Gynecologic Sarcomas Research Articles

Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair-Deficient Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired. Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

Radiation-Induced Uterine Stromal Sarcoma: A Case Report and Review of the Literature

The radio-induced stromal sarcoma (RISS) is a rare clinical entity, being the second most common type of uterine mesenchymal neoplasm after leiomyosarcoma. Its incidence increases as survival after radiotherapy improves, and it often poses a therapeutic challenge. We report the case of a 58-year-old patient, followed since 2014 for initially classified stage IIb squamous cell carcinoma of the uterine cervix, treated with external pelvic radiotherapy and brachytherapy. After 6 years of surveillance, the patient presented with persistent pelvic pain. Clinical examination and pelvic MRI revealed the presence of a tumoral process in the uterine cervix with suspicious thickening of the endometrium. Morphological and immunohistochemical pathological study of the lesion confirmed its tumoral nature, indicative of a high-grade stromal sarcoma. Radiotherapy can induce malignant tumors after a latent period of several years. Radio-induced gynecological sarcomas are most often associated with a poor prognosis, emphasizing the need for careful and close monitoring after pelvic irradiation.

Impact of Hospital Case Volume on Uterine Sarcoma Prognosis: SARCUT Study Subanalysis.

High-complexity and low-prevalence procedures benefit from treatment by referral centers. The volume of cases necessary to maintain high training in the treatment of gynecologic sarcoma is currently unknown. This study aimed to determine differences in survival and recurrence as a function of the volume of patients treated per center. The multicentric cross-sectional SARComa of the Uterus (SARCUT) study retrospectively collected cases of uterine sarcomas from 44 centers in Europe from January 2001 to December 2007. The survival of patients treated in high case-volume (HighCV) centers was compared with the survival of patients treated in low case-volume (LowCV) centers. The study enrolled 966 patients: 753 in the LowCV group and 213 in the HighCV. Overall survival (OS) was 117 months, and cancer-specific survival (CSS) was 126 months. The difference was significant (respectively p = 0.0003 and 0.0004, log rank). After adjustment for other confounding factors, the remaining significant factors were age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03-1.05), histology (HR, 1.19; 95% CI, 1.06-1.34), extrauterine involvement (HR, 1.61; 95% CI, 1.24-2.10) and persistent disease after treatment (HR, 3.22; 95% CI, 2.49-4.18). The cytoreduction performed was significantly associated with the CSS and OS in both groups. The log rank for surgical cytoreduction was a p value lower than 0.0001 for OS, lower than 0.0001 for the LowCV centers, and 0.0032 for the HighCV centers. The prognosis for patients with uterine sarcoma is directly related to complete tumor cytoreduction, histologic type, and FIGO stage, with significant differences between low and high case-volume centers. Patients with uterine sarcomas should be centralized in HighCV centers to improve their oncologic outcomes.

Uterine sarcoma patients who underwent morcellation: Who are they? Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA- NOGGO RU1).

e17632 Background: Uterine sarcomas represent a group of rare malignant mesenchymal neoplasms with most types of them being associated with poor prognosis. In clinical practice, it is challenging to distinguish them from the most common benign tumors in women, so-called leiomyomas. Due to erroneous diagnosis, there is a risk of morcellating an occult sarcoma. This often leads to the distribution of malignant tissue in the abdominal cavity and a worse prognosis in most of the patients. In order to better understand this high-risk group of patients we analyzed their characteristics and management based on data of the real-world German registry for gynecological sarcoma (REGSA). Methods: REGSA is a real-world multicenter prospective registry including patients with gynecologic sarcomas in the primary and the recurrent situation of disease. For this work, we performed a descriptive analysis with data from all available patients with documented morcellation of uterine sarcoma. Results: 8.7% (n=76) of a total of 874 patients (registration period 09/2015-05/2022) were morcellated. Those 76 patients had a median age of 50.5 years. Thirty-seven patients (48.7%) were ≥50 years of age at the time of surgery. Leiomyosarcoma was the most common histopathological subtype (n=42; 50.3%). Fifty-eight patients (76.3%) had laparoscopic operations. A subtotal hysterectomy was the most common procedure used in 40.8% (n=31). Diagnostic curettage was performed in 5.3% of all cases (n=4). The predominant preoperative symptom was "bleeding disorders" in 19 patients (25.0%). Follow-up treatment after morcellation was heterogeneous. 17 patients received chemotherapy, with docetaxel and gemcitabine being the most frequently used regimen (n=8; 47.1%), followed by combinations with anthracyclines in 5 patients (29.4%). Conclusions: Many patients were over 50 years of age at the time of morcellation, although it is undisputed that the risk of morcellating occult uterine sarcoma increases with age. Whether curettage has diagnostic value needs to be further investigated. There is a high clinical need to define a consensus on further management of this high-risk group, regarding adjuvant therapy and follow-up care for there seems to be a great deal of uncertainty regarding adjuvant management.

Abstract LB291: Uncovering gene fusions with 3D genomics: from clinical validation to actionable insights for undiagnosable solid tumors

Abstract Identifying gene fusions in tumor biopsies is critical for understanding disease etiology; however, clinical NGS panels often fail to yield clear genetic drivers. A key challenge is that RNA-seq does not perform well in FFPE tissue blocks due to RNA degradation and/or RNA panel design, and cannot detect breakpoints outside of the gene body, which are established clinical biomarkers with mechanistic significance and clinical utility in solid hematological cancers. We developed a novel DNA-based partner-agnostic approach for identifying fusions from FFPE tumors using 3D genomics based on Arima-HiC technology and NGS. We profiled 184 FFPE tumors across various tumor types. This cohort includes 33 tumors with known gene fusions detected by RNA panels for clinical concordance analysis. It also includes 151 FFPE tumors, including 62 CNS tumors, 59 gynecological sarcomas, and 22 solid heme tumors, with no detectable genetic drivers from prior DNA and RNA panel CLIA assays. For clinical concordance, Arima-HiC technology detected 33/33 fusions previously detected by RNA panels. For clinical validation and utility studies in our driver-negative cohort, Arima-HiC detected 1 or more fusions in 72% (109/151) of tumors. To attribute clinical significance, we compared the genes implicated in our fusion calls with NCCN and WHO guidelines, and OncoKB, and assigned which tumors had an FDA-approved therapeutic level biomarker (“Tier 1”), a biomarker targeted in an ongoing clinical trial (“Tier 2”), or a diagnostic/prognostic biomarker (“Tier 3”). Arima-HiC analysis found 33.8% (51/151) of tumors had Tier 1 biomarkers, 4.0% (6/151) had Tier 2 biomarkers, and a further 14.6% (22/151) had Tier 3 biomarkers, indicating an overall yield of clinically actionable biomarkers at 52.3%. Several cases with Tier 1-3 fusions underwent confirmatory immunohistochemistry testing for oncoprotein expression, and 91.6% (11/12) showed diffuse or focally positive staining. To highlight examples from prospectively analyzed cases from this cohort, we identified a novel PD-L1 rearrangement in a pediatric glioma tumor that was not detected by DNA or RNA panels, which we confirmed by PD-L1 IHC, and the patient was administered pembrolizumab after tumor recurrence and has since exhibited stable disease. We also identified a MYBL1 fusion in a glioma that spared the patient unnecessary chemotherapy post-resection. Our findings provide evidence of clinical concordance, validation, and utility, and underscore the need for 3D genome profiling to increase diagnostic yield by finding clinically actionable fusions in FFPE solid tumors. Citation Format: Anthony Schmitt, Kristin Sikkink, Kristyn Galbraith, Misha Movahed-Ezazi, George Jour, Matija Snuderl. Uncovering gene fusions with 3D genomics: from clinical validation to actionable insights for undiagnosable solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB291.

Abstract 4749: Effects of miR-34a-5p and miR-181b-5p silencing and induction on their potential targets in uterine leiomyosarcoma cells

Abstract Background: Leiomyosarcoma (LMS) is a malignant tumor of the uterine body that represents 40-60% of all gynecological sarcomas. Up to now, there is no specific treatment or diagnostic biomarkers for this tumor. The identification and characterization of miRNAs signature could help to its management. In addition, miRNAs represent targets for therapies due to their ability to modulate various signaling pathways simultaneously. Thus, the present study aimed to evaluate the effects of genetic manipulation of miR-34a and miR-181b on their predicted target genes in LMS cells. Methods: SK-UT-1 cells from uterine LMS were transfected with synthetic miRNA mimics and inhibitors (siRNA) of miR-34a and miR-181b. The efficacy of transfection was assessed by miRNA expression (qRT-PCR) assays. In order to identify potential genetic interactions network of miR-34a and 181b, predicted target genes were selected by in silico analysis (miRTargetLink 2.0 and miRDB). After SK-UT-1 cells transfection, the expression of target genes was evaluated by qRT-PCR. Results: SK-UT-1 cells showed greater efficiency of mimics and siRNA transfections after 48h treatment for both miR-34a and 181b. MDM4, TP53, BCL2, KMT2D, NOTCH2, and CCND1 were identified as predicted target genes of miR-34a; and the TIMP3, FGFR1, BCL2, NOTCH2, ATM, and IRS1 target genes for miR-181b. Expression profile of selected target genes was assessed after each treatment. The miR-34a mimic significantly increased the expression of MDM4 after 96h of treatment, while the BCL2 and TP53 showed an increase in expression with siRNA after 48h of treatment. CCND1 showed a greater expression in both treatments at 48h. An increase in KMT2D and NOTCH2 expression was also observed after treatment, even though without statistically significant. Treatment with miR-181b mimic led to increased FGFR1 expression within 72h. Although some expression alterations were observed in TIMP3, BCL2, NOTCH2, ATM, and IRS1 genes after mimic and siRNA treatments, there was no statistical significance. Conclusion: The effect of miR-34a upregulation leads to induction MDM4 and CCND1 expression, the first being a TP53 inhibitor and the second, responsible for cell cycle maintenance. The miR-34a downregulation had an inductor effect on expression of MDM4, BCL2 (apoptosis regulator), TP53 (tumor suppressor), and CCND1. The miR-181b upregulation induced the expression of fibroblast growth factor receptor, FGFR1. In uterine LMS cells, miR-34a seems to exert an important role in regulating the expression of cell cycle and apoptosis-related genes. Citation Format: Bruna C. de Almeida, Laura G. dos Anjos, Katia C. Carvalho. Effects of miR-34a-5p and miR-181b-5p silencing and induction on their potential targets in uterine leiomyosarcoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4749.

Sonographic and Magnetic Resonance Characteristics of Gynecological Sarcoma.

Gynecological sarcomas are rare malignant tumors with an incidence of 1.5-3/100,000 and are 3-9% of all malignant uterine tumors. The preoperative differentiation between sarcoma and myoma becomes increasingly important with the development of minimally invasive treatments for myomas, as this means undertreatment for sarcoma. There are currently no reliable laboratory tests or imaging-characteristics to detect sarcomas. The objective of this article is to gain an overview of sarcoma US/MRI characteristics and assess their accuracy for preoperative diagnosis. A systematic literature review was performed and 12 studies on ultrasound and 21 studies on MRI were included. For the ultrasound, these key features were gathered: solid tumor > 8 cm, unsharp borders, heterogeneous echogenicity, no acoustic shadowing, rich vascularization, and cystic changes within. For the MRI, these key features were gathered: irregular borders; heterogeneous; high signal on T2WI intensity; and hemorrhagic and necrotic changes, with central non-enhancement, hyperintensity on DWI, and low values for ADC. These features are supported by the current literature. In retrospective analyses, the ultrasound did not show a sufficient accuracy for diagnosing sarcoma preoperatively and could also not differentiate between the different subtypes. The MRI showed mixed results: various studies achieved high sensitivities in their analysis, when combining multiple characteristics. Overall, these findings need further verification in prospective studies with larger study populations.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1)

ObjectiveGynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus...

Trends in incidence, survival and initial treatments of gynecological sarcoma: a retrospective analysis of the United States subpopulation

BackgroundTo estimate the incidence, prevalence and incidence-based mortality in patients with gynecologic sarcoma (GS), and described the trends of survival and initial treatments in the US by using the Surveillance, Epidemiology, and End Results (SEER) database.MethodsGS cases aged 20 years or older between 1975 and 2015 were identified from SEER 9 registries. Incidence, prevalence, and incidence-based mortality were estimated, all rates were age adjusted to the 2000 US standard population and presented as per 100,000 persons. Annual percentage change (APC) and average APC (AAPC) were calculated to describe the trends. In addition, stage distribution, cancer-specific survival (CSS) and initial treatment pattern over time were also reported.ResultsThe overall age-adjusted incidence of GS increased from 2.38 to 3.41 per 100,000 persons from 1975 to 2015, with an AAPC of 1.0 (P < 0.05), and the AAPC increased to 1.3 (P < 0.05) in the last decade. The incidence of population aged ≥ 55 years was three or more times than that of population aged 20–54 year from 1975 to 2015. Corpus and uterus GS was the main subtype, and it increased significantly during last three decades (an APC of 1.5). In addition, the prevalence of corpus and uterus GS increased mostly among all GSs. The incidence of GS with regional and distant stages increased pronouncedly, but not for local stage. GS cases showed increasing 3-year and 5-year CSS rates except for other sites GS. Approximately 87.7% GS cases received surgery during the first-course treatment, but the proportion decreased over years. In contrast, the proportion of receiving multiple treatment modalities increased.ConclusionsThe incidence of GS increased significantly with improved survival, which might due to the strategy of combination of multiple treatment. However, no obvious improvement on the early detection of GS was found, which should be facilitated to further improve the prognosis of GS.

1524P Epidemiology and demography of gynecological sarcoma: Results of the prospective intergroup registry for gynecological sarcoma REGSA (NOGGO RU1)

Gynecological sarcomas (GS) are orphan diseases associated with poor prognosis. With the aim to improve our understanding of GS, the German registry for gynecological sarcoma (REGSA) prospectively recorded patients’ data with GS treated in real-life clinical practice at initial diagnosis and relapse. We present demographic and epidemiological data of patients with GS at the time of initial diagnosis.

Epidemiological and demographic characteristics of gynecological sarcoma: Results of the prospective intergroup registry for gynecological sarcoma in Germany (REGSA–NOGGO RU1).

e17630 Background: Gynecological sarcomas (GS) are orphan diseases associated with poor prognosis. With the aim to improve our understanding of GS, the German registry for gynecological sarcoma (REGSA) prospectively recorded patients’ data with GS treated in real-life clinical practice at initial diagnosis and the time of relapse. Herein, we present the analysis of demographic and epidemiological data of patients with GS at the time of initial diagnosis. Methods: An exploratory analysis among different histological subtypes of GS was performed and patients’ data were compared to data of the healthy standard population. We analyzed the following variables: age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, ethnicity, lifestyle habits, pregnancies, and comorbidities. Results: Data of 389 patients with GS were descriptively evaluated. Leiomyosarcoma (LMS) was the most common histological subtype (47.3%), followed by low-grade endometrial stromal sarcoma (LG-ESS; 17.7%), high-grade ESS (HG-ESS; 10.4%), adenosarcoma (AS; 9.1%) and undifferentiated uterine sarcoma (UUS; 6.2%). Overall, 9.4% of all GS were classified as “other” rarer histological subtypes. The mean age of patients was 57.4 years. The youngest were the patients with LG-ESS (54.3 years), whereas patients with AS were the oldest ones (61.7 years). There were no statistically significant differences in average age nor in BMI among patients with different histological subtypes of GS. In contrast, compared to the standard population, the BMI of patients with GS was significantly higher (27.5 kg/m² vs 25.1 kg/m², p&lt; 0.001). Overall, 70.7% of all patients with LMS had FIGO stage I or II. Therefore, it is not surprising that most of patients had ECOG performance status 0 (68.3%). According to the countries of recruitment (i.e. Germany, Austria, Switzerland), 92.8% of patients were Caucasian. REGSA patients were less likely to be smokers compared to the national average of German women (13.4% vs 18.6%). One or two births per patient were reported in 58.2% of patients. In comparison the current birth ratio in Germany is approximately 1.5 children per woman. Hypertension was the most common comorbidity as observed in 33.2% of all cases, followed by thyroid diseases (18.6%). The prevalence of hypertension in the German female standard population is approximately 30% and approximately every third person will be affected by thyroid diseases in their lifetime. Conclusions: REGSA data showed no statistically significant differences in terms of demographic variables between different histological subtypes of GS, whereas statistically significant difference such as BMI was identified as compared to the standard population. Further research is needed to specify risk factors of GS in order to promote primary prevention of this fatal disease.

Embryological Aspects and Anatomical Variations of the Inferior Vena Cava – Its Importance in Gynecologic Oncology Surgery

Summary Surgical procedures of the retroperitoneum are often performed in gynecologic oncology surgery clinics. The most complex among them is paraaortic lymphadenectomy. It is generally performed in cases of bulky lymph nodes in ovarian carcinomas and sarcomas to achieve optimal cytoreduction. In the early stages of ovarian cancer, type II non-endometrioid endometrial cancer, and in advanced stages of cervical cancer, paraaortic lymphadenectomy is an integral part of staging. Moreover, the retroperitoneum is approached in cases of retroperitoneal gynecologic sarcomas. The largest vessels of the human body – the inferior vena cava and the abdominal aorta are localized in the retroperitoneum. Therefore, iatrogenic vessel injury during oncogynecological surgery is more likely to affect the inferior vena cava. Anatomical variations of the vein additionally increase the risk of vascular lesions. Therefore, surgeons should be aware of possible anatomical variations. The present article aimed to highlight the heterogeneity of anatomical variations of the inferior vena cava related to gynecologic oncology surgery. Embryogenesis of the vein and its variations are also discussed. Additionally, some anomalies of the ureter, associated with the embryogenesis of the inferior vena cava, are mentioned.

Overall and net survival of patients with sarcoma between 2005 and 2010: Results from the French Network of Cancer Registries (FRANCIM).

Sarcomas are rare, heterogeneous, ubiquitously localized malignancies with many histologic subtypes and genomic patterns. The survival of patients with sarcoma has rarely been described based on this heterogeneity; therefore, the authors' objective was to estimate survival outcomes in patients who had sarcomas using the 2020 version of the World Health Organization classification of soft tissue and bone tumors. Patients older than 15 years who had incident sarcoma diagnosed between 2005 and 2010 were extracted from 14 French population-based cancer registries covering 18% of the French metropolitan population. Vital status for each patient was actively followed up to June 30, 2013. Net survival (NS) was estimated using the unbiased Pohar-Perme method. Overall, 4202 patients were included. NS declined with increasing age at diagnosis. According to topographic groups, large 5-year NS disparities were observed, ranging from 47% among women with gynecologic sarcomas to 89% among patients with skin sarcomas. Patients with soft tissue, bone, and gastrointestinal sarcomas had 5-year NS rates of 53%, 61%, and 70%, respectively. Similar heterogeneity was observed according to histologic subtypes, with 5-year NS ranging from 19% for patients with angiosarcomas to 96% for patients with dermatofibrosarcomas. Patients with sarcoma who displayed missense mutations had a better 5-year NS (74%); those with MDM2-amplified sarcomas had the worst NS (45%). NS rates in patients with sarcoma are presented here for the first time based on the 2020 World Health Organization classification applied to population-based registry data. Large prognostic heterogeneity was observed based on age, topographic and histologic groups, and genomic alteration profiles, constituting a benchmark for future studies and clinical trials.

High incidence of gynecologic sarcomas in Israel—A comparison to European and American reports: Gynecologic Sarcoma in Israel

ObjectiveGynecologic Sarcomas are rare, aggressive tumors. The aim of this study was to explore the incidence and outcomes of gynecologic sarcomas in a large national data registry and to compare them with reports from other countries. Study DesignRecords of gynecologic sarcomas diagnosed in Israel (1980–2014) were extracted from the National Cancer Registry and classified according to International Classification of Diseases for Oncology-3 and characterized according to anatomical site, morphology and demographics. Age-standardized incidence rates and 1, 3, 5 and 10-year relative survival rates were calculated for 3 time periods (1980–1994, 1995–2001 and 2005–2014) according to patient age, stage and years of diagnosis. ResultsDuring 1980–2014, 1271 new gynecologic sarcomas were diagnosed in Israel, with incidence slightly increasing in 1980–2004, to an age-standardized incidence rate of 13 per million women. The most common histologic diagnosis was leiomyosarcoma (48%) and the most common anatomical site was the uterus (89%). The age-standardized incidence rate for uterine sarcoma is higher in Israel (10.55 per million) than in England (7.4 per million) and Germany (5.8 per million) respectively. The 5-year overall survival was significantly poorer in patients >70-years, as compared to younger patients (p<0.001) and in those with leiomyosarcoma compared to endometrial stromal sarcoma (p<0.001). The survival rate of patients with leiomyosarcoma in Israel are comparable to survival rates reported by other studies, although substantially lower regarding endometrial stromal sarcoma. ConclusionsUterine leiomyosarcoma was the most common gynecologic sarcoma found in the Israeli, European and American registries. Older patients and those with leiomyosarcoma have the worst prognoses. Histological and anatomical variations in Israel are comparable with global statistics, but the incidence in Israel seems higher than in Europe.

PO-1302 Intraoperative electron radiation after salvage surgery in gynecological cancers and sarcomas

PO-1302 Intraoperative electron radiation after salvage surgery in gynecological cancers and sarcomas

Gynecological sarcomas: literature review of 2020.

This article, focus on recently published data of the last 18 months on the management of gynecologic sarcomas. Different tools have been studied to identify the differences between benign from malignant uterine conjonctive tumor.Molecular biology impact more and more on the diagnosis of uterine sarcoma with new definitions of very specific groups. This will make it possible to better define the last group of endometrial sarcoma which has been defined as undifferentiated.In several articles, surgical approaches and fertility-sparing surgery were described including the role of surgery for recurrences.Some other articles have evaluated the potential benefice of adjuvant therapy for uterine sarcoma with early stages.Several new targeted therapies are in development. Notably deoxyribonucleic acid repair machinery in uterine leiomyosarcoma and also immune therapies, transforming growth factor beta pathway, mechanistic target of rapamycin inhibitor, anti angiogenics, etc. This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature compared to previous years. Despite this greater interest over time, the standard of care for uterine sarcoma does not change and we are always waiting for new innovative therapies able to change routine practice and survival of patients. Currently, the result of different clinical trials, which include new options as targeted molecular approach or immune checkpoint inhibitors are closed to be reported.

The Many Uses of p53 Immunohistochemistry in Gynecological Pathology: Proceedings of the ISGyP Companion Society Session at the 2020 USCAP Annual9 Meeting.

Ancillary immunohistochemistry (IHC) has become a reliable adjunct for subclassification of gynecological neoplasms. An important recent development was optimization and validation of p53 IHC, where 3 abnormal IHC patterns (nuclear overexpression, complete absence, cytoplasmic) were shown to predict underlying TP53 mutations with high accuracy in ovarian carcinomas. p53 IHC now helps in distinguishing high-grade serous from low-grade serous carcinomas. Thereafter, the new interpretation of p53 IHC was quickly adapted for other purposes and similar accuracies were shown in endometrial carcinomas, vulvar squamous cell carcinomas, and ovarian mucinous tumors. However, it required further refinement of the p53 IHC interpretation criteria for each tumor site. A proportion of endometrial endometrioid carcinomas shows an ultramutated or hypermutated genotype due to underlying POLE mutations or mismatch repair deficiency sometimes causing subclonal TP53 mutations, and their distribution can be visualized by p53 IHC. Squamous cell carcinomas and ovarian mucinous tumors show a phenomenon called terminal differentiation where basal cells demonstrate an abnormal pattern of p53 IHC but apical cells do not despite an underlying TP53 mutation. High-grade progression of adult granulosa cell tumors due to a subclonal TP53 mutation has been recently described. Another use of p53 IHC is triaging gynecological sarcomas for molecular testing based on the assumption that TP53-mutated gynecological sarcomas do not harbor cancer driving translocations. Therefore, familiarity with interpretation of p53 IHC is becoming increasingly important for the practicing gynecological pathologist. Furthermore, local optimization of the p53 IHC assay using validated protocols including appropriate low expressing control tissues (eg, tonsil) is vital in order to achieve high diagnostic accuracy, especially for abnormal staining patterns such as complete absence or cytoplasmic, and interlaboratory concordance. p53 IHC is a reliable diagnostic adjunct for histotyping and molecular subtyping of ovarian and endometrial carcinomas, and it paves the way for large-scale studies to validate the prognostic value of p53 IHC in several gynecological tumor types. The technical advances, validated interpretation criteria, and its growing versatility in identifying high-risk neoplasms paired with its widespread availability in pathology departments make p53 IHC perhaps the single most useful IHC stain in gynecological pathology.

DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing.

Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of "new" morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1-associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.

Incidence patterns of gynecological sarcomas in Iran analysis of National Cancer Registry data between 2009 and 2014.

Gynecological sarcomas (GS) are rare malignant tumors arising in the female genital organs. Due to the low incidence and diverse histology, information on the epidemiology of these tumors is sparse. We aimed to investigate the incidence rates of GS in Iran that in our knowledge is the first report from Eastern Mediterranean Region. In this retrospective study, all malignant tumors with a sarcoma morphology arising in the female genital organs diagnosed between 2009 and 2014 were extracted from the Iran National Cancer Registry dataset. All the cancer cases were categorized according to ICD-O-3 morphologic and topographic codes. Age-standardized incidence rates, age-specific incidence rates, morphologic and geographic distribution of all cases were analyzed and compared with other parts of the world. A total of 1174 cases were diagnosed over the period 2009-2014. The overall age-standardized incidence rate for all sites combined was 6.13 per million females. Analysis of trends in incidence did not show a significant change over time according to annual average percent change analysis (P-value = 0.300). The most common anatomical site was the uterus, accounting for 77% of all cases. The mean (±SD) age at diagnosis, irrespective of tumor site, was 52.3 (±15) years. In terms of morphology, leiomyosarcoma was the most frequently observed subtype, constituting 34% of all GS. Also, the highest ASIR was observed in women aged 60-64 years. Based on the findings, GS are relatively rare tumors that occur more in old women. The results of this study provide a comprehensive picture of GS incidence patterns in Iran for more investigation.

Comparing overall survival in women diagnosed and treated for a gynecological sarcoma at a private versus county hospital

Objective: Sarcomas are rare heterogeneous mesenchymal tumors that account for approximately 3% of all gynecological cancers with aggressive features, diverse histological subtypes, and poor clinical outcomes. The aim of this study was to determine whether treatment in a private versus county hospital was an independent risk factor in patients with gynecological sarcomas.