RNA Sequencing for Personalized Treatment of Metastatic Leiomyosarcoma: Case Report

Uterine leiomyosarcoma (UL) is a rare malignant tumor that develops from the uterine smooth muscle tissue. Due to the low frequency and lack of sufficient data from clinical trials there is currently no effective treatment that is routinely accepted for UL. Here we report a case of a 65-years-old female patient with metastatic UL, who progressed on ifosfamide and doxorubicin therapy and developed severe hypertensive crisis after administration of second line pazopanib, which lead to treatment termination. Rapid progression of the tumor stressed the need for the alternative treatment options. We performed RNA sequencing and whole exome sequencing profiling of the patient’s biopsy and applied Oncobox bioinformatic algorithm to prioritize targeted therapeutics. No clinically relevant mutations associated with drug efficiencies were found, but the Oncobox transcriptome analysis predicted regorafenib as the most effective targeted treatment option. Regorafenib administration resulted in a complete metabolic response which lasted for 10 months. In addition, RNA sequencing analysis revealed a novel cancer fusion transcript of YWHAE gene with fusion partner JAZF1. Several chimeric transcripts for YWHAE and JAZF1 genes were previously found in uterine neoplasms and some of them were associated with tumor prognosis. However, their combination was detected in this study for the first time. Taken together, these findings evidence that RNA sequencing may complement analysis of clinically relevant mutations and enhance management of oncological patients by suggesting putative treatment options.

Uterine rhabdomyosarcoma complicated by cerebral venous thrombosis and uterine inversion in a young woman: case report and literature review

Background Uterine rhabdomyosarcoma is an extremely rare malignant tumor that usually affects young women and has a poor prognosis. Case presentation A 19-year-old nulliparous woman presented to the emergency department under sedation due to seizures. Imaging examination revealed cerebral venous thrombosis. During thrombolytic therapy, she developed vaginal bleeding followed by uterine inversion secondary to uterine rhabdomyosarcoma. The inverted uterus was mistaken for a cervical tumour and was removed vaginally. The patient’s disease progressed despite chemotherapy with vincristine, actinomycin D and cyclophosphamide and she died within 6 months. To our knowledge, this is the first case of uterine rhabdomyosarcoma complicated with cerebral venous thrombosis. Conclusions Malignancy is an important diagnostic in patients with cerebral venous thrombosis with no obvious cause. This case demonstrates the importance of considering uterine neoplasms in the differential diagnosis of adolescent girls with abnormal uterine bleeding. Further, careful anatomical evaluation of vaginal masses should be performed prior to surgical intervention.

NCCN Guidelines® Insights: Uterine Neoplasms, Version 3.2021

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer or uterine sarcoma. These NCCN Guidelines Insights focus on the recent addition of molecular profiling information to aid in accurate diagnosis, classification, and treatment of uterine sarcomas.

Clinical and morphological portrait of tumors with microsatellite instability

Background. Microsatellites are short tandem nucleotide repeats, the change in length of which plays a key roles in the pathogenesis of various malignant neoplasms. This change is called microsatellite instability. It is caused by aberrations in the genes of DNA mismatch repair system. Tumors with microsatellite instability are a special subtype regardless of location and are characterized by high sensitivity to immune checkpoint inhibitors.Objective – determination of characteristic clinical and morphological patterns of tumors of various localizations with microsatellite instability.Materials and methods. The study included 512 patients with malignant tumors of different localizations. Of these, 359 patients were diagnosed with colorectal cancer, 57 with uterine body cancer, and 57 with stomach cancer. Determination of the status of microsatellite instability was performed by a PCR-based method using 5 mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, NR-27.Results. The prevalence of microsatellite instability in colorectal cancer, uterine neoplasm and gastric cancer was 6.4; 22.8 and 1.75 %, respectively. Patients with MSI-positive colorectal cancer are characterized by yonger age (p = 0.023), right-sided localization of the tumor (p <0.0001), presence of multiple primary tumors (p = 0.0299), poorly differentiation (p = 0.0025), mucinous component (p <0.0001), tumor-infiltrating lymphocytes (p <0.0001) and Crohn-like reaction (p = 0.0006). Patients with uterine neoplasms with microsatellite instability are characterized by the presence of endometrial adenocarcinoma (p = 0.047), as well as the presence of tumor-infiltrating lymphocytes (p = 0.0022) and cribriform growth (p = 0.0011).Conclusion. A common pattern for colorectal cancer and uterine neoplasms is the presence of tumor-infiltrating lymphocytes. Certain clinical and morphological features of tumors of these localizations will more accurately identify candidates for microsatellite instability status determination for further immunotherapy.

The Immunohistochemical Expression of MCM-3, -5, and -7 Proteins in the Uterine Fibroids

Uterine fibroids are the most common mesenchymal uterine neoplasms; their prevalence is estimated in 40%–60% of women under 35 and in 70%–80% of women over 50 years of age. The current research aims to focus on the etiopathogenesis of uterine fibroids, the factors that affect their growth, and markers with diagnostic and prognostic properties. The MCM (minichromosome maintenance) protein family consists of peptides whose primary function is participation in the molecular mechanism of creating replication forks while regulating DNA synthesis. The aim of this work was to determine the proliferative potential of uterine fibroid cells based on the expression of the Ki-67 antigen and the MCMs—i.e., MCM-3, MCM-5, and MCM-7. In addition, the expression of estrogen (ER) and progesterone (PgR) receptors was evaluated and correlated with the expression of the abovementioned observations. Ultimately, received results were analyzed in terms of clinical and pathological data. Materials and methods: In forty-four cases of uterine fibroids, immunohistochemical reactions were performed. A tissue microarray (TMA) technique was utilized and analyzed cases were assessed in triplicate. Immunohistochemistry was performed using antibodies against Ki-67 antigen, ER, PgR, MCM-3, MCM-5, and MCM-8 on an automated staining platform. Reactions were digitalized by a histologic scanner and quantified utilizing dedicated software for nuclear analysis. Assessment was based on quantification expression of the three histiospots, each representing one case in TMA. Results: In the study group (uterine fibroids), statistically significant stronger expression of all the investigated MCMs was observed, as compared to the control group. In addition, moderate and strong positive correlations were found between all tested proliferative markers. The expression of the MCM-7 protein also correlated positively with ER and PgR. With regard to clinical and pathological data, there was a negative correlation between the expression of MCMs and the number of both pregnancies and births. Significant reductions in MCM-5 and MCM-7 expression were observed in the group of women receiving oral hormonal contraceptives, while smoking women showed an increase in MCM-7, ER, and PgR. Conclusions: Uterine fibroid cells have greater proliferative potential, as evaluated by expression of the Ki-67 antigen and MCMs, than unaltered myometrial cells of the uterine corpus. The expression of MCM-7 was found to have strong or moderate correlations in all assessed relations. In the context of the clinical data, as well evident proliferative potential of MCMs, further studies are strongly recommended.

Management of Fibroids Prior to in Vitro Fertilization. Case Reports

BACKGROUND. Uterine fibroids are common benign uterine neoplasms in women in reproductive age and pregnancy desire. Several surgical approaches for symptomatic fibroids are available, such as surgical or pharmacologic treatments. We report three cases of fibroids treatment in women with primary sterility. CASE PRESENTATION. The first case of a successful in vitro fertilization (IVF) after ulipristal acetate (UPA) as an alternative treatment to reduce the fibroids size in a patient with two previous abdominal myomectomies, resulting in an evolutive pregnancy. The second patient underwent several myomectomies (both abdominal and hysteroscopic) in a long period of time. And the third one of a successful IVF after UPA in a patient with a submucous fibroid which induced myoma migration leading to its prolapse.CONCLUSIONS. Myomectomy appears to be the gold standard treatment for fibroids in women with reproductive desires. Nevertheless, more series are essential for establishing the safety of UPA as a treatment of symptomatic fibroids prior to pregnancy.

Malignant Uterine Neoplasms Attended at a Brazilian Regional Hospital: 16-years Profile and Time Elapsed for Diagnosis and Treatment

Objective The present study aims to evaluate the profile of endometrial carcinomas and uterine sarcomas attended in a Brazilian cancer center in the period from 2001 to 2016 and to analyze the impact of time elapsed from symptoms to diagnoses or treatment in cancer stage and survival. Methods This observational study with 1,190 cases evaluated the year of diagnosis, age-group, cancer stage and histological type. A subgroup of 185 women with endometrioid histology attended in the period from 2012 to 2017 was selected to assess information about initial symptoms, diagnostic methods, overall survival, and to evaluate the influence of the time elapsed from symptoms to diagnosis and treatment on staging and survival. The statistics used were descriptive, trend test, and the Kaplan-Meier method, with p-values < 0.05 for significance. Results A total of 1,068 (89.7%) carcinomas (77.2% endometrioid and 22.8% non-endometrioid) and 122 (10.3%) sarcomas were analyzed, with an increasing trend in the period (p < 0.05). Histologies of non-endometrioid carcinomas, G3 endometrioid, and carcinosarcomas constituted 30% of the cases. Non-endometrioid carcinomas and sarcomas were more frequently diagnosed in patients over 70 years of age and those on stage IV (p < 0.05). The endometrioid subgroup with 185 women reported 92% of abnormal uterine bleeding and 43% diagnosis after curettage. The average time elapsed between symptoms to diagnosis was 244 days, and between symptoms to treatment was 376 days, all without association with staging (p = 0.976) and survival (p = 0.160). Only 12% of the patients started treatment up to 60 days after diagnosis. Conclusion The number of uterine carcinoma and sarcoma cases increased over the period of 2001 to 2016. Aggressive histology comprised 30% of the patients and, for endometrioid carcinomas, the time elapsed between symptoms and diagnosis or treatment was long, although without association with staging or survival.

Extra-Uterine Fibroids

Leiomyomas are the most common gynecologic and uterine neoplasms. Uterine leiomyomas present in approximately 25% of women during reproductive age. Extrauterine leiomyomas (EULs) are rarer and usually arise in the genitourinary tract, however, may arise at nearly any anatomic location and possess a great diagnostic challenge. Moreover, the EULs may also present with unusual growth patterns such as disseminated peritoneal leiomyomatosis, intravenous leiomyomatosis, benign metastasizing leiomyoma, parasitic leiomyoma, and retroperitoneal mass. However, the cell of origin from smooth muscle cells and histological benign characteristics is similar to their uterine counterpart. The presence of a synchronous uterine leiomyoma or history of previous hysterectomy is a considerable evidence for the diagnosis of these abnormally located and unusual growth pattern displaying EULs. Different imaging modalities like ultrasonography, computed tomography, and magnetic resonance imaging are helpful in the diagnosis of EULs, however, sometimes a histopathological examination is required for the confirmation.