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.

Short tandem repeats genotyping of gestational choriocarcinoma - our experiences.

OBJECTIVE: This short communication demonstrates how short tandem repeat genotyping can identify the origin of gestational choriocarcinoma. MATERIALS AND METHODS: The origin of gestational choriocarcinoma in our three cases was determined using the short tandem repeats genotyping technique, which involved quantitative fluorescent PCR and fragmentation analysis. RESULTS: In Case 1 despite no medical history of molar pregnancy, DNA analysis indicated that the choriocarcinoma originated from a homozygous complete hydatidiform mole. We conclude, that the patient's complete abortion 10 years prior to the choriocarcinoma diagnosis was an undiagnosed complete hydatidiform mole. In Case 2 and Case 3 the clinically presumed origin of choriocarcinoma was confirmed. CONCLUSION: Determining the origin of choriocarcinoma is essential for clinical application, as it affects the FIGO scoring system for gestational trophoblastic neoplasia, which determines the patient's prognosis and treatment approach.

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.

Impact of molecular genotyping on the diagnosis and treatment of human chorionic gonadotropin-producing tumors.

OBJECTIVES: To assess the use of molecular genotyping to accurately diagnose and treat human chorionic gonadotropin (hCG)-producing tumors and to evaluate the discriminating capacity of molecular testing on prognosis and overall survival. METHODS: We conducted a retrospective descriptive study of patients registered with the French Reference Center for Trophoblastic Disease between 1999 and 2021. We included all patients with hCG-producing tumors for whom results of molecular genotyping were available. RESULTS: Fifty-five patients with molecular genotyping were included: 81.2 % (n = 45) had tumors of gestational origin, 12.7 % (n = 7) of non-gestational origin and 5.5 % (n = 3) of undetermined origin. The results of molecular genotyping influenced the treatment decisions for 17 % of patients in this cohort. Overall survival was 93.3 % for patients with gestational tumors (after a median follow-up of 74 months) compared to 71.4 % for patients with non-gestational tumors (after a median follow-up of 23 months). CONCLUSION: In atypical presentations of hCG-producing tumors, molecular genotyping is a valuable tool to guide diagnosis and tailor treatment recommendations.

Extrauterine epithelioid trophoblastic tumour and its somatic carcinoma mimics: short tandem repeat genotyping meets the diagnostic challenges.

AIMS: While epithelioid trophoblastic tumour (ETT) primarily arises from the uterus, cases have been increasingly documented at extrauterine sites, originating from an ectopic gestation or presenting as a metastatic tumour, leading to the major differential diagnosis of somatic carcinoma with trophoblastic differentiation. The precise separation of a gestational trophoblastic tumour from its somatic carcinoma mimics is highly relevant and crucial for patient management and prognosis. METHODS AND RESULTS: We summarise the clinicopathological and molecular features of four challenging epithelioid malignancies presenting at extrauterine sites, with ETT as the main differential diagnosis. All four tumours demonstrated histological and immunohistochemical features overlapping between a somatic carcinoma and an ETT, combined with inconclusive clinical and imaging findings. Serum beta-hCG elevation was documented in two cases. Short tandem repeat (STR) genotyping was performed and was informative in all cases. The presence of a unique paternal allelic pattern in the tumour tissue confirmed the diagnosis of ETT in two cases with an initial consideration of either somatic carcinoma or suspicion of a gestational trophoblastic tumour. The presence of matching genetic profile with the patient's paired normal tissue was seen in two other cases (both initially considered as ETT), confirming their somatic origin, including one metastatic triple-negative breast carcinoma and one primary lung carcinoma. CONCLUSIONS: Diagnostic separation of ETT at an extrauterine site from its somatic carcinoma mimics can be difficult at the histological and immunohistochemical levels. STR genotyping offers a robust ancillary tool that precisely separates ETT from somatic carcinomas with trophoblastic differentiation.

Reconsideration of the Diagnostic Criteria for an Atypical Placental Site Nodule Comparing Typical Placental Site Nodule of the Uterus: A Report of Two Cases.

Placental site nodules (PSNs) are non-neoplastic remnants of chorionic-type intermediate trophoblastic cells from a previous gestation that form a well-defined single nodule or multiple nodules in the uterine and extrauterine sites. As the cases of PSNs transformed into gestational trophoblastic tumors were described in the literature, "atypical placental site nodules" (APSNs) have been considered as putative transitional lesions between PSNs and gestational trophoblastic tumors. Although histologic criteria and cutoff point of Ki-67 proliferation index for differentiating an APSN from a typical PSN have not been clearly defined, nodules larger than 5 mm with increased cellularity, a corded or nested appearance, marked nuclear atypia, increased mitotic activity, and an increased Ki-67 proliferation index (>5% or >8%) of intermediate trophoblastic cells seem to be accepted as diagnostic criteria for APSNs. However, some of the criteria, including lesion size and histologic features of the trophoblastic cells in the nodule are not only subjective but have features inherent of the intermediate trophoblastic cells of the fetal membrane and a typical PSN. We thought that it is not reasonable to consider them as diagnostic features of APSNs, if not associated with cellular proliferation. We present 2 cases of incidentally identified PSNs that were larger than 10 mm in size with a corded or nested arrangement of trophoblastic cells, which could have been categorized as APSNs according to the currently proposed criteria to discuss whether the currently proposed diagnostic criteria for APSNs are appropriate.

High HIV prevalence in gestational trophoblastic neoplasia patients.

OBJECTIVE: To assess the HIV prevalence in patients diagnosed with gestational trophoblastic neoplasia (GTN). DESIGN: A retrospective single centre cohort study. METHODS: A database from the Sheffield Trophoblastic Disease Centre (STDC), Sheffield, UK was searched between 1st January 2015 and 31st December 2021. A total of 3,591 patients were referred to STDC with a diagnosis of gestational trophoblastic disease (GTD), of which 221 (6.2%) were treated for GTN. The prevalence of HIV-positive tests in GTN patients was assessed. RESULTS: HIV testing was performed in 93% GTN patients ( n  = 205/221). Overall, 1.3% of GTN patients ( n  = 3/221) were HIV-positive, involving two known HIV-positive patients and one new diagnosis. This equates to a HIV prevalence of 14 : 1000, which is ∼7 to 9× higher than the HIV prevalence in Sheffield (1.9 per 1000) and Yorkshire and Humber (1.5 per 1000). CONCLUSION: Given the extremely high HIV prevalence in our population, 'opt out' HIV testing is recommended within our specialist trophoblastic centre for all referred GTD and GTN patients. There is little reason to suspect that the prevalence of HIV-positive patients is any lower in the cohort of GTD patients referred to specialist trophoblastic centres for hCG screening alone, without requiring chemotherapy, particularly considering that most GTN arises from GTD.

Gestational Trophoblastic Disease with Coexisting Progressing Pregnancy: Personalised Treatment Modalities.

Purpose: Gestational trophoblastic disease (GTD) coexisting with a steadily progressing pregnancy is an extremely rare condition presented in the literature as a single case or case series of successful delivery. The purpose of this study was to describe five cases of GTD and present possible management strategies for such patients. Methods: Clinical data of five pregnancies with coexisting GTD were identified within the Almazov National Medical Research Centre from 2018 to 2021. Results: Three cases of multiple pregnancies with complete hydatidiform moles and two cases of singleton pregnancies with intraplacental choriocarcinoma and invasive hydatidiform moles were identified. Three pregnancies were prolonged and ended with preterm deliveries. Malignant transformation of the GTD accounted for 60% of the cases. The condition of newborns was based on the level of prematurity and functional immaturity, and in all cases, it was aggravated by anemia. Conclusion: GTD coexisting with progressing pregnancy is threatened by the risks of preterm delivery, miscarriage, hemorrhage, and disease progression and requires monitoring in a multidisciplinary clinic experienced in the management of patients with malignant tumors during pregnancy. In cases of prolonged pregnancy against the background of GTD, we suggest the following monitoring during pregnancy: pelvic, abdominal ultrasound/MRI (without contrast), prenatal invasive fetal karyotype testing in cases of singleton pregnancy, lung X-ray/CT with uterine shielding, weekly assessment of ß-hCG levels, and dynamic monitoring of the fetus. The following postnatal monitoring should be performed: morphological examination of the placenta, weekly assessment of ß-hCG levels up to normalization, then monthly assessment up to six months, and control of ß-hCG level of the newborn.

Fertility-Sparing Treatment in Gestational Choriocarcinoma: Evaluating Oncological and Obstetrical Outcomes in Young Patients.

BACKGROUND Gestational choriocarcinoma (GC) is an uncommon neoplasia that occurs in women who may not have completed a procreation plan. The aim of this study was to evaluate oncological and obstetrical outcomes in young patients with GC after fertility-sparing treatment. MATERIAL AND METHODS The eligibility criteria for the study were histopathological diagnosis of GC, age ≤40 years, and treatment with systemic chemotherapy. Patients who underwent upfront hysterectomy were excluded. The response to treatment was assessed according to beta-human chorionic gonadotropin (beta-hCG) serum measurement. Complete response and progression were considered if the beta-hCG dropped to a normal range and increased (or reached a plateau), respectively. The birth rate was calculated as the number of women who gave birth after treatment divided by the total number of patients. RESULTS A total of 18 patients fulfilled the study's eligibility criteria. A complete response and progression to first-line chemotherapy were found in 13 (72.22%) and 5 (27.78%) patients, respectively. Salvage treatment was administered to patients with progression. Overall, 16 (88.88%) patients achieved complete response after treatment and 2 (11.12%) died. GC relapse was diagnosed in 1 patient 62 months after treatment. The birth rate was 22.22%, and a total of 6 children were born. All pregnancies ended in term delivery. No congenital abnormalities were detected in the newborns. CONCLUSIONS GC is a life-threatening form of gestational trophoblastic neoplasia, mainly due to its rapid course and resistance to chemotherapy. Most patients with GC will not be able to bear children after treatment.

Review of current literature on gestational trophoblastic neoplasia.

BACKGROUND: Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment. MAIN BODY: In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions. CONCLUSION: The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life.

Challenging gestational trophoblastic disease cases and mimics: An exemplar for the management of rare tumours.

OBJECTIVE: Rare tumour management is challenging for clinicians as evidence bases are limited and clinical trials are difficult to conduct. It is even more difficult for patients where self-reliance alone is insufficient to overcome the challenges of navigating care which is often poorly evidence based. In Ireland, a national Gestational Trophoblastic Disease (GTD) service was established as one of 3 initiatives for rare tumours by the National Cancer Control Programme. The service has a national clinical lead, a dedicated supportive nursing service and a clinical biochemistry liaison team. This study sought to assess the impact of a GTD centre using national clinical guidelines and integrating and networking with European and International GTD groups on the clinical management of challenging GTD cases and to consider the application of this model of care to other rare tumour management. STUDY DESIGN: In this article, we analyse the impact of a national GTD service on five challenging cases, and review how the service affects patient management in this rare tumour type. These cases were selected from a cohort of patients who were voluntarily registered in the service based on the diagnostic management dilemma they posed. RESULTS: Case management was impacted by the identification of GTD mimics, the provision of lifesaving treatment of metastatic choriocarcinoma with brain metastasis, networking with international colleagues, the identification of early relapse, the use of genetics to differentiate treatment pathways and prognosis, and supportive supervision of treatment courses of up to 2 years of therapy in a cohort of patients starting or completing families. CONCLUSION: The National GTD service could be an exemplar for the management of rare tumours (such as cholangiocarcinoma) in our jurisdiction which could benefit from a similar constellation of supports. Our study demonstrates the importance of a nominated national clinical lead, dedicated nurse navigator support, registration of cases and networking. The impact of our service would be greater if registration was mandatory rather than voluntary. Such a measure would also ensure equity of access for patients to the service, assist in quantifying the need for resourcing and facilitate research to improve outcomes.

Case report: Two rare uterine cesarean scar mass cases.

RATIONALE: Gestational trophoblastic neoplasia (GTN) located in the cesarean scar is a rare disease that has imaging appearances similar to those of an exogenous scar incision pregnancy and is often misdiagnosed due to insufficient clinical experience. PATIENT CONCERNS: We report 2 cases of uterine cesarean scar mass. Two patients with different diagnoses had similar clinical complaints as abnormal vaginal bleeding, enlargement of uterus isthmus by physical examination, and mixed echo mass in uterine low segment by ultrasound examination; however, their magnetic resonance imaging images showed very different features. DIAGNOSES: One patient was diagnosed with cesarean scar pregnancy (CSP) and one patient was diagnosed with cesarean scar GTN. INTERVENTIONS: The CSP patient underwent surgery by laparoscopy combined with hysteroscopy after uterine artery embolism and obtained pathological confirmation. The GTN patient received chemotherapy. OUTCOMES: For the CSP patient, her serum ß-human chorionic gonadotropin (hCG) concentration returned to normal 2 weeks later, and B-ultrasound showed that the niche was completely repaired 3 months after the operation. The intrauterine lesions of the GTN patient disappeared completely 3 months after serum ß-hCG normalization. And her ß-hCG was normal at all follow-up visits until now. LESSONS: Clinicians should consider GTN when identifying masses at scar incision sites. Magnetic resonance imaging images improve the understanding of the imaging features in patients suspected of having CSP/GTN.

Gestational trophoblastic neoplasia with primary lung cancer and mesenchymal tumor of sigmoid colon: a case report and literature review.

BACKGROUND: Gestational trophoblastic neoplasia (GTN) is rare, and it is even rarer for GTN to merge with primary malignant tumors in other organs. Herein is described a rare clinical case of GTN combined with primary lung cancer and mesenchymal tumor of the sigmoid colon, followed with literature review. CASE PRESENTATION: The patient was hospitalized due to diagnosis of GTN with primary lung cancer. Firstly, two cycles of chemotherapy including 5-fluorouracil (5-FU) and actinomycin-D(Act-D) was given. Laparoscopic total hysterectomy and right salpingo-oophorectomy was performed during the third chemotherapy. During the operation, a 3*2 cm nodule was removed which was protruded from the serous surface of the sigmoid colon, and the nodule was confirmed mesenchymal tumor pathologically, in accord with gastrointestinal stromal tumor. During the treatment of GTN, Icotinib tablets were taken orally to control the progression of lung cancer. After 2 cycles of consolidation chemotherapy of GTN, she received thoracoscopic lower lobe of right lung lobectomy and the mediastinum lymph nodes removal. She undertook gastroscopy and colonoscopy and the tubular adenoma of the descending colon was removed. At present, the regular follow-up is taken and she remains free of tumors. CONCLUSIONS: GTN combined with primary malignant tumors in other organs are extremely rare in clinical practice. When imaging examination reveals a mass in other organs, clinicians should be aware of the possibility of a second primary tumor. It will increase the difficulty of GTN staging and treatment. We emphasis the importance of the collaboration of multidisciplinary teams. Clinicians should choose a reasonable treatment plan according to the priorities of different tumors.

Epithelioid trophoblastic tumor: A case series.

An epithelioid trophoblastic tumor (ETT) is an extremely rare gestational trophoblastic tumor. Cases of ETT present with abnormal vaginal bleeding in women of reproductive age group with marginally elevated beta human chorionic gonadotrophin (B-hCG) levels. Here, we describe a series of four patients (all were females) including histomorphology, immunoprofiles, and diagnostic difficulty of this rare entity. All cases were in their reproductive age group. The mean pre-treatment hCG level was 665.24 (mIU/mL). Microscopically, all cases had a tumor showing an epithelioid appearance arranged in large nests and sheets. Individual tumor cells were round to polygonal with abundant eosinophilic cytoplasm, with central vesicular nuclei and prominent nucleoli. Areas of hemorrhage, necrosis, and intercellular hyaline-like material deposition were identified in all cases (100%). Immunohistochemically, tumor cells in all cases showed diffuse positivity for AE1/AE3 and p63 (100%). GATA3 was available in one case (25%), which was positive in the tumor cells. In one case (25%), hPL was focally positive, and in one case (25%), it was negative. SALL4 was performed in two cases (50%) and was negative in tumor cells. The mean Ki67 labeling index was 19.2 (range 10-30%). All four patients underwent surgical intervention and were treated with hysterectomy. The mean follow-up in this series was 39.4 months (range 6-70), and all patients are alive to date with a mean survival of 32.8 months (range, 4-67).

Gestational trophoblastic disease and associated factors among women experiencing first trimester pregnancy loss at a regional referral hospital in central Tanzania: a cross-sectional study.

BACKGROUND: Gestational trophoblastic diseases (GTDs) may follow any form of pregnancy or a pregnancy loss. Early detection of GTDs is important, as some benign forms of the disease may progress into a chemoresistant and metastatic disease. This study aimed at determining the frequency of GTDs among women experiencing first trimester pregnancy loss and the associated patients' characteristics. METHODS: This was a cross-sectional study that included 200 conveniently sampled women who experienced first trimester pregnancy loss from January to December 2019 at a Regional Referral Hospital in central Tanzania. The specimen obtained from products of conception were collected, formalin-fixed and paraffin-embedded and submitted for histopathological evaluation, for which haematoxylin and eosin stain was used. Data were analysed using SPSS version 23.0. The χ2 test was used to determine the association between categorical variables. p-Values ˂0.05 were considered statistically significant. RESULTS: Among 200 study participants, the overall frequency of GTDs was 42 (21%). Among those with GTDs, the most common histopathological diagnosis was partial hydatidiform mole (18 [42.9%]), followed by complete hydatidiform mole (17 [40.5%]) and choriocarcinoma (7 [16.5%]). In the studied participants, only increased human chorionic gonadotropin hormone levels were found to be statistically significantly associated with GTDs (p=0.000). CONCLUSIONS: Results from this study suggest that routine histopathological evaluation of the products of conception is recommended in order to allow early detection of GTDs, including choriocarcinoma, which usually carries a poor prognosis. The histopathological reporting of choriocarcinoma among first trimester products of conception from Tanzania is novel.

Current chemotherapeutic options for the treatment of gestational trophoblastic disease.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a rare tumor that arises from trophoblastic tissues with high remission rates after chemotherapy treatment. GTN can develop from any gestational events, such as miscarriage, ectopic pregnancy, and preterm/term pregnancy, but is more frequent after hydatidiform mole. The sensitivity of this tumor to chemotherapy and the presence of an exceptional tumor marker allow high remission rates, especially when patients are treated in referral centers. AREAS COVERED: Observational, retrospective, prospective, systematic reviews, and meta-analysis studies focusing on GTN treatment. We searched PubMed, Medline, and the Library of Congress from January 1965 to May 2022. EXPERT OPINION: Early GTN diagnosis allows low-toxic and highly effective treatment. Even multimetastatic disease has high rates of remission with multiagent regimen chemotherapy. Surgery is reserved for uterine disease in patients who have completed childbearing, in cases of chemoresistance to multiagent regimens or in the rare cases of placental site trophoblastic tumor or epithelioid trophoblastic tumor. While resistance is managed by salvage chemotherapy, cases with limited clinical response to sequential regimens have been successfully treated with immunotherapy.