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.

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.

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.

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.

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.

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.

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.

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.

Roles of Matrix Metalloproteinases 2 and 9 in Uterine Leiomyosarcoma.

BACKGROUND/AIM: Uterine leiomyosarcoma (uLMS) is a rare, highly malignant, and invasive cancer, with early metastasis. Mismatch repair (MMR) proteins and matrix metalloproteinases (MMPs) are associated with the occurrence, proliferation, and invasion of most malignant cancers; however, their abnormal expression in uLMS remains poorly clarified. PATIENTS AND METHODS: Immunohistochemistry was performed to assess MMR protein and MMP2/9 expression as well as Ki67 marker proliferation in benign and malignant uterine smooth muscle tumors. Data from 28 cases of uterine leiomyoma and 31 cases of uLMS were analyzed. RESULTS: Tumor tissues from patients with uLMS had higher expression levels of MMP2 (p<0.001), MMP9 (p<0.05), and Ki67 (p<0.001) than those from patients with uterine leiomyoma; MMR protein expression showed the opposite trend (p<0.05). uLMS proliferation and metastasis correlated positively with MMP2 (p=0.012 and 0.015, respectively) but negatively with MMP9 (p=0.021 and 0.04, respectively). MMR protein expression did not correlate with uLMS proliferation or metastasis (p>0.05). CONCLUSION: Expression levels of MMP2 and MMP9 were upregulated in malignant uLMS tumors when compared with those in benign uterine leiomyoma tumors. Increased MMP2 expression might promote uLMS invasion and migration. MMP9 overexpression might be related to uLMS occurrence; however, it protects against uLMS invasion and metastasis. MMP2 and MMP9 may be potential predictors of uLMS cell proliferation, metastasis, and prognosis. These findings could be helpful in developing new strategies for diagnosing and treating uLMS.

Postpartum choriocarcinoma - a rare cause of delayed postpartum hemorrhage: Four case reports and literature review.

BACKGROUND: Delayed postpartum hemorrhage is rare, with an incidence of 0.5% to 2.0% in all pregnancies. The most important causes are placental remnants, infections, and placental bed subinvolution. Postpartum choriocarcinoma, a highly malignant complication of pregnancy, is a rare condition that can be easily misdiagnosed as other common causes, such as gestational remnants, and delays the diagnosis. METHODS: Four patients visited our clinic complaining of delayed postpartum hemorrhage, combined with respiratory and neurological symptoms in 2 cases. Two cases were confirmed by histopathological examination and in addition, medical history, elevated human chorionic gonadotropin (hCG) level, and imaging findings help confirm the diagnosis of delayed postpartum hemorrhage caused by postpartum choriocarcinoma in other cases. Individualized combination chemotherapies were prescribed. In the light of massive cerebral metastasis in case 2, intrathecal methotrexate injection combined with whole-brain radiotherapy was prescribed. RESULTS: Due to the absence of routine monitoring of ß-hCG following full-term delivery, there was widespread metastasis at the time of diagnosis. Three patients got complete remission and there is no sign of recurrence. One patient had relapse and widespread metastasis and died at home 6 months after the last chemotherapy. CONCLUSION: It is important to be aware of the possibility of choriocarcinoma in patients with delayed postpartum hemorrhage. Clinicians should improve the recognition of choriocarcinoma following full-term delivery, emphasize the monitoring of ß-hCG, comprehensively analyze the general condition of patients, and conduct standardized and individualized chemotherapy protocols.

Recurrence complicated with peritoneal dissemination after single-port gasless myomectomy for cellular uterine leiomyoma: A case report and literature review.

RATIONALE: Cellular uterine leiomyomas (CL) represent the prevailing subtype among uterine leiomyomas. In this study, we report a case of recurrent peritoneal disseminated uterine fibroids 2 years after single-port laparoscopic gasless myomectomy. This article endeavors to examine the potential limitations of the aforementioned surgical procedure and outline the distinguishing features of recurrent cases with primary postoperative pathology as CL. Additionally, it aims to provide a summary of previous retrospective studies on CL and propose the existence of immunohistochemical molecules that may serve as predictors for the postoperative recurrence of cellular uterine fibroids. The ultimate objective is to enhance clinicians' comprehension of the disease. PATIENT CONCERNS: Two years ago, the patient underwent a single-port gasless laparoscopic myomectomy for uterine fibroids. Gynecological color Doppler ultrasound conducted 3 months ago revealed recurrence of uterine fibroids, and the patient experienced abdominal distension, mild urinary frequency, and constipation for the past month. DIAGNOSES: After the second surgical procedure, a comprehensive pathological examination and immunohistochemical analysis of both the uterine mass and metastatic lesions revealed that the definitive diagnosis was CLs. INTERVENTIONS: The patient underwent the total hysterectomy, bilateral salpingectomy, pelvic adhesiolysis, omental mass resection, mesenteric mass resection, and pelvic peritoneal mass resection. All specimens were sent for rapid frozen examination and showed to be leiomyomas. OUTCOMES: The patient was discharged from the hospital on the 10th day after the operation. At the date of writing the article, the patient had no recurrence for 1 year and 5 months. LESSONS: The single-port gasless approach did not achieve the desired reduction in fibroid recurrence, as anticipated by the surgeon. The act of pulling the tumor towards the abdominal incision for resection, on the contrary, may serve as an iatrogenic factor contributing to postoperative recurrence of CL into peritoneal dissemination leiomyomatosis. The single-port gasless assisted bag may be a more suitable option for myomectomy. The utmost effort should be made to prevent the potential recurrence of myoma caused by iatrogenic factors.

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.

Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

An analysis of adjuvant chemoradiotherapy versus chemotherapy on the survival rates for patients with stage IB-III uterine serous carcinoma.

The aim of the present study was to investigate whether a combination of chemotherapy plus radiotherapy was able to increase the overall survival rates compared with chemotherapy alone in stage IB-III uterine serous carcinoma. A total of 1096 patients (593 who had not received radiotherapy, and 503 who had) with primary stage IB-III uterine serous carcinoma who underwent surgery and received chemotherapy were included in the present study. The Kaplan-Meier method and Log-Rank tests showed that radiotherapy did not increase 5-year overall survival rates compared with the no-radiotherapy groups (52.3 cf. 50.8%, respectively; P = 0.641). Cox regression analysis subsequently corroborated that radiotherapy did not affect the 5-year overall survival rate (P = 0.635). Patients who were aged ≥ 60 years had a higher mortality rate [hazard ratio (HR), 1.712; 95% confidence interval (95% CI), 1.385-2.117; P < 0.05]. The 5-year overall survival rates were found to be lower in the groups where the regional lymph nodes had not been removed (HR 0.645; 95% CI 0.508-0.821; P < 0.05). Chemotherapy plus radiotherapy was found to not be associated with improved 5-year overall survival rates. However, chemotherapy may be a better treatment option for patients with primary stage IB-III uterine serous carcinoma who have undergone surgery.

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.

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.