Search Results (65)

Background/Objectives: Biallelic mutations of NLRP7, a maternal-effect gene encoding a key component of the subcortical maternal complex, are the major monogenic cause of recurrent hydatidiform mole (RHM) and confer a substantial lifetime risk of gestational trophoblastic neoplasia (GTN), including choriocarcinoma. Although oocyte donation is currently the standard reproductive option, anecdotal live births from autologous oocytes in carriers of specific missense variants raise mechanistic and clinical questions that have not been integrated. We aimed to synthesize the current understanding of NLRP7 biology, oncogenic mechanisms in GTN, and genotype-stratified reproductive outcomes, and to propose a genetic permissiveness framework that links cancer surveillance with reproductive decision-making. We also place this monogenic disease in an epidemiological context, given the marked geographical variation in molar pregnancy incidence. Methods: PubMed, Embase and Web of Science were searched from January 2006 to December 2025 using terms related to NLRP7, hydatidiform mole, GTN, choriocarcinoma, maternal-effect genes, genomic imprinting, and assisted reproduction. Original studies, case series, expert consensus statements, and reviews were included. Results: NLRP7 loss disrupts subcortical maternal complex assembly, maternal-DMR methylation, trophoblast differentiation, and HLA-C-dependent immune privilege; in choriocarcinoma, NLRP7 is conversely reported to be up-regulated, where it has been implicated in tumor proliferation and immune evasion through inflammasome-independent pathways. Genetic permissiveness for autologous-oocyte pregnancy is mutation-type dependent: complete loss-of-function variants confer near-zero permissiveness, whereas missense variants with retained partial function may permit rare normal pregnancies. Conclusions: A genetic-permissiveness framework integrating variant-level functional data, GTN risk, and reproductive priorities can support shared decision-making in this rare but high-stakes clinical scenario, and it identifies clear directions for future translational research. We emphasize, however, that this framework has not been prospectively validated and should be regarded as hypothesis-generating rather than as a clinically established decision-making model. Recognizing the biallelic NLRP7 mutation as a heritable cancer-predisposition state further supports genotype-informed, risk-stratified oncological surveillance. Full article

Background: Gestational trophoblastic neoplasia (GTN) is rare but highly curable. This study compared clinical characteristics and outcomes between molar and non-molar disease. Methods: This retrospective cohort included 550 patients at a Brazilian reference center (1985–2025). Survival was assessed using Kaplan–Meier methods. Multivariable analyses included Poisson and Cox regression models. Results: Molar GTN comprised 86% of cases. Non-molar GTN (14%) presented with more advanced FIGO stages, higher WHO risk scores, and more metastases (p < 0.001). Overall five-year disease-specific survival (DSS) was 97.4% (95% CI 95.9–98.9) and progression-free survival (PFS) was 92.4% (95% CI 90.1–94.7). Non-molar disease had lower DSS (84.4% vs. 99.8%; p < 0.001) and PFS (85.3% vs. 93.5%; p = 0.049) in unadjusted analyses. However, after multivariable adjustment, GTN type was not independently associated with DSS (HR 9.41; 95% CI 0.70–127; p = 0.092) or PFS (HR 1.61; 95% CI 0.57–4.60; p = 0.372). Non-molar patients had a lower likelihood of subsequent pregnancy (RR 0.60; 95% CI 0.36–1.00; p = 0.049). Conclusions: Although non-molar GTN presents with more aggressive clinical features, survival outcomes appear to be primarily driven by baseline disease severity rather than GTN subtype itself. Full article

Background and Clinical Significance: Placental site trophoblastic tumour (PSTT) is a malignant tumour of the implantation site intermediate trophoblasts. It has historically been described using terms such as atypical chorioepithelioma, atypical choriocarcinoma, syncytioma, and chorioepitheliosis. It belongs to one of the heterogeneous spectrums of gestational trophoblastic disease. It accounts for about 0.25 to 5% of all gestational trophoblastic neoplasia. The typical clinical presentation is alternating menorrhagia and amenorrhea, mildly elevated β-hCG, and radiological findings of a uterine mass. Case Presentation: A 32-year-old woman presented with a history of intermittent menorrhagia and amenorrhea, with a persistent mildly raised β-hCG level. Ultrasonography showed a hypoechoic lesion on the right side of the posterior wall of the uterus. She was diagnosed with a missed miscarriage, and an evacuation of the products of conception was performed. Histologically, the tissue fragments comprised cords and sheets of atypical intermediate trophoblast cells, with characteristic features of myometrial smooth muscle infiltration, vascular invasion, and vascular wall replaced by the neoplastic cells. Immunohistochemically, these cells are positive for β-hCG and GATA3, while negative for P63. Conclusions: PSTT is a rare form of gestational trophoblastic neoplasia. Early recognition of PSTT is essential because its clinical presentation may mimic benign pregnancy-related conditions, and diagnosis relies heavily on histopathological and immunohistochemical evaluation. Full article

Endometrial carcinoma (EC) with choriocarcinomatous differentiation is an exceptionally rare malignancy for which standardized postoperative treatment strategies are lacking. Herein, we describe two postmenopausal patients with endometrioid carcinoma containing a choriocarcinomatous component. One patient had an EC-dominant tumor with low and rapidly normalized postoperative serum human chorionic gonadotropin (hCG) levels and received paclitaxel plus carboplatin. The other patient had a choriocarcinomatous-dominant tumor with markedly elevated postoperative serum hCG levels and was treated with gestational trophoblastic neoplasia (GTN)-oriented chemotherapy using etoposide, methotrexate, actinomycin D/cyclophosphamide, and vincristine (EMA/CO). Both patients remain disease-free. A review of representative published cases revealed two competing treatment paradigms, EC-oriented and GTN-oriented, applied inconsistently and without unified selection criteria. On the basis of integrated clinicopathological assessment, we propose that postoperative treatment consideration should be guided primarily by dominant tumor biology, rather than the International Federation of Gynecology and Obstetrics stage alone. Tumors with a dominant choriocarcinomatous component accompanied by elevated postoperative serum hCG levels may benefit from GTN-oriented chemotherapy, whereas EC-dominant tumors with low or normalized hCG levels may benefit from EC-oriented regimens. Reassessment of dominant tumor biology using postoperative pathological findings and serum hCG dynamics may provide a pragmatic, decision-support framework for adjuvant treatment consideration in this rare and clinically challenging entity. Full article

Pre-eclampsia and foetal growth restriction (FGR) are major pregnancy complications primarily driven by placental dysfunction, and remain leading causes of maternal and perinatal morbidity. Ultrasound imaging, Doppler studies, and angiogenic biomarkers like placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) constitute the main diagnostic modalities; however, these predominantly reflect established disease rather than early molecular disturbances underlying placentation. The identification of biomarkers directly associated with trophoblast signalling pathways has the potential to improve early risk stratification and enable mechanistic classifications. Kisspeptin signalling via its receptor (KISS1R) regulates trophoblast invasion, extracellular matrix remodelling, ERK1/2 activation, and angiogenic balance, thereby modulating spiral artery transformation. Kisspeptin-10 (KP-10), the minimal bioactive fragment of KISS1, is highly expressed in placental syncytiotrophoblasts and exerts its effects through the G-protein-coupled receptor KISS1R. Core features of early-onset FGR and pre-eclampsia (PE)—including defective placentation, maternal vascular malperfusion, and angiogenic imbalance—have been linked to dysregulation of this pathway. During normal gestation, maternal circulating kisspeptin concentrations rise exponentially. In contrast, pregnancies subsequently complicated by FGR or PE, particularly in the early gestation, are associated with reduced levels. However, the comparability of existing studies and their translational applicability are limited by a substantial methodological heterogeneity, including assay variability, gestational age dependence, and inadequate adjustment for maternal confounders. These limitations hinder robust conclusions regarding the role of kisspeptin in placental pathology. This review critically integrates molecular, pathophysiological, and clinical evidence relating to the role of KP-10 in placental dysfunction. The key question is whether KP-10 represents a mechanistic biomarker of trophoblast signalling dysfunction or merely a secondary marker of reduced placental mass; resolving this distinction is essential. Full article

Background: Ectopic pregnancy occurs in about 1–2% of all pregnancies, with 95% implanting in the fallopian tubes. Hepatic implantation is one of the rarest and most dangerous forms of abdominal ectopic pregnancy. Its diagnosis is often delayed because of nonspecific symptoms, and it is also often difficult for routine ultrasound imaging to visualize ectopic pregnancy sites that are not in the pelvis. Since this type of pregnancy carries a risk of severe hemorrhage, early identification is crucial. Case: A 30-year-old woman, gravida 3 para 2, presented with a serum β-hCG of 66,408 mIU/mL, but no intrauterine pregnancy was detected on ultrasound imaging. At an outside facility, a laparoscopy was performed, which also failed to show a pelvic ectopic pregnancy. The patient then received her first dose of methotrexate and was subsequently transferred to a tertiary care center for further evaluation. MRI and liver ultrasound showed a 2.3 cm subcapsular lesion in segment 5 of the liver that was suspicious for a hepatic ectopic pregnancy. However, these imaging studies could not exclude a gestational trophoblastic disease or hepatic neoplasm. A dilation and curettage revealed no trophoblastic tissue. The patient next received two additional doses of methotrexate on hospital days 4 and 7 due to an inadequate decline in interval β-hCG; β-hCG levels declined gradually but steadily over several months until they became undetectable and indicated a successful medical treatment of her hepatic ectopic pregnancy. Conclusions: This case highlights the complex diagnostic and treatment challenges presented by a hepatic ectopic pregnancy. Multimodal imaging, serial monitoring of β-hCG levels, and the engagement of a multidisciplinary team were essential factors in achieving a safe, nonsurgical, and successful resolution of this condition. When a pregnancy of unknown location is suspected, extended imaging studies are critical tools for patient evaluation after initial imaging studies and laparoscopy are inconclusive. Full article

The connection between the mother and the child has been considered one of the strongest bonds in nature. Though there are numerous factors that can influence the establishment of pregnancy, in its essence, three are considered major: a good quality embryo, a receptive endometrium, and successful cross-talk between them. The placenta, which derives from the trophoblast of the embryo, develops when a successful implantation occurs. It is an ephemeral organ through which the turnover of nutrients, gases, and waste molecules is realized. It serves as a barrier and can provide the embryo with immune factors. Placental disorders are observed in some rare but life-threatening obstetric conditions like preeclampsia (PE), fetal growth restriction (FGR), gestational trophoblastic diseases (GTDs), and gestational diabetes mellitus (GDM). The etiology and pathogenesis of some are still partially enigmatic. Our attention in this review was driven by the participation of small RNA molecules—miRNAs and piRNAs—as potential epigenetic modulators of genes that play a pivotal role in placental functioning. In this study, we analyze the influence of these epigenetic factors on the mechanisms of the development of preeclampsia. The molecular approach for understanding placental disorders may help new diagnostic and therapeutic solutions to be found. Full article

A hydatidiform mole (HM) is the most common form of gestational trophoblastic disease (GTD). Differentiating hydatidiform moles (HMs) from non-molar pregnancies and distinguishing complete HMs (CHMs) from partial HMs (PHMs) remains challenging due to overlapping morphological features and a high rate of misclassification. This study aimed to evaluate reliable immunohistochemical markers for improving diagnostic accuracy and addressing the limitations of current molecular techniques. We retrospectively analyzed 64 cases of HMs and hydropic abortions (HAs), diagnosed in women aged 17–36 years between 2010 and 2024, at the Pathology Department of “Elena Doamna” Clinical Hospital, Iași, Romania. Routine histology was supplemented with immunohistochemistry (IHC) using p57, Ki-67, β-hCG, and E-cadherin, with semiquantitative immunoscores applied. Histology revealed 38 PHMs (59.37%), 16 CHMs (23.88%), and 10 HAs (15.62%). p57 was positive in 100% of PHMs and HAs but only in 18% of CHMs. Ki-67 expression was predominantly strong in CHMs, variable in PHMs, and weak in all HAs. β-hCG showed the highest expression in CHMs, followed by PHMs and HAs, while E-cadherin was strongest in HAs. Morphological features alone are insufficient for HM diagnosis; thus, ancillary techniques like p57 IHC and DNA genotyping are crucial to differentiate complete, partial moles, and non-molar specimens by revealing unique genetic patterns, especially p57 absence in CHMs and ploidy/parental origin in PHMs. In this context, an algorithmic approach integrating histology, immunohistochemistry, and genotyping reduces interobserver variability and refines diagnostic precision. Full article

Transcription factor EB (TFEB) is expressed at high levels in the trophoblast cells of the placenta, where it plays a critical role in regulating normal vascularization. Preeclampsia (PE) is a severe complication of pregnancy with a high incidence of maternal and fetal morbidity and mortality. Gestational diabetes (GD) is a metabolic disease that can affect placental villous maturation and villous vascularity. We analyzed the expression of three different antibodies: TFEB from Invitrogen (TFEB-INV), which detects endogenous levels of TFEB only when phosphorylated at Ser211; TFEB from Bethyl Labs (TFEB-B), which recognizes and binds E-box sequences; and TFEB from Santa Cruz (C-6) (TFEB-SC), which is specifically used for epitope mapping between 440 and 470. We evaluated the presence/absence of TFEB in six placental districts: syncytiotrophoblast (STB), cytotrophoblast (CTB), extravillous trophoblast (EVT), syncytial knots, stem villi vessels, and villous capillaries. TFEB-B was significantly expressed in the stem villi vessels, STB, and villi vessels of GD cases. The lack of TFEB expression in late-onset PE appears to corroborate the role of TFEB in vascular remodeling during placental development. The positive results in STB and vessels in GD cases, regardless of the histological diagnosis, may suggest that the expression of TFEB mitigates hypoxic injury via the Akt/mTOR pathway. Full article

Preeclampsia affects 2–8% of pregnancies globally and remains a leading cause of maternal and perinatal morbidity, with limited preventive options beyond low-dose aspirin. Low-molecular-weight heparin (LMWH) has emerged as a promising therapeutic candidate due to its pleiotropic effects extending beyond anticoagulation, including anti-inflammatory, pro-angiogenic, and placental-protective properties. This comprehensive narrative review examines LMWH’s effects on preeclampsia-associated biomarkers and evaluates clinical evidence for its preventive efficacy. LMWH exerts multifaceted effects on disease pathophysiology, including restoration of angiogenic balance through sFlt-1 reduction and PlGF preservation, attenuation of inflammatory responses via decreased TNF-α and IL-6 production, normalization of coagulation parameters, and enhancement of trophoblast invasion and placental vascularization. Clinical trials reveal heterogeneous results, with meta-analyses suggesting significant benefit primarily in high-risk subgroups. Women with previous severe placenta-mediated complications demonstrate relative risk reductions of 40–60% for recurrent preeclampsia with LMWH prophylaxis, particularly when initiated before 16 weeks’ gestation. Combination therapy with low-dose aspirin appears to enhance protective effects. However, larger trials in unselected populations have failed to demonstrate significant benefit, highlighting the importance of appropriate patient selection. Current international guidelines reflect this evidence heterogeneity, with most recommending against routine LMWH use while acknowledging potential benefit in selected high-risk populations, particularly those with antiphospholipid syndrome or previous severe early-onset disease. Future research should focus on biomarker-guided patient selection, optimal dosing regimens, and integration with multimodal preventive strategies to maximize therapeutic benefit while minimizing unnecessary interventions. Full article

Background/objectives: Gestational trophoblastic diseases (GTDs) are rare premalignant and malignant conditions characterized by abnormal proliferation of trophoblastic tissue. They are often asymptomatic but may present with vaginal bleeding. GTDs include hydatidiform moles and gestational trophoblastic neoplasms (GTNs). Current research aims to improve diagnostic tools and treatment strategies to reduce cancer risk and improve survival. Increasing attention is being paid to immunotherapy and treatment personalization, with the goal of minimizing long-term side effects and enhancing quality of life. Less toxic therapies are ideal for low-risk patients to reduce drug-related toxicity. Materials and Methods: A narrative review was conducted to analyze studies from the last twenty years on the diagnosis, staging, and treatment of GTDs. Sources included PubMed, Scopus, and Cochrane Library, using keywords such as “trophoblastic disease,” “hydatidiform mole,” and “gestational trophoblastic neoplasia.” Results: In recent years, the clinical management of gestational trophoblastic disease (GTD) has made significant progress through diagnostic, prognostic, and therapeutic innovations. More sensitive imaging techniques and serial monitoring of serum β-hCG now allow early diagnosis of hydatidiform mole and gestational trophoblastic neoplasia (GTN), reducing the risk of complications and metastasis. Conclusions: In the last decade, GTD management has improved significantly, with better diagnostic techniques, standardized staging, and more effective treatments. However, challenges persist, including relapse management, long-term monitoring, and psychological support. Early diagnosis is key, with ultrasound being essential for detecting abnormalities in the first weeks of pregnancy. Staging follows FIGO and WHO criteria, considering hCG levels and metastasis. This review highlights recent advances in diagnostic tools, emerging therapies—including immunotherapy—and the need for personalized, less toxic treatment approaches to improve patient outcomes. Full article

Retained products of conception (RPOC) represent a significant cause of morbidity in the post-abortive and postpartum periods, potentially leading to abnormal uterine bleeding, pelvic pain, infections, and intrauterine adhesions. Accurate diagnosis is crucial to avoid unnecessary surgical interventions and to preserve future fertility. Transvaginal ultrasound constitutes the primary imaging modality for identifying RPOC, but the lack of standardized diagnostic criteria complicates clinical decision-making. This narrative review explores the current literature on sonographic findings associated with RPOC, focusing on the diagnostic value of endometrial thickness (ET), the presence of intrauterine echogenic masses, and the use of Color Doppler imaging. Although an ET ≥15 mm is frequently used to suspect RPOC, the variability in cut-off thresholds and limited specificity reduce its diagnostic reliability. The detection of an echogenic intrauterine mass appears to be the most sensitive and specific sonographic feature. Color Doppler assessment, particularly the presence of enhanced myometrial vascularity (EMV) and classification systems like the Gutenberg score, offers further insight by stratifying hemorrhagic risk and guiding therapeutic choices. However, vascular parameters such as peak systolic velocity (PSV) and resistive index (RI) demonstrate a substantial overlap between benign and pathological conditions, limiting their stand-alone utility. The review also addresses the differential diagnosis of RPOC, including blood clots, arteriovenous malformations, placental polyps, gestational trophoblastic disease, and endometrial osseous metaplasia. The role of three-dimensional ultrasound remains limited in clinical practice, offering no significant advantage over two-dimensional imaging. Finally, the timing of follow-up ultrasound after medical treatment with misoprostol is critical: delayed assessment reduces overtreatment by allowing time for spontaneous resolution. In conclusion, despite advances in ultrasound technology, the diagnosis of RPOC remains challenging due to heterogeneity in imaging findings and inter-observer variability. A multimodal approach integrating grayscale and Doppler ultrasound with clinical evaluation is essential for optimal management. Full article

Hydatidiform mole is a trophoblastic disorder resulting from abnormal fertilization. Diagnosis is established through a combination of clinical findings, elevated serum human chorionic gonadotropin (hCG) levels, and characteristic features on transvaginal ultrasound. Timely and accurate diagnosis is essential for initiating prompt treatment and preventing medical complications. Uterine evacuation, preferably via vacuum aspiration, is the treatment of choice due to its high efficacy and safety profile. Adjunctive techniques, such as hysteroscopy and intraoperative ultrasonography, enhance the safety and effectiveness of uterine evacuation and should be available to patients, especially at specialized referral centers equipped to manage this diagnosis. In selected cases, particularly in women with fulfilled reproductive goals or those at a high risk of developing post-molar gestational trophoblastic neoplasia (GTN), total abdominal hysterectomy is appropriate. Postoperative follow-up with serial measurements of hCG is essential for monitoring remission and for the early detection of post-molar GTN, which develops in approximately 20% of cases of complete molar pregnancies and 1–4% of partial molar pregnancies. This article provides a comprehensive review of the diagnosis of hydatidiform mole and the surgical techniques employed in the treatment of this condition, emphasizing individualized care and the use of appropriate surgical strategies to treat complications associated with this trophoblastic disease. Full article

Background and Clinical Significance: Ovarian ectopic pregnancy (OEP) is a rare occurrence, and molar degeneration is even more exceptional. Differential diagnosis between a partial and complete hydatidiform mole is paramount as the complete type carries a higher risk of post-molar gestational trophoblastic neoplasia. Herein, we describe a case of a partial mole in an OEP (OPHM) with thorough investigations. Case Presentation: A 39-year-old woman presented at 6 weeks of amenorrhea with abdominal pain and vaginal bleeding. Ultrasound showed no intrauterine pregnancy, but an ovarian cyst suspicious for OEP. The patient underwent surgical removal of the cyst. Histological diagnosis was suspicious for OPHM with only one abnormal villous. Immunohistochemistry for p57^kip2 and fluorescent in situ hybridization (FISH) were not conclusive. STR-based (Short Tandem Repeat) molecular technique demonstrated the chromosomal asset of 69,XXX, confirming the diagnosis of OPHM. The patient was fully monitored for 1 year with periodic measurements of beta-hCG levels. After that period, the patient was in good health and disease-free. Conclusions: Histologically, ancillary techniques might not be sufficient to confirm the diagnosis of a hydatidiform mole, especially if the tissue available is scarce. In this case, STR has been demonstrated an effective tool in defining the chromosomal asset, even in paraffin-embedded samples. Full article