Development Of Gestational Trophoblastic Neoplasia Research Articles

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations.

Pathogenic variations of the NLRP7 and KHDC3L genes are responsible for familial recurrent hydatidiform moles, a rare autosomal recessive phenomenon that can lead to severe comorbidities. Little is known about the diversity of genetic defects or the natural course of disease progression among recurrent hydatidiform mole cases from distinct ethnicities. In this study, we aimed to investigate the mutation profile and pregnancy outcomes in patients with multiple molar pregnancies. Three unrelated cases with recurrent molar pregnancies are included in this study. None of the patients had a known family history of molar pregnancy. Clinical findings and follow-up results are documented. Sanger sequencing is used to reveal genetic defects in exons and exon-intron boundaries of NLRP7 and KHDC3L genes. NLRP7 pathogenic variants were found in all three cases. In two cases, homozygous, c.2471+1G>A canonical splice cite variant was identified and in one case a homozygous, c.2571dupC (p.Ile858HisfsTer11) frameshift variant was identified. No variant in the KHDC3L gene was found in any case. In all cases, the development of gestational trophoblastic neoplasia complicated the clinical course and the treatment plans. We found that defects of the NLRP7 gene are principally responsible for etiology in our region, and the mutation profile suggests a founder effect in the Turkish population. We suggest early genetic diagnosis and counseling in molar pregnancies and recommend close follow-up in terms of conversion to gestational trophoblastic neoplasia.

Prophylactic Chemotherapy for the Prevention of Gestational Trophoblastic Neoplasia- A descriptive study

Background: Gestational trophoblastic neoplasia develops from the trophoblastic cells which later form the placenta. It ranges from the relatively benign partial and complete hydatidiform mole while choriocarcinoma and the rare placental site trophoblastic tumor are its malignant variants. The risk of developing gestational trophoblastic neoplasia (GTN) is 15-17% after complete mole and 3.5-4% after partial mole1,2. This risk is more in patients with high-risk molar pregnancy1,2. Aim: To evaluate the role of prophylactic chemotherapy in prevention of gestational trophoblastic neoplasia in patients who fall in high-risk molar category. Place and duration of study: Ghurki Trust Teaching Hospital and Surgimed Hospital, 2016-2020 (4 years duration) Study design: Descriptive case series Methodology: Twenty three patients who presented with high-risk molar pregnancy in the study period were included in this study after takinginformed consent.These patients were divided into two groups. Group A included those patients who underwent suction evacuation followed by prophylactic chemotherapy; they were 13 in number, while group B had 10 patients and they underwent suction and evacuation only. Single dose of methotrexate 1mg/kg body weight was given to the patients in group A. Patients were asked about the history of excessive vaginal bleeding and serial beta hcg levels were carried out on follow up. Results: The patients average age was 32 years with the range between 25-42 years.14 patients (61%) were more than 40 years old while 9 patients (39%) were less than 40 years old. Three patients had beta hcg levels above 100,000 IU/ml. Patients were followed up withserial beta hcg levels till they became negative.No patient (0%) in group A developed gestational trophoblastic neoplasia while two patients (15.3%) in group B developed persistent vaginal bleeding and 1 patient (7%) developed choriocarcinoma involving the brain. Conclusion: Prophylactic chemotherapy reduces the risk of development of gestational trophoblastic neoplasia as concluded by thisstudy. However, only 16% of patients in high-risk molar category develop gestational trophoblastic neoplasia2 which means this will expose 84% patients to unnecessary chemotherapy. This will increase the cost of treatment also. Keywords: Molar pregnancy, Prophylactic chemotherapy, Gestational trophoblastic neoplasia

Presentation, medical complications and development of gestational trophoblastic neoplasia of hydatidiform mole after intracytoplasmic sperm injection as compared to hydatidiform mole after spontaneous conception - a retrospective cohort study and literature review

ObjectiveTo describe the natural history of hydatidiform mole (HM) after intracytoplasmic sperm injection (ICSI), emphasizing the clinical and oncological outcomes, as compared to patients who had HM after spontaneous conception (SC). Study designRetrospective historical cohort study of patients with HM followed at the Rio de Janeiro Federal University, from January 1st 2000-December 31st 2020. ResultsComparing singleton HM after SC to those following ICSI there were differences in terms of maternal age (24 vs 34 years, p < 0.01), gestational age at diagnosis (10 vs 7 weeks, p < 0.01), preevacuation human chorionic gonadotropin levels (200,000 vs 99,000 IU/L, p < 0.01), occurrence of genital bleeding (60.5 vs 26.9%, p < 0.01) and hyperemesis (23 vs 3.9%, p = 0.02) at presentation, and time to remission (12 vs 5 weeks, p < 0.01), respectively. There were no differences observed in the cases of twin mole, regardless of the form of fertilization that gave rise to HM, except molar histology with greater occurrence of partial hydatidiform mole (10.7 vs 40.0%, p = 0.01) following ICSI. Univariate logistic regression for occurrence of postmolar GTN after ICSI identified no predictor variable for this outcome. However, after adjusting for maternal age and complete hydatidiform mole histology, multivariable logistic regression showed the risk of GTN with HM after ICSI had an adjusted odds ratio of 0.22 (95%CI:0.05–0.93, p = 0.04), suggesting a possible protective effect when compared to HM after SC. ConclusionsSingleton HM after ICSI are diagnosed earlier in gestation, present with fewer medical complications, and may be less likely to develop GTN when compared with HM after SC.

Neutrophil/lymphocyte ratio and other blood cell component counts are not associated with the development of postmolar gestational trophoblastic neoplasia.

To relate preevacuation platelet count and leukogram findings, especially neutrophil/lymphocyte ratios (NLR) and platelet/lymphocyte ratios with the occurrence of gestational trophoblastic neoplasia (GTN) after complete hydatidiform mole (CHM) among Brazilian women. Retrospective cohort study of patients with CHM followed at Rio de Janeiro Federal University, from January/2015-December/2020. Before molar evacuation, all patients underwent a medical evaluation, complete blood count and hCG measurement, in addition to other routine preoperative tests. The primary outcome was the occurrence of postmolar GTN. From 827 cases of CHM treated initially at the Reference Center, 696 (84.15%) had spontaneous remission and 131 (15.85%) developed postmolar GTN. Using optimal cut-offs from receiver operating characteristic curves and multivariable logistic regression adjusted for the possible confounding variables of age and preevacuation hCG level (already known to be associated with the development of GTN) we found that ≥2 medical complications at presentation (aOR: 1.96, CI 95%: 1.29-2.98, p<0.001) and preevacuation hCG ≥100,000 IU/L (aOR: 2.16, CI 95%: 1.32-3.52, p<0.001) were significantly associated with postmolar GTN after CHM. However, no blood count profile findings were able to predict progression from CHM to GTN. Although blood count is a widely available test, being a low-cost test and mandatory before molar evacuation, and prognostic for outcome in other neoplasms, its findings were not able to predict the occurrence of GTN after CHM. In contrast, the occurrence of medical complications at presentation and higher preevacuation hCG levels were significantly associated with postmolar GTN and may be useful to guide individualized clinical decisions in post-molar follow-up and treatment of these patients.

Combined analysis of clinical features, human chorionic gonadotropin (hCG) value, and hCG ratios for early prediction of postmolar gestational trophoblastic neoplasia.

To investigate factors predicting postmolar gestational trophoblastic neoplasia (GTN) by combined analysis of clinical features, human chorionic gonadotropin (hCG) value, and hCG ratios. This retrospective study enrolled patients with histopathologically proven molar pregnancy. Patients lost to follow-up before remission or developing postmolar GTN were excluded. Demographic and clinical characteristics and hCG data obtained before and after molar evacuation were collected. Area under the receiver operating characteristic curve (AUC) analysis was used to identify the hCG and hCG ratio cutoff values that predict postmolar GTN. Multivariate analysis was employed to identify independent predictors of GTN. There were 113 complete moles, 11 partial moles, and 52 unspecified moles included in the final analysis. Of the 176 cases, 90 achieved remission and 86 developed post-molar GTN. The incidence of postmolar GTN was 48.9%, with a median time to GTN development of 5weeks. Univariate analysis showed age, molar evacuation performed elsewhere, pre-evacuation hCG, hCG at 2ndweek post-evacuation, and ratio of hCG at 2ndweek post-evacuation to post-evacuation hCG significantly predict GTN. Multivariate analysis revealed an hCG value ≥ 1400IU/L at 2nd week post-evacuation (AUC: 0.92, aOR: 6.51, 95% CI 1.28-33.16; p = 0.024) and a ratio of hCG at 2nd week post-evacuation to post-evacuation hCG of ≥ 0.02 (AUC: 0.88, aOR: 12.27, 95% CI 2.15-70.13; p = 0.005) to independently predict GTN. An hCG value ≥ 1400IU/L at 2ndweek post-evacuation and a ratio of hCG at 2ndweek post-evacuation to post-evacuation hCG of ≥ 0.02 independently and reliably predict postmolar GTN.

Obstetrical and oncological outcomes of twin pregnancies with hydatidiform mole and coexisting fetus

ObjectiveTo evaluate the obstetrical and oncological progression of twin pregnancies with hydatidiform mole coexisting fetus (HMCF). Materials and methodsUsing 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. ResultsAmong 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. ConclusionIn 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.

Cardiomyopathy During A Partial Molar Pregnancy

<h3>Background</h3> Molar pregnancies are associated with increased maternal complications, notably hyperemesis gravidarum, pre-eclampsia, or development of gestational trophoblastic neoplasia, but rarely cardiomyopathy. We present a case of a partial molar pregnancy complicated by new-onset heart failure. <h3>Case</h3> A 38-year-old female G9P7017 patient at 17 weeks gestation with an unremarkable past medical history presented to the emergency department with worsening dyspnea, orthopnea, peripheral edema, and a 20-pound weight gain. Initial vital signs were notable for sinus tachycardia with a heart rate of 120 beats/min and a blood pressure of 131/94 mmHg. Her BNP was >35,000 pg/mL, with an initial troponin of 0.08 ng/mL peaking at 0.092 ng/mL. TSH was 0.07 uIU/mL, and free T4 was 0.95 ng/dL. ECG showed no acute ischemic changes. Transthoracic echocardiography (TTE) showed a dilated cardiomyopathy with global hypokinesis and a newly reduced left ventricular ejection fraction (LVEF) of 21%. Right heart catheterization showed CVP 9, PCWP 29, and CI 2.33. Pelvic ultrasonography demonstrated omphalocele, intracranial abnormalities, and placentomegaly with beta-hCG >1,000,000 mIU/mL, consistent with a partial molar pregnancy. <h3>Decision-making</h3> Multidisciplinary teams from maternal fetal medicine, general cardiology, and heart failure collaborated to provide care for this patient. The mechanism by which her molar pregnancy led to her cardiomyopathy is unclear, but it was believed that continuation of the pregnancy could lead to worsening or persistent heart failure. She underwent successful dilation and evacuation and products of conception confirmed a partial mole with karyotype of 69 XXX. She was ultimately discharged on neurohormonal blockade. TTE three months post discharge demonstrated an improved LVEF of 40%. Her beta-hCG level downtrended appropriately to 9 mIU/mL at the most recent follow-up. <h3>Conclusion</h3> Partial molar pregnancy can be a rare but important cause of heart failure during pregnancy. Removal of the molar pregnancy and initiating neurohormonal blockade can lead to myocardial recovery. The mechanism by which molar pregnancy leads to cardiomyopathy is unclear, warranting additional research.

Evaluation of Incidence, Risk Factors, Diagnosis and Management of Gestational Trophoblastic Neoplasia: A Retrospective Study

Introduction: Detection of any definite established pattern in aetiological factors can help identify high risk groups among vesicular mole patients, so that the development of Gestational Trophoblastic Neoplasia (GTN) can be anticipated to avoid delay in management of this disease with almost 100% cure rate. Aim: To determine the incidence of GTN, various factors associated with the condition, and any difference in risk factors between low risk and high risk disease and to evaluate the efficacy of the different treatment protocols used. Materials and Methods: A retrospective descriptive study done in the Department of Obstetrics and Gynaecology in a tertiary level hospital in South India which included 100 cases of GTN who were registered in the Gestational Trophoblastic Disease (GTD) clinic for a period of ten years from January 2002 to December 2011. Data analysis was done from January 2020 to August 2020 The hospital incidence of GTN and proportion of GTN among vesicular mole was calculated. The different sociodemographic factors, clinical features and hormonal profile of all cases of GTN were studied in detail. Results: The incidence of GTN was 0.76 per 1000 deliveries. The proportion of GTN among molar pregnancy was 10.7%. Uterine size greater than period of amenorrhoea, bilateral theca leutin cysts especially with size &gt;6 cm and pre-evacuation Human Chorionic Gonadotropin (hCG) &gt;100,000 mIU/mL was associated with development of GTN. GTN was found more in those with complete mole and that was around 71%. Around 81% had low risk GTN and 19% had high risk GTN. Major indication for starting chemotherapy was rising βhCG (72%). Presence of theca lutein cysts and uterine size greater than period of amenorrhoea were statistically significant risk factors for high risk GTN (p=0.022 and p&lt;0.001, respectively). Conclusion: Identification of risk factors helps in early recognition of GTN and improves the overall outcome. The choice of chemotherapy depends on risk categorisation based on International Federation of Gynaecology and Obstetrics (FIGO) scoring system. Single agent for low risk and combination chemotherapy for high risk group is often sufficient.

Hot or not: defining trophoblast PD-L1 expression and lymphohistiocytic density in gestational trophoblastic neoplasia

<h3>Objectives:</h3> PD-L1 is an important axis of immunotolerance in normal pregnancy and this may be perpetuated as a mechanism of immune evasion in the pathobiologic development of gestational trophoblastic neoplasia (GTN). There are early efficacy signals for anti-PD-1 immunotherapy in chemoresistant GTN, however response rates are variable. The characteristics of predictive biomarkers used for triaging anti-PD-1 immunotherapy are not well-known in GTN. The aim of this study was to quantify trophoblast PD-L1 expression in GTN using the FDA approved PD-L1 22C3 immunohistochemical (IHC) companion assay and to profile GTN-infiltrating immune cells. <h3>Methods:</h3> Choriocarcinoma (CC), epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT) cases with available tissue blocks in the Johns Hopkins GTN library were used for this investigation. IHC staining for PD-L1 and each immune marker (CD68, CD8, CD4, FOXP3) was performed on paired, fresh cut 4 micrometer tissue sections. Tumor proportion scores (TPS, percentage of viable tumor cells with any PD-L1 membrane staining) were assigned by 2 independent gynecologic pathologists. Discrepancies in scoring were adjudicated by a third gynecologic pathologist. Digital image analyses using QuPath v0.2.3 to average CD68, CD8, CD4 and FOXP3 immune cell density in three 40x hotspots per case was performed. Hotspots were targeted to the tumor-immune cell interface. Descriptive statistics and the Wilcoxon Rank Sum Test were performed for analysis. <h3>Results:</h3> A large proportion of PSTT (n=6/8,75%) and CC (n=22/32, 69%) and approximately half of ETT (n=9/19, 47%) cases have highpositive PD-L1 expression defined as the clinically relevant TPS cutoff of >50%. These exceed the rates of high PD-L1 positivity observed in all other solid tumor sites, which ranges from 2-31%. PSTT and CC have significantly higher trophoblast PD-L1 expression than ETT; the median TPS for PSTT and CC is 90% and 85%, compared to 35% for ETT (p=0.02). CD68 monocytes were more abundant in CC and PSTT compared to ETT. However, CD8 cytotoxic T (p<0.01) and CD4 T (p=0.04) regulatory cell densities are significantly higher in ETT. ETT has a wider spectrum of tumor PD-L1 expression than PSTT and CC. ETT cases with low/negative trophoblast PD-L1 (TPS <5%) have fewer immune infiltrating lymphocytes than ETT cases with TPS >5% (Table). <h3>Conclusions:</h3> PD-L1 expression in GTN is heterogeneous, yet disproportionately high compared to other primary tumor sites. Of the 3 GTN subtypes, ETT has the lowest and broadest range of PD-L1 expression; this is associated with lower CD68 monocyte infiltration and correlates with degree of lymphocytic infiltration. How these expression patterns predict response to anti-PD-L1/PD-1 agents in GTN will be need to be explored. In a tumor type with such lineage inherent PD-L1 expression, characterization of tumor cell PD-L1 expression in conjunction with the tumor immune-microenvironment may provide a unique opportunity to study mechanisms of immune escape.Funding was provided by the Bruce Patsner Research Grant for Innovative Research and Technology through the Foundation for Women's Cancer.

Surveillance for gestational trophoblastic neoplasia following molar pregnancy: a cost-effectiveness analysis

Historically, published guidelines for care after molar pregnancy recommended monitoring human chorionic gonadotropin levels for the development of gestational trophoblastic neoplasia until normal and then for 6 months after the first normal human chorionic gonadotropin. However, there are little data underlying such recommendations, and recent evidence has demonstrated that gestational trophoblastic neoplasia diagnosis after human chorionic gonadotropin normalization is rare. We sought to estimate the cost-effectiveness of alternative strategies for surveillance for gestational trophoblastic neoplasia after human chorionic gonadotropin normalization after complete and partial molar pregnancy. A Markov-based cost-effectiveness model, using monthly cycles and terminating after 36 months/cycles, was constructed to compare alternative strategies for asymptomatic human chorionic gonadotropin surveillance after the first normal (none; monthly testing for 1, 3, 6, and 12 months; or every 3-month testing for 3, 6, and 12 months) for both complete and partial molar pregnancy. The risk of reduced surveillance was modeled by increasing the probability of high-risk disease at diagnosis. Probabilities, costs, and utilities were estimated from peer-reviewed literature, with all cost data applicable to the United States and adjusted to 2020 US dollars. The primary outcome was cost per quality-adjusted life year ($/quality-adjusted life year) with a $100,000/quality-adjusted life year willingness-to-pay threshold. Under base-case assumptions, we found no further surveillance after the first normal human chorionic gonadotropin to be the dominant strategy from both the healthcare system and societal perspectives, for both complete and partial molar pregnancy. After complete mole, this strategy had the lowest average cost (healthcare system, $144 vs maximum $283; societal, $152 vs maximum $443) and highest effectiveness (2.711 vs minimum 2.682 quality-adjusted life years). This strategy led to a slightly higher rate of death from gestational trophoblastic neoplasia (0.013% vs minimum 0.009%), although with high costs per gestational trophoblastic neoplasia death avoided (range, $214,000 to >$4 million). Societal perspective costs of lost wages had a greater impact on frequent surveillance costs than rare gestational trophoblastic neoplasia treatment costs, and no further surveillance was more favorable from this perspective in otherwise identical analyses. No further surveillance remained dominant or preferred with incremental cost-effectiveness ratio of <$100,000 in all analyses for partial mole, and most sensitivity analyses for complete mole. Under the assumption of no disutility from surveillance, surveillance strategies were more effective (by quality-adjusted life year) than no further surveillance, and a single human chorionic gonadotropin test at 3 months was found to be cost-effective after complete mole with incremental cost-effectiveness ratio of $53,261 from the healthcare perspective, but not from the societal perspective (incremental cost-effectiveness ratio, $288,783). Largely owing to the rare incidence of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization after molar pregnancy, prolonged surveillance is not cost-effective under most assumptions. It would be reasonable to reduce, and potentially eliminate, current recommendations for surveillance after human chorionic gonadotropin normalization after molar pregnancy, particularly among partial moles. With any reduction in surveillance, patients should be counseled on symptoms of gestational trophoblastic neoplasia and established in routine gynecologic care.

Distinct microRNA profiles for complete hydatidiform moles at risk of malignant progression

MicroRNAs are small noncoding RNAs with important regulatory functions. Although well-studied in cancer, little is known about the role of microRNAs in premalignant disease. Complete hydatidiform moles are benign forms of gestational trophoblastic disease that progress to gestational trophoblastic neoplasia in up to 20% of cases; however, there is no well-established biomarker that can predict the development of gestational trophoblastic neoplasia. This study aimed to investigate possible differences in microRNA expression between complete moles progressing to gestational trophoblastic neoplasia and those regressing after surgical evacuation. Total RNA was extracted from fresh frozen tissues from 39 complete moles collected at the time of uterine evacuation in Brazil. In the study, 39 cases achieved human chorionic gonadotropin normalization without further therapy, and 9 cases developed gestational trophoblastic neoplasia requiring chemotherapy. Total RNA was also extracted from 2 choriocarcinoma cell lines, JEG-3 and JAR, and an immortalized normal placenta cell line, 3A-subE. MicroRNA expression in all samples was quantified using microRNA sequencing. Hits from the sequencing data were validated using a quantitative probe-based assay. Significantly altered microRNAs were then subjected to target prediction and gene ontology analyses to search for alterations in key signaling pathways. Expression of potential microRNA targets was assessed by quantitative real-time polymerase chain reaction and western blot. Finally, potential prognostic protein biomarkers were validated in an independent set of formalin-fixed paraffin-embedded patient samples from the United States (15 complete moles progressing to gestational trophoblastic neoplasia and 12 that spontaneously regressed) using quantitative immunohistochemistry. In total, 462 microRNAs were identified in all samples at a threshold of <1 tag per million. MicroRNA sequencing revealed a distinct set of microRNAs associated with gestational trophoblastic neoplasia. Gene ontology analysis of the most altered transcripts showed that the leading pathway was related to response to ischemia (P<.001). Here, 2 of the top 3 most significantly altered microRNAs were mir-181b-5p (1.65-fold; adjusted P=.014) and mir-181d-5p (1.85-fold; adjusted P=.014), both of which have been shown to regulate expression of BCL2. By quantitative real-time polymerase chain reaction, BCL2 messenger RNA expression was significantly lower in the complete moles progressing to gestational trophoblastic neoplasia than the regressing complete moles (-4.69-fold; P=.018). Reduced expression of BCL2 was confirmed in tissue samples by western blot. Immunohistochemistry in the independent patient samples revealed significantly lower cytoplasmic expression of BCL2 in the villous trophoblasts from cases destined for progression to gestational trophoblastic neoplasia compared with those that regressed, both with respect to staining intensity (optic density 0.110±0.102 vs 0.212±0.036; P<.001) and to the percentage of positive cells (16%±28% vs 49.4%±28.05%; P=.003). Complete moles progressing to gestational trophoblastic neoplasia are associated with a distinct microRNA profile. miR-181 family members and BCL2 may be prognostic biomarkers for predicting gestational trophoblastic neoplasia risk.

Role of hysteroscopy and ultrasound in early identification of post-molar gestational trophoblastic neoplasia

ObjectiveTo evaluate the role of hysteroscopy and ultrasound in early identification of gestational trophoblastic neoplasia (GTN) after molar evacuation. MethodsThis was a prospective study involving 52 women with an ultrasound diagnosis of complete hydatidiform mole, attending a tertiary centre in south India between August 2016 and August 2019. Baseline characteristics such as age, serum beta-human chorionic gonadotropin(β-hCG) level, gestational age, and uterine size were noted. After the evacuation of molar pregnancy, weekly follow-up with β-hCG was performed, until three consecutive values were normal and then monthly for six months. Findings of transvaginal ultrasound and diagnostic hysteroscopy, performed on follow up at three weeks, were noted. Primary outcome was the development of GTN. Area under the curve(AUC) was calculated to assess the usefulness of these methods in early identification of GTN. ResultsThirteen women (25 %) developed GTN during follow up, within 6 months. Twenty six(50 %) cases had high-risk molar pregnancy. Positive findings on hysteroscopy and ultrasonography were noted in 44.2 % and 19.2 % respectively. AUC was 0.83(95 % CI, 0.70−0.97) for ultrasound and 0.82(95 % CI, 0.72–.92) for hysteroscopy. Sensitivity and specificity were 69.2 % and 97.4 % for ultrasound and it was 92.3 % and 71.8 % respectively for hysteroscopy in identifying those who developed GTN on follow-up. ConclusionsTransvaginal ultrasound as well as hysteroscopy may help in early identification of women at risk of developing GTN following a molar evacuation. Being a non-invasive method with similar discriminative value, ultrasonographic evaluation may be used for early identification of women with GTN after validation in future studies.

Expression pattern Nanog is associated with the development of gestational trophoblastic neoplasia in Chinese women from Fujian province: a case-control study

Background Gestational trophoblastic disease (GTD) is a group of interrelated but distinct diseases and has a serious impact on the reproductive health of women. To analyze the expression of Nanog in GTD and to evaluate its potential to predict the development of gestational trophoblastic neoplasia (GTN). Methods The study included 41 normal first-trimester placentas matched by gestational age to 53 regressed-hydatidiform-moles (rHMs), 56 malignant-HMs (mHMs) and 17 choriocarcinomas (CCAs) and evaluated the Nanog expression by immunohistochemistry. The chi-square test, ANOVA, Fisher’s exact test and logistic regression were performed to assess the Nanog expression and clinical prognostic factors in GTD. Results Compared to normal placenta levels, the Nanog expression was increased in GTD samples (p < .05). In HMs, Nanog expression was positively correlated with serum β-hCG levels,uterine size and theca-lutein cysts (p < .05). Compared with the low-risk metastatic group (Federation of Gynecology and Obstetrics (FIGO) score ≤ 6), the high-risk metastatic group (FIGO score >7) had higher Nanog expression (p = .030). Moreover, logistic regression analysis showed that the positive expression of Nanog had the highest risk of developing into GTN (OR = 4.764, p < .001). Conclusions Nanog is an independent predictor of clinical outcomes. It can also be a reliable predictor for GTN development from GTD.

ABO blood type compatibility is not a risk factor for gestationaltrophoblastic neoplasia development from androgenetic completehydatidiform moles.

Complete hydatidiform moles (CHMs) are allografts to patients in terms of an androgenetic origin. Thus, some immunological reactions may be involved in the development of gestational trophoblastic neoplasia (GTN) from CHMs. This study aimed to evaluate the effect of ABO blood group on the prognosis of androgenetic CHMs. A total of 129 patients who were diagnosed as having CHMs based on multiplex short tandem repeat polymorphism analysis were included. The ABO blood types of molar tissues were determined by single-nucleotide polymorphisms in the ABO gene using a high-resolution melting assay. The incidence of GTN was compared based on ABO compatibility between the patients and their molar tissues. The overall incidence of GTN was 17.1% (22/129). Gestational trophoblastic neoplasia occurred in 10.8% (4/37), 14.8% (8/54), 22.2% (6/27), and 36.4% (4/11) of type O, A, B, and AB patients, respectively. Type AB patients tended to develop GTN compared with other blood type patients (P=.093). In ABO type of CHMs, GTN occurrence was not significantly different as it was 16.4% (10/64), 16.0% (8/50), and 22.2% (4/18) for types O, A, and B, respectively (P=.854). According to the ABO incompatibility between patients and molar tissues, GTN occurred in 19.1% (18/94) of the compatible cases and 11.4% (4/35) of the incompatible cases; the occurrence was not significantly different (P=.223). Patients with type AB tended to develop GTN. However, ABO compatibility between patients and molar tissues had no relationship with GTN occurrence.

Accuracy of p57KIP2 compared with genotyping to diagnose complete hydatidiform mole: a systematic review and meta-analysis.

BackgroundDistinguishing hydatidiform moles (HMs) from nonmolar specimens and the subclassification of HM are important because complete hydatidiform mole (CHM) is associated with an increased risk of development of gestational trophoblastic neoplasia. However, diagnosis based solely on morphology has poor inter‐observer reproducibility. Recent studies have demonstrated that the use of p57KIP 2 immunostaining improves diagnostic accuracy for CHM.ObjectivesTo evaluate the accuracy of p57KIP 2 immunostaining compared with molecular genotyping for the diagnosis of CHM.Search strategyMajor databases were searched from inception to March 2017 using the terms ‘hydatidiform mole’, ‘p57’, and ‘genotyping’, with their variations, and the search limit for the relevant study design.Selection criteriaAny cross‐sectional study, case series, case–control study, cohort study, or clinical trial that evaluated the accuracy of p57KIP 2 immunostaining for the diagnosis of CHM compared with genotyping was included. Case reports, narrative reviews, expert opinions, and animal testing were excluded.Data collection and analysisExtracted accuracy data were tabulated and pooled using a hierarchical bivariate random effects model.Main resultsBivariate meta‐analysis produced a summary sensitivity of 0.984 (95% CI: 0.916–1.000) and specificity of 0.625 (95% CI: 0.503–0.736) with significant heterogeneity for specificity (I 2 = 71.8, chi‐square P = 0.029). The pooled summary diagnostic odds ratio was 56.54 (95% CI: 11.03–289.74) with no heterogeneity (I 2 = 0.00%, chi‐square P = 0.67). The diagnostic performance of the test was high with an area under the curve of (AUC) 0.980.Conclusionsp57KIP 2 immunostaining is accurate when diagnosing CHM. It can be used as an adjunct test in a combination algorithmic approach.Tweetable abstractA meta‐analysis to evaluate the accuracy of p57KIP 2 compared with genotyping to diagnose CHM.

Multiple pregnancies with complete mole and coexisting normal fetus in North and South America: A retrospective multicenter cohort and literature review

ObjectiveTo determine the clinical characteristics of multiple gestation with complete mole and coexisting fetus (CHMCF) in North and South America. MethodsRetrospective non-concurrent cohorts compromised of CHMCF from New England Trophoblastic Disease Center (NETDC) (1966–2015) and four Brazilian Trophoblastic Disease Centers (BTDC) (1990–2015). ResultsFrom a total of 12,455 cases of gestational trophoblastic disease seen, 72 CHMCF were identified. Clinical characteristics were similar between BTDC (n=46) and NETDC (n=13) from 1990 to 2015, apart from a much higher frequency of potentially life-threatening conditions in Brazil (p=0.046). There were no significant changes in the clinical presentation or outcomes over the past 5 decades in NETDC (13 cases in 1966–1989 vs 13 cases in 1990–2015). Ten pregnancies were electively terminated and 35 cases resulted in viable live births (60% of 60 continued pregnancies). The overall rate of gestational trophoblastic neoplasia (GTN) was 46%; the cases which progressed to GTN presented with higher chorionic gonadotropin levels (p=0.026) and higher frequency of termination of pregnancy due to medical complications (p=0.006) when compared to those with spontaneous remission. ConclusionsThe main regional difference in CHMCF presentation is related to a higher rate of potentially life-threatening conditions in South America. Sixty percent of the expectantly managed CHMCF delivered a viable infant, and the overall rate of GTN in this study was 46%. Elective termination of pregnancy did not influence the risk for GTN; however the need for termination due to complications and higher hCG levels were associated with development of GTN in CHMCF.

Expression patterns of maspin and mutant p53 are associated with the development of gestational trophoblastic neoplasia.

Gestational trophoblastic disease (GTD) is a group of conditions that originate from the abnormal proliferation of trophoblastic cells. GTDs encompass hydatidiform moles (HMs) and gestational trophoblastic neoplasia (GTN). GTNs are a group of malignant diseases that require chemotherapy, or more aggressive treatment. There is a requirement for more tumor markers to predict the development of GTN from HMs. The current study evaluated the expression of maspin and tumor protein p53 (p53) in GTD, and their role in predicting the development of GTN. Expression of maspin and mutant p53 (m-p53) was detected by immunohistochemistry in 48 normal first trimester placentas, matched for gestational age to 49 HMs that regressed, 39 malignant HMs and 11 invasive moles or choriocarcinomas. Spearman's rank correlation analysis and logistic regression were performed on the expression patterns of maspin and m-p53, and on the clinical prognostic factors in GTD. Compared with normal placenta levels, the expression levels of maspin were decreased, whereas the expression levels of m-p53 were increased in GTDs (P<0.05). The expression levels of maspin and m-p53 in complete and partial HMs were not significantly different (P>0.05). In HMs, maspin expression was inversely correlated with serum β human chorionic gonadotropin, uterine size and diameter of theca-lutein cysts; however, m-p53 expression demonstrated a positive correlation with these factors (all P<0.05). Compared with the high-risk metastatic group (FIGO score ≥7), the low-risk group (FIGO score <7) exhibited a higher rate of positive maspin expression (P=0.041), and the frequency of positive m-p53 expression was significantly higher in patients with an advanced FIGO stages (FIGO stage ≥III) compared with patients in early stages (FIGO stage ≤II; 87.9 vs. 58.8%; P=0.019). The combination of maspin negative expression with m-p53 positive expression had an 84% specificity value, 76% positive predictive value and 70% negative predictive value for the development of GTN. In conclusion, maspin-negative and m-p53-positive expression is associated with the development of GTN in HMs.

Changing Trends in the Clinical Presentation and Management of Complete Hydatidiform Mole Among Brazilian Women.

The aim of the study was to evaluate potential changes in the clinical, diagnostic, and therapeutic parameters of complete hydatidiform mole in the last 25 years in Brazil. A retrospective cohort study was conducted involving the analysis of 2163 medical records of patients diagnosed with complete hydatidiform mole who received treatment at the Rio de Janeiro Reference Center for Gestational Trophoblastic Disease between January 1988 and December 2012. For the statistical analysis of the natural history of the patients with complete molar pregnancies, time series were evaluated using the Cox-Stuart test and adjusted by linear regression models. A downward linear temporal trend was observed for gestational age of complete hydatidiform mole at diagnosis, which is also reflected in the reduced occurrence of vaginal bleeding, hyperemesis and pre-eclampsia. We also observed an increase in the use of uterine vacuum aspiration to treat molar pregnancy. Although the duration of postmolar follow-up was found to decline, this was not accompanied by any alteration in the time to remission of the disease or its progression to gestational trophoblastic neoplasia. Early diagnosis of complete hydatidiform mole has altered the natural history of molar pregnancy, especially with a reduction in classical clinical symptoms. However, early diagnosis has not resulted in a reduction in the development of gestational trophoblastic neoplasia, a dilemma that still challenges professionals working with gestational trophoblastic disease.

Effect of race/ethnicity on clinical presentation and risk of gestational trophoblastic neoplasia in patients with complete and partial molar pregnancy at a tertiary care referral center

The reported incidence of molar pregnancy varies widely among different geographic locations. This variation has been attributed, at least in part, to racial/ethnic differences. While the incidence of molar pregnancies is decreasing, certain ethnic groups such as Hispanics, Asians, and American Indians continue to have an increased risk of developing gestational trophoblastic disease across the globe. We sought to describe the potential effect of ethnicity/race on the presentation and clinical course of complete mole and partial mole. All patients followed up for complete mole and partial mole at a single institution referral center from 1994 through 2013 were identified. Variables including age, race, gravidity, parity, gestational age, presenting signs/symptoms, serum human chorionic gonadotropin values, and development of gestational trophoblastic neoplasia were extracted from medical records and patient surveys. Patients with complete mole and partial mole were categorized into race/ethnicity groups defined as white, black, Asian, or Hispanic. Due to low numbers of non-white patients with partial mole in each non-white category, patients with partial mole were grouped as white or non-white. Continuous variables were compared using the Kruskal-Wallis test and binary variables were compared using the Fisher exact test. A total of 167 complete mole patients with known race/ethnicity status were included (57.48% white, 14.97% Asian, 14.37% black, 13.17% Hispanic). Hispanics presented at younger age (median 24.5 years) compared to whites (median 32.0 years, P= .04) and Asians (median 31.0 years, P= .03). Blacks had higher gravidity than whites (P< .001) and Hispanics (P= .05). There was no significant difference in presenting symptoms, gestational age at diagnosis, and preevacuation serum human chorionic gonadotropin level by race/ethnicity. Hispanics were significantly less likely than whites to develop gestational trophoblastic neoplasia (absolute risk difference, 28.6%; 95% confidence interval, 8.1-39.2%; P= .02). A total of 144 patients with partial mole were analyzed. There were 108 white and 36 non-white patients. Median age was 31 years for white and 29 years for non-white patients (P= .006). Median gravidity was 2 for white and 3 for non-white patients (P < .001), and median parity was 0 for white patients and 1 for non-white patients (P= .003). There were no significant differences with respect to presenting signs and symptoms, gestational age, preevacuation human chorionic gonadotropin level, or risk of progression to gestational trophoblastic neoplasia. Hispanic patients with complete molar pregnancy had a significantly lower risk of developing gestational trophoblastic neoplasia than white patients. There were no significant differences among groups interms of presenting symptoms, gestational age at diagnosis, or preevacuation human chorionic gonadotropin levels for either complete mole or partial mole patients.

Apoptotic index for prediction of postmolar gestational trophoblastic neoplasia

Although 85% of patients with a complete hydatidiform mole achieve spontaneous remission after a few months, 15% of them will experience gestational trophoblastic neoplasia, which requires chemotherapy. To date, there is no biomarker to predict post-molar gestational trophoblastic neoplasia before the initiation of human chorionic gonadotropin surveillance. The purpose of this study was to assess the relationship between the expression of apoptosis markers in the molar villous trophoblasts and the subsequent development of gestational trophoblastic neoplasia after the evacuation of a complete hydatidiform mole. This was a retrospective cohort study of patients withcomplete hydatidiform mole who were diagnosed, treated, and followed at the Center of Trophoblastic Diseases (Botucatu/São Paulo State and Rio de Janeiro/Rio de Janeiro State, Brazil) from 1995-2014. Patients were divided temporally into derivation (1995-2004) and validation (2005-2014) cohorts. Immunohistochemistry was used to examine tissue expression of the apoptosis inhibitor survivin or the pro-apoptotic enzyme caspase-3. Survivin stains for cytoplasmic and nuclear expression were evaluated independently. Caspase-3 expression was measured as an apoptotic index of positive staining cells over negative staining cells multiplied by 100. Receiver operating characteristic curves were then constructed, and the area under the curve was calculated to test the performance characteristics of the staining to predict the subsequent development of gestational trophoblastic neoplasia. The final study population comprised 780 patients, with 390 patients in each temporal cohort: 590 patients entered spontaneous remission, and 190 patients experienced post-molar gestational trophoblastic neoplasia. Neither nuclear nor cytoplasmic survivin expression performed well as a predictor of subsequent gestational trophoblastic neoplasia. The caspase-3 apoptotic index was a strong risk factor for subsequent gestational trophoblastic neoplasia development. When the apoptotic index was <4%, the risk of gestational trophoblastic neoplasia had an odds ratio of 35.55 (95% confidence interval, 14.02-90.14; P < .0001) in the derivation cohort and an odds ratio of25.71 (95% confidence interval, 10.13-65.29; P < .0001) in the validation cohort. However, in both cohorts, the positive predictive value for gestational trophoblastic neoplasia of an apoptotic index <4.0% was modest (49% in the derivation cohort and 41% in the validation cohort); the negative predictive value for gestational trophoblastic neoplasia of an apoptotic index ≥4.0% was high (97% in both cohorts). The subsequent development of gestational trophoblastic neoplasia after evacuation of complete hydatidiform mole is tied closely to the apoptotic index, which may be a useful biomarker for future prospective studies.