in incidence and mortality highlight the urgent need for targeted interventions, particularly in low-resource settings. Healthcare providers must weigh individual risk profiles and medical eligibility criteria when discussing contraceptive options. Enhanced health literacy through direct patient education is essential for leveraging low-cost behavioral interventions to mitigate reproductive cancer risks.

Hysterectomy versus chemotherapy for low-risk non-metastatic gestational trophoblastic neoplasia (GTN): A cost-effectiveness analysis.

OBJECTIVE: Determine the cost-effectiveness for hysterectomy versus standard of care single agent chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). METHODS: A cost-effectiveness analysis was conducted comparing single agent chemotherapy with hysterectomy using decision analysis and Markov modeling from a healthcare payer perspective in Canada. The base case was a 40-year-old patient with low-risk non-metastatic GTN that completed childbearing. Outcomes were life years (LYs), quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and adjusted 2022 costs (CAD). Discounting was 1.5% annually and the time horizon was the patient's lifetime. Model validation included face validity, deterministic sensitivity analyses, and scenario analysis. RESULTS: Mean costs for chemotherapy and hysterectomy arms were $34,507 and $17,363, respectively, while effectiveness measure were 30.37 QALYs and 31.04 LYs versus 30.14 QALYs and 30.82 Lys, respectively. The ICER was $74,526 (USD $54,516) per QALY. Thresholds favoring hysterectomy effectiveness were 30-day hysterectomy mortality below 0.2% and recurrence risk during surveillance above 9.2% (low-risk) and 33.4% (high-risk). Scenario analyses for Dactinomycin and Methotrexate led to similar results. Sensitivity analysis using tornado analysis found the cost to be most influenced by single agent chemotherapy cost and risk of resistance, number of weeks of chemotherapy, and probability of postoperative mortality. CONCLUSION: Compared to hysterectomy, single agent chemotherapy as a first-line treatment costs $74,526 for each additional QALY gained. Given that this cost falls below the accepted $100,000 willingness-to-pay threshold and waitlist limitations within public healthcare systems, these results support the continued use of chemotherapy as standard of care approach for low-risk GTN.

Contraceptive use following gestational trophoblastic disease: A systematic review.

OBJECTIVE: To systematically review the effect of contraceptive methods following gestational trophoblastic disease (GTD) on timing of beta-human chorionic gonadotropin (hCG) remission, risk of post-molar gestational trophoblastic neoplasia (GTN), risk of unintended incident pregnancy, and interactions between contraceptive methods and disease treatment. STUDY DESIGN: We conducted a search of primary literature with search terms related to GTD and contraception through April 2023 in PubMed and extrapolated our search to other platforms. Randomized controlled trials, observational studies and case reports were eligible for inclusion if they reported on patients with known GTD who received a contraceptive method for pregnancy prevention. Data was abstracted on our main outcomes of interest: timing of beta-hCG remission, risk of post-molar GTN, risk of unintended incident pregnancy, and interactions between contraceptive methods and cancer-directed systemic disease treatment (e.g., chemotherapy). At least two authors reviewed manuscripts at each screening stage with consensus reached before data extraction. Quality assessment checklists were used to assess risk of bias for the different study types. RESULTS: Five thousand one hundred and five studies were identified in the database search, of which 42 were included for analysis. Eight thousand two hundred and ninety four participants were evaluated. Over half of the studies were case reports and only two were randomized controlled trials. While there was sparse data on all outcomes, no differences were noted in beta-hCG monitoring, risk of post-molar GTN or incident pregnancies between different contraceptive types. Interactions between contraceptive methods and cancer-directed systemic disease treatment (e.g., chemotherapy) or specific adverse events of contraceptive methods were not identified. CONCLUSIONS: Data on contraceptive use following GTD is limited, but use of both hormonal and non-hormonal modern contraceptive methods appears safe. Counseling patients on the full range of contraceptive methods is important to help patients achieve their reproductive health goals and minimize the risk of disease progression through incomplete beta-hCG monitoring prior to future pregnancy. IMPLICATIONS: Hormonal and non-hormonal contraceptive options may be used by patients following gestational trophoblastic disease without apparent changes in beta-hCG regression or risk of post-molar gestational trophoblastic neoplasia.

A prospective cohort study with serum anti-mullerian hormone levels change in patients undergoing uterine preservation after gestational trophoblastic neoplasia treatment with a methotrexate regimen.

Objectives: To monitor changes in serum anti-Mullerian hormone (AMH) levels of the patients with gestational trophoblastic neoplasia (GTN) who have undergone uterine preservation during treatment with a Methotrexate (MTX) regimen and associations with AMH variations. Methods: This observational prospective cohort study included 35 patients with low-risk GTN with uterine preservation during single-agent MTX chemotherapy at Hanoi Obstetrics and Gynecology Hospital from August 2021 to August 2022. Serum AMH levels were measured before initiation of chemotherapy and after the 1st, 2nd, and 3rd chemotherapy cycles. AMH evolution and its associations with some factors were analyzed. Results: The median basal AMH level before chemotherapy was 2.87 ng/mL (0.96 - 7.9 ng/mL) and negatively correlated with age. The serum AMH levels decreased significantly after each chemotherapy cycle (2.87 vs. 1.16, 0.91, 0.41 ng/mL). The median magnitude of the AMH levels decline after 1st, 2nd, and 3rd chemotherapy cycles were 51.2%, 69.4%, and 84.6% (p<0.001), respectively. AMH variation was associated with the basal AMH level, but not with age, ßhCG at diagnosis and menstrual status. Conclusion: Our study has shown that the serum AMH levels declined rapidly and steadily in all patients during chemotherapy for GTN. Although AMH cannot be used to monitor fertility potential lonely, these new studies improve our knowledge of ovarian toxicity and ovarian reserve during chemotherapy and strongly support the use of fertility preservation strategies.

N-linked α2,6-sialylation of integrin ß1 by the sialyltransferase ST6Gal1 promotes cell proliferation and stemness in gestational trophoblastic disease.

INTRODUCTION: Gestational trophoblastic disease (GTD) encompasses a spectrum of rare pre-malignant and malignant entities originating from trophoblastic tissue, including partial hydatidiform mole, complete hydatidiform mole and choriocarcinoma. ß-galactoside α2,6 sialyltransferase 1 (ST6Gal1), the primary sialyltransferase responsible for the addition of α2,6 sialic acids, is strongly associated with the occurrence and development of several tumor types. However, the role of ST6Gal1/α2,6 -sialylation of trophoblast cells in GTD is still not well understood. METHODS: The expression of ST6Gal1 was investigated in GTD and human immortalized trophoblastic HTR-8/SVneo cells and human gestational choriocarcinoma JAR cells. We evaluated the effect of ST6Gal1 on proliferation and stemness of trophoblastic cells. We also examined the effect of internal miR-199a-5p on ST6Gal1 expression. The role of ST6Gal1 in regulating α2,6-sialylated integrin ß1 and its significance in the activation of integrin ß1/focal adhesion kinase (FAK) signaling pathway were also explored. RESULTS: ST6Gal1 was observed to be highly expressed in GTD. Overexpression of ST6Gal1 promoted the proliferation and stemness of HTR-8/SVneo cells, whereas knockdown of ST6Gal1 suppressed the viability and stemness of JAR cells. MiR-199a-5p targeted and inhibited the expression of ST6Gal1 in trophoblastic cells. In addition, we revealed integrin ß1 was highly α2,6-sialylated in JAR cells. Inhibition of ST6Gal1 reduced α2,6-sialylation on integrin ß1 and suppressed the integrin ß1/FAK pathway in JAR cells, thereby affecting its biological functions. DISCUSSION: This study demonstrated that ST6Gal1 plays important roles in promoting proliferation and stemness through the integrin ß1 signaling pathway in GTD. Therefore, ST6Gal1 may have a potential role in the occurrence and development of GTD.

A meta-analysis of predictive value of blood biomarkers in gestational trophoblastic neoplasia.

Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to play a diagnostic and predictive role in gestational trophoblastic disease. However, the conclusions are still ambiguous. This meta-analysis aimed to evaluate the combined predictive value of NLR and PLR in the malignant progression of gestational trophoblastic disease. Method: Electronic databases including PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and China Biomedical Literature Database were searched for the relevant literature published up to 1 October 2022. Study selection and data extraction were performed independently by two reviewers. All analyses were performed using Revman, MetaDisc and STATA software. Results: A total of 858 patients from five studies were included in this meta-analysis. The pooled sensitivity and specificity of NLR were 0.8 (95% CI: 0.71-0.88) and 0.73 (95% CI: 0.69-0.76), respectively, and the area under curve of the summary receiver operating curve was 0.81. The pooled sensitivity and specificity of PLR were 0.87 (95% CI: 0.75-0.95) and 0.49 (95% CI: 0.44-0.54), respectively, and the area under curve of the summary receiver operating curve was 0.88. I2 statistic and Deek's funnel plot showed no heterogeneity and publication bias. Conclusion: NLR can accurately predict the progression from hydatidiform mole to gestational trophoblastic neoplasia and is a promising biomarker in further follow-up.

The role of surgery in gestational trophoblastic disease: an overview.

Gestational trophoblastic disease comprises a group of rare, and potentially malignant, conditions that arise from abnormal trophoblastic proliferation. When there is invasion and evidence of metastatic disease, gestational trophoblastic neoplasia is used. While chemotherapy is the mainstay of treatment for gestational trophoblastic neoplasia, the role of surgery has come full circle in recent years. Before the introduction of highly effective systemic treatment options, surgery was the default treatment. Surgery for gestational trophoblastic neoplasia often yielded unsatisfactory results and mortality remained high. In recent years, the role of adjuvant surgery in the management of gestational trophoblastic neoplasia has been examined with great interest. We aim to provide an overview of the various surgical approaches employed in managing gestational trophoblastic neoplasia, including their indications, techniques, and outcomes. Additionally, we discuss whether there is a role to do less in surgery for gestational trophoblastic neoplasia and describe our experience with a modified surgical technique for its treatment. By summarizing the current evidence, this article highlights the significant contributions of surgery to the holistic management of patients with gestational trophoblastic neoplasia and provides a framework on which to base management and treatment programs.

Role of immune checkpoint inhibitors combined with chemotherapy in recurrent drug-resistant gestational trophoblastic neoplasia: Four case reports and literature review.

BACKGROUND: Multiple studies have confirmed that programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) is widely expressed in gestational trophoblastic neoplasia (GTN) tissues. Therefore, immune checkpoint inhibitors may be an option for the treatment of recurrent and drug-resistant GTN. CASE: Four patients with recurrent or drug-resistant GTN who were treated with PD-1/PD-L1 checkpoint inhibitor agents combined with chemotherapy were reported. The mean age of recurrence was 45.8 years (35-56 years), including three cases of choriocarcinoma (CC) and one case of invasive mole (IM). International Federation of Gynecology and Obstetrics (FIGO) prognosis score: ≤6 (low risk) in one case, 7-12 (high risk) in one case, ≥13 (very high risk) in two cases. There were two cases of lung metastasis and one case of vulvar and inguinal lymph node metastasis. One of the four patients underwent total hysterectomy and one patient underwent resection of lung metastases. All the four patients received comprehensive treatment of immunotherapy combined with chemotherapy after relapse, among which one patient achieved complete response (CR), two patients achieved partial response (PR), and one patient developed progressive disease (PD). Three patients who achieved PR or CR were maintained by single agent immunotherapy after combination therapy, and there was no disease recurrence during follow-up. One patient with PD also achieved CR after using salvage chemotherapy after recurrence, and there was no disease recurrence during follow-up. During the treatment, four patients had different degrees of immune-related adverse reactions, all of which were grade I-II, and no severe adverse reactions were found. CONCLUSION: Immune checkpoint inhibitors combined with chemotherapy has an impressive therapeutic effect on recurrent or drug-resistant GTN with mild adverse reactions, which can be used as a treatment option for such patients. However, due to the lack of large sample data support, the specific time and treatment course of its use, long-term use of adverse reactions and whether it affects fertility function remain to be solved.

Postpartum choriocarcinoma - a rare cause of delayed postpartum hemorrhage: Four case reports and literature review.

BACKGROUND: Delayed postpartum hemorrhage is rare, with an incidence of 0.5% to 2.0% in all pregnancies. The most important causes are placental remnants, infections, and placental bed subinvolution. Postpartum choriocarcinoma, a highly malignant complication of pregnancy, is a rare condition that can be easily misdiagnosed as other common causes, such as gestational remnants, and delays the diagnosis. METHODS: Four patients visited our clinic complaining of delayed postpartum hemorrhage, combined with respiratory and neurological symptoms in 2 cases. Two cases were confirmed by histopathological examination and in addition, medical history, elevated human chorionic gonadotropin (hCG) level, and imaging findings help confirm the diagnosis of delayed postpartum hemorrhage caused by postpartum choriocarcinoma in other cases. Individualized combination chemotherapies were prescribed. In the light of massive cerebral metastasis in case 2, intrathecal methotrexate injection combined with whole-brain radiotherapy was prescribed. RESULTS: Due to the absence of routine monitoring of ß-hCG following full-term delivery, there was widespread metastasis at the time of diagnosis. Three patients got complete remission and there is no sign of recurrence. One patient had relapse and widespread metastasis and died at home 6 months after the last chemotherapy. CONCLUSION: It is important to be aware of the possibility of choriocarcinoma in patients with delayed postpartum hemorrhage. Clinicians should improve the recognition of choriocarcinoma following full-term delivery, emphasize the monitoring of ß-hCG, comprehensively analyze the general condition of patients, and conduct standardized and individualized chemotherapy protocols.

Comparison of the multiples of the median of serum anti-müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case-control study.

INTRODUCTION: Chemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear. MATERIALS AND METHODS: This case-control study included 57 GTN patients and 19 age-matched patients with molar pregnancies (MP) in 2012-2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single-agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared. RESULTS: There was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single-agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single-agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = -2.69, p = 0.007) but not at 24 months (Z = -1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4-year pregnancy rate and the livebirth rate between the single-agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single-agent group (2.88 vs. 1.88 years). CONCLUSION: This study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1-2 years after treatment or with other risk factors.

Molecular profiling of gestational trophoblastic neoplasia: Identifying therapeutic targets.

OBJECTIVE: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets. METHODS: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT). RESULTS: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases. CONCLUSIONS: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.

Chemotherapy is not needed when complete evacuation of gestational choriocarcinoma leads to hCG normalization.

BACKGROUND: The standard treatment for gestational choriocarcinoma is chemotherapy. OBJECTIVE: To describe the risk of recurrence with expectant management of gestational choriocarcinoma that has reached a normal human chorionic gonadotropin level after tumor removal without adjuvant chemotherapy. METHODS: A retrospective multicenter international cohort study was conducted from 1981 to 2017 involving 11 gestational trophoblastic disease reference centers with patient's follow-up extended until 2023. Clinical and biological data of included patients were extracted from each center's database. The inclusion criteria were i) histological diagnosis of gestational choriocarcinoma in any kind of placental tissue retrieved, ii) spontaneous normalization of human chorionic gonadotropin level following choriocarcinoma retrieval, iii) patient did not receive any oncological treatment for the choriocarcinoma, iv) and at least 6 months of follow-up after the first human chorionic gonadotropin level normalization. RESULTS: Among 80 patients with retrieved gestational choriocarcinoma and whose human chorionic gonadotropin level normalized without any other oncological therapy, none had a recurrence of choriocarcinoma after a median follow-up of 50 months. The median interval between choriocarcinoma excision and human chorionic gonadotropin level normalization was 48 days. The International Federation of Gynecology and Obstetrics/World Health Organization risk score was ≤6 in 93.7% of the cases. CONCLUSIONS: This multicenter international study reports that selected patients with gestational choriocarcinoma managed in gestational trophoblastic disease reference centers did not experience any relapse when the initial tumor evacuation is followed by human chorionic gonadotropin level normalization without any additional treatment. Expectant management may be a safe approach for highly selected patients.

Effect of lung metastasis on the treatment and prognosis of patients with gestational trophoblastic neoplasia: A systematic review and meta-analysis.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a highly invasive tumor, mainly spreading to the lungs. However, lung metastasis in GTN is usually not considered as an adverse prognostic factor. Therefore, the aim of this study was to summarize the results of previous studies and evaluate the effects of lung metastasis on the treatment and prognosis of GTN. MATERIAL AND METHODS: The study was prospectively registered in PROSPERO (CRD42023372371). Electronic databases including PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and China Biomedical Literature Database were used for a systematical search of relevant studies published up to November 21, 2022. The observational studies reporting the clinical outcomes of GTN patients with and without lung metastasis were selected. The incidences of resistance, relapse, and mortality of GTN patients were extracted and successively grouped based on the presence of lung metastasis. The pooled relative risks (RRs) and 95% confidence interval (95% CI) of the eligible studies were calculated. The qualities of included studies were assessed with the Newcastle-Ottawa Scale and the certainty of evidence was graded based on the GRADE. The meta-analysis was performed using Stata 12.0 and GradePro software. RESULTS: Five publications with 3629 GTN patients were included. The meta-analysis revealed that the GTN with lung metastasis was strongly correlated with first-line chemoresistance (pooled RR = 1.40, 95% CI: 1.22 to 1.61, p < 0.001), recurrence (pooled RR = 3.03, 95% CI: 1.21 to 7.62, p = 0.018), and disease-specific death (pooled RR = 22.11, 95% CI: 3.37 to 145.08, p = 0.001). Ethnicity was also an important factor and Caucasian GTN patients with lung metastasis showed a higher risk of recurrence as revealed by the subgroup analysis (pooled RR = 5.10, 95% CI: 2.38 to 10.94, p < 0.001). CONCLUSIONS: GTN patients with lung metastasis exhibited a higher risk of chemoresistance, relapse, and disease-specific death. Patients with lung metastasis among the Caucasian population had a higher risk of recurrence than Asian populations. Therefore, the presence of lung metastases might be considered as a high-risk factor for prognosis of GTN and deserves more attention in the choice of first-line chemotherapy regimens and follow-up.

Expert Pathology for Gestational Trophoblastic Disease: Towards an International Multidisciplinary Team Meeting.

BACKGROUND: Gestational trophoblastic disease (GTD), comprising hydatidiform moles and gestational trophoblastic tumours, is extremely rare. Exact diagnosis is crucial to indicate the appropriate treatment and to prevent complications. The scarcity and variability in the number of cases available for reporting, lack of specialised training in GTD, and non-existence of refresher courses implies that the pathologist dealing with these rare and, at times, extremely challenging cases is not completely confident in their diagnosis. OBJECTIVES: The objective of this study was to explore the benefits of implementation of an international multidisciplinary conference (virtual) to aid diagnosis of difficult cases and support clinical management of GTD. METHODS: A short survey was circulated to all 46 members of the EOTTD pathology and genetics working party and further spread to other colleagues who practice GTD. This showed that the pathologists and geneticists working with GTD patients do not feel adequately supported and equipped with dealing with these rare diseases. OUTCOME: Virtual cross-border multidisciplinary team meetings (MDTs) were initiated in April 2022, bringing together participants from 11 European countries on a bi-yearly basis. Mean numbers of 3 patients are discussed during the MDTs followed by 3-4 quality assessment cases. A participant survey was conducted at the end of virtual meeting with an average satisfaction rate of 9.5. The pathologists felt supported and benefited from networking and clinical collaboration. CONCLUSIONS AND OUTLOOK: This international MDT continues to provide support in managing the uncertainty with difficult and rare cases and enhances the pathologists training and experience. The frequency of meetings and the number of cases discussed per meeting will be increased in 2023 given the positive response. This will empower individuals and organisations to work together and improve diagnosis and the prognosis for these young patients.

Intracardiac metastasis of gestational choriocarcinoma: a case report and literature review.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) with intracardiac metastasis is rare, and here we reported a patient with intracardiac metastasis of high-risk and refractory gestational choriocarcinoma and reviewed relevant literatures. CASE PRESENTATION: A 37-year-old woman presented with vaginal bleeding and high level of ß-human chorionic gonadotropin (ß-hCG) at 199,060 (mIU/mL). It was clinically diagnosed with gestational choriocarcinoma. The patient initially received eight cycles of chemotherapy but unsatisfactory response was observed, and the level of ß-hCG still ranged between 5000 and 10,000. Then there was found intracardiac masses in the right atrium (2.6*1.7 cm), anterior chordae tendineae of the tricuspid valve (1.4*0.7 cm) and the right ventricle (4.1*2.9 cm) by ultrasonic cardiogram (UCG). PET/CT highly suspected the intracardiac metastasis of choriocarcinoma (SUVmax = 9.3) and no disease was found in the lung and pelvis. The patient undertook complete intracardiac masses resection. The pathology confirmed the intracardiac metastasis of disease. After a week of operation, the UCG found a 5.4*4.2 cm mass in the right atrium again. Considering the poor prognosis, the patient received palliative care and eventually died of disease progression. CONCLUSION: Intracardiac metastasis of GTN is an aggressive sign of disease. Patients can benefit from chemotherapy and surgery. Future investigation of PD-1 immunotherapy combines with chemotherapy are expected to improve the prognosis in this group of patients.

Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm.

We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.