Giant uterine tumor and miscarriage: how to proceed?

Expanding uterine masses can be the cause of pregnancy loss and add technical difficulties to uterus evacuation due to the intense anatomical distortion of the endocervical canal and uterine cavity. The literature is scarce in the peculiarities of the management of missed abortions in uterus with important distorted anatomies. We report a case of a primigravida patient who presented a rapid and expressive increase of abdominal volume due to a giant uterine mass, evolving to miscarriage. Ultrasound can be a useful tool, allowing visualization of the endocervical path and uterine cavity, helping to perform uterine evacuation in the presence of anatomical distortion without compromising the reproductive future. To the best of our knowledge, no such case has been previously reported.

Killer Function of Circulating Neutrophils in Relation to Cytokines in Uterine Myoma and Endometrial Cancer.

The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).

Successful treatment of a rare giant accessory cavitated uterine mass: a case report.

An accessory cavitated uterine mass (ACUM) is a very rare obstructive genital malformation characterized by pelvic pain and severe dysmenorrhea. It is easily mistaken for other obstructive genital malformations in women, such as cystic uterine adenomyosis or cystic degeneration of uterine fibroids. This case report describes a 30-year-old patient with a huge uterine cornual mass. Successful resection was performed by surgical excision, and the lesion was diagnosed as an ACUM. Given the rarity of a giant ACUM, this report also includes a brief review of the relevant literature.

Senescence-associated secretory phenotype (SASP) and uterine fibroids: Association with PD-L1 activation and collagen deposition.

Uterine fibroids (or uterine leiomyoma, UFs) are one of the most prevalent benign uterine tumors with high proliferation and collagen synthesis capabilities. UFs are a significant worldwide health issue for women, affecting their physical and financial well-being. Risk factors for UFs include age, racial disparities, obesity, uterine infections, hormonal variation, and lifestyle (i.e., diet, exercise, stress, and smoking). Senescence and its associated secretory phenotypes (SASPs) are among the most salient changes accompanying the aging process. As a result, SASPs are suggested to be one of the major contributors to developing UFs. Interleukin 6 (IL-6), IL-8, IL-1, chemokine ligand 20 (CCL-20), and transforming growth factor-beta (TGF-ß) are the most prominent SASPs associated with aging. In addition, different processes contribute to UFs such as collagen deposition and the changes in the immune microenvironment. Programmed death ligand 1 is a major player in the tumor immune microenvironment, which helps tumor cells evade immune attacks. This review focuses on the correlation of SASPs on two axes of tumor progression: immune suppression and collagen deposition. This review opens the door towards more investigations regarding changes in the UF immune microenvironment and age-UFs correlation and thus, a novel targeting approach for UF treatment.

Partial Molar Ectopic Pregnancy: A diagnostic challenge.

Here, we present a rare case of a primigravida who presented to us with symptoms and signs suggestive of an ectopic gestation, which turned out to be a partial mole in histopathological examination. Since it is a very rare occurrence, we would like to publish the case details in this case report.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

Navigating an unexpected diagnosis - experience of a tertiary referral centre with two cases of intraplacental choriocarcinoma.

Intraplacental choriocarcinoma is a rare tumour, with approximately 62 reported cases. It may manifest as a spectrum of disease ranging from an incidental lesion diagnosed on routine placental examination to disseminated maternal and/or neonatal disease. In this case series, we presented two rare cases of intraplacental choriocarcinoma with extremely varied clinical presentations. The extremely varied clinical presentations of both patients described in the case series complicated the process of arriving at the diagnosis. In both cases, subsequent investigations showed no maternal or neonatal metastasis, and maternal serum beta-hCG levels downtrended with conservative management. We aim to highlight the importance of performing a detailed physical examination and evaluation of the patient and multidisciplinary management with oncology opinion. A detailed examination of the placenta should also be considered when faced with obstetric complications so that early diagnosis and the required management can be executed in a prompt fashion.

FOXO3a deregulation in uterine smooth muscle tumors.

OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.

Diffusion-weighted imaging as a potential non-gadolinium alternative for immediate assessing the hyperacute outcome of MRgFUS ablation for uterine fibroids.

The aim of this study was to investigate the value of diffusion-weighted imaging (DWI) as a potential non-gadolinium alternative for promptly assessing the hyperacute outcome of magnetic resonance-guided focused ultrasound (MRgFUS) treatment for uterine fibroids. In this retrospective study we included 65 uterine fibroids from 44 women, who underwent axial DWI (b-value: 800 s/mm2) and contrast-enhanced (CE) MR within 15 min post-ablation. Two blinded observers independently reviewed the DWI findings of ablated necrotic lesions and measured their volumes on DWI and CE images. The post-ablation DWI images revealed clear depiction of ablative necrotic lesions in all fibroids, which were classified into two types: the bull's eye sign (type 1) and the bright patch sign (type 2). The inter-observer intraclass correlation coefficient for classifying DWI signal types was 0.804 (p < 0.001). Volumetric analysis of ablated necrosis using DWI and CE T1-weighted imaging showed no significant variance, nor did the non-perfused volume ratios (all p > 0.05). Bland-Altman analysis revealed a mean difference of 2.38% and 1.71% in non-perfused volume ratios between DWI and CE, with 95% limits of agreement from - 19.06 to 23.82% and - 18.40 to 21.82%, respectively. The findings of this study support the potential of DWI as a viable non-gadolinium alternative for evaluating the hyperacute outcomes of MRgFUS ablation in uterine fibroids.

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata.

Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Empowering Strategies for Lifestyle Interventions, Diet Modifications, and Environmental Practices for Uterine Fibroid Prevention; Unveiling the LIFE UP Awareness.

Uterine fibroids (UFs) are the most common prevalent benign tumor among women of reproductive age, disproportionately affecting women of color. This paper introduces an innovative management strategy for UFs, emphasizing the curbing of disease prevention and progression. Traditionally, medical intervention is deferred until advanced stages, necessitating invasive surgeries such as hysterectomy or myomectomy, leading to high recurrence rates and increased healthcare costs. The strategy, outlined in this review, emphasizes UF disease management and is named LIFE UP awareness-standing for Lifestyle Interventions, Food Modifications, and Environmental Practices for UF Prevention. These cost-effective, safe, and accessible measures hold the potential to prevent UFs, improve overall reproductive health, reduce the need for invasive procedures, and generate substantial cost savings for both individuals and healthcare systems. This review underscores the importance of a proactive UF management method, paving the way for future research and policy initiatives in this domain.

Post molar choriocarcinoma with solitary renal metastasis in the absence of primary uterine tumor: a case report and review of the literature.

BACKGROUND: Choriocarcinoma is a rare and highly malignant form of gestational trophoblastic disease that may develop following pregnancy, abortion, or a hydatiform mole. Renal metastatic involvement by post molar choriocarcinoma is even rarer. In this case report, we describe a unique case of post molar choriocarcinoma with a solitary renal metastasis in the absence of a primary uterine tumor and metastases in other sites, which presented with urological symptoms and spontaneous renal hemorrhage. CASE PRESENTATION: A 41-year-old Persian woman with history of complete hydatiform mole presented with severe flank pain, nausea, vomiting, gross hematuria, and vaginal bleeding. Laboratory tests demonstrated a serum beta human chorionic gonadotropin hormone level of 60,000 mIU/mL. Imaging studies showed a lesion at the lower pole of the left kidney with active bleeding surrounded by hematoma, as well as an empty uterine cavity. Additionally, bilateral pleural effusion was detected without any lesion within the lungs. Subsequently, the patient underwent laparotomy, partial nephrectomy, and left para-ovarian cystectomy. Endometrial curettage was also carried out. The histopathology report revealed choriocarcinoma renal metastasis with high expression of beta human chorionic gonadotropin, cytokeratin 7, and Ki 67. Moreover, there were no malignant cells in the endometrial curettage specimens, and a corpus luteum cyst was found within the para-ovarian cyst. Further investigations revealed that the pleural effusion was free of malignant cells, and there was no evidence of metastatic lesions in the brain. As a result, the patient was referred to the oncology department to receive chemotherapy, and the beta human chorionic gonadotropin levels dropped to 5 mIU/mL after receiving courses of a standard regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine/oncovin over 3 weeks. Finally, monthly measurements of beta human chorionic gonadotropin levels for 6 months indicated that levels have constantly remained within normal ranges, showing no evidence of recurrence or new metastasis. CONCLUSIONS: Urological symptoms such as hematuria or spontaneous renal hemorrhage might be the only presentation of post molar choriocarcinoma with renal involvement. Thus, it can be beneficial to measure serum beta human chorionic gonadotropin levels among females of childbearing age who present with unexplained urological symptoms, especially if there is a history of prior hydatiform mole.

Analysis of risk factors for post-operative recurrence or progression of intravenous leiomyomatosis.

OBJECTIVE: To analyse the risk factors for post-operative recurrence or progression of intravenous leiomyomatosis and explore the impact of different treatment strategies on patient prognosis. METHODS: Patients with intravenous leiomyomatosis who underwent surgery from January 2011 to December 2020 and who were followed for ≥3 months were included. The primary endpoint was recurrence (for patients with complete resection) or progression (for patients with incomplete resection). Kaplan-Meier survival analysis was used to analyse the factors affecting recurrence. RESULTS: A total of 114 patients were included. The median age was 45 years old (range 24-58). The tumors were confined to the uterus and para-uterine vessels in 48 cases (42.1%), while in 66 cases (57.9%) it involved large vessels (iliac vein or genital vein and/or proximal large veins). The median follow-up time was 24 months (range 3-132). Twenty-nine patients (25.4%) had recurrence or progression. The median recurrence or progression time was 16 months (range 3-60). Incomplete tumor resection (p=0.019), involvement of the iliac vein or genital vein (p=0.042), involvement of the inferior vena cava (p=0.025), and size of the pelvic tumor ≥15 cm (p=0.034) were risk factors for recurrence and progression. For intravenous leiomyomatosis confined to the uterus or para-uterine vessels, no post-operative recurrence after hysterectomy and bilateral oophorectomy occurred in this cohort. Compared with hysterectomy and bilateral oophorectomy, the risk of recurrence after tumorectomy (with the uterus and ovaries retained) was significantly greater (p=0.009), while the risk of recurrence after hysterectomy was not significantly increased (p=0.058). For intravenous leiomyomatosis involving the iliac vein/genital vein and the proximal veins, post-operative aromatase inhibitor treatment (p=0.89) and two-stage surgery (p=0.86) were not related to recurrence in patients with complete tumor resection. CONCLUSION: Incomplete tumor resection, extent of tumor lesions and size of the pelvic tumor were risk factors for post-operative recurrence and progression of intravenous leiomyomatosis.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. EXPERIMENTAL DESIGN: We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. RESULTS: In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. CONCLUSIONS: Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Uterine Leiomyosarcoma Associated With Perivascular Epithelioid Cell Tumor: A Phenomenon of Differentiation/Dedifferentiation and Evidence Suggesting Cell-of-Origin.

Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor thought to originate from perivascular epithelioid cells (PECs). The normal counterpart to PEC, however, has not been identified in any human organ, and the debate as to whether PEComa is related to smooth muscle tumors has persisted for many years. The current series characterizes 4 cases of uterine leiomyosarcoma (LMS) coexisting with PEComas. All cases exhibited an abrupt transition from the LMS to PEComa components. The LMS component displayed typical spindled morphology and fascicular growth pattern and was diffusely positive for desmin and smooth muscle myosin heavy chain, completely negative for HMB-45 and Melan A, and either negative or had focal/weak expression of cathepsin K and GPNMB. In contrast, the PEComa tumor cells in case 1 contained glycogen or lipid-distended cytoplasm with a foamy appearance (low grade), and in cases 2, 3, and 4, they displayed a similar morphology characterized by epithelioid cells with eosinophilic and granular cytoplasm and high-grade nuclear atypia. Different from the LMS component, the epithelioid PEComa cells in all cases were focally positive for HMB-45, and diffusely immunoreactive for cathepsin K and GPNMB. Melan A was focally positive in cases 1 and 3. Loss of fumarate hydratase expression (case 1) and RB1 expression (cases 2, 3, 4) was identified in both LMS and PEComa components, indicating that they are clonally related. In addition, both components showed an identical TP53 p.R196* somatic mutation and complete loss of p53 and ATRX expression in case 2 and complete loss of p53 expression in case 3. We hypothesize that LMSs containing smooth muscle progenitor cells may give rise to divergent, lineage-specific PEComatous lesions through differentiation or dedifferentiation. While we do not dispute the recognition of PEComas as a distinct entity, we advocate the hypothesis that modified smooth muscle cells represent the origin of a subset of PEComas, and our case series provides evidence to suggest this theory.

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer.

The clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5-year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

Submucous leiomyoma: an uncommon cause of heavy menstrual bleeding in early adolescence.

Uterine leiomyomas are rare in the paediatric population. This report describes a rare case of a submucous leiomyoma in an adolescent girl. The patient presented with a history of abnormal and painful period which was refractory to medical treatment. Sonographic findings revealed a uterine mass that protruded through the cervix until the upper third of the vagina. A hysteroscopic resection was performed, and a pathological examination confirmed a leiomyoma. 12 months after surgery, there were no signs of recurrence. Conservative sparing-fertility management, such as hysteroscopic resection, is the best option with a type 0 submucosal fibroid, especially in adolescents and young women.

Hydropic leiomyoma-like ovarian tumor: a case report.

Uterine leiomyomas, benign tumors common in reproductive-aged women, can display rare variants such as hydropic leiomyoma (HL), which exhibit unique histological features like zonal edema and increased vascularity. However, due to its rarity, comprehensive clinical knowledge about HL is limited. We report a case of a 49-year-old Japanese woman who was premenopausal and nulliparous, presenting with a two-year history of abdominal distension. An MRI scan revealed a 20 cm mass in the posterior part of the uterus, exhibiting characteristics suggestive of an ovarian tumor. During laparotomy, a cystic tumor connected with a swollen fibroid was found, and pathology confirmed HL. This case emphasizes that hydropic leiomyomas can mimic malignant tumors on ultrasonography due to their atypical features, necessitating additional evaluations using alternative imaging techniques or histopathological examinations for accurate diagnosis and appropriate management. The patient recovered uneventfully, broadening our understanding of HL's clinical presentation.