Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) Applied to Platinum-Resistant Recurrence of Ovarian Tumor: A Single-Institution Experience (ID: PARROT Trial).

BACKGROUND: We aimed to investigate the therapeutic efficacy and safety of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in platinum-resistant recurrence of ovarian cancer and peritoneal carcinomatosis, while our secondary endpoint was to establish any changes in quality of life estimated via the EORTC QLQ-30 and QLQ-OV28 questionnaires. METHODS: In this monocentric, single-arm, phase II trial, women were prospectively recruited and every 28-42 days underwent courses of PIPAC with doxorubicin 2.1 mg/m2 followed by cisplatin 10.5 mg/m2 via sequential laparoscopy. RESULTS: Overall, 98 PIPAC procedures were performed on 43 women from January 2016 to January 2020; three procedures were aborted due to extensive intra-abdominal adhesions. The clinical benefit rate (CBR) was reached in 82% of women. Three cycles of PIPAC were completed in 18 women (45%), and 13 (32.5%) and 9 (22.5%) patients were subjected to one and two cycles, respectively. During two PIPAC procedures, patients experienced an intraoperative intestinal perforation. There were no treatment-related deaths. Nineteen patients showed no response according to the Peritoneal Regression Grading Score (PRGS) and 8 patients showed minor response according to the PRGS. Median time from ovarian cancer relapse to disease progression was 12 months (95% confidence interval [CI] 6.483-17.517), while the median overall survival was 27 months (95% CI 20.337-33.663). The EORTC QLQ-28 and EORTC QLQ-30 scores did not worsen during therapy. CONCLUSIONS: PIPAC seems a feasible approach for the treatment of this subset of patients, without any impact on their quality of life. Since this study had a small sample size and a single-center design, future research is mandatory, such as its application in addition to systemic chemotherapy.

The emerging and challenging role of PD-L1 in patients with gynecological cancers: An updating review with clinico-pathological considerations.

Over recent years, there has been significant progress in the development of immunotherapeutic molecules designed to block the PD-1/PD-L1 axis. These molecules have demonstrated their ability to enhance the immune response by prompting T cells to identify and suppress neoplastic cells. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in gynecological malignancies is extremely variable based on tumor stage and molecular subtypes. As a result, a class of monoclonal antibodies targeting the PD-1 receptor and PD-L1, known as immune checkpoint inhibitors, has found successful application in clinical settings. In clinical practice, the standard method for identifying suitable candidates for immune checkpoint inhibitor therapy involves immunohistochemical assessment of PD-L1 expression in neoplastic tissues. The most commonly used PD-L1 assays in clinical trials are SP142, 28-8, 22C3, and SP263, each of which has been rigorously validated on specific platforms. Gynecologic cancers encompass a wide spectrum of malignancies originating from the ovaries, uterus, cervix, and vulva. These neoplasms have shown variable response to immunotherapy which appears to be influenced by genetic and protein expression profiles, including factors such as mismatch repair status, tumor mutational burden, and checkpoint ligand expression. In the present paper, an extensive review of PD-L1 expression in various gynecologic cancer types is discussed, providing a guide for their pathological assessment and reporting.

Raf kinase inhibitor protein expression in smooth muscle tumours of the uterus: a diagnostic marker for leiomyosarcoma?

RESEARCH QUESTION: What is the expression pattern of Raf kinase inhibitory protein (RKIP) in different subtypes of leiomyoma (usual type, cellular, apoplectic or haemorrhagic leiomyoma, leiomyoma with bizarre nuclei and lipoleiomyoma) and leiomyosarcoma specimens, and what is its biological role in leiomyosarcoma cells? DESIGN: Leiomyoma and leiomyosarcoma specimens underwent immunohistochemistry staining. Leiomyosarcoma SK-LMS-1 cell line was RKIP knocked down and RKIP overexpressed, and cell viability, wound healing migration and clonogenicity assays were carried out. RESULTS: A higher immunohistochemical expression of RKIP was observed in bizarre leiomyomas, than in usual-type leiomyomas. Decreased expression was also found in cellular leiomyoma, with generally absent staining in leiomyosarcomas. Upon RKIP expression manipulation in SK-LMS-1 cell line, no major differences were observed in cell viability and migration capacity over time. RKIP knockout, however, resulted in a significant increase in the cell's ability to form colonies (P = 0.011). CONCLUSION: RKIP distinct expression pattern among leiomyoma histotype and leiomyosarcoma, and its effect on leiomyosarcoma cells on colony formation, encourages further studies of RKIP in uterine smooth muscle disorders.

Integrated histological parameters define prognostically relevant groups in atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia.

OBJECTIVE: To assess the risk of endometrial carcinoma following a diagnosis of atypical hyperplasia/endometrioid intraepithelial neoplasia by endometrial biopsy, stratified based on integrated histological parameters. METHODS: All women with atypical hyperplasia/endometrioid intraepithelial neoplasia undergoing hysterectomy within 1 year of diagnosis without progestin treatment were included. Patients were subdivided into three study groups, based on two criteria: (a) grade of nuclear atypia and (b) foci (<2 mm) of confluent glands with no intervening stroma: low-grade, high-grade, and confluent glands. The rate of endometrial carcinoma on the subsequent hysterectomy was assessed in each study group, and differences between study groups were assessed using Fisher's exact test, with a significant p value <0.05. Reproducibility was assessed by using Cohen's κ. RESULTS: Ninety-six patients were included. Overall, 36 of 96 patients (37.5%) had endometrial carcinoma on the subsequent hysterectomy. The number of endometrial carcinomas was 4 of 42 (9.5%) in the low-grade group, 14 of 28 (50.0%) in the high-grade group, and 18 of 26 (69.2%) in the confluent glands group. The rate of endometrial carcinoma was significantly higher in the high-grade group than in the low-grade group (p<0.001), whereas it did not significantly differ between the high-grade group and the confluent glands group (p=0.176). The reproducibility among pathologists was moderate for low-grade versus high-grade (κ=0.58) and substantial for confluent glands versus low-grade (κ=0.63) and high-grade (κ=0.63). CONCLUSION: Atypical hyperplasia/endometrioid intraepithelial neoplasia can be stratified into prognostically relevant groups based on integrated histological parameters, with a possible major impact on patient management.

Diagnostic Accuracy of Ultrasound in the Diagnosis of Uterine Leiomyomas and Sarcomas.

BACKGROUND: Differential diagnosis between uterine leiomyomas and sarcomas is challenging. Ultrasound shows an uncertain role in the clinical practice given that pooled estimates about its diagnostic accuracy are lacking. OBJECTIVES: To assess the accuracy of ultrasound in the differential diagnosis between uterine leiomyomas and sarcomas. DATA SOURCES: A systematic review was performed searching 5 electronic databases (MEDLINE, Web of Sciences, Google Scholar, Scopus, and ClinicalTrial.gov) from their inception to June 2023. METHODS OF STUDY SELECTION: All peer-reviewed observational or randomized clinical trials that reported an unbiased postoperative histologic diagnosis of uterine leiomyoma or uterine sarcoma that also comprised a preoperative ultrasonographic evaluation of the uterine mass. TABULATION, INTEGRATION, AND RESULTS: Sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and area under the curve on summary receiver operating characteristic were calculated for each included study and as pooled estimate, with 95% confidence interval (CI); 972 women (694 with uterine leiomyomas and 278 with uterine sarcomas) were included. Ultrasound showed pooled sensitivity of 0.76 (95% CI, 0.70-0.81), specificity of 0.89 (95% CI, 0.87-0.92), positive and negative likelihood ratios of 6.65 (95% CI, 4.45-9.93) and 0.26 (95% CI, 0.07-1.0) respectively, diagnostic odds ratio of 23.06 (95% CI, 4.56-116.53), and area under the curve of 0.8925. CONCLUSIONS: Ultrasound seems to have only a moderate diagnostic accuracy in the differential diagnosis between uterine leiomyomas and sarcomas, with a lower sensitivity than specificity.

Atypical glandular cells and predictive features of malignancy in Pap smears: A retrospective monocentric study.

OBJECTIVE: The introduction of cytological screening with the Papanicolau smear significantly reduced cervical cancer mortality. However, Pap smear examination can be challenging, being based on the observer ability to decode different cytological and architectural features. This study aims to evaluate the malignancy rate of AGC (atypical glandular cells) category, investigating the relationships between cytological and histological diagnosis. METHODS: Eighty-nine patients, diagnosed as AGC at cytological evaluation and followed up with biopsy or surgical procedure at Policlinico Gemelli Hospital, Rome, Italy, were included in the study. The cytopathological architectural (feathering, rosette formation, overlapping, loss of polarity, papillary formation, three-dimensional formation) and nuclear (N/C ratio, nuclear enlargement and hyperchromasia, mitoses, nuclei irregularity, evident nucleoli) features of AGC were evaluated. Statistical analyses were performed to assess cyto-histological correlation and determine the relevance of architectural and nuclear features in the diagnosis of malignancy. RESULTS: Of the 89 AGC patients, 48 cases (53.93%) were diagnosed as AGC-NOS and 41 (46.07%) were diagnosed as AGC-FN, according to the Bethesda classification system. The follow-up biopsies or surgical resections revealed malignancy in 46 patients (51.69%). The rates of malignancy for AGC-NOS and AGC-FN were 35.41% and 70.73% respectively. Furthermore, analysing cytopathological features, we found that both architectural and nuclear criteria were statistically significant (p < 0.05). Only overlapping, nuclear irregularity and increased N/C ratio were not found to be statistically significant for detecting malignancy. CONCLUSIONS: Cytological diagnosis of glandular lesions remains a valid tool, when appropriate clinical correlation and expert evaluation are available.

Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Endometrial Cancer: A Review on Immunohistochemistry Staining Patterns and Clinical Implications.

Among the four endometrial cancer (EC) TCGA molecular groups, the MSI/hypermutated group represents an important percentage of tumors (30%), including different histotypes, and generally confers an intermediate prognosis for affected women, also providing new immunotherapeutic strategies. Immunohistochemistry for MMR proteins (MLH1, MSH2, MSH6 and PMS2) has become the optimal diagnostic MSI surrogate worldwide. This review aims to provide state-of-the-art knowledge on MMR deficiency/MSI in EC and to clarify the pathological assessment, interpretation pitfalls and reporting of MMR status.

Biomarker characterization in endometrial cancer in Europe: first survey data analysis from 69 pathological academic and hospital labs.

Introduction: Endometrial carcinoma (EC) is the commonest gynecological cancer affecting women in Western populations. To predict patient risk, the 2020 edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract stressed the importance of integrated histo-molecular classification of the disease. This survey analysis poses attention on the most frequently used immunohistochemical and molecular markers adopted in daily categorization of ECs in European laboratories. Methods: We analyzed data collected through questionnaires administered to 40 Italian, 20 Spanish, 3 Swiss and 6 United Kingdom (UK) laboratories. We collected information regarding daily practice in EC evaluation, specifically concerning mismatch repair status (MMR) and microsatellite instability (MSI). Summary and descriptive statistical analyses were carried out to evaluate the current practice of each laboratory. Results: The results show that MMR status is mainly evaluated by using immunohistochemistry (IHC) on most EC samples. The most frequent approach for the analysis of MMR status is IHC of four proteins (PMS2, MSH6, MSH2, MLH1). MSI analysis by molecular methods is uncommon but useful as a supplemental tool in specific conditions. MLH1 promoter hypermethylation and BRAF V600 mutations analysis are performed in case of negative expression of MLH1/PMS2. Other markers (mainly p53 followed by POLE and PTEN) are investigated in particular in Spain and Switzerland in a consistent number of cases. Conclusion: Guidelines consultation and standardization of laboratory procedures are efficient means for EC prognostic risk stratification and improving the quality of care.

Fumarate Hydratase and S-(2-Succinyl)-Cysteine Immunohistochemistry Shows Evidence of Fumarate Hydratase Deficiency in 2% of Uterine Leiomyosarcomas: A Cohort Study of 348 Tumors.

Approximately 1% to 1.5% of uterine leiomyomas are fumarate hydratase (FH)-deficient (FHd). A subset of these are associated with germline FH mutations. However, the prevalence and clinicopathologic characteristics of FHd uterine leiomyosarcoma (uLMS) remain unknown. Clinicopathologic data were collected for 348 uLMS. Morphologic features associated with FH deficiency (staghorn-type vessels, alveolar-pattern edema, macronucleoli with perinucleolar clearing, eosinophilic cytoplasmic inclusions, and chain-like nuclear arrangement) were documented. All 348 tumors were studied by FH immunohistochemistry. Eighty-nine were also studied by S-(2-succinyl)-cysteine (2SC) immunohistochemistry. Seven (2%) FHd uLMS were identified. Five showed uniformly negative FH and diffusely positive 2SC immunostaining; 1 showed variably negative to weak to strong FH and diffusely positive 2SC immunostaining; and 1 showed retained FH staining alongside positive 2SC confined to a morphologically distinct subclone. Three of 7 patients had extrauterine disease at presentation, and 3 of 6 had persistent disease or died from disease. Macronucleoli with perinucleolar clearing were significantly more common in FHd uLMS (7/7) than in uLMS with retained FH (182/341; P =0.017). Disease-specific survival, disease-free survival, and other morphologic features of FH deficiency did not differ significantly between FHd and FH-retained tumors. Our data emphasize that immunohistochemical FH deficiency does not preclude malignancy in uterine smooth muscle tumors. However, the biological significance and molecular basis of FH deficiency in uLMS, including any relationship to germline FH mutation, remain unknown, and a larger multi-institutional effort is necessary to gather sufficient FHd uLMS for more robustly powered clinicopathologic and for molecular characterization.

Predictive factors of sentinel lymph node failed mapping in endometrial carcinoma patients: a systematic review and meta-analysis.

OBJECTIVE: In endometrial carcinoma patients, sentinel lymph node bilateral mapping fails in 20-25% of cases, with several factors affecting the likelihood of detection. However, pooled data about predictive factors of failure are lacking. The aim of this systematic review and meta-analysis was to assess the predictive factors of sentinel lymph node failed mapping in endometrial cancer patients undergoing sentinel lymph node biopsy. METHODS: A systematic review and a meta-analysis was performed searching all studies assessing predictive factors of sentinel lymph node failed mapping in apparent uterine-confined endometrial cancer patients undergoing sentinel lymph node biopsy through the cervical injection of indocyanine green. The associations between sentinel lymph node failed mapping and predictive factors of failure were assessed, calculating the odds ratio (OR) with 95% confidence intervals. RESULTS: Six studies with a total of 1345 patients were included. Compared with patients with sentinel lymph node bilateral successful mapping, patients with sentinel lymph node failed mapping showed: OR 1.39 (p=0.41) for body mass index >30 kg/m2; OR 1.72 (p=0.24) for menopausal status; OR 1.19 (p=0.74) for adenomyosis; OR 0.86 (p=0.55) for prior pelvic surgery; OR 2.38 (p=0.26) for prior cervical surgery; OR 0.96 (p=0.89) for prior Cesarean section; OR 1.39 (p=0.70) for lysis of adhesions during surgery before sentinel lymph node biopsy; OR 1.77 (p=0.02) for indocyanine green dose <3 mL; OR 1.28 (p=0.31) for deep myometrial invasion; OR 1.21 (p=0.42) for International Federation of Gynecology and Obstetrics (FIGO) grade 3; OR 1.89 (p=0.01) for FIGO stages III-IV; OR 1.62 (p=0.07) for non-endometrioid histotype; OR 1.29 (p=0.25) for lymph-vascular space invasion; OR 4.11 (p<0.0001) for enlarged lymph nodes; and OR 1.71 (p=0.022) for lymph node involvement. CONCLUSION: Indocyanine green dose <3 mL, FIGO stage III-IV, enlarged lymph nodes, and lymph node involvement are predictive factors of sentinel lymph node failed mapping in endometrial cancer patients.

Evaluation of the one-step nucleic acid amplification method for rapid detection of lymph node metastases in endometrial cancer: prospective, multicenter, comparative study.

OBJECTIVE: To evaluate the diagnostic performance of the one-step nucleic acid amplification (OSNA) method for the detection of sentinel lymph node (SLN) metastases in women with apparent early-stage endometrial cancer compared with standard ultrastaging. METHODS: Prospective, multicentric, interventional study. Patients with apparent early-stage endometrial cancer who underwent primary surgical staging with SLN mapping were included. SLNs were serially sectioned with 2 mm slices perpendicular to the longest axis of the node: the odd slices were submitted to ultrastaging, whereas the even slices were submitted to the OSNA analysis. Diagnostic performance was calculated taking ultrastaging as referral standard. RESULTS: Three-hundred and sixteen patients with 668 SLNs were included. OSNA assay detected 22 (3.3%) positive SLNs, of which 17 (2.5%) were micrometastases and 5 (0.7%) macrometastases, whereas ultrastaging detected 24 (3.6%) positive SLNs, of which 15 (2.2%) were micrometastases and 9 (1.3%) macrometastases (p=0.48). Regarding negative SLNs, OSNA detected 646 (96.7%) negative nodes, including 8 (1.2%) isolated tumor cells, while ultrastaging detected 644 (96.4%) negative nodes with 26 (3.9%) isolated tumor cells. Specificity of OSNA was 98.4% (95% CI 97.5 to 99.4), accuracy was 96.7% (95% CI 95.4 to 98.1), sensitivity was 50% (95% CI 30.0 to 70.0), while negative predictive value was 98.1% (95% CI 97.1 to 99.2). Discordant results were found in 22 SLNs (3.3%) corresponding to 20 patients (6.3%). These were 10 (1.5%) false-positive SLNs (all micrometastases): one (0.1%) of these was a benign epithelial inclusion at ultrastaging. There were 12 (1.8%) false-negative SLNs of OSNA, of which 9 (1.3%) were micrometastases and 3 (0.5%) macrometastases. Overall, 17/668 (2.5%) benign epithelial inclusions were detected at ultrastaging. CONCLUSION: The OSNA method had high specificity and high accuracy in detecting SLN metastasis in apparent early-stage endometrial cancer. The advantage of the OSNA method could be represented as the possibility to analyze the entire lymph node thus eliminating sampling bias.

European Society of Gynaecological Oncology Guidelines for the Management of Patients with Vulvar Cancer - Update 2023.

BACKGROUND: As part of its mission to improve the quality of care for women with gynecological cancers across Europe, the European Society of Gynaecological Oncology (ESGO) first published in 2017 evidence-based guidelines for the management of patients with vulvar cancer. OBJECTIVE: To update the ESGO guidelines based on the new evidence addressing the management of vulvar cancer and to cover new topics in order to provide comprehensive guidelines on all relevant issues of diagnosis and treatment of vulvar cancer. METHODS: The ESGO Council nominated an international development group comprised of practicing clinicians who provide care to vulvar cancer patients and have demonstrated leadership through their expertize in clinical care and research, national and international engagement and profile as well as dedication to the topics addressed to serve on the expert panel (18 experts across Europe). To ensure that the statements were evidence-based, new data identified from a systematic search were reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the international development group. Prior to publication, the guidelines were reviewed by 206 international practitioners in cancer care delivery and patient representatives. RESULTS: The updated guidelines cover comprehensively diagnosis and referral, staging, pathology, pre-operative investigations, surgical management (local treatment, groin treatment, sentinel lymph node procedure, reconstructive surgery), (chemo)radiotherapy, systemic treatment, treatment of recurrent disease (vulvar, inguinal, pelvic, and distant recurrences), and follow-up. Management algorithms are also defined.

Further refining 2020 ESGO/ESTRO/ESP molecular risk classes in patients with early-stage endometrial cancer: A propensity score-matched analysis.

BACKGROUND: The integration of molecular features with clinicopathological findings in endometrial cancer classification seems to be able to significantly refine risk assessment. Nevertheless, clinical management remains challenging, and different therapeutic options are available for each class. Further prognostic characterization of the subgroups within each risk class could be helpful in the decision-making process. METHODS: This study evaluated the role of the 2020 European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) risk assessment system and the three prognostic profiles adopted in the PORTEC-4a trial in predicting disease-free and overall survival in a retrospective study cohort of patients with early-stage endometrial cancer. Patients were selected according to a 1:2 propensity score matching analysis. Moreover, the sequencing of 29 genes was undertaken for tumor samples. RESULTS: The study included 137 patients. No differences in disease-free or overall survival at 5 years were observed among the 2020 ESGO/ESTRO/ESP risk classes without molecular features (p = .766 and p = .176, respectively). Once molecular features were integrated, the probability of overall survival was significantly different (p = .011). When the three prognostic profiles were applied, the probability of recurrence had a p value of .097, and significant differences were observed in overall survival (p = .004). Among patients experiencing recurrence, 17.6% showed mutations in BRCA1/2, RAD50, BRIP1, and XRCC2, whereas 22.5% had PD-L1-positive expression and an MUTYH mutation. CONCLUSIONS: Further stratification within each risk class according to the most relevant prognostic features could better define the prognosis of patients with early-stage endometrial cancer. Nearly half of the patients who experienced recurrence showed a targetable molecular alteration for which dedicated trials should be encouraged.

Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22).

BACKGROUND: Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published. METHODS: A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®). RESULTS: A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found. CONCLUSIONS: MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics. CLINICAL TRIAL REGISTRATION: This study is registered under NCT02408536 on ClinicalTrials.gov .

A novel morphology-based risk stratification model for stage I uterine leiomyosarcoma: an analysis of 203 cases.

Uterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I, and clinical outcomes vary widely. However, no widely accepted risk stratification system for stage I uterine leiomyosarcoma is currently available. We studied 17 routinely evaluated clinicopathologic parameters in 203 stage I uterine leiomyosarcoma from three institutions to generate a novel risk stratification model for these tumors. Mitoses >25 per 2.4 mm2 (10 high-power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion, and serosal abutment were significantly associated with disease-free and disease-specific survival in univariate and multivariate analyses. These prognostic parameters were each scored as binary ("yes" or "no") variables and fitted to a single optimized algebraic risk model:Risk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4 mm2)(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)By logistic regression, the risk model was significantly associated with 5-year disease-free (AUC = 0.9270) and 5-year disease-specific survival (AUC = 0.8517). Internal and external validation substantiated the model. The continuous score (range, 0-13) was optimally divided into 3 risk groups with distinct 5-year disease-free and disease-specific survival: low risk (0-2 points), intermediate risk (3-5 points), and high risk (6-13 points) groups. Our novel risk model performed significantly better than alternative uterine leiomyosarcoma risk stratification systems in predicting 5-year disease-free and disease-specific survival in stage I tumors. A simplified risk model, omitting terms for serosal abutment and lymphovascular invasion, can be accurately applied to myomectomy or morcellated specimens. We advocate routine application of this novel risk model in stage I uterine leiomyosarcoma to facilitate patient counseling and proper risk stratification for clinical trials.

The immunohistochemical molecular risk classification in endometrial cancer: A pragmatic and high-reproducibility method.

INTRODUCTION: The aim of this study is to assess the clinical reproducibility and the potential oncological validity of the molecular information provided by the immunohistochemistry (IHC) to properly stratify the endometrial cancer patients. METHODS: Retrospective IHC analyses were conducted in a large series of 778 pre-operative uterine-confined ECs, studying the presence/absence of MLH1, MSH2, MSH6 and PMS2 to define the mismatch repair (MMR) stable or instable phenotype; the presence of p53 mutations and other molecular features. The molecular profile was correlated with histological, clinical and prognostic data. RESULTS: Based on IHC assessment, we defined 3 EC populations: stable MMR patients (MMRs), instable patients (MMRi) and p53 mutated patients (p53+). Our result demonstrated that the IHC stratification statistically correlated with the most relevant pathologic-clinical features: FIGO stage (p < 0.001), grading (p < 0.001), histotype (p < 0.001), presence of LVSI (p < 0.001), myometrial invasion and tumor dimension (p = 0.003 for both). These 3 IHC populations statistically reflected the EC risk class ESGO-ESMO-ESP classification 2021 (p < 0.001). These results were also confirmed in the Kaplan-Meier curves in terms of overall survival (OS) and disease-free survival (DFS) (p < 0.0001). The multivariate analyses demonstrated that absence of estrogen receptor (ER) impacted the OS (p = 0.011) and, the Age > 60 years and the ER-status the DFS (p = 0.041 and p = 0.004). CONCLUSION: In this large series, we demonstrated that the pragmatic and systematic use of IHC may have an important role to properly stratify, in terms of histological features and clinical outcomes, the EC patients.

Lymphovascular space invasion in endometrial carcinoma: A prognostic factor independent from molecular signature.

BACKGROUND: The 2020 ESGO/ESTRO/ESP guidelines stratify the prognosis of endometrial carcinoma (EC) patients combining The Cancer Genome ATLAS (TCGA) molecular signature and pathological factors, including lymphovascular space invasion (LVSI). However, little is known about the prognostic independence of LVSI from molecular signature. AIM: To assess whether the prognostic value of LVSI is independent from the TCGA signature. MATERIAL AND METHODS: A systematic review and meta-analysis was performed by searching 5 electronic databases from their inception to March 2021. All peer-reviewed studies reporting assessing LVSI as a prognostic factor independent from the TCGA groups in EC were included. Multivariate HRs with 95% confidence interval (CI) were pooled separately for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). The absence of LVSI was considered as a reference. In DFS analyses, locoregional and distant recurrence were separately considered for one study. RESULTS: Six studies with 3331 patients were included in the systematic review and three studies with 2276 patients in the meta-analysis. LVSI showed a pooled multivariate HR of 1.818 (CI 95%, 1.378-2.399) for OS, 1.849 (CI 95%, 1.194-2.863) for DSS, 1.377 (CI 95%, 1.008-1.880) for DFS excluding one study, 1.651 (CI 95%, 1.044-2.611) for DFS additionally considering locoregional recurrence from one study, and 1.684 (CI 95%, 1.05-2.701) for DFS additionally considering distant recurrence from the same study. CONCLUSION: LVSI has a prognostic value independent of TCGA signature, as well as age and adjuvant treatment, increasing the risk of death of any cause, death due to EC and recurrent or progressive disease by 1.5-2 times.

Clear cell carcinoma of the endometrium.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.

Clinicopathological Features Associated with Microsatellite Instability/Mismatch Repair Deficiency in Uterine Carcinosarcoma: A Quantitative Systematic Review.

INTRODUCTION: Recent studies suggested that microsatellite instability/mismatch repair deficiency (MSI/MMR-d) might define a clinicopathologically distinct subset of uterine carcinosarcomas (UCSs). OBJECTIVE: The aim of this study was to compare clinicopathological features between MSI/MMR-d and microsatellite-stable/mismatch repair-proficient (MSS/MMR-p) UCSs. METHODS: A quantitative systematic review was performed by searching electronic databases from January 2000 to January 2021. All studies assessing MSI/MMR status in UCS were included. Odds ratio (OR) with a significant two-tailed p value <0.05 was used to assess the association of MSI/MMR-d with clinicopathological features. RESULTS: Eleven studies with 783 patients were included. MSI/MMR-d was directly associated with endometrioid (pure: p < 0.001; pure + mixed: p < 0.001), undifferentiated/dedifferentiated (p < 0.001), and clear cell carcinoma component (p = 0.046), and inversely associated with age >60 (p = 0.034), serous carcinoma component (pure: p < 0.001; pure + mixed: p < 0.001), heterologous sarcoma component (p = 0.027), TP53-mutation/p53-abnormal expression (p < 0.001), and recurrence (p < 0.001). MSI/MMR-d showed no significant association with advanced FIGO stage (OR = 1.259; p = 0.517), low-grade carcinoma component (pure: p = 0.596; pure + mixed: p = 0.307), mixed carcinoma component (p = 1), and proportion of patients "dead of disease" (p = 0.352), "alive with disease" (p = 1) or with "no evidence of disease" (p = 0.458). CONCLUSION: MSI/MMR-d UCSs show younger age, more common endometrioid, undifferentiated or clear cell carcinoma component, and less common serous carcinoma component, heterologous sarcoma component, and TP53 mutation than MSS/MMR-p UCSs. Given the discrepancy between recurrence rate and oncologic outcomes at the last follow-up, further studies are necessary to define whether MSI/MMR-d UCSs have better prognosis.

Histological Prognostic Factors of Endometrial Cancer in Patients with Adenomyosis: A Systematic Review and Meta-Analysis.

BACKGROUND: A better endometrial cancer (EC) prognosis in patients with coexistent adenomyosis has been hypothesized based on a different prevalence of favorable EC histological prognostic factors. However, pooled risk of EC unfavorable histological prognostic factors in patients with adenomyosis has never been calculated. OBJECTIVES: We aimed to assess the risk of EC unfavorable histological prognostic factors in patients with adenomyosis. METHODS: All studies with data about histological prognostic factors of EC in patients with and without adenomyosis were included. Relative risk for each unfavorable histological prognostic factor of EC, such as nonendometrioid histotype, FIGO grade 3, FIGO stage II-IV, lymphovascular space invasion (LVSI), and deep myometrial invasion, was calculated in patients with adenomyosis compared to patients without adenomyosis. RESULTS: Seven studies with 4,439 patients were included in the quantitative analysis. EC patients with adenomyosis showed a pooled RR of 0.77 (p = 0.05) for nonendometrioid histotype, 0.55 (p < 0.00001) for FIGO grade 3, 0.60 (p = 0.005) for FIGO stage II-IV, 0.75 (p = 0.004) for LVSI, and 0.65 (p = 0.001) for deep myometrial invasion. CONCLUSION: EC patients with adenomyosis have a significantly decreased risk for unfavorable histological prognostic factors of EC compared to EC patients without adenomyosis. Such findings might explain the supposed better EC prognosis in patients with adenomyosis.