RESUMO
Endometrial carcinomas are histologically classified as endometrioid, assumed to originate from hyperplastic endometrium, or non-endometrioid carcinomas, assumed to originate from atrophic endometrium. However, both on a histological and a molecular level there are indications that there are more carcinoma types and carcinogenetic pathways. This study aims to analyze endometrial carcinogenesis on a molecular level. The presence of known KRAS, PIK3CA, AKT1, CTNNB1, BRAF, EGFR and NRAS mutations was studied in proliferative, atrophic and hyperplastic endometrium, endometrioid and serous carcinomas, and the endometrium next to these carcinomas, using single molecule Molecular Inversion Probes. Mutations were found in 9 (15%) of the 62 non atypical, and in 6 (18%) of the 34 atypical hyperplasia cases. In comparison, mutations were found in 1 (3%) of the simple, and 8 (30%) of the 27 complex hyperplasia cases. In 12/22 (55%) endometrioid carcinomas, a mutation was found. The KRAS gene was most often mutated in carcinomas next to hyperplastic endometrium, whereas PIK3CA and CTNNB1 mutations were found in endometrioid carcinomas with adjacent atrophic endometrium. Complex hyperplasia rather than atypical hyperplasia appears to be the most important lesion in the carcinogenesis of endometrioid carcinomas, and KRAS, PIK3CA and CTNNB1 mutations appear to play an important role in this process. Carcinogenesis of endometrioid carcinomas next to hyperplasia seems to be different to that of those next to atrophia. The value of these findings in managing endometrial hyperplasia and carcinoma should be studied.
Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Doenças Uterinas/genética , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/patologia , Classe I de Fosfatidilinositol 3-Quinases , DNA de Neoplasias/genética , Hiperplasia Endometrial/enzimologia , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Receptores ErbB/genética , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Lesões Pré-Cancerosas/enzimologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Doenças Uterinas/enzimologia , Doenças Uterinas/patologiaRESUMO
OBJECTIVE: Endometrial carcinomas are divided into type I endometrioid endometrial carcinomas (EECs), thought to arise from hyperplastic endometrium, and type II nonendometrioid endometrial carcinomas, thought to arise from atrophic endometrium. However, a minority (20%) of EECs have atrophic background endometrium, which was shown to be a marker of a worse prognosis. This study compares the immunohistochemical and genetic profiles of this possible third type to that of the known two types. METHODS: 43 patients with grade 1 EEC and hyperplastic background endometrium (type I), 43 patients with grade 1 EEC and atrophic background endometrium (type III) and 21 patients with serous carcinoma (type II) were included (n=107). Tissue microarrays of tumor samples were immunohistochemically stained for PTEN, L1CAM, ER, PR, p53, MLH1, PMS2, ß-catenin, E-cadherin and MIB1. The BRAF, KRAS, and PIK3CA genes were analyzed for mutations. RESULTS: A significantly higher expression of ER and PR, and a lower expression of L1CAM, p53 and MLH1 were found in type I and III compared to type II carcinomas. Expression of E-cadherin was significantly reduced in type III compared to type I carcinomas. Mutation analysis showed significantly less mutations of KRAS in type III compared to type I and II carcinomas (p<0.01). CONCLUSION: There appear to be slight immunohistochemical and genetic differences between EECs with hyperplastic and atrophic background endometrium. Carcinogenesis of EEC in atrophic endometrium seems to be characterized by loss of E-cadherin and a lack of KRAS mutations. As expected, endometrioid and serous carcinomas were immunohistochemically different.
Assuntos
Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Endométrio/patologia , Atrofia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Estudos de Coortes , Análise Mutacional de DNA , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Imuno-HistoquímicaRESUMO
A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and should be identified to individualize treatment. Immunohistochemical markers have been studied, but most have not been directly linked to metastasis. This study analyzes the immunohistochemical profile of endometrioid endometrial carcinomas (EECs) with and without metastases, and corresponding metastases. Tissue microarray slides from stage I EECs, stage III-IV EECs, and corresponding metastases were stained and scored for expression of ß-catenin, E-cadherin, ER, PR, PTEN, p16, MLH1, PMS2, L1CAM, p53, p21, and MIB1. Scores were compared between primary stage I and III-IV EECs, stage III-IV EECs, and the corresponding metastases, and between intra-abdominal and distant metastases. Primary tumors with distant metastases had a significantly lower ER expression than those without metastases or with intra-abdominal metastases. Distant metastases had a significantly lower PR expression than the corresponding primary tumor and intra-abdominal metastases. In contrast, p16 and PTEN expression was significantly higher in intra-abdominal metastases compared with corresponding primary tumors. Immunohistochemistry predicts both presence and location of EEC metastases. Loss of ER and PR was related to distant spread, and increased expression of PTEN and p16 was related to intra-abdominal spread. Additional research should assess the use of these markers in the diagnostic workup as well as the possibility to target metastases through these markers.
Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/imunologia , Carcinoma Endometrioide/fisiopatologia , Carcinoma Endometrioide/secundário , Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/fisiopatologia , Neoplasias do Endométrio/secundário , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores de Progesterona/metabolismo , Padrões de ReferênciaRESUMO
Whipple's disease is a multisystem, and often chronic, disease caused by infection with the bacterium Tropheryma whipplei, and mainly occurs in middle-aged Caucasian men. In most cases, histological detection of large numbers of bacteria-laden macrophages in the mucosa of the small intestine confirms the diagnosis. Less commonly, these macrophages may be sparse and predominantly located beneath the mucosa. In these submucosally presenting cases, endoscopic and classic histological clues are absent and, therefore, the diagnosis can be missed. As a result, further periodic acid-Schiff (PAS) staining and PCR analysis are of great importance in arriving at the correct diagnosis.
Assuntos
Tropheryma/isolamento & purificação , Doença de Whipple/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Diagnóstico Diferencial , Humanos , Masculino , Doença de Whipple/microbiologiaRESUMO
OBJECTIVE: Type I endometrial carcinomas are characterized by endometrioid histology, develop from hyper-plastic endometrium, and have a good prognosis. Type II, nonendometrioid carcinomas, arise in atrophic endometrium and have a poor prognosis. However, approximately 20% of cases do not fit within this dualistic model and include endometrioid carcinomas associated with recurrence and possibly with atrophy. We aimed to evaluate grade 1 endometrioid endometrial carcinomas with atrophic endometrium, a putative third type of endometrial carcinoma. METHODS: Histologic slides of all grade 1 endometrioid endometrial cancers from the Radboud University Medical Centre and Canisius-Wilhelmina Hospital from 1999-2009 and from the Mayo Clinic from 2002-2008 were reviewed. Comparisons were made between patients with atrophic and hyperplastic endometrium. RESULTS: After review, 527 patients were identified. In 88 patients (16.8%), background endometrium was atrophic and 387 patients (73.3%) had hyperplastic endometrium. Fifty-two patients (9.9%) had proliferative endometrium or no background endometrium and were excluded. Atrophy correlated with older age, low body mass index, advanced International Federation of Gynecology and Obstetrics stage, malignant cells in peritoneal cytology, lymph node metastases, cervical involvement, lymphovascular space invasion, and deep myometrial invasion. Multivariable analysis showed that age (hazard ratio 1.06, 95% confidence interval [Cl] 1.01-1.12), International Federation of Gynecology and Obstetrics stage (hazard ratio 8.47, 95% Cl 1.73-41.57), and background endometrium (hazard ratio 3.11, 95% Cl 1.11-8.70) were predictors of progression-free survival. CONCLUSION: Atrophic endometrium is an independent prognostic factor for patients with grade 1 endometrioid endometrial carcinoma. Endometrioid carcinoma with atrophy may not follow the hypothesized progression model for type I tumors and may arise through unique carcinogenic pathways. LEVEL OF EVIDENCE: II.