Gestational Trophoblastic Disease: Complete versus Partial Hydatidiform Moles.

Hydatidiform moles, including both complete and partial moles, constitute a subset of gestational trophoblastic diseases characterized by abnormal fertilization resulting in villous hydrops and trophoblastic hyperplasia with or without embryonic development. This involves chromosomal abnormalities, where one or two sperms fertilize an empty oocyte (complete hydatidiform mole (CHM); mostly 46,XX) or two sperms fertilize one oocyte (partial hydatidiform mole (PHM); mostly 69,XXY). Notably, recurrent occurrences are associated with abnormal genomic imprinting of maternal effect genes such as NLRP7 (chromosome 19q13.4) and KHDC3L (chromosome 6q1). Ongoing efforts to enhance identification methods have led to the identification of growth-specific markers, including p57 (cyclin-dependent kinase inhibitor 1C; CDKN1C), which shows intact nuclear expression in the villous cytotrophoblast and villous stromal cells in PHMs and loss of expression in CHMs. Treatment of hydatidiform moles includes dilation and curettage for uterine evacuation of the molar pregnancy followed by surveillance of human chorionic gonadotropin (HCG) levels to confirm disease resolution and rule out the development of any gestational trophoblastic neoplasia. In this review, we provide a synopsis of the existing literature on hydatidiform moles, their diagnosis, histopathologic features, and management.

Analysis of Fertility Prognosis and Risk Factors in Patients Post-Gestational Trophoblastic Disease.

To retrospectively analyze the fertility outcomes and prognosis of gestational trophoblastic disease (GTD) patients, providing a basis for targeted fertility guidance and counseling. 82 GTD patients of childbearing age who received treatment at the Obstetrics and Gynecology Department of Lanzhou University First Hospital from January 2016 to January 2023 were stratified into re-pregnancy (n = 20) and non-re-pregnancy (n = 33) cohorts based on their pregnancy outcomes. The impacts of various factors on pregnancy outcomes were subsequently evaluated, encompassing the rates of subsequent pregnancies, live births, miscarriages, ectopic pregnancies, and ongoing pregnancies. Finally, logistics regression model was employed to analyze the risk factors affecting re-pregnancy in GTD patients. The study delineated those patients with different GTD pathologies had varying re-pregnancy rates (mole, erosive mole and choriocarcinoma accounted for 66.04%, 30.19% and 3.77%, respectively). Treatment predominantly involved uterine curettage, with fewer cases receiving chemotherapy alone or in conjunction with curettage accounted for 67.92%, 5.66%, and 26.42%, respectively. The average chemotherapy frequency was 4.59 ± 2.43 sessions, and a majority sought reproductive counseling. Re-pregnancy occurred in 37.74% of patients. The live birth rate was 65.00%, with miscarriage and ectopic pregnancy rates at 25.00% and 5.00% respectively. Logistic regression analysis pinpointed the absence of pre-pregnancy counseling as a significant independent risk factor for re-pregnancy in GTD patients (p < 0.05). While chemotherapy may influence ovarian function, with the majority of patients desiring children post-recovery, pregnancy rates remain high. Fertility counseling significantly enhances re-pregnancy success rates in GTD survivors, emphasizing its recommendation for those aiming to conceive post-recovery.

Reappraisal and refined diagnosis of ultrasonography and histological findings for hydatidiform moles: a multicentre retrospective study of 821 patients.

AIMS: Specific identification of a hydatidiform mole (HM) and subclassification of a complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) are critical. This study aimed to reappraise the diagnostic performance of ultrasonography and histology with a refined diagnosis. METHODS: This was a retrospective, multicentre cohort study of 821 patients with histologically suspected HM specimens. Refined diagnostic algorithms with p57 immunohistochemistry and short tandem repeat (STR) genotyping were performed and used as the true standard for assessing the diagnostic performance of the original ultrasonography and morphology methods. The diagnostic performance was calculated using accuracy, agreement rate, sensitivity and the positive predictive value (PPV) compared with refined diagnostic results. RESULTS: Of the 821 histologically suspected HM cases included, 788 (95.98%) were successfully reclassified into 448 CHMs, 213 PHMs and 127 non-molar (NM) abortuses. Ultrasonography showed an overall accuracy of 44.38%, with a sensitivity of 44.33% for CHM and 37.5% for PHM. The overall classification accuracy of the original morphological diagnosis was 65.97%. After exclusion of the initially untyped HMs, the overall agreement rate was 59.11% (κ=0.364, p<0.0001) between the original and refined diagnoses, with a sensitivity of 40.09% and PPV of 96.05% for diagnosing CHMs and a sensitivity of 84.98% and a PPV of 45.59% for diagnosing PHMs. The interinstitutional variability of morphology in diagnosing HMs was significant among the 15 centres (range, 8.33%-100.00%, p<0.0001). CONCLUSION: The current diagnosis of HM based solely on ultrasound or morphology remains problematic, and ancillary techniques, particularly p57 immunohistochemistry and DNA genotyping, should be integrated into routine practice as much as possible.

Giant complete hydatidiform mole: a case report and review of the literature.

BACKGROUND: This case describes the youngest patient documented in the literature who presented with a giant hydatidiform mole, effectively addressed through conservative treatment. CASE PRESENTATION: Our department received a 20-year-old Caucasian patient who was admitted due to significant metrorrhagia in an undisclosed pregnancy. During examination, we identified a massive, highly vascularized hydatidiform mole measuring 22 cm (cm). We performed a surgical dilatation and curettage. The anatomopathological findings confirmed the presence of a complete hydatidiform mole (CHM). Following the established guidelines, we conducted weekly monitoring of human chorionic gonadotropin (hCG). Unfortunately, the patient discontinued the follow-up and became pregnant again before achieving hCG negativation. CONCLUSION: This case suggests that conservative treatment is a viable option regardless of the size of gestational trophoblastic disease (GTD), especially when the preservation of fertility is a crucial consideration, as effectively demonstrated in our case.

Invasive and metastatic hydatidiform moles in Slovakia in 1993‒2022.

OBJECTIVE: A retrospective analysis of invasive and metastatic hydatidiform moles (HM) in the Slovak Republic (SR)‒epidemiology, patient characteristics and treatment outcomes. BACKROUND: Invasive and metastatic mole is a highly curable type of gestational trophoblastic neoplasia. Both invasive and metastatic HM may be cured by hysterectomy without adjuvant chemotherapy. METHODS: Nineteen cases of histopathologically confirmed HM (10 invasive and 9 metastatic) were treated in SR from 1993 to 2022. Patients were divided into two groups according to treatment modality (hysterectomy only ‒ 8; hysterectomy and chemotherapy ‒ 11). The parameters included in the analysis were patient age, antecedent pregnancy, human chorionic gonadotropin level, tumor size and time to remission. RESULTS: The incidence of invasive and metastatic HM in the SR was 1:121,253 pregnancies, or 1:86,589 live births. The overall cure rate was 100%, without recurrence. Hysterectomy was performed as first-line therapy in 14 patients, with a cure rate of 57.1%. 4 out of 8 patients (50%) with metastatic moles, who underwent first-line hysterectomy, were cured without chemotherapy. There was no statistically significant difference between the two groups in all selected parameters. CONCLUSION: First-line hysterectomy may lead to remission without adjuvant chemotherapy or reduce the number of chemotherapies in invasive and metastatic HM (Tab. 4, Fig. 2, Ref. 21).

A phantom human chorionic gonadotropin in the case of molar pregnancy.

Accurately interpreting persistent, low human chorionic gonadotropin (hCG) levels is essential for managing gestational trophoblastic disease. Erroneous interpretation can lead to inappropriate interventions, including unnecessary chemotherapy or hysterectomy, or unjustified changes in chemotherapeutic regimens due to misidentification of a false-positive hCG as a true positive. The predominant etiology of phantom hCG is the presence of heterophilic antibodies. Consequently, screening for urine hCG is indispensable for its diagnosis because immunoglobulin is not generally present in urine. Here, we report about phantom hCG after a complete hydatidiform mole. Initial urine hCG evaluations were negative, although the serum hCG levels remained positive, leading to the diagnosis of phantom hCG. After subsequent delivery, urine hCG levels persisted at diminished levels. However, a different assay yielded negative hCG results for both serum and urine samples. The patient subsequently gave birth. The absence of hCG was consistently confirmed over five years.

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.

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.

Post molar choriocarcinoma with solitary renal metastasis in the absence of primary uterine tumor: a case report and review of the literature.

BACKGROUND: Choriocarcinoma is a rare and highly malignant form of gestational trophoblastic disease that may develop following pregnancy, abortion, or a hydatiform mole. Renal metastatic involvement by post molar choriocarcinoma is even rarer. In this case report, we describe a unique case of post molar choriocarcinoma with a solitary renal metastasis in the absence of a primary uterine tumor and metastases in other sites, which presented with urological symptoms and spontaneous renal hemorrhage. CASE PRESENTATION: A 41-year-old Persian woman with history of complete hydatiform mole presented with severe flank pain, nausea, vomiting, gross hematuria, and vaginal bleeding. Laboratory tests demonstrated a serum beta human chorionic gonadotropin hormone level of 60,000 mIU/mL. Imaging studies showed a lesion at the lower pole of the left kidney with active bleeding surrounded by hematoma, as well as an empty uterine cavity. Additionally, bilateral pleural effusion was detected without any lesion within the lungs. Subsequently, the patient underwent laparotomy, partial nephrectomy, and left para-ovarian cystectomy. Endometrial curettage was also carried out. The histopathology report revealed choriocarcinoma renal metastasis with high expression of beta human chorionic gonadotropin, cytokeratin 7, and Ki 67. Moreover, there were no malignant cells in the endometrial curettage specimens, and a corpus luteum cyst was found within the para-ovarian cyst. Further investigations revealed that the pleural effusion was free of malignant cells, and there was no evidence of metastatic lesions in the brain. As a result, the patient was referred to the oncology department to receive chemotherapy, and the beta human chorionic gonadotropin levels dropped to 5 mIU/mL after receiving courses of a standard regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine/oncovin over 3 weeks. Finally, monthly measurements of beta human chorionic gonadotropin levels for 6 months indicated that levels have constantly remained within normal ranges, showing no evidence of recurrence or new metastasis. CONCLUSIONS: Urological symptoms such as hematuria or spontaneous renal hemorrhage might be the only presentation of post molar choriocarcinoma with renal involvement. Thus, it can be beneficial to measure serum beta human chorionic gonadotropin levels among females of childbearing age who present with unexplained urological symptoms, especially if there is a history of prior hydatiform mole.

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.

Uterine perforation associated with gestational trophoblastic disease and arteriovenous malformation: A case report.

This case report outlines the clinical course of a young woman who presented as haemodynamically unstable due to uterine perforation. She had undergone suction dilation and curettage three weeks prior and received a diagnosis of complete molar pregnancy. During her most recent acute presentation, an emergency laparotomy revealed a full-thickness fundal uterine rupture in a region of newly identified arteriovenous malformation. Haemostasis was achieved with the primary repair of the perforation. She was subsequently diagnosed with gestational trophoblastic neoplasm (GTN), a condition characterised by abnormal proliferation of trophoblastic tissue. She received three courses of methotrexate followed by a two-month course of dactinomycin. At one-year surveillance, she had made a complete recovery.

Severe, very early onset preeclampsia in a Covid 19-positive woman with a twin pregnancy presenting with a hydatidiform mole and coexisting normal fetus: a case report.

Cases of hydatidiform moles with a coexisting fetus are sparse and patients are at high risk for severe complications. Patients and physicians often face the dilemma of the wish to continue pregnancy until viability of the fetus while the risk for maternal complications increases. We present an educational case of a twin pregnancy presenting with a hydatidiform mole and coexisting normal fetus with a placenta praevia. The patient developed severe, early onset preeclampsia with beginning HELLP-syndrome and was tested Covid-19 positive in the further course. Termination of pregnancy was conducted via caesarean section at 18 + 6 weeks of pregnancy. Histopathology and genetic analysis confirmed a complete hydatidiform mole next to a normal placenta. Close follow-up examinations were conducted and showed normal findings including ß HCG levels normalizing within 5 months. This case combines several rare, difficult and severe medical conditions and demonstrates how an individualized therapy by an interdisciplinary team covering a highly sensitive topic was developed in a situation where no guidelines exist.

The Rare of the Rarest: Placental Site Trophoblastic Tumor, Epithelioid Trophoblastic Tumor, Atypical Placental Site Nodule.

BACKGROUND: Epithelioid Trophoblastic Tumor (ETT) and Placental Site Trophoblastic Tumor (PSTT) are two of the rarest GTNs that share certain features at diagnosis and management. Atypical Placental Site Nodule (APSN) is a relatively new entity considered as a premalignant lesion. OBJECTIVES AND METHODS: The aim of this review was to summarize the main characteristics of each of these entities, their diagnostic features, and their treatment's standard of care including fertility-sparing treatments. OUTCOME: This study provides a thorough review of ETT, PSTT, and APSN. CONCLUSIONS: The reader will gain an insight view of these rare tumors arising from the intermediate trophoblast.

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.

PREDICT-GTN 2: Two-factor streamlined models match FIGO performance in gestational trophoblastic neoplasia.

OBJECTIVE: The International Federation of Gynecology and Obstetrics (FIGO) scoring system uses the sum of eight risk-factors to predict single-agent chemotherapy resistance in Gestational Trophoblastic Neoplasia (GTN). To improve ease of use, this study aimed to generate: (i) streamlined models that match FIGO performance and; (ii) visual-decision aids (nomograms) for guiding management. METHODS: Using training (n = 4191) and validation datasets (n = 144) of GTN patients from two UK specialist centres, logistic regression analysis generated two-factor models for cross-validation and exploration. Performance was assessed using true and false positive rate, positive and negative predictive values, Bland-Altman calibration plots, receiver operating characteristic (ROC) curves, decision-curve analysis (DCA) and contingency tables. Nomograms were developed from estimated model parameters and performance cross-checked upon the training and validation dataset. RESULTS: Three streamlined, two-factor models were selected for analysis: (i) M1, pre-treatment hCG + history of failed chemotherapy; (ii) M2, pre-treatment hCG + site of metastases and; (iii) M3, pre-treatment hCG + number of metastases. Using both training and validation datasets, these models showed no evidence of significant discordance from FIGO (McNemar's test p > 0.78) or across a range of performance parameters. This behaviour was maintained when applying algorithms simulating the logic of the nomograms. CONCLUSIONS: Our streamlined models could be used to assess GTN patients and replace FIGO, statistically matching performance. Given the importance of imaging parameters in guiding treatment, M2 and M3 are favoured for ongoing validation. In resource-poor countries, where access to specialist centres is problematic, M1 could be pragmatically implemented. Further prospective validation on a larger cohort is recommended.

Non-gestational choriocarcinoma: unraveling the similarities and distinctions from its gestational counterpart.

Choriocarcinoma is a highly vascular and invasive tumor of anaplastic trophoblast, predominantly made up of cytotrophoblasts and syncytiotrophoblasts without villi. Based on its origin, choriocarcinoma can be either gestational or non-gestational. Non-gestational choriocarcinoma can be of germ cell origin, or can be seen in association with a somatic high-grade malignancy. It is difficult to differentiate gestational from non-gestational choriocarcinoma, especially in the reproductive age group. It is important to distinguish between the two, for accurate staging and prognostication, deciding the primary treatment modality, (ie, surgery or chemotherapy), and tailoring follow-up timeframes after diagnosis. An extensive literature search was performed regarding all cases of non-gestational choriocarcinoma, published before March 2023. A note was made of whether the origin of choriocarcinoma was ascertained and how gestational choriocarcinoma was differentiated from non-gestational choriocarcinoma. The keywords used for literature search were "non-gestational choriocarcinoma", "primary choriocarcinoma", "ovarian choriocarcinoma", "ovarian germ cell tumors", or "choriocarcinomatous differentiation". This review aims to summarize the similarities and differences in the epidemiology, pathogenesis, clinical presentation, and management guidelines between gestational and non-gestational choriocarcinoma, which can form an important educational resource for clinicians and laboratory physicians dealing with such cases.