Molecular testing of endometrial carcinoma in real-world clinical practice.

BACKGROUND: Molecular classification has brought significant changes in the management of endometrial cancer (EC). In this article, we aim to analyze our first experience with an implementation of molecular testing into daily clinical practice. MATERIALS AND METHODS: In all newly diagnosed EC, the status of mismatch repair (MMR) and p53 proteins has been evaluated immunohistochemically as a part of the routine histopathological examination since May 2021. In tumors that do not meet clinical criteria for a low risk and those with MMR deficiency or p53 mutation, the molecular genetic testing of the POLE gene is performed as well. Recommendations for adjuvant treatment or follow-up are subsequently made based on the risk of recurrence. Genetic counselling is proposed to all patients with MMR-deficient tumors or family history of cancer. RESULTS: A total of 85 patients with newly diagnosed EC between May 2021 and May 2022 were enrolled in the analysis. The median age was 66 years. The results of molecular testing were as follows: 22 (26%) MMR-deficient, 8 (9%) p53-mutated and none POLE-ultramutated of those 40 tumors with performed POLE sequencing. A total of 46 (51%) patient had a low risk, 2 (2%) intermediate, 14 (16%) high-intermediate and 20 (24%) patients had a high risk of recurrence. Advanced or metastatic diseases were diagnosed in 6 (7%) patients. The median time between surgery and multidisciplinary tumor board decision was 21 days (8-36). A total of 76 (90%) patients underwent the whole treatment plan according to the recurrence risk. At the time of analysis, the results of genetic testing were available in 18 patients and revealed 4 (22%) carriers of a pathogenic variant in any of the genes associated with Lynch syndrome. CONCLUSION: Molecular testing combining immunohistochemical analyses of MMR and p53 proteins in all newly diagnosed EC patients with sequencing analysis of POLE in those with non-low-risk disease is feasible and does not prolong the time needed for treatment decision.

Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.

OBJECTIVE: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. METHODS: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. RESULTS: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. CONCLUSION: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.

Is the finding of endometrial hyperplasia or corporal polyp an mandatory indication for biopsy?

OBJECTIVE: The aim of our study was to analyze a group of patients referred for endometrial biopsy. To evaluate the ultrasound finding of hyperplasia/polyp, the symptomatology of patients related to the result of definitive histology, to determine the severity of individual variables in connection with the detection of precancerosis/cancer. Due to the complexity of information identify women who are suitable for conservative approach. DESIGN: Unicentric retrospective observational study. SETTING: Department of Obstetrics and Gynecology, Masaryk University, University Hospital Brno. METHODS: All patients over 50 years who underwent surgical endometrial biopsy at our department in the period of 2017-2018 (n = 754) were included. We were interested in reasons of indication, the age of patients at the time of the procedure and at the menopause, the presence of risk factors for development precancerosis/cancer (hypertension, diabetes mellitus, using of tamoxifen), number of deliveries and pregnancies, symptomatology, the description of ultrasound scans, the result of histology examination, peroperative and postoperative complications. RESULTS: Perimenopause - the median of endometrial thickness in both benign and malignant histology was 8 mm (p = 0.448), the median of the largest polyp dimension was 18 mm. All patients with precancerosis/malignancy were symptomatic with irregular/excessive bleeding, no carcinoma was found in polyp. Postmenopause - the median of endometrial thickness in benign histology was 7 mm versus 16 mm in precancerosis/malignancy (p < 0.001), the median of the largest polyp dimension was the same in both histologies (13 mm, p = 0.274). The risk of malignancy was more than threefold in bleeding versus asymptomatic patients with both hyperplasia and polyp (OR 3.39, 3.79). In asymptomatic patients the risk of cancer was similar for selected cut-offs (5, 8 and 12 mm), statistically significant only for 12 mm (OR 3.54), while in symptomatic patients the risk was high for all cut-offs, however with wide confidence intervals, statistically significant for cut-offs of 8 mm (minimum 3.58) and 12 mm (minimum 4.94). CONCLUSION: We have shown that symptomatology is a strong risk factor for the presence of precancerosis/malignancy in patients with endometrial hyperplasia or polyp. The thickness of the endometrium or polyp size in asymptomatic patients does not play a major role. Ultrasound alone does not have sufficient accuracy for detection or even screening of endometrial cancer. We recommend a conservative procedure, monitoring changes in the ultrasound scan and symptomatology of the patient over time.

The role of hormonal therapy in patients with uterine carcinoma.

OBJECTIVE: The aim of the study was to describe the role of hormonal therapy in the treatment of malignant uterine tumors, indications, the effect of the treatment and to verify its safety in our study cohort. We also present an overview of recent studies on that topic. DESIGN: Unicentric retrospective observational study and review of recent literature. SETTING: Department of Obstetrics and Gynecology, Masaryk University, University Hospital Brno. METHODS: The results of recent relevant studies and reviews published in English until December 2017 were used for the review. The publications were searched using the PubMed server. All patients diagnosed in our oncogynecological center between 2010 and 2016 and who were treated hormonally - either in primary therapy or in relapse settings, were included in our study. We were interested in age, BMI, stage of disease, histological type and grade of tumor, occurrence of adverse effects, duration of survival, reasons for choosing hormonal therapy. Medroxyprogesterone-acetate or megestrol-acetate was used in the treatment. RESULTS: Between 2010 and 2016, 415 malignant tumors of the uterus were diagnosed in our oncology center. Recurrence of the disease occurred in 31 patients (8%), on average 16 months after primary treatment. Primary hormonal therapy was used in only 19 patients (5%), mostly because of contraindications of another treatment due to high age, comorbidities or obesity. Median age of patients was 83 years, mean BMI 41, median survival of patients who died was 8 months. Five patients (16%) were treated hormonally for the recurrence. Median survival from diagnosis of recurrence was 20 months. One patient (4%) experienced partial pulmonary embolism. CONCLUSION: Hormonal therapy plays an irreplaceable role in uterine cancer patients, especially in primary non-operable patients, in treatment of a relapse, or in a fertility-sparing procedure. This treatment option is safe, with minimal adverse effects.

[Current FIGO staging classification for cancer of ovary, fallopian tube and peritoneum]. / Novinky ve FIGO stagingu karcinomu ovaria, tuby a peritonea.

INTRODUCTION: Pelvic high-grade serous carcinomas (HGSCs) include carcinoma of ovary, fallopian tube, and peritoneum. Five-year survival, irrespective of the stage, is between 35-40%. Most patients are diagnosed in advanced stages of the disease. The new revised and expanded dualistic model of ovarian carcinogenesis shows that type II tumors are composed for the most part of high-grade serous ovarian carcinoma, carcinosarcoma, undifferentiated carcinoma and can be further subdivided into morphologic and molecular subtypes. Many type II carcinomas develop from STIC predominantly in the distal portion of the fallopian tube and it is very likely the point of the origin of a significant subset of the pelvic high-grade serous carcinomas. OBJECTIVE: To provide an overview of major changes in our understanding of the origin of ovarian cancer, that led to the revision of FIGO (International Federation of Gynecology and Obstetrics) classification and its unification for the ovary, fallopian tube and peritoneum. We summarize the new classification, main changes compared to the former one and their clinical impact. METHODS: For this review, we have used the results of studies and review articles on the subject published in English up to October 2016. They were identified through a search of literature using PubMed, MEDLINE-Ovid, Scopus and Cochrane Library with the keywords ("serous tubal intraepithelial carcinoma" or "high-grade serous ovarian carcinoma" or "FIGO ovarian cancer staging 2014"). We retrieved and assessed potentially relevant studies, and checked the reference lists of all papers of interest to identify additional relevant publications. CONCLUSION: The origin of most cases of pelvic HGSC (carcinoma of ovary, the fallopian tube, and peritoneum) is expected in the fallopian tube epithelium. The main changes in the revised FIGO classification for extrauterine pelvic serous carcinomas were subdivision of stages IC, III and IV and elimination of the stage IIC, based on new knowledge and prognostic data. A prerequisite for the proper treatment of patients is to perform adequate surgical and pathological staging, including determining the grade of carcinoma. These factors, coupled with appropriately performed operation with zero postoperative residuum (R0), are the most important prognostic factors for patients with carcinoma of the ovary, fallopian tube, and peritoneum.

[Standardization of pancreatic cancer specimen pathological examination]. / Standardizace patologického vysetrení resekátu pankreatu.

INTRODUCTION: The frequency of R1 resections for pancreatic cancer in studies where a non-standardized protocol of pathological evaluation of the specimen is used varies from 17 to 30%. The aim of our study is to apply the standardized (so-called Leeds) protocol of resected pancreatic specimen pathological examination, and to evaluate the frequency of R1 resections for pancreatic cancer using this new protocol. MATERIAL AND METHODS: Ninety-one patients who underwent pancreatoduodenectomy for pancreatic cancer were included in the study. This group was divided into two subgroups: patients examined by the Leeds protocol (n=20) and those examined by a non-standardized pathological protocol (n=71). The R1 resection rate was evaluated separately in each group. The positivity rate of every individual resection margin was specified in the Leeds protocol group. The correlation of R1 resection rate and "tumour - resection margin distance" parameter was evaluated. The tumour infiltration of peripancreatic adipose tissue was assessed in the non-standardized group. RESULTS: In the Leeds protocol subgroup, R1 and R0 resection rate was 60% (12/20) and 40% (8/20), respectively. Resection line positivity rates were as follows: dorsal 45% (9/20), ventral 35% (7/20), VMS 20% (4/20), cervical 20% (4/20), AMS 15% (3/20). The correlation between the tumour - resection line distance and R1 resection frequency was the following: direct infiltration 30% R1, tumour-resection margin border 0.5 mm 50% R1, 1mm 60%, 1.5 mm 75% R1, 2 mm 80% R1, >2 mm 80% R1. If the criterion of resection line positivity ( 1mm) was set, the R1 resection rate difference between the two groups was of statistical significance. In the subgroup where the non-standardized protocol was used (n=71), R1 resection was recorded in 25 (35.2%) patients. The main cancer-positive areas were peripancreatic adipose tissue in 26.8% (19/71) of cases, and VMS, AMS or retroperitoneal line in 8.5% (6/71), respectively. R0 resection was achieved in 46 (64.8%) patients. The statistically significant (p=0.046) difference in R0 and R1 resection rates was detected (Leeds protocol and non-standardized one: R0 40.0% vs. 64.8% and R1 60.0% vs. 35.2%, respectively) in the studied groups. CONCLUSION: The rate of R1 resections for pancreatic cancer increased in all studies, including ours, where the standardized (Leeds) protocol of pancreatic specimen pathological examination was used. The higher R1 resection rate when using the Leeds protocol is approaching to the local recurrence rate of pancreatic cancer. Therefore, the Leeds protocol can provide more realistic evaluation of local radicality of pancreatoduodenectomy and can also offer more accurate evaluation of the surgical and adjuvant therapy of pancreatic cancer.

[Molecular biological diagnostics of KRAS and BRAF mutations in patients with colorectal cancer - laboratory experience]. / Molekulárne biologická diagnostika mutací genu KRAS a BRAF u pacientu s kolorektálním karcinomem - zkusenosti laboratorního pracoviste

BACKGROUND: Targeted biological therapy based on blocking growth factor receptors and inhibition of cancer-inducing signaling pathways is a new treatment facility for patients with colorectal cancer (CRC). Therapeutic agents are monoclonal antibodies targeting epidermal growth factor receptor (EGFR). Gene aberrations in the EGFR-induced pathways are negative predictors of therapeutic response. Determination of -non-mutated KRAS is a requirement for the indication of targeted anti-EGFR therapy in the present time, BRAF mutation analysis is recommended. Comparison of our results with published data and verification of routine laboratory methods in relation to diagnostic kits were the purposes of this study. PATIENTS AND METHODS: In addition to routine methods based on PCR, direct sequencing as well as two diagnostic kits for KRAS (codon 12 and 13) and BRAF (codon 600) mutation analysis were used for 132 patients. RESULTS: KRAS mutations were detected in 45 patients (34%), V600E mutation of the BRAF gene in 9 patients (7%). Both mutations simultaneously were not detected. Tissues from primary tumor and metastases were available from 33 patients. KRAS mutation was detected in 13 cases of this group. KRAS mutations in tumor and metastasis were of the same type in 9 patients; types of mutation in both tissues were different in one case. KRAS mutation only in one tissue was detected in 3 cases. BRAF mutation in both tissues was detected in the 4 patients. A low percentage of tumor cells in 17 patients specimen did not allow performance of routine analysis and diagnostic kit was used. CONCLUSION: The frequency of KRAS and BRAF mutations in our cohort of patients corresponds to published data. The suitability of metastatic tissue analysis due to tumor heterogeneity was confirmed. KRAS analysis requires a comprehensive methodological approach with regard to reduced DNA quality and different percentage of tumor cells in tissue. For this reason, commercial diagnostic kits constitute a suitable supplement to standard methods.