Automatic ultrasensitive lateral flow immunoassay based on a color-enhanced signal amplification strategy.

Lateral flow immunoassays (LFIAs) are an essential and widely used point-of-care test for medical diagnoses. However, commercial LFIAs still have low sensitivity and specificity. Therefore, we developed an automatic ultrasensitive dual-color enhanced LFIA (DCE-LFIA) by applying an enzyme-induced tyramide signal amplification method to a double-antibody sandwich LFIA for antigen detection. The DCE-LFIA first specifically captured horseradish peroxidase (HRP)-labeled colored microspheres at the Test line, and then deposited a large amount of tyramide-modified signals under the catalytic action of HRP to achieve the color superposition. A limit of detection (LOD) of 3.9 pg/mL and a naked-eye cut-off limit of 7.8 pg/mL were achieved for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein. Additionally, in the inactivated virus detections, LOD equivalent to chemiluminescence (0.018 TCID50/mL) was obtained, and it had excellent specificity under the interference of other respiratory viruses. High sensitivity has also been achieved for detection of influenza A, influenza B, cardiac troponin I, and human chorionic gonadotrophin using this DCE-LFIA, suggesting the assay is universally applicable. To ensure the convenience and stability in practical applications, we created an automatic device. It provides a new practical option for point-of-care test immunoassays, especially ultra trace detection and at-home testing.

Accuracy of Serum Human Chorionic Gonadotrophin for Estimating Gestational Age in the First Trimester of Pregnancy: Population-Based Study.

This study determined the accuracy of first-trimester serum human chorionic gonadotrophin (hCG) for estimating gestational age (GA). We included 273 584 singleton live births that had a first-trimester ultrasound and measured serum hCG at 4-12 weeks gestation in Ontario from 2012 to 2018. We estimated hCG accuracy compared to known GA, within a boundary of ± 1 week. Between 4 to 8 weeks gestation, sensitivity of hCG was over 88% and specificity over 51%. However, at 9-12 weeks gestation, sensitivity declined from 72% to 0%, and specificity rose from 86% to 100%. At all GA, the positive predictive value was consistently under 42%, while negative predictive values were over 96%. Within epidemiological studies in which GA is otherwise unknown, first-trimester serum hCG may aid somewhat in estimating GA between 4 to 6 weeks gestation, but much less so thereafter. Thus, there remains an ongoing need for an accurate method for estimating missing GA within large datasets.

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

PURPOSE: To investigate factors predicting postmolar gestational trophoblastic neoplasia (GTN) by combined analysis of clinical features, human chorionic gonadotropin (hCG) value, and hCG ratios. METHODS: 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. RESULTS: 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 5 weeks. Univariate analysis showed age, molar evacuation performed elsewhere, pre-evacuation hCG, hCG at 2nd week post-evacuation, and ratio of hCG at 2nd week post-evacuation to post-evacuation hCG significantly predict GTN. Multivariate analysis revealed an hCG value ≥ 1400 IU/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. CONCLUSIONS: An hCG value ≥ 1400 IU/L at 2nd week post-evacuation and a ratio of hCG at 2nd week post-evacuation to post-evacuation hCG of ≥ 0.02 independently and reliably predict postmolar GTN.

Elevated hCG Concentration in a Patient after an Unsuccessful in vitro Fertilization.

A patient had a positive serum human chorionic gonadotropin (hCG) 22 days after a failed in vitro fertilization (IVF). The result was confirmed by repeating the test using quantitative and qualitative assays after 48 hours, but the quantitative result did not double compared to the previous concentration. Heterophilic antibody interference was ruled out. The above results indicated true-positive hCG, but inconsistent with normal pregnancy. Medical history excluded hCG produced by pituitary gland, malignancy and exogenous hCG use. Ectopic pregnancy (EP) was suspected and methotrexate was initiated. Ultrasound showed periadnexal fluid suggesting separation phenomenon on the right adnexal EP and hCG was decreased one weeks after the treatment. Two weeks later, hCG became negative. The above data suggest that the elevated hCG was most likely due to EP following IVF.

Serum vascular endothelial growth factor as a marker for tubal pregnancy.

OBJECTIVE: The objective of this study was to evaluate whether a single measurement of vascular endothelial growth factor could distinguish between intrauterine pregnancy and ectopic pregnancy and to correlate the levels of vascular endothelial growth factor with serum levels of progesterone andß-human chorionic gonadotropin in each subgroup. METHODS: Ninety patients with a positive human chorionic gonadotropin test and either abdominal pain or vaginal bleeding were selected; pregnancies were singletons, spontaneously conceived, 42-56 days of gestational age. All patients had a transvaginal ultrasound examination and were divided into three subgroups: abnormal intrauterine pregnancy, tubal pregnancy, and normal intrauterine pregnancy. Tubal pregnancies were surgically treated and histologically confirmed. Blood samples were collected for the determination of ß-human chorionic gonadotropin, progesterone, and vascular endothelial growth factor and their concentrations were compared in each subgroup. Receiver operating characteristic curve was calculated by comparing the subgroup of tubal pregnancy to the other groups. A Fisher discriminant function analysis was performed. The level of significance was 5%. RESULTS: One-way analysis of variance revealed a significant correlation between the different subgroups and ß-human chorionic gonadotropin, progesterone, and vascular endothelial growth factor serum levels (p<0.001). Vascular endothelial growth factor concentration was significantly higher for patients with tubal pregnancy than for other subgroups (p<0.05). ß-Human chorionic gonadotropin and progesterone levels were higher in the subgroup with normal intrauterine pregnancies compared with the subgroups with tubal and abnormal intrauterine pregnancies (p<0.05). Serum vascular endothelial growth factor level >188.7 ng/mL predicted tubal pregnancy with 96.7% sensitivity, 95.0% specificity, 90.6% positive predictive value, and 98.3% negative predictive value. CONCLUSIONS: Serum vascular endothelial growth factor could be a marker in discriminating intrauterine pregnancy from tubal pregnancy; its levels are increased in women with ectopic pregnancy compared with women with normal and abnormal intrauterine pregnancies.

Changes in Serum Levels of Ketone Bodies and Human Chorionic Gonadotropin during Pregnancy in Relation to the Neonatal Body Shape: A Retrospective Analysis.

Among the physiological changes occurring during pregnancy, the benefits of morning sickness, which is likely mediated by human chorionic gonadotropin (HCG) and induces serum ketone production, are unclear. We investigated the relationship between serum levels of ketone bodies and HCG in the first, second, and third trimesters and neonatal body shape (i.e., birth weight, length, head circumference, and chest circumference) in 245 pregnant women. Serum levels of 3-hydroxybutyric acid peaked in late-stage compared with early stage pregnancy (27.8 [5.0−821] vs. 42.2 [5.0−1420] µmol/L, median [range], p < 0.001). However, serum levels of ketone bodies and HCG did not correlate with neonatal body shape. When weight loss during pregnancy was used as an index of morning sickness, a higher pre-pregnancy body mass index was associated with greater weight loss. This study is the first to show that serum ketone body levels are maximal in the third trimester of pregnancy. As the elevation of serum ketone bodies in the third trimester is a physiological change, high serum levels of ketone bodies may be beneficial for mothers and children. One of the possible biological benefits of morning sickness is the prevention of diseases that have an increased incidence due to weight gain during pregnancy.

[Evaluation of the success of medical abortion by a plasma hCG control threshold]. / Évaluation du succès de l'interruption volontaire de grossesse médicamenteuse par un seuil d'hCG sérique.

OBJECTIVES: In France, monitoring of the success of medical abortion is recommended 2 to 3 weeks after the procedure. However, there is no clear consensus on the modalities of this monitoring. The main objective of this study is to identify a threshold of serum hCG (human chorionic gonadotropin) control for medical abortions ≤7 weeks of gestation below which success can be confirmed without recourse to pelvic ultrasound. METHODS: This is a retrospective multicenter study conducted over a 14-month period. The serum hCG level, measured between the 15th and 25th day following the abortion, was compared with the results of the pelvic ultrasound performed at the follow-up visit. Ultrasound failure was defined as retention or persistent pregnancy. RESULTS: Among the 624 women included, the failure rate was 22.3%, including 86.3% of retentions, 8.6% of pregnancies stopped and 5% of pregnancies progressed. Using a ROC curve, the threshold value of hCG found to exclude failure at 95% was 253 IU/l (AUC=0.9202, sensitivity=84.17%, specificity=85.95% and positive predictive value [PPV]=63%). CONCLUSIONS: A serum hCG level ≤253 IU/l is sufficient to affirm the efficacy of medical abortion. However, since PPV is only 63% for this threshold, ultrasound should be reserved for women with high hCG levels.

Postchemotherapy Residual Tumor Resection in Patients with Elevated Tumor Markers.

PURPOSE: The oncologic benefit of postchemotherapy (PC) residual tumor resection (RTR) in patients with germ cell tumors and elevated serum tumor markers (STMs) remains unclear. This analysis was performed to better define patients who benefit from surgery in this setting. MATERIALS AND METHODS: Of 575 PC-RTR procedures (July 2008-July 2019) 153 were performed in patients with elevated STMs (human chorionic gonadotropin [HCG] >2.0 mIU/ml, alpha-fetoprotein [AFP] >7.0 µg/l), including 55 after first line and 98 after second or later line chemotherapy. RESULTS: Viable cancer in the resected specimen was significantly more common in the salvage group than in the first line group (48.98% vs 16.36%, p=0.0001988) and was a predictor of survival in both groups. A preoperative serum level of AFP ≥30 µg/l was a significant predictor of viable cancer in the first line and salvage groups (55.56% [p=0.0157] and 66.67% [p=0.0017], respectively). The overall relapse-free survival rate (22.7% and 50%, p=0.00032) and overall survival rate (37.8% and 65%, p=0.0059) were significantly worse in the salvage group than in the first line group. A preoperative serum level of AFP ≥30 µg/l and viable cancer/teratoma found in the histological examination of the RTR specimens were significant predictors of relapse after first line chemotherapy. Serum AFP ≥30 µg/l and HCG ≥20 mIU/ml were significant factors affecting survival in the first line group. CONCLUSIONS: Patients with AFP serum levels >30 µg/l and HCG ≥20 mIU/ml after first line chemotherapy should receive salvage chemotherapy instead of surgery. After second or later line therapy, the prognosis of patients with elevated markers and surgery is poor regardless of the tumor marker levels. However, 38% of these patients are long-term survivors, which justifies PC-RTR in this setting.

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.

Reproduction-Associated Hormones and Adult Hippocampal Neurogenesis.

The levels of reproduction-associated hormones in females, such as estrogen, progesterone, prolactin, and oxytocin, change dramatically during pregnancy and postpartum. Reproduction-associated hormones can affect adult hippocampal neurogenesis (AHN), thereby regulating mothers' behavior after delivery. In this review, we first briefly introduce the overall functional significance of AHN and the methods commonly used to explore this front. Then, we attempt to reconcile the changes of reproduction-associated hormones during pregnancy. We further update the findings on how reproduction-related hormones influence adult hippocampal neurogenesis. This review is aimed at emphasizing a potential role of AHN in reproduction-related brain plasticity and its neurobiological relevance to motherhood behavior.

Hyperreactio luteinalis incidentally found in the second trimester of pregnancy with normal hCG levels: a case report.

Hyperreactio luteinalis (HL) is a rare entity in which both ovaries are multicystic and enlarged under the action of human chorionic gonadotropin (hCG), mostly seen in the third trimester of pregnancy. This benign condition is usually asymptomatic and doesn't need any specific treatment, as the ovaries spontaneously reduce in size after birth. This is a case report of a 33-year-old woman diagnosed with hyperreactio luteinalis during the second trimester of her induced pregnancy. An ultrasound scan at 22 weeks of gestation revealed bilateral multicystic enlarged ovaries along with multiple fetal malformations and hydropsfetalis. Usually, HL is most commonly seen in situations in which there are high levels of hCG, but our patient had normal levels of hCG during all her pregnancy, which makes our case even rarer. In conclusion, the most important challenge when faced with HL is to differentiate between it and other differential diagnosis especially malignant tumors, because unlike them, this benign condition doesn't need surgical treatment.

Tumor markers and 18F-FDG PET/CT after orchiectomy in seminoma: Is there any correlation?

OBJECTIVE: The aim of our study was to analyze the potential relationship between tumor markers and 18F-fluorodoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) results in patients affected by seminoma. MATERIAL AND METHODS: 65 18F-FDG PET/CT scans of 41 patients with diagnosis of seminoma were analyzed and compared to alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG). PET/CT studies were analyzed qualitatively and measuring the maximum and mean standardized uptake value body weight max (SUVbwmax, SUVbwmean), maximum SUV lean body mass (SUVlbm), maximum SUV body surface area (SUVbsa), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of hypermetabolic lesions. All values were compared with serum markers. RESULTS: 31 PET/CT studies were true negative, 28 true positive, 6 false positive and 0 false negative with sensitivity of 100%, specificity of 84%, negative predictive value of 100%, positive predictive value of 82% and accuracy of 91%. No correlation between PET results and tumor marker levels was found and also between AFP and PET/CT semiquantitive parameters. All semiquantitative PET parameters were significantly related to hCG level. CONCLUSIONS: 18F-FDG PET/CT has good accuracy in evaluating patients with relapsed seminoma. HCG levels were significantly correlated with metabolic PET/CT parameters.

Serum miR371 in testicular germ cell cancer before and after orchiectomy, assessed by digital-droplet PCR in a prospective study.

MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and ß-human chorionic gonadotropin (hCGß). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCGß had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.

Predictive Performance of Serum ß-hCG MoM Levels for Preeclampsia Screening: A Meta-Analysis.

Objective: The aim of the present study was to investigate the predictive value of using the multiple of the median (MoM) of ß-human chorionic gonadotropin (ß-hCG) levels in patients with preeclampsia (PE) and healthy pregnant women. Methods: Electronic databases including PubMed, EBSCO, Ovid, Web of Science, China National Knowledge Infrastructure (CNKI), SinoMed, Wangfang and the Weipu Journal were searched up to May 31, 2020. Two reviewers independently selected the articles and extracted data on study characteristics, quality and results. A random-effects model was employed, and standardized mean difference and 95% confidence intervals were calculated. Twenty-one case-control studies were analyzed in the present meta-analysis, including a total of 2,266 cases and 25,872 healthy controls. Results: Women who were diagnosed with PE were found to have higher early second-trimester levels of serum ß-hCG MoM compared with healthy controls, although the levels in the first trimester were not significantly different. Ethnicity subgroup analysis demonstrated that the MoM of ß-hCG serum levels was significantly higher in PE patients in both Asian and Caucasian populations during the early second trimester. Conclusion: The MoM of ß-hCG serum levels was found to be a valuable clinical indicator for predicting PE in the early second trimester, but had little predictive value in the first trimester. However, further assessment of the predictive capacity of ß-hCG within larger, diverse populations is required.

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

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

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.

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).