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2.
Gynecol Oncol ; 157(1): 245-251, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31980219

RESUMO

OBJECTIVES: To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects. METHODS: Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA. RESULTS: FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status. CONCLUSION: The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers.


Assuntos
Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Neoplasias do Endométrio/classificação , Idoso , Idoso de 80 Anos ou mais , DNA Polimerase II/genética , DNA Polimerase II/metabolismo , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/deficiência , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteína Supressora de Tumor p53/genética
3.
Gynecol Oncol ; 157(1): 252-259, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31932106

RESUMO

BACKGROUND: After the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) development, endometrial cancer (EC) may be reclassified in four novel prognostic groups: POLE-mutated (POLE-mt), mismatch-repair-deficient (MMR-d), p53-abnormal (p53abn), p53-wild-type (p53wt). However, histopathological characteristics of each ProMisE group are still undefined. Such characterization may be useful to understand how this novel molecular classifier may change the current patient management, reducing over- and undertreatment. AIM: To provide a histopathological characterization of ProMisE groups of EC, in terms of histological grade (G3 vs G1-2), histotype, lymphovascular space invasion (LVSI), deep myometrial invasion (>50%), lymph node involvement, and European Society for Medical Oncology (ESMO) risk category. MATERIALS AND METHODS: A systematic review and meta-analysis was performed by searching seven electronic databases from their inception to May 2019, for studies that reported histopathological characteristics of each ProMisE group. Pooled prevalence of each histopathological characteristic of EC in each ProMisE group was calculated. RESULTS: Four studies with 1171 patients were included in the systematic review, out of which three studies with 912 patients were included in the meta-analysis. Pooled prevalence estimates were: CONCLUSIONS: The histopathological characterization of the ProMisE groups suggests that many patients are currently undertreated or overtreated (especially in the POLE-mt and MMR-d groups).


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Carcinoma Endometrioide/classificação , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/genética , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/terapia , Feminino , Humanos , Metástase Linfática , Gradação de Tumores , Invasividade Neoplásica , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Proteína Supressora de Tumor p53/genética
4.
Am J Pathol ; 190(1): 234-251, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733184

RESUMO

Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Carcinogênese/patologia , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/patologia , Regulação Neoplásica da Expressão Gênica , Adenocarcinoma/genética , Carcinogênese/genética , Carcinoma Endometrioide/genética , Estudos de Casos e Controles , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/genética , Endométrio/metabolismo , Endométrio/patologia , Epigênese Genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Genômica , Humanos , Mutação , Prognóstico , Receptores Estrogênicos/metabolismo , Transcriptoma
5.
Am J Clin Pathol ; 153(1): 40-48, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433834

RESUMO

OBJECTIVES: To assess congruence between World Health Organization (WHO) 1994 and endometrial intraepithelial neoplasia (EIN) classification systems of endometrial hyperplasia. METHODS: Systematic review and meta-analysis were performed by searching electronic databases for studies that classified endometrial hyperplasia according to both WHO 1994 and EIN systems. Congruence was based on the rate of specimens classified as EIN in WHO categories, which should be virtually 0.000 in nonatypical hyperplasia (NAH) and 1.000 in atypical hyperplasia (AH). Subgroup analyses were performed based on architecture complexity. RESULTS: Eight studies with 1,352 hyperplasias were included. Congruence with EIN criteria was fair in NAH (0.241) and moderate in AH (0.815). Subgroup analyses of NAH showed high congruence in simple NAH (0.065), null in complex NAH (0.517), null in simple AH (0.148), and high in complex AH (0.901). CONCLUSIONS: WHO 1994 system is not congruent with the EIN system and cannot be directly translated into a dual classification.


Assuntos
Hiperplasia Endometrial/classificação , Neoplasias do Endométrio/classificação , Hiperplasia/classificação , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Hiperplasia/patologia , Organização Mundial da Saúde
7.
Int J Gynecol Pathol ; 39(1): 26-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30741844

RESUMO

Recent advances in molecular studies, especially genome-wide analyses, have revealed the landscape of genomic alterations present in endometrial carcinomas, and have provided valuable insight into the pathogenesis of this disease. The current challenges are in developing a molecular-morphologic classification system to enhance traditional pathologic diagnosis and in determining the optimal approach to using this new information to guide clinical management. Molecular assays may be particularly beneficial in allowing the earlier detection of endometrial cancer or precursor lesions and in guiding personalized treatment approaches. In this review, we describe the current molecular landscape of endometrial cancers, efforts underway to incorporate molecular alterations into the current classification systems, and the development of diagnostic tools for the early detection of endometrial cancer. Finally, we present opportunities for using these data to tailor therapeutic strategies. A comprehensive understanding of the molecular alterations responsible for the origination, relapse, and resistance patterns of this disease will ultimately improve outcomes for patients with endometrial cancer.


Assuntos
Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Terapia de Alvo Molecular , Detecção Precoce de Câncer , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Feminino , Genes Neoplásicos , Humanos , Mutação
8.
Ginekol Pol ; 90(10): 571-576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686413

RESUMO

OBJECTIVES: Endometrial cancers (ECs) are the most common gynaecological cancers in well developed countries. Diabetes and metabolic syndrome are among the biggest risk factors. Nesfatin-1, the adipokine derivative of NUCB2 (nucleobindin derivative 2) is linked to the clinical course of EC. Molecular factors, including mutations in MLH1 and MHS2 genes, c-MET and ARID1A are also related to prognosis in endometrial cancer. MATERIAL AND METHODS: Using sections of paraffin-embedded preparations and immunohistochemistry, the expression of NESF1, MLH1, MSH2,c-MET and ARID1A were examined. RESULTS: In this study on protein expression, EC tissues manifested (although insignificantly) an elevated expression of NESF-1 in type II EC. In type I EC, NESF-1 expression was significantly higher in G1 in comparison to G2 and G3 together. A significantly lower expression of MLH1 was demonstrated in type I EC. CONCLUSIONS: The most pronounced expression involved c-MET in all EC I and EC II tissues (in over 80% of cases). A tendency was detected for a high expression of NESF-1 in patients with type II EC, who also exhibited a high expression of MSH2.


Assuntos
Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/metabolismo , Nucleobindinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/química , Neoplasias do Endométrio/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Nucleobindinas/análise , Prognóstico , Estudos Retrospectivos , Fatores de Transcrição/análise , Fatores de Transcrição/metabolismo
9.
Adv Anat Pathol ; 26(6): 421-427, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31567131

RESUMO

Endometrial carcinoma has been traditionally divided into type 1 or endometrioid type that is usually moderate to well differentiated and type 2 that is usually poorly differentiated with high histologic grade and aggressive clinical behavior. However, interobserver diagnostic agreement is suboptimal, particularly among the high-grade histotypes. Furthermore, recent data indicate that this histotype assignment does not independently correlate with survival. In recent years, there has been remarkable progress in our understanding of the molecular basis of endometrial carcinoma and extensive molecular studies have been performed under The Cancer Genome Atlas Program (TCGA) leading to molecular classification of endometrial carcinoma that has been shown to be significantly prognostic. This classification system divides the tumors into 4 subgroups namely, polymerase ε exonuclease (POLE) ultramutated, hypermutated microsatellite instability, copy number low, and copy number high (serous-like). Carcinomas with POLE domain hotspot mutations are highly prognostically favorable; those with copy number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and "copy number low" endometrioid are associated with intermediate prognoses. The TCGA applied methods that are too costly and cumbersome for widespread implementation into routine clinical practice. Several other groups have attempted to identify these categories by using immunohistochemical biomarkers rather than molecular studies. Immunohistochemical biomarkers have been used successfully to identify all the subgroups except for POLE ultramutated, which requires sequencing for proper categorization. It is hoped that future studies will identify a suitable biomarker for POLE mutation so that this classification can be routinely used in all medical centers.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/diagnóstico , Feminino , Humanos , Instabilidade de Microssatélites , Mutação/genética , Prognóstico
10.
Int J Gynecol Cancer ; 29(7): 1086-1093, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31474587

RESUMO

BACKGROUND: Randomized trials describe differing sets of high-intermediate risk criteria. OBJECTIVE: To use the National Cancer Database to compare the impact of radiation therapy in patients with stage I endometrial cancer meeting different criteria, and define a classification of "unfavorable risk." METHODS: Patients with stage I endometrial cancer between January 2010 and December 2014 were identified in the National Cancer Database and stratified into two cohorts: (1) patients meeting Gynecologic Oncology Group (GOG)-99 criteria only for high-intermediate risk, but not Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 criteria and (2) those meeting PORTEC-1 criteria only. High-risk stage I patients with both FIGO stage IB (under FIGO 2009 staging) and grade 3 disease were excluded. In each cohort, propensity score-matched survival analyses were performed. Based on these analyses, we propose a new classification of unfavorable risk. We then analyzed the association of adjuvant radiation with survival, stratified by this classification. RESULTS: We identified 117,272 patients with stage I endometrial cancer. Of these, 11,207 patients met GOG-99 criteria only and 5,920 patients met PORTEC-1 criteria only. After propensity score matching, adjuvant radiation therapy improved survival (HR=0.73; 95% CI 0.60 to 0.89; p=0.002) in the GOG-99 only cohort. However, there was no benefit of adjuvant radiation (HR=0.89; 95% CI 0.69 to 1.14; p=0.355) in the PORTEC-1 only cohort. We, therefore, defined unfavorable risk stage I endometrial cancer as two or more of the following risk factors: lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB. Adjuvant radiation improved survival in stage I patients with adverse risk factors (HR=0.74; 95% CI 0.68 to 0.80; p<0.001), but not in other stage I patients (HR=1.02; 95% CI 0.91 to 1.15; p=0.710; p interaction <0.001). CONCLUSION: Our study showed that adjuvant radiation was associated with an overall survival benefit in patients meeting GOG-99 criteria only; however, no survival benefit was seen in patients meeting PORTEC-1 criteria only. We propose a definition of unfavorable risk stage I endometrial cancer: ≥2 risk factors from among lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB disease.


Assuntos
Neoplasias do Endométrio/classificação , Idoso , Estudos de Coortes , Bases de Dados Factuais , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco/métodos , Análise de Sobrevida
12.
Clin Cancer Res ; 25(24): 7517-7526, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31492746

RESUMO

PURPOSE: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. EXPERIMENTAL DESIGN: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic." RESULTS: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%). CONCLUSIONS: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Adulto , Idoso , Estudos de Coortes , Neoplasias do Endométrio/classificação , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores
13.
Curr Opin Oncol ; 31(5): 411-419, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31261170

RESUMO

PURPOSE OF REVIEW: Currently, endometrial carcinoma diagnosis is based on morphology, often supplemented by immunohistochemistry. However, especially with high-grade endometrial carcinomas, there is considerable interobserver variability in diagnosis calling into question the value of morphology in stratifying these tumours into different prognostic and therapeutic groups. The purpose of this review is to provide an update on the recently described molecular classification of endometrial carcinoma. RECENT FINDINGS: In 2013, the Cancer Genome Atlas (TCGA) published a seminal molecular study of endometrial carcinomas of endometrioid, serous and mixed types. This revealed that endometrial carcinoma consists of four intrinsic molecular subtypes: POLE (ultramutated), microsatellite instabilty (hypermutated), copy-number low (also referred to as microsatellite stable or no specific molecular profile) and copy-number high (serous-like). These four molecular subtypes are of prognostic significance with POLE tumours having the best and copy-number high, the worst prognosis. SUMMARY: It is likely that TCGA classification will become the mainstay of endometrial carcinoma diagnosis in the coming years and various strategies (Proactive Molecular Risk Classifier for Endometrial Cancer and the TransPORTEC classifiers) have been proposed for a combined morphological-molecular classification which can be undertaken in most pathology laboratories. This will necessitate routine undertaking of POLE mutation analysis in some endometrial carcinomas and require an appropriate infrastructure.


Assuntos
Neoplasias do Endométrio/classificação , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Mutação , Gradação de Tumores , Proteínas de Ligação a Poli-ADP-Ribose/genética
14.
J Gynecol Obstet Hum Reprod ; 48(10): 863-871, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31176047

RESUMO

INTRODUCTION: Endometrial cancer (EC) is a major cause of mortality worldwide with nearly 200 000 cases diagnosed annually. The recent ESMO-ESGO-ESTRO guidelines include a new classification defining a heterogeneous high-risk group of recurrence (HR) comprising: (i) endometrioid (type 1) FIGO stage IB grade 3 tumors (type 1/G3ECs), (ii) non-endometrioid tumors (type 2) and (iii) advanced stages whatever the histological type (Colombo et al., 2016). AREAS COVERED: The aim of this review is to summarize current evidence for therapeutic approaches in HR-EC according to the updated ESMO-ESGO-ESTRO classification by discussing the following issues: i) HR-EC heterogeneity, (ii) prognostic factors and current classification, and (iii) optimal staging strategies (site and extent) and the role of adjuvant treatment. EXPERT COMMENTARY: HR-EC treatment is based on surgery, radiation therapy, brachytherapy, and chemotherapy, either alone or sequentially, in combination with other treatments depending on disease stage, histological grade and risk group. Specific trials are needed to establish the role of systematic pelvic and paraaortic lymphadenectomy, adjuvant therapies and targeted drugs. Although molecular characterization has been reported to customize therapeutic strategies and thereby improve therapeutic outcomes in EC, none of the targeted agents investigated (antiangiogenic and mTOR/PI3K pathway inhibitor agents) have resulted in a change in clinical practice in HR-EC.


Assuntos
Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/terapia , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/terapia , Guias de Prática Clínica como Assunto , Quimioterapia Adjuvante/métodos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante/métodos
15.
Gynecol Oncol ; 154(3): 467-474, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31248668

RESUMO

BACKGROUND: The current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma. MATERIALS AND METHODS: Fifty biopsies with corresponding hysterectomy specimens for endometrial carcinomas were collected. Additionally, 10 cases of biopsy proven atypical hyperplasia/EIN who were found to have endometrial carcinoma on resection were included. IHC for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) and P53 was performed. Microsatellite instability analysis was performed by PCR and Sanger sequencing was performed to detect mutations in exons 9 and 13 of the POLE gene. The level of concordance for tumor grade, histologic subtype, immunohistochemical and molecular profile in both specimens was determined using Cohen's kappa estimates. RESULTS: A high level of concordance was achieved for MMR-loss, MSI-high, P53-wild and abnormal types. In contrast, grade and histologic subtype showed only moderate levels of agreement. POLE gene mutation was detected in two patients. For both cases, mutations were detected only in resection specimens. When comparing atypical hyperplasia/EIN with subsequent hysterectomy tumor, the profile was identical to that of endometrial carcinoma. CONCLUSION: In our cohort of endometrial carcinoma, a high level of concordance was achieved between biopsy and hysterectomy specimens for MMR-loss, MSI-high, P53-wild and abnormal types, superior to that of grade and histologic subtype, providing earlier and more reliable prognostic information to inform management. Similar concordance could not be achieved for POLE mutation, given the low frequency of this mutation in our study.


Assuntos
Neoplasias do Endométrio/classificação , Medicina de Precisão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Histerectomia , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Gradação de Tumores
16.
Gynecol Oncol ; 153(3): 487-495, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30922603

RESUMO

OBJECTIVE: Approximately 15% of endometrial carcinomas (ECs) arise in young women who may wish to avoid surgical menopause and/or preserve fertility. Our aim was to evaluate the prognostic significance of Proactive Molecular risk classifier for Endometrial Carcinoma (ProMisE) in young (<50 yo) women with EC. METHODS: ProMisE was applied to a retrospective cohort of women with ECs <50 yo at diagnosis, and associations between the four ProMisE molecular subtypes (MMR deficient (MMRd), POLE mutated (POLE), p53 wild type (p53wt), and p53 abnormal (p53abn)) and clinicopathological parameters, including outcomes, were assessed. RESULTS: Of 257 ECs, there were 48 (19%) MMRd, 34 (13%) POLE, 164 (64%) p53wt and 11 (4%) p53abn. ProMisE subtypes were associated with differences in all measured clinicopathological parameters except for presence of synchronous ovarian tumours and fertility. Age at diagnosis was youngest and BMI highest in women with p53wt ECs. MMRd and p53abn tumours were more likely to be advanced stage (III/IV), high-risk (ESMO), and receive chemotherapy. ProMisE subtypes were strongly associated with outcomes (overall, disease-specific, and progression-free survival (p < 0.0001 for all)). Advanced stage, grade, LVSI, myometrial invasion and ESMO risk groups showed associations with some but not all survival parameters. ProMisE maintained a strong association with OS and DSS on multivariable analysis. CONCLUSIONS: ProMisE molecular classification is prognostic in young women with EC, enabling early stratification and risk assignment to direct care. Further studies can assess response to therapy, fertility, and cancer-related outcomes within the framework of molecular subtype.


Assuntos
Carcinoma/classificação , DNA Polimerase II/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/classificação , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteína Supressora de Tumor p53/metabolismo , Adulto , Fatores Etários , Índice de Massa Corporal , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/secundário , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida
17.
Arch Gynecol Obstet ; 299(5): 1233-1242, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30810881

RESUMO

PURPOSE: Benign and precancerous endometrial hyperplasias (EH) are differentiated thorough two possible histomorphologic classifications: WHO (adopting the subjective evaluation of cytologic atypia) and EIN (adopting several histomorphologic parameters, evaluable subjectively, or objectively with a computerized analysis calculating a prognostic score, the D score). ACOG recommends the use of EIN system although no distinction was made between objective assessment (not widely available), and subjective assessment (more applicable in the common practice). Moreover, it is still unclear if subjective EIN system is actually preferable to WHO classification. We aimed to assess the reliability of WHO system, D score and subjective EIN system in stratifying the risk of progression to cancer in EH. METHODS: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Cochrane Library and Google Scholar were searched for relevant articles from the inception to August 2018. All studies assessing the rates of progression of EH to cancer were included. RESULTS: Twelve cohort studies and one case-control study, assessing 3629 EH, were included. Relative risk (RR) for cancer progression was calculated with 95% confidence interval (CI), and results were compared using Chi-square test (significant p value < 0.05). WHO system showed a RR of 8.74 (95% CI 6.66-11.47). Objective D score showed a RR of 29.22 (95% CI 13.24-64.51), significantly higher than WHO (p = 0.005). Subjective EIN system showed a RR of 19.37 (95% CI 5.86-64.01), intermediate between WHO and D score, without significant differences (p = 0.20 and p = 0.57, respectively). CONCLUSION: Objective EIN criteria with D score are significantly more reliable than WHO criteria in stratifying the risk of progression of EH to cancer. Subjective EIN criteria did not show significant superiority over WHO instead. Further studies are necessary to determine if subjective EIN system should replace WHO system in the routine diagnosis of EH.


Assuntos
Hiperplasia Endometrial/classificação , Hiperplasia Endometrial/diagnóstico , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/diagnóstico , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Lesões Pré-Cancerosas , Prognóstico , Estudos Retrospectivos
18.
APMIS ; 127(6): 427-434, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30802329

RESUMO

The 2014 World Health Organization (WHO) classification of endometrial hyperplasia (EH) defines premalignant EH based on only cytologic atypia, disregarding architecture complexity. We aimed to assess the impact of architecture complexity on the risk of cancer in non-atypical EH. A systematic review and meta-analysis was performed by searching electronic databases form their inception to October 2018. All studies assessing the rates of progression to cancer in non-atypical EH (simple vs complex) were included. Pooled relative risk (RR) for cancer progression was calculated; a p-value < 0.05 was considered significant. Eight studies with 1066 women were included. The risk for progression of non-atypical EH to cancer was significantly higher in complex EH than in simple EH (p < 0.0001), with an RR of 4.90. In conclusion, the complexity of glandular architecture significantly increases the risk of cancer in non-atypical EH. Complex non-atypical EH may be regarded as a low-risk premalignant lesion rather than a benign condition.


Assuntos
Hiperplasia Endometrial/classificação , Viés , Hiperplasia Endometrial/patologia , Hiperplasia Endometrial/terapia , Neoplasias do Endométrio/classificação , Feminino , Humanos , Lesões Pré-Cancerosas/classificação , Organização Mundial da Saúde
19.
Int J Gynecol Cancer ; 29(2): 290-298, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30718311

RESUMO

OBJECTIVE: To evaluate the risk of a second primary cancer after endometrial cancer according to histological subtype. METHODS: Using data from the 13 National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registries we identified women diagnosed with a primary endometrial cancer between 1992 and 2014. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for second primary cancer risk (all anatomical sites combined and for individual anatomical sites) among patients with endometrial cancer compared with the general population, in the overall study population and according to histological subtype. RESULTS: Among 96 256 women diagnosed with endometrial cancer, 8.4% (n=8083) developed a second primary cancer. The risk of second primary cancer was higher among patients with endometrial cancer than in the general population (SIR=1.05, 95% CI 1.03 to 1.07). We observed significantly higher second primary cancer risk among women with high grade endometrioid (SIR=1.12, 95% CI 1.05 to 1.19), serous (SIR=1.24, 95% CI 1.11 to 1.38), carcinosarcoma (SIR=1.18, 95% CI 1.02 to 1.35), mixed epithelial (SIR=1.22, 95% CI 1.06 to 1.40), and sarcoma (SIR=1.28, 95% CI 1.12 to 1.45) compared with the general population, but not for women with low grade endometrioid (SIR=1.01, 95% CI 0.98 to 1.03) or clear cell (SIR=1.09, 95% CI 0.88 to 1.33) endometrial cancer. Women with low grade endometrioid endometrial cancer had significantly lower second primary cancer risks in the gum and other mouth (SIR=0.57, 95% CI 0.30 to 0.97), lung and bronchus (SIR=0.72, 95% CI 0.66 to 0.77), and lymphocytic leukemia (SIR=0.71, 95% CI 0.54 to 0.93) while women with high risk endometrial cancer histological subtypes experienced significantly higher second primary cancer risk at several anatomical sites. CONCLUSIONS: Risk of developing second primary cancersat all anatomic sites combined and at individual anatomical sites varied according to histological subtype. Clinicians should be aware that women with different histological subtypes carry different second primary cancer risks .


Assuntos
Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/patologia , Segunda Neoplasia Primária/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Ohio/epidemiologia , Prognóstico , Fatores de Risco , Programa de SEER , Adulto Jovem
20.
Gynecol Obstet Invest ; 84(3): 290-297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30602164

RESUMO

AIMS: To compare baseline risk factors for type 1 vs. 2 endometrial cancers and analyze these risk factors for association with overall survival and time to recurrence. METHODS: Retrospective review of 816 consecutive endometrial cancer cases was conducted with diagnosis from January 2005 to December 2010 and clinical course until 2016. Risk factors, treatment, recurrence, and death were compared using 2 sample t tests, χ2 test and Cox Regression models. RESULTS: There were 550 cases of type 1 and 266 cases of type 2 cancer. Patients with type 2 disease were older (p < 0.001), less obese (p = 0.03), non-white (p < 0.001), and menopausal (p = 0.02). There was no difference in use of oral contraceptives, hormone replacement therapy (HRT), smoking, or major cardiovascular disease. Cox Regression models showed that type 2 disease (p < 0.001) and advanced stage (p = 0.001) were associated with recurrence. CONCLUSIONS: Consistent with previous literature, our analysis found that type 2 cancer is more common in non-white, older, and less obese patients and associated with higher mortality and recurrence. However, inconsistent with previous literature, we found no association between type 2 cancer and diabetes mellitus or use of HRT. These factors should be considered when approaching patients with endometrial cancer.


Assuntos
Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/epidemiologia , Adulto , Fatores Etários , Idoso , Anticoncepcionais Orais , Neoplasias do Endométrio/terapia , Grupos Étnicos , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Menopausa , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Obesidade/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
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