Complete and partial molar pregnancies arise from abnormal fertilization with marked proliferation of syncytiotrophoblasts. Earlier diagnosis has reduced the frequency of severe medical complications at presentation; however, the risk of progression to gestational trophoblastic neoplasia (GTN) has remained unchanged. Initial assessment should include serum hCG measurement after physical examination, laboratory testing for organ dysfunction, and Doppler ultrasound. Following uterine evacuation, pathologic assessment can distinguish complete from partial moles or non-molar gestations. Close surveillance is essential for the timely diagnosis of GTN. Cure rates and subsequent obstetrics outcomes are excellent, but all patients should be referred for psychologic support and expert level care.

OBJECTIVE: A complete hydatidiform mole (CHM) is a common disease and is known to develop post-molar gestational trophoblast neoplasia (GTN). However, the molecular mechanisms underlying the progression of CHM to post-molar GTN remain largely unknown. In this study, we investigated the molecular factors associated with the progression using RNA-seq.
METHODS: We included 13 patients with CHM and performed RNA-seq using freshly frozen samples. We identified differentially expressed genes between patients who developed GTN (GTN group) and those who achieved spontaneous remission after uterine evacuation (SR group), and performed pathway analysis. Then, functional analyses were performed on choriocarcinoma (JAR and JEG-3) and CHM (Hmol1-3B and Hmol1-2C) cells. Moreover, we evaluated the in vivo tumorigenicity of XBP1-overexpressed Hmol1-3B cells.
RESULTS: The gene expression profiles were separated into two groups, and an upstream regulator analysis was performed using 281 differentially expressed genes. We focused on transcription factors and identified that 33 transcription factors were activated in the GTN group. Then, excluding those with low expression levels in clinical samples and cell lines, XBP1 was selected for further analysis. Additionally, XBP1 downregulation significantly decreased the migration and invasive abilities of choriocarcinoma cells, whereas XBP1 overexpression significantly increased the migration and invasive abilities of CHM cells. Furthermore, animal experiments showed that tumor weight and blood human chorionic gonadotropin (hCG) levels were significantly higher in the XBP1-overexpressing Hmol1-3B-bearing mice than those in the control mice.
CONCLUSIONS: RNA-seq identified XBP1 as a key factor in post-molar GTN, suggesting it contributes to the development of post-molar GTN.

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.

Complete hydatidiform mole (CHM) with co-existing fetus (CHMCF) is very uncommon. In this study, we investigated the clinicopathological features and DNA genotype in 15 CHMCF. Seven patients (46.7%) developed post-molar gestational trophoblastic disease (GTD), 5 of which had lung metastasis. CHMCF was histologically characterized by a mixed pattern of CHM and the non-molar placenta, mimicking partial hydatidiform mole and placental mesenchymal dysplasia. p57 immunostaining showed a divergent staining pattern, positive in the normal placenta and negative in the CHM component. DNA genotyping of the CHM villi demonstrated exclusively paternal alleles consisting of homozygous/monospermic (n = 9) and heterozygous/dispermic patterns (n = 5) at multiple informative loci. We conclude that CHMCF confers a high risk for post-molar GTD. DNA genotyping contributes significantly to the precision diagnosis of CHMCF.

UNASSIGNED: Here, we discuss novel management with methotrexate for the rare case of a complete hydatidiform mole with a co-existing fetus (CHMCF). The management of CHMCF is controversial, and methotrexate might represent a solution. CHMCF management with methotrexate needs more study, especially its side effects, safe dosage, and the permissible period of pregnancy.
METHODS: A 23-year-old Syrian primigravida came to our hospital with vaginal bleeding. The patient was diagnosed with a complete hydatidiform mole with a co-existing fetus. The mother had no complications but elevated B-HCG. After counseling, the decision was made to continue pregnancy with methotrexate to control B-HCG levels. The outcome was favorable though the infant had tetralogy of Fallot.
UNASSIGNED: In our case, the patient was stable except for the elevation of B-hCG levels, so we considered methotrexate to control it. On the other hand, methotrexate is considered a human teratogen. Case reports and case series of exposure to it during pregnancy began appearing in the 1960s. The sensitive period is suggested to be 6 to 8 weeks after conception. After discussing the choices with the patient, she elected to continue pregnancy and accepted methotrexate exposure to control B-hCG levels despite its risks.
CONCLUSIONS: Methotrexate usage within a safe dosage should be studied more to determine the benefits and risks it carries in cases such as ours.

OBJECTIVE: To evaluate the obstetrical and oncological progression of twin pregnancies with hydatidiform mole coexisting fetus (HMCF).
METHODS: Using a retrospective method based on patients from the Women\'s Hospital, Zhejiang University School of Medicine database between January 1990 and October 2020, 17 patients were histologically confirmed as having HMCF, and the patients\' prenatal diagnosis, outcomes and development of gestational trophoblastic neoplasia (GTN) were reviewed.
RESULTS: Among these 17 cases, 11 (64.71%) cases were complete hydatidiform mole coexisting fetus (CHMCF), and 6 (35.29%) cases were partial hydatidiform mole coexisting fetus (PHMCF). The gestational age at diagnosis of CHMCF was significantly earlier than that of PHMCF [9 (8-24) vs. 18 (11-32) weeks, respectively, P < 0.05]. The live birth rate of PHMCF was slightly higher than that of CHMCF (33.33%; 18.18%), but this difference was not statistically significant. The overall rate of GTN incidence of HMCF was 47.06% (8/17), and the GTN rates of PHMCF and CHMCF were 33.33% (2/6) and 54.55% (6/11), respectively. There was no significant difference in the GTN rate between patients who chose to continue pregnancy and those who terminated pregnancy before 24 weeks of gestation. The GTN rate of patients with term delivery was not significantly higher than that of preterm delivery.
CONCLUSIONS: In HMCF cases, the incidence rate of CHMCF was higher than that of PHMCF, and PHMCF is more difficult to diagnose in the early stage. Continuing pregnancy does not increase the risk of GTN compared to terminating pregnancy. In cases of HMCF, when the fetal karyotype is normal and maternal complications are controlled, it is safe to continue the pregnancy and extend it to term.

OBJECTIVE: We present two cases of triplet pregnancy with complete hydatidiform mole (CHM) in contrasting outcomes and discuss the complications of mothers and outcomes of fetuses through a literature review, raising an important issue on the management of this special pregnancy.
METHODS: We share our manage experience for two cases of triplet pregnancy with CHM and retrospectively analyze 18 similar pregnancies reported previously with different pregnancy outcomes.
RESULTS: In our cases, one case receiving Clomiphene ovulation induction delivered two live fetuses by cesarean section at 30+ weeks without GTN (gestational trophoblastic neoplasia), unfortunately, the other case following ICSI-ET terminated the pregnancy in the setting of complications at 18+ weeks without GTN. No severe complications were detected during pregnancy and no pGTD was developed after delivery in neither of the pregnant.
CONCLUSIONS: Co-existing complete hydatidiform mole in multiple pregnancies may become more common owing to the spreading use of ART. The decision for whether continue pregnancy depending on the personalized conditions including the complications of the pregnancy, the outcomes of the fetuses, the gestational age for delivery, and the potential progression of persistent gestational trophoblastic disease (pGTD). Furthermore, close monitor is necessary for the pregnant with triplet pregnancy with CHM who want to continue pregnancy.

Decidual natural killer cells (dNK) have been the focus of many studies because of their unique roles in both the anti-tumor immune response and healthy placental formation. Revealing the immunological mechanisms by which they interact with their target cells may lead to a better understanding of immune evasion of certain tumor cells, including abnormal cells of the different forms of gestational trophoblast disease and miscarriages of immunologic origin. Efforts to perform functional immunological studies on dNK cells have been limited by difficulty obtaining sufficent quantities of cells and sustaining the dNK phenotype. A novel protocol was developed to isolate and culture dNK cells from fresh, term placentas and complete hydatidiform moles.The placental samples were collected from healthy women undergoing scheduled elective cesarean delivery. The molar samples were collected after evacuation and curettage. Tissue samples were made into single cell suspensions using mechanical and enzymatic degradation, followed by fluorescence-activated cell sorting (FACS) using surface markers. The dNK cells were then expanded in cell culture. Their surface markers and cytotoxicity were reassessed by flow cytometry and functional assays. The protocol produces high quantities of enriched dNK cells which can be sustained in cell culture for at least a month, preserving their phenotype and funcionality for a week.

Gestational trophoblastic diseases (GTDs) are a heterogeneous group of lesions, the most frequent being the hydatidiform mole (HM). HMs are usually cured after surgical treatment or after chemotherapy in the case of a persistent trophoblastic activity. Immunotherapy could be an interesting alternative as a first-line or second-line treatment. However, only a few studies have explored the immune microenvironment of HMs. In the present retrospective study including 19 complete and 17 partial moles, we examined the composition of the immune cell microenvironment by immunohistochemistry using the following antibodies: CD4, CD8, CD56, PD-L1, S100, CD83, CD207, CD123, CD1a, CD11c, CD163, PAX5, and MUM1. In the decidual cells compartment, CD11c+ cells were the predominant population, followed by CD4+ cells, CD56+ NK cells, CD163+ macrophages, and CD8+ T lymphocytes.In the endometrial glands compartment, CD11c+ cells were the predominant population, followed by CD4+ cells, CD56+ NK cells, and CD8+ T lymphocytes. In the villi compartment, the predominant immune cells were CD4+ cells, followed by CD163+ macrophages and CD11c+ cells. Statistically significant differences were observed between partial and complete moles in all three compartments. The immune microenvironment of HMs is immunosuppressive, but it differs between complete and partial moles, the latter having a higher infiltrate of cells with phenotypes suggestive of immunosuppressive activities.

BACKGROUND: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement.
METHODS: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment.
RESULTS: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity.
CONCLUSIONS: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.