Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

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. CONCLUSION: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.

Gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in a retrospective cohort of 7761 patients in France.

BACKGROUND: The risk of malignant transformation of molar pregnancies after human chorionic gonadotropin levels return to normal is low, roughly 0.4%, but may justify an adaptation of monitoring strategies for certain patients. OBJECTIVE: This study aimed to determine the risk of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in women with molar pregnancy and identify risk factors for this type of malignant transformation to optimize follow-up protocols after human chorionic gonadotropin normalization. STUDY DESIGN: This was a retrospective observational national cohort study based at the French National Center for Trophoblastic Diseases of 7761 patients, treated between 1999 and 2020 for gestational trophoblastic disease, whose human chorionic gonadotropin levels returned spontaneously to normal. RESULTS: Among 7761 patients whose human chorionic gonadotropin levels returned to normal, 20 (0.26%) developed gestational trophoblastic neoplasia. The risk of malignant transformation varied with the type of mole, from 0% (0 of 2592 cases) for histologically proven partial mole to 0.36% for complete mole (18 of 5045) and 2.1% (2 of 95) for twin molar pregnancy. The median time to diagnosis of malignant transformation after human chorionic gonadotropin normalization was 11.4 months (range, 1-34 months). At diagnosis, 16 of 20 patients (80%) had the International Federation of Gynecology and Obstetrics stage I tumor, and 10 of 20 patients (50%) had a tumor classified as low risk in terms of the International Federation of Gynecology and Obstetrics score. In 9 of 20 patients (45%), the most common first-line treatment was combination chemotherapy. A quarter of these tumors (5 of 20) were histologically proven placental site or epithelioid trophoblastic tumors. In univariate analysis, the factors significantly associated with a higher risk of developing gestational trophoblastic neoplasia after the end of the normal human chorionic gonadotropin monitoring period were age of ≥45 years (odds ratio, 8.3; 95% confidence interval, 2.0-32.7; P=.004) and time to human chorionic gonadotropin normalization of ≥8 weeks (odds ratio, 7.7; 95% confidence interval, 1.1-335; P=.03). The risk was even higher for human chorionic gonadotropin normalization times of ≥17 weeks (odds ratio, 19.5; 95% confidence interval, 3.3-206; P<.001). CONCLUSION: In this group of patients with gestational trophoblastic disease, none of the those with pathologically verified partial mole had malignant transformation, supporting the current recommendation of stopping human chorionic gonadotropin monitoring after 3 successive negative tests. In cases of complete mole or twin molar pregnancy, we proposed to extend the monitoring period with quarterly human chorionic gonadotropin measurements for an additional 30 months in patients with the identified risk factors for late malignant transformation (age, ≥45 years; time to human chorionic gonadotropin normalization, ≥8 weeks).

Cytological features of a complete hydatidiform mole in a cervicovaginal smear: A case report.

Exfoliated trophoblastic cells can be seen in a cervicovaginal smear in cases of normal pregnancy or gestational trophoblastic disease (GTD) and can mimic high-grade squamous intraepithelial lesion (HSIL) or malignancy. Although they appear highly anaplastic, cytological features such as high nuclear to cytoplasmic ratio, irregular nuclear contours and scanty basophilic cytoplasm admixed with cytologically benign squamoid and endocervical cells can aid in differentiating them from malignant cells. We present a case of a 37-year-old woman with abnormal uterine bleeding for 3-months. There was no history of recent pregnancy or previous GTD. Her cervicovaginal smear showed a hypercellular smear exhibiting cytologically benign superficial and intermediate squamous cells along with clusters of benign endocervical cells with interspersed mononucleate cells. These mononucleate cells were large, with a hyperchromatic, pleomorphic nuclei, and scant basophilic cytoplasm. Cytological features were suggestive of trophoblastic cells and workup for pregnancy and GTD was advised. Her laboratory investigations showed markedly raised levels of ß human chorionic gonadotropins (ß-HCG) and ultrasound showed a uterine mass with snowstorm appearance. A uterine evacuation was performed after which histopathological examination showed microscopic features consistent with a complete hydatidiform mole. The rare presence of trophoblastic cells in a cervicovaginal smear can easily be confused with malignant cells and can be misleading to the pathologist. Trophoblastic cells should always be kept in mind when evaluating a cytology smear of a young patient irrespective of gestational status.

Immune cell composition in the endometrium of patients with a complete molar pregnancy: Effects on outcome.

OBJECTIVE: In 15% of patients with complete hydatidiform mole (CHM), disease progresses to post-molar gestational trophoblastic neoplasia (GTN) after curettage. Tumor infiltrating lymphocytes (TILs) are essential in overcoming disease in many tumors. Infiltrating lymphocyte composition and density may influence trophoblast regression and development of post-molar GTN. We analyzed immune cell composition and density in curettaged endometrium of patients with CHM which spontaneously regressed, and of patients with CHM which progressed to post-molar GTN. METHODS: Sixteen patients with CHM and spontaneous regression, and 16 patients with CHM which progressed to post-molar GTN were selected. Immune cell composition and density of natural killer (NK) cells, natural killer T (NKT)-like cells, Cytotoxic T cells, T-Regulatory and T-Helper cells, were determined by multiplex immunohistochemistry (mIHC). RESULTS: Curettaged endometrium of patients with CHM and spontaneous regression contained a slightly higher number of immune cells compared to patients with CHM which progressed to post-molar GTN. NKT-like cell density was significantly higher in patients with spontaneous regression compared to patients with CHM which progressed to post-molar GTN (483 ± 296 vs.295 ± 143 (mean ± SD), p = 0.03) respectively. NKT-like cell density in the spontaneous regression group was split in 'high' and 'low' (i.e. above and below the median number of NKT-like cells). In patients with high NKT-like cell density, hCG normalized earlier than in patients with low NKT-like cell density (9.5 weeks, (range 3.7-14) vs. 12.9 weeks, (range 8.6-17.9), p = 0.05). CONCLUSION: A high number of NKT-like cells in the endometrium of CHMs may contribute to spontaneous regression of molar trophoblast cells.

Evaluation of High-Dose Vitamin A Treatment in Postmolar Patients with Low and Plateauing Serum Human Chorionic Gonadotropin Levels.

OBJECTIVE: To compare the effect of high-dose vitamin A (HD Vit-A) use during postmolar follow-up of patients with low and plateauing (L&P) serum human chorionic gonadotropin (hCG) levels, from the moment serum hCG plateaued (P-hCG) to the first normal serum hCG value (< 5 IU/L). METHODS: The present retrospective series case study compared two nonconcurrent cohorts of patients. Control group (CG): 34 patients with L&P serum hCG levels who underwent expectant management for 6 months after uterine evacuation, from 1992 to 2010; study group (SG): 32 patients in similar conditions who received 200,000 IU of Vit-A daily, from the identification of a P-hCG level to the first normal hCG value or the diagnosis of progression to gestational trophoblastic neoplasia (GTN), from 2011 to 2017. The present study was approved by the Ethics Committee of the institution where it was conducted. RESULTS: In both groups, the prevalence of persistent L&P serum hCG levels was < 5%. In the SG, hCG levels at plateau were higher (CG = 85.5 versus SG = 195 IU/L; p = 0.028), the rate of postmolar GTN was lower (CG = 29.4% versus SG = 6.3%, p = 0.034) and follow-up was shorter (CG = 14 versus SG = 10 months, p < 0.001). During GTN follow-up, there were no differences in GTN staging or treatment aggressiveness in both groups. High-dose Vit-A use did not have any relevant toxic effect. There were no GTN relapses or deaths. CONCLUSION: The limited use of HD Vit-A seems to have a safe and significant effect on the treatment of postmolar patients with L&P serum hCG levels and may decrease the development of postmolar GTN in this population.

OBJETIVO: Comparar o efeito de alta dose de vitamina A (VitA) no seguimento pós-molar de pacientes com gonadotrofina coriônica humana (hCG) sérica apresentando valores baixos e em platô (L&P). MéTODOS: Estudo retrospectivo de série de casos comparando duas coortes não simultâneas. Grupo controle (CG): 34 pacientes com títulos de hCG sérico L&P submetidos a manejo expectante por 6 meses após o esvaziamento uterino, de 1992 a 2010; Grupo de Estudo (SG): de 2011 a 2017, 32 pacientes em condições semelhantes de hCG receberam Vit-A na dose de 200.000 IU por dia, do momento da identificação do hCG em platô ate o primeiro hCG normal ou diagnóstico de progressão para neoplasia trofoblástica gestacional (NTG). O presente estudo foi aprovado pelo Comitê de Ética da Instituição na qual foi desenvolvido. RESULTADOS: Em ambos os grupos, a prevalência de hCG L&P foi < 5%. No SG, os níveis de hCG em platô foram maiores (CG = 85.5 versus SG = 195 IU/L; p = 0,028), e foram significantemente menores tanto a prevalência de NTG pós-molar (CG = 29.4% versus SG = 6.3%, p = 0,034) como o tempo de seguimento (CG = 14 versus SG = 10 meses, p < 0.001). Na evolução para NTG não houve diferença no estadiamento da International Federation of Gynecology and Obstetrics (FIGO, na sigla em inglês) ou na agressividade do tratamento. Com altas doses de Vit-A não houve qualquer efeito tóxico relevante. Não houve casos de recidiva de NTG ou de óbito. CONCLUSãO: O uso limitado de altas doses de Vit-A parace ser seguro e apresenta efeitos significativos na evolução de pacientes em controle pós-molar com títulos de hCG sérico L&P, e pode diminuir o desenvolvimento de NTG pós-molar nessa população.

Evaluation of high-dose vitamin A treatment in postmolar patients with low and plateauing serum human chorionic gonadotropin levels / Avaliação de alta dose de vitamina A em pacientes pósmola hidatiforme, com valores baixos e em platô de gonadotrofina coriônica humana

Abstract Objective To compare the effect of high-dose vitamin A (HD Vit-A) use during postmolar follow-up of patients with low and plateauing (L&P) serum human chorionic gonadotropin (hCG) levels, from the moment serum hCG plateaued (P-hCG) to the first normal serum hCG value (< 5IU/L). Methods The present retrospective series case study compared two nonconcurrent cohorts of patients. Control group (CG): 34 patients with L&P serum hCG levels who underwent expectant management for 6 months after uterine evacuation, from 1992 to 2010; study group (SG): 32 patients in similar conditions who received 200,000 IU of Vit-A daily, from the identification of a P-hCG level to the first normal hCG value or the diagnosis of progression to gestational trophoblastic neoplasia (GTN), from 2011 to 2017. The present study was approved by the Ethics Committee of the institution where it was conducted. Results In both groups, the prevalence of persistent L&P serum hCG levels was < 5%. In the SG, hCG levels at plateau were higher (CG = 85.5 versus SG = 195 IU/L; p = 0.028), the rate of postmolar GTN was lower (CG = 29.4% versus SG = 6.3%, p = 0.034) and follow-up was shorter (CG = 14 versus SG = 10 months, p < 0.001). During GTN follow-up, there were no differences in GTN staging or treatment aggressiveness in both groups. High-dose Vit-A use did not have any relevant toxic effect. There were no GTN relapses or deaths. Conclusion The limited use of HD Vit-A seems to have a safe and significant effect on the treatment of postmolar patients with L&P serum hCG levels and may decrease the development of postmolar GTN in this population.

Resumo Objetivo Comparar o efeito de alta dose de vitamina A (VitA) no seguimento pósmolar de pacientes com gonadotrofina coriônica humana (hCG) sérica apresentando valoresbaixoseem platô(L&P). Métodos Estudo retrospectivo de série de casos comparando duas coortes não simultâneas. Grupo controle (CG): 34 pacientes com títulos de hCG sérico L&P submetidos a manejo expectante por 6 meses após o esvaziamento uterino, de 1992 a 2010; Grupo de Estudo (SG): de 2011 a 2017, 32 pacientes em condições semelhantes de hCG receberam Vit-A na dose de 200.000 IU por dia, do momento da identificação dohCG em platôate o primeirohCG normaloudiagnóstico de progressão para neoplasia trofoblástica gestacional (NTG). O presente estudo foi aprovado pelo Comitê de Ética da Instituição na qual foi desenvolvido. Resultados Em ambososgrupos, aprevalência de hCGL&P foi < 5%. No SG, os níveis de hCGemplatô forammaiores (CG = 85.5 versus SG = 195 IU/L; p = 0,028), e foram significantemente menores tanto a prevalência de NTG pós-molar (CG = 29.4% versus SG = 6.3%, p = 0,034) como o tempo de seguimento (CG = 14 versus SG = 10 meses, p < 0.001). Na evolução para NTG não houve diferença no estadiamento da Interna tional Federation of Gynecology and Obstetrics (FIGO, na sigla em inglês) ou na agressividade do tratamento. Com altas doses de Vit-A não houve qualquer efeito tóxico relevante. Não houve casos de recidiva de NTG ou de óbito. Conclusão O uso limitado de altas doses de Vit-A parace ser seguro e apresenta efeitos significativos na evolução de pacientes em controle pós-molar com títulos de hCG sérico L&P, e pode diminuir o desenvolvimento de NTG pós-molar nessa população.

The impact of previous cesarean section (C/S) on the risk for post-molar gestational trophoblastic neoplasia (GTN).

OBJECTIVE: To investigate the relationship between previous cesarean section (C/S) and risk for post-molar gestational trophoblastic neoplasia (GTN). METHODS: Data from patients who were treated for hydatidiform moles between 1995 and 2016 were retrospectively reviewed. Patient age, gravidity, parity, abortion history, gestational age, pretreatment beta-human chorionic gonadotropin (HCG), previous molar pregnancy, clinical symptoms, enlarged uterus, theca lutein cyst, type of GTN, World Health Organization risk score, chemotherapy, and mode of delivery were recorded. Hazard ratios (HR) and 95% confidence intervals (CI) for variables associated with the occurrence of post-molar GTN and invasive mole were estimated by univariate and multivariate Cox proportional hazards models. RESULTS: From 1995 to 2016, 182 patients were diagnosed with molar pregnancy and underwent treatment. Patients with previous C/S (C/S group) had higher age (37.0 vs 32.8. p = 0.004), gravidity (3.1 vs 2.0, p < 0.001), and parity (1.6 vs 0.9, p < 0.001) than patients without previous C/S (non-C/S group). Post-molar GTN (43.5 vs 26.5%, p < 0.001), invasive mole (21.7 vs 3.7%, p < 0.001), hysterectomy (28.3 vs 6.6%, p < 0.001), and chemotherapy (45.7 vs 28.7%, p = 0.03) were more frequent in the C/S group. In multivariate analysis, independent risk factors for post-molar GTN were previous C/S (HR 5.1, 95% CI 2.1-12.7), abortion history (HR 6.3, 95% CI 2.5-15.6), and pretreatment ß-hCG (HR 1.3, 95% CI 1.1-1.6). CONCLUSIONS: In this study, C/S was a strong risk factor for occurrence of post-molar GTN and invasive mole. Aggressive treatment, such as multi-agent chemotherapy or hysterectomy, can be considered for hydatidiform moles in patients with a C/S history.

Gestational Trophoblastic Neoplasia After Human Chorionic Gonadotropin Normalization Following Molar Pregnancy: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the incidence of gestational trophoblastic neoplasia following complete and partial molar pregnancy after reaching normal human chorionic gonadotropin (hCG) levels to guide evidence-based follow-up recommendations. DATA SOURCES: MEDLINE, EMBASE, Web of Science, POPLINE, Cochrane, and ClinicalTrials.gov were searched from inception to November 2018, using the intersection of "gestational trophoblastic disease," "molar pregnancy," and "human chorionic gonadotropin" themes. METHODS OF STUDY SELECTION: Search results were screened to identify cohort studies of molar pregnancy reporting gestational trophoblastic neoplasia development, with at least 6 months of intended normal hCG follow-up. TABULATION, INTEGRATION, AND RESULTS: Two reviewers independently identified articles for inclusion. Data were extracted using a standardized form. For meta-analysis, cumulative incidence of gestational trophoblastic neoplasia, with CIs by the Agresti-Coull method, and pooled risk ratios (RRs) comparing complete and partial mole were calculated. Among the 19 eligible studies that reported adequate data for inclusion in the primary meta-analysis, we found low incidence of gestational trophoblastic neoplasia after normal hCG level following both complete mole (64/18,357, 0.35%, 95% CI 0.27-0.45%), and partial mole (5/14,864, 0.03%, 95% CI 0.01-0.08%). There was a significantly higher risk of gestational trophoblastic neoplasia after complete compared with partial molar pregnancy (RR 4.72, 95% CI 1.81-12.3, P=.002). Among gestational trophoblastic neoplasia cases after normal hCG level following complete mole, 89.6% occurred when the time from evacuation to normalization was 56 days or longer, and 60.7% were diagnosed beyond the commonly recommended 6-month surveillance interval. Sensitivity analyses, including those limiting to studies at low risk of bias, did not significantly affect results. We found an overall incidence of gestational trophoblastic neoplasia of 15.7% for complete mole (1,354/8,611, 95% CI 15.0-16.5%) and 3.95% for partial mole (221/5,593, 95% CI 3.47-4.50%). CONCLUSION: Gestational trophoblastic neoplasia development after normal hCG level following molar pregnancy is rare. Recommendations for frequency and duration of hCG follow-up can be minimized to lessen burden on patients and informed by the type of molar pregnancy and time interval from uterine evacuation to hCG normalization. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019116414.

Incidence and outcome of gestational trophoblastic disease in lower Egypt.

BACKGROUND: Gestational trophoblastic disease (GTD) defines a spectrum of proliferative disorders of trophoblastic epithelium of the placenta. Incidence, risk factors, and outcome may differ from one country to another. OBJECTIVE: To describe incidence, patient characteristics, treatment modalities, and outcome of GTD at Mansoura University which is a referral center of Lower Egypt. METHODS: An observational prospective study was conducted at the GTD Clinic of Mansoura University. The patients were recruited for 12 months from September 2015 to August 2016. The patients' characteristics, management, and outcome were reported. RESULTS: We reported 71 clinically diagnosed GTD cases, 62 of them were histologically confirmed, 58 molar (33 CM and 25 PM) in addition to 4 initially presented GTN cases. Mean age of the studied cases was 26.22 years ± 9.30SD. Mean pre-evacuation hCG was 136170 m.i.u/ml ±175880 SD. Most of the cases diagnosed accidentally after abnormal sonographic findings (53.2%). Rate of progression of CM and PM to GTN was 24.2% and 8%, respectively. CONCLUSION: The incidence of molar pregnancy and GTN in our locality was estimated to be 13.1 and 3.2 per 1000 live births respectively. We found no significance between CM and PM regarding hCG level, time to hCG normalization, and progression rate to GTN.

Increased LIGHT leading to sFlt-1 elevation underlies the pathogenic link between hydatidiform mole and preeclampsia.

Hydatidiform moles are known to pose an extremely high risk of severe early-onset preeclampsia if left untreated. TNF superfamily cytokine, LIGHT has recently been reported to contribute to pathophysiology of preeclampsia. The present study aimed to investigate the involvement of LIGHT in hydatidiform moles. We measured the serum levels of LIGHT and sFlt-1 by ELISA in 17 women with complete hydatidiform mole (HM) and 20 gestational-age-matched normal pregnant women (control). As a result, the serum LIGHT levels were significantly higher in HM as compared with those in control (69.9 ± 9.6 pg/ml vs 25.4 ± 5.3 pg/ml, p = 0.0001) and the serum levels of LIGHT were significantly positively correlated with those of sFlt-1 in HM (r = 0.68, p = 0.0029). Immunohistochemical analysis revealed that the expression levels of LIGHT were increased in HM placentas as compared with controls, and LIGHT and sFlt-1 were co-localized in the trophoblast cells of HM. In vitro studies using primary syncytiotrophoblast cells demonstrated that LIGHT directly induced sFlt-1 expression in trophoblast cells. Our results indicated that elevated LIGHT in the trophoblast cells of hydatidiform mole induces sFlt-1, which might underlie the pathogenic mechanism of early-onset preeclampsia developing secondary to molar pregnancies.

Spontaneous regression of quiescent gestational trophoblastic disease after pregnancy: a case report.

BACKGROUND: A persistent low-level elevation of serum human chorionic gonadotropin (hCG) without clinical or radiological evidence of pregnancy or tumors was recently defined as quiescent gestational trophoblastic disease (Q-GTD). Whether patients with Q-GTD should be treated or allowed to become pregnant remains unclear. We herein report a rare case of Q-GTD in which the hCG level spontaneously returned to normal after a successful pregnancy. CASE PRESENTATION: The patient was a 37-year-old primigravida who presented with a persistent low-level elevation of hCG after uterine evacuation of a hydatidiform mole. There was no evidence of neoplasia in the uterus or distant metastasis. The low-level elevation of hCG persisted for at least 2 years but never exceeded 200 mIU/mL. The patient had a successful pregnancy at the age of 40 years. CONCLUSIONS: Interestingly, her hCG level subsequently normalized without chemotherapy. The present case may imply the safety and therapeutic effect of pregnancy in women with Q-GTD.

Do we need post-pregnancy screening with human chorionic gonadotrophin after previous hydatidiform mole to identify patients with recurrent gestational trophoblastic disease?

OBJECTIVE: To determine whether post-pregnancy human chorionic gonadotrophin screening after previous hydatidiform mole identifies patients with recurrent gestational trophoblastic disease. STUDY DESIGN: A retrospective evaluation of 9315 patients who underwent post-pregnancy screening from 2000 to 2009, as part of the National Gestational Trophoblastic Disease Service in the UK. RESULTS: Patients with previous hydatidiform mole, who had human chorionic gonadotrophin screening after one or more subsequent pregnancies, were identified (n = 9315). Of these, 8630 patients had an initial hydatidiform mole that did not require chemotherapy. In 12,329 subsequent pregnancy events, screening with human chorionic gonadotrophin identified 3 cases of gestational trophoblastic neoplasm. The remaining 685 patients developed gestational trophoblastic neoplasm, following their initial hydatidiform mole and required chemotherapy. In this group there were 1012 further pregnancy events, human chorionic gonadotrophin screening identified 3 patients with gestational trophoblastic neoplasm. The overall recurrence rate was 6 in 13,341 events (risk 1: 2227). The rate was 3 in 12,329 (risk 1:4110) for HM that did not require chemotherapy and 3 in 1012 (1:337) for previously treated gestational trophoblastic neoplasm. All 6 patients with recurrent disease were successfully treated with chemotherapy. CONCLUSION: Routine post-pregnancy human chorionic gonadotrophin screening may be safely discontinued in patients with one previous uncomplicated hydatidiform mole.

Invasive molar pregnancy in rudimentary uterine horn.

OBJECTIVE: Incidence of molar pregnancy is 1-3/1000 pregnancies. Invasive mole is a local invasive form of gestational trophoblastic neoplasias which is mostly seen in reproductive age and usually follows a molar pregnancy and rarely has an initial presentation. Ectopic pregnancy in rudimentary uterine horn is extremely rare and is seen in 1/100,000 - 140,000 pregnancies. Invasive mole has seldom been reported in ectopic localizations but not in a patient with Müllerian duct anomaly. Here we represent a case of invasive mole in a reproductive age patient with unicornuate uterus and rudimentary communicating uterine horn. Invasive mole presented initially, mimicking ectopic pregnancy. The patient underwent diagnostic laparoscopy and resection of rudimentary uterine horn was performed. The pathology result was reported as an invasive mole. Serum b-hCG levels normalized on post-operative first month and no additional chemotherapy was needed.

Human Chorionic Gonadotropin Regression Curves after Partial or Complete Molar Pregnancy in Flanders: Are They Different from Regression Curves from the Eighties?

BACKGROUND/AIMS: We updated human chorionic gonadotropin (hCG) regression curves created in the eighties after evacuation of complete and partial molar (CM and PM, respectively) pregnancies using modern hCG assays. We created similar curves for patients in need of chemotherapy (gestational trophoblastic neoplasia [GTN]). METHODS: A total of 126 patients who were diagnosed with gestational trophoblastic disease from 1990 to 2014 were included. We compared curves from 2 groups, CM and PM, with historical ones. The third group was a comparison of GTN patients receiving first-line chemotherapy and patients in need of a switch of chemotherapy. RESULTS: The regression curves were comparable to historical ones. According to the latter, mean time to normalization was 14-15 weeks after evacuation. We observed a normalization within 12 (CM) and 12.7 (PM) weeks. In addition, a remarkable but not statistically significant vertical shift (20 IU/L higher) was observed prior to day 60 compared with historical curves. The comparison in GTN patients showed a statistical significant difference, even at day 7. CONCLUSION: The presented hCG regression curves in the Flemish region were comparable with the ones of the eighties but with a vertical shift, hypothetically due to more sensitive assays. In addition, regression curves in GTN patients receiving chemotherapy can be used to evaluate response.

What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients.

OBJECTIVE: To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. METHODS: The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. RESULTS: We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. CONCLUSIONS: Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged.

Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience.

OBJECTIVES: To assess the outcomes and toxicity of first-line methotrexate (MTX) chemotherapy in low-risk postmolar gestational trophoblastic neoplasia (GTN) patients receiving 8-day methotrexate or one-day methotrexate infusion regimens. METHODS: This retrospective cohort study was conducted at the New England Trophoblastic Disease Center (NETDC), between 1974 and 2014, and included 325 patients with FIGO-defined low-risk postmolar GTN receiving first-line 8-day MTX/folinic acid (FA) or one-day MTX infusion and FA. Demographics, disease presentation, initial treatment plan, treatment outcome, and treatment-related adverse events were assessed. RESULTS: Sustained remission (84% vs 62%, p<0.001) and need to switch to second-line therapy due to treatment-related adverse events (5.3% vs 0%, p=0.001) were higher for 8-day MTX/FA compared to one-day MTX infusion. MTX resistance, however, was more frequent with one-day MTX (34.5%) than with 8-day MTX/FA (7.3%, p<0.001). Relapse rates were similar with both regimens (3.0%). Compared to one-day MTX infusion, 8-day MTX/FA was associated with significantly higher gastrointestinal disorders (48% vs 24%), abnormal laboratory findings (48% vs 28%), eye disorders (37% vs 19%) and general disorders (22% vs 5%) (p<0.001). Only infection frequency did not differ between 8-day MTX/FA and one-day MTX infusion (20% vs 12%, p=0.083). CONCLUSIONS: This is one of the largest studies to comprehensively catalogue toxicities associated with 8-day MTX/FA and one-day MTX infusion. Although treatment-related adverse events were more frequent with 8-day MTX/FA, these were all self-limited and resolved with no long-term sequelae. Given this and its higher effectiveness, 8-day MTX/FA remains the treatment of choice at NETDC for patients with low-risk postmolar GTN.

Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?

OBJECTIVE: To evaluate the influence of hormonal contraception (HC) on the development and clinical aggressiveness of gestational trophoblastic neoplasia (GTN) and the time for normalization of human chorionic gonadotropin (hCG) levels. METHODS: A retrospective cohort study was conducted with women diagnosed with molar pregnancy, followed at the Rio de Janeiro Trophoblastic Disease Center, between January 2005 and January 2015. The occurrence of postmolar GTN and the time for hCG normalization between users of HC or barrier methods (BM) during the postmolar follow-up or GTN treatment were evaluated. RESULTS: Among 2828 patients included in this study, 2680 (95%) used HC and 148 (5%) used BM. The use of HC did not significantly influence the occurrence of GTN (ORa: 0.66, 95% CI: 0.24-1.12, p=0.060), despite different formulations: progesterone-only (ORa: 0.54, 95% CI: 0.29-1.01, p=0.060) or combined oral contraception (COC) (ORa: 0.50, 95% CI: 0.27-1.01, p=0.60) or with different dosages of ethinyl estradiol: 15mcg (ORa, 1.33, 95% CI 0.79-2.24, p=0.288), 20mcg (ORa: 1.02, 95% CI: 0.64-1.65, p=0.901), 30mcg (ORa: 1.17, 95% CI: 0.78-1.75, p=0.437) or 35mcg (ORa: 0.77, 95% CI: 0.42-1.39, p=0.386). Time to hCG normalization ≥10weeks (ORa: 0.58, 95% CI: 0.43-1.08, p=0.071) or time to remission with chemotherapy≥14weeks (ORa: 0.60, 95% CI: 0.43-1.09, p=0.067) did not significantly differ among HC users when compared to patients using BM, when controlling for other risk factors using multivariate logistic regression. CONCLUSIONS: The use of HC during postmolar follow-up or GTN treatment does not seem to increase the risk of GTN or its severity and does not postpone the normalization of hCG levels.

Comparison of 2 Human Chorionic Gonadotropin Immunoassays Commercially Available for Monitoring Patients With Gestational Trophoblastic Disease.

OBJECTIVE: The aim of this study was to compare serum human chorionic gonadotropin (hCG) levels in patients with gestational trophoblastic disease (GTD) using 2 commercially available hCG immunoassays. METHODS: Serum samples were obtained from patients with GTD attending the Botucatu Medical School Trophoblastic Diseases Center of São Paulo State University (UNESP), from November 2014 to October 2015. Serum hCG levels were measured with both Architect i2000SR and Immulite 2000 XPi chemiluminescence assays. Serum hCG levels were compared against the null hypothesis. Agreement in clinical management decisions based on the hCG results was determined by comparing baseline hCG measurements and the hCG curves obtained with both assays. RESULTS: Seventy-three patients with GTD were included in the analysis. Of these, 45 had hydatidiform mole and spontaneous remission, whereas 28 had gestational trophoblastic neoplasia (GTN). There was a perfect (zero difference) agreement in mean hCG levels between Immulite 2000 XPi and Architect i2000 when hCG is less than 100 mIU/mL. For hCG values greater than 100 mIU/mL, there was a significant difference between assays (P < 0.05), with levels measured via Architect i2000SR being higher than those measured by Immulite 2000 XPi in patients with hydatidiform mole/spontaneous remission (R = 90%, P < 0.01) and GTN (R = 98%, P < 0.01). Baseline clinical management decisions showed agreement in 100% (73/37) of cases (κ = 1.0, P < 0.001), whereas decisions based on hCG curve agreed in 98% (71/72) of cases (κ = 0.93, P < 0.001). CONCLUSIONS: Immulite 2000 XPi is the most frequently recommended assay for diagnosing and monitoring patients with GTD. However, our results suggest that because Immulite 2000 XPi and Architect i2000 show very similar performance in measuring hCG levels and in determining clinical management, Architect may be used as an alternative.

Serum Human Chorionic Gonadotropin Normogram for the Detection of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to develop a serum human chorionic gonadotropin (hCG) normogram for both uneventful complete and partial hydatidiform moles in the first-trimester ultrasound era. METHODS: An hCG normogram for both complete and partial hydatidiform moles was constructed, based on 639 patients with uneventful serum hCG regression after evacuation between 1990 and 2014. Serum hCG was measured by an in-house-developed radioimmunoassay, detecting both intact hCG and free ß-subunit. It has been in use for all serum measurements sent to the Dutch Central Registry for Hydatidiform Moles since 1977. RESULTS: Since introduction of routine first-trimester ultrasonography, lower pre-evacuation and follow-up serum hCG concentrations were observed. When compared with complete hydatidiform moles, patients with a partial hydatidiform mole had significantly lower pre-evacuation serum hCG concentration (median, 4400 and 875 ng/mL, respectively; P < 0.001) and earlier hCG normalization (median, 7 and 6 weeks, respectively; P < 0.001) but higher gestational age (mean, 11.5 and 13.0 weeks, respectively; P < 0.001). For both complete and partial hydatidiform moles, 95% of patients reached normal serum hCG concentrations within 14 weeks after evacuation. CONCLUSIONS: A normogram for the detection of gestational trophoblastic neoplasia was developed for complete and partial hydatidiform moles. Although interesting from a scientific perspective, the small divergence in hCG regression between complete and partial hydatidiform moles will be of little importance in clinical practice, as actual differences in regression will encompass only days. To promote clarity and unity in daily practice, we therefore propose a combined normogram to be used as a reference guideline for follow-up after evacuation of a hydatidiform mole. This normogram will be compliant with patients in today's clinical practice.