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2.
Sci Rep ; 9(1): 2996, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816121

RESUMO

The presence of leukocyte subpopulations in malignant pleural effusions (MPEs) can have a different impact on tumor cell proliferation and vascular leakiness, their analysis can help to understand the metastatic microenvironment. We analyzed the relationship between the leukocyte subpopulation counts per ml of pleural fluid and the tumor cell count, molecular phenotype of lung adenocarcinoma (LAC), time from cancer diagnosis and previous oncologic therapy. We also evaluated the leukocyte composition of MPEs as a biomarker of prognosis. We determined CD4+ T, CD8+ T and CD20+ B cells, monocytes and neutrophils per ml in pleural effusions of 22 LAC and 10 heart failure (HF) patients by flow cytometry. Tumor cells were identified by morphology and CD326 expression. IFNγ, IL-10 and IL-17, and chemokines were determined by ELISAs and migratory response to pleural fluids by transwell assays. MPEs from LAC patients had more CD8+ T lymphocytes and a tendency to more CD4+ T and CD20+ B lymphocytes than HF-related fluids. However, no correlation was found between lymphocytes and tumor cells. In those MPEs which were detected >1 month from LAC diagnosis, there was a negative correlation between pleural tumor cells and CD8+ T lymphocytes. CXCL10 was responsible for the attraction of CD20+ B, CD4+ T and CD8+ T lymphocytes in malignant fluids. Concentrations of IL-17 were higher in MPEs than in HF-related effusions. Survival after MPE diagnosis correlated positively with CD4+ T and CD8+ T lymphocytes, but negatively with neutrophils and IL-17 levels. In conclusion, lymphocyte enrichment in MPEs from LAC patients is mostly due to local migration and increases patient survival.

3.
Hum Pathol ; 80: 11-27, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29944973

RESUMO

Based on histopathology and molecular genetics, ovarian carcinomas are divided into five main types: high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous (<5%) carcinomas. These tumors, which account for over 95% of cases, represent distinct diseases with different prognoses and treatments. TP53 mutations are identified in almost all (96%) high-grade serous carcinomas (HGSCs). Early p53 loss followed by BRCA loss leads to deficiency in homologous recombination (DHR) repair, which in turn triggers chromosomal instability and widespread somatic copy number changes. An undetermined number of cases of HGSCs originate in the tubal fimbria; however, an origin from the ovarian surface epithelium cannot be totally excluded. Low-grade serous carcinomas (LGSCs) most likely represent progression of SBTs. BRAF or KRAS mutations occur in one-third to one-half of cases. Mucinous carcinomas (MCs) typically show benign-appearing, borderline, non-invasive and invasive components indicating tumor progression. KRAS mutations occur in 43.6% of cases and overexpression/amplification of HER2 in 18.8%. Endometrioid and clear cell carcinomas (EC and CCC) originate from ovarian endometriosis. Compared with their uterine counterparts, ECs have a similar frequency of ß-catenin abnormalities but lower rate of microsatellite instability (MI) and PTEN alterations. ARID1A mutations occur in both ECs (30%) and CCCs (50%) and may be encountered in adjacent endometriosis. CCCs carry inactivating PTEN mutations and activating mutations in PIK3CA in 8% and 33% of cases, respectively. This review summarizes recent advances in the molecular pathology, which have greatly improved our understanding of the biology of ovarian carcinomas and are also relevant to patient management.


Assuntos
Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/patologia , Neoplasias Ovarianas/patologia , Neoplasias Uterinas/patologia , Adenocarcinoma de Células Claras/genética , Adenocarcinoma Mucinoso/genética , Animais , Feminino , Humanos , Mutação/genética , Neoplasias Ovarianas/genética , Patologia Molecular/métodos , Neoplasias Uterinas/genética
4.
Hum Pathol ; 71: 65-73, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29079180

RESUMO

Recently, we reported 2 mixed endometrioid endometrial carcinomas with a "low-grade serous"-like component, which does not fit into any of the 4 molecular groups described by The Cancer Genome Atlas. To understand the nature of these tumors, we have done an immunohistochemical and molecular genetic study of these 2 cases and added a third case. Immunoreactivity for p53, ER, Ki67, WT1, MLH1, PMS2, MSH2, and MSH6 was assessed. Targeted next-generation sequencing for somatic mutations, including genes commonly implicated in carcinogenesis including TP53, KRAS, and PIK3CA, and Sanger sequencing for PTEN and POLE were also performed. All patients were nulliparous and had morbid obesity. Their tumors showed a micropapillary component that resembled that of ovarian low-grade serous carcinoma and merged with villoglandular endometrioid carcinoma. The invasive tumor glands exhibited a microcystic, elongated, or fragmented pattern and contained psammoma bodies. Two tumors showed aberrant p53 expression, and all 3 were positive for ER. All showed KRAS mutations, and TP53 mutations were found in 2 cases. One patient developed peritoneal carcinomatosis, one patient is alive with disease, and another died of a brain tumor. The third patient, whose tumor was confined to the uterus (stage IA), is alive without evidence of disease, but she has been followed for only 6 months. Mixed endometrial carcinomas with a "low-grade" serous-like component exhibit a morphologic spectrum of endometrioid and serous differentiation with microcystic, elongated, or fragmented features; ER expression; KRAS and TP53 mutations; and aggressive behavior.


Assuntos
Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Neoplasias Complexas Mistas/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma Endometrioide/genética , Cistadenocarcinoma Seroso/genética , Análise Mutacional de DNA , Neoplasias do Endométrio/genética , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Neoplasias Complexas Mistas/genética , Neoplasias Ovarianas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores Estrogênicos/biossíntese , Proteína Supressora de Tumor p53/genética
5.
Hum Pathol ; 72: 100-106, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29133142

RESUMO

Undifferentiated endometrial carcinoma is an aggressive type of uterine cancer, which is occasionally associated with a low-grade endometrioid carcinoma component. This combination is referred to as "dedifferentiated endometrioid endometrial carcinoma." Neuroendocrine expression may occur in undifferentiated endometrial carcinoma, but its significance in dedifferentiated endometrial carcinomas is unknown. To gain insight into the pathogenesis of these tumors we have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, ß-catenin, SMARCB1, synaptophysin, chromogranin A, and CD56) and mutational status (PTEN, KRAS, PIK3CA, TP53 and POLE) of 4 dedifferentiated endometrial carcinomas with strong and diffuse neuroendocrine expression. All tumors demonstrated neuroendocrine expression in ≥70% of the cells in the undifferentiated carcinoma areas. Loss of expression of at least 1 DNA mismatch repair protein was observed in 2 cases, and p53 immunoreaction was aberrant (mutated/inactivated) in one case. All carcinomas were negative for ß-catenin and maintained nuclear SMARCB1 (INI1) and ARID1A expression. Three tumors shared identical endometrioid molecular profile (PTEN and/or PIK3CA mutations) in both components. One tumor had POLE exonuclease domain mutation in the undifferentiated component. In one case, TP53 mutation was found exclusively in the undifferentiated component. Two patients died with peritoneal carcinomatosis and abdominal metastases, respectively; one patient died of a renal failure without evidence of disease, and the last patient is alive and free of disease at 3.3 years. Dedifferentiated endometrial carcinomas with neuroendocrine features are clinically and molecularly heterogeneous tumors. Probably, these carcinomas might acquire undifferentiated phenotype through mutations in TP53 and POLE.


Assuntos
Carcinoma Endometrioide/patologia , DNA Polimerase II/genética , Neoplasias do Endométrio/patologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , Neoplasias Uterinas/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Mutação/genética , Proteínas Nucleares/metabolismo , Proteína SMARCB1/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética
6.
Hum Pathol ; 70: 6-13, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28601659

RESUMO

In endometrioid endometrial carcinomas (EECs), microcystic, elongated, and fragmented (MELF) myoinvasion is associated with easily overlooked lymph node metastases; however, the role of immunohistochemistry in their detection and their clinical significance have not been addressed. We identified MELF in 43 of 101 (43%) myoinvasive EECs. Nodes were removed in 49 (49%), 25 with MELF and 24 without MELF. Metastases were initially reported in 3 of the former (12%) and 2 of the latter (8%). All negative nodes were reviewed, and cytokeratin immunohistochemistry was performed. Three metastases were identified in the MELF group but none in the EECs without MELF. By immunohistochemistry, metastatic nodal isolated tumor cells (ITCs) were found in 6 of the remaining 19 MELF-positive cases. In contrast, lymph node metastases were detected in only 2 of the 22 EECs without MELF. MELF-positive cases had more lymph node metastases (P=.03) than myoinvasive EECs without MELF. At follow-up, all 6 patients with grade 1-2 EECs and nodal ITCs/micrometastases were alive (5 no evidence of disease and 1 with perineal disease). In contrast, 3 of 4 patients with grade 3 EECs and nodal ITCs/micrometastases died of disease, and the other patient was alive with tumor. In MELF, the frequency of ITCs/micrometastases in apparently negative lymph nodes is high. In patients with grade 1-2 EEC who had not received chemotherapy, the presence of nodal ITCs/micrometastases did not affect survival. In contrast, in high-grade tumors, ITCs/micrometastases were associated with unfavorable prognosis. Immunohistochemistry should be done in MELF-positive cases to detect occult lymph node metastases, especially in high-grade tumors.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Carcinoma Endometrioide/secundário , Neoplasias do Endométrio/química , Neoplasias do Endométrio/patologia , Imuno-Histoquímica , Linfonodos/química , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Miométrio/química , Miométrio/patologia , Gradação de Tumores , Invasividade Neoplásica , Micrometástase de Neoplasia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
7.
Am J Surg Pathol ; 41(8): 1121-1128, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28498284

RESUMO

POLE exonuclease domain mutations have recently been described in undifferentiated endometrial carcinoma but, because of the rarity of this aggressive type of endometrial cancer, their prognostic significance is unknown. We have analyzed the immunophenotype (ARID1A, MLH1, PMS2, MSH2, MSH6, p53, ß-catenin, and SMARCB1) and mutational status (POLE, PIK3CA, and PTEN) of 21 undifferentiated carcinomas (8 undifferentiated and 13 dedifferentiated carcinomas). Loss of ARID1A expression was observed in 9 of 19 cases (47%), loss of expression of at least 1 DNA mismatch repair protein in 7 (7/21; 33%), and p53 immunoreaction was aberrant (mutated/inactivated) in 11 cases (11/21; 52%). All tumors were negative for ß-catenin. Normal nuclear SMARCB1 (INI1) staining was found in all but 1 dedifferentiated case. Two undifferentiated and 7 dedifferentiated carcinomas showed POLE exonuclease domain mutations (9/21; 42%). PIK3CA mutations occurred in six tumors (6/21; 28%) (2 undifferentiated and 4 dedifferentiated carcinomas). PTEN mutations were found in 7 of 15 cases (47%) (4 undifferentiated and 3 dedifferentiated carcinomas). POLE-mutated undifferentiated and dedifferentiated endometrial carcinomas were more frequently stage I tumors than similar carcinomas lacking exonuclease domain mutations (7/9; 78% vs. 3/12; 25%; P=0.023) and patients had significantly better outcome (disease-specific survival) than those without POLE exonuclease domain mutations (P=0.02). Determination of the POLE mutation status is important for the management of these patients.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Desdiferenciação Celular , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação , Adulto , Idoso , Exonucleases , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico
8.
Hum Pathol ; 56: 180-8, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27346574

RESUMO

Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti-tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group. Tumor and non-tumoral endometrium samples were obtained. Immunohistochemistry revealed a high number of CTLs and T helper lymphocytes in the tumor stroma of myoinvasive EECs. T lymphocytes were mostly located in the invasive front. By flow cytometry, the percentages of CTLs and T helper lymphocytes were significantly higher in the tumor compared with the non-neoplastic endometrium (P = .0492 and P = .002). The mean fluorescence intensity of CD8 staining was lower in the tumor compared to the non-neoplastic endometrium (P = .001). There was also reduction of the mean fluorescence intensity of CD8 staining on peripheral blood from patients with grade 3 EECs compare to the peripheral blood from healthy donors (P = .0093). No alterations in the expression of granzymes A and B were found in the CTLs from the EEC cases. Finally, in a proteome profiler cytokine array we found that the growth differentiation factor 15 (GDF15) increased in blood in parallel to the tumor grade. EECs are capable of down-regulating CD8 expression of CTLs. Most likely, this effect is mediated by a soluble molecule present in plasma and is not a result of anergy or exhaustion state.


Assuntos
Biomarcadores Tumorais/análise , Antígenos CD8/análise , Carcinoma Endometrioide/imunologia , Neoplasias do Endométrio/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Endometrioide/sangue , Carcinoma Endometrioide/patologia , Citocinas/sangue , Regulação para Baixo , Neoplasias do Endométrio/sangue , Neoplasias do Endométrio/patologia , Feminino , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Linfócitos T Citotóxicos/patologia , Microambiente Tumoral
9.
Am J Surg Pathol ; 40(7): 972-81, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26975040

RESUMO

Besides endometrioid, serous, and clear cell carcinomas, there are endometrial carcinomas exhibiting mixed and ambiguous morphologic features. We have analyzed the immunophenotype (p53, p16, ß-catenin, ER, HNF-1B, MLH1, and Ki-67) and mutational status (PTEN, KRAS, PIK3CA, and POLE) of 7 mixed carcinomas and 13 ambiguous carcinomas, all of them classified initially as mixed carcinomas. Only 2 of the 7 (28%) mixed carcinomas showed different immunophenotypes in different components. All but 2 tumors (5/7, 71%) overexpressed p53 and p16 and were negative for ER. Both carcinomas (2/7, 28%) showed a prominent micropapillary component that resembled an ovarian low-grade serous carcinoma and merged with villoglandular endometrioid carcinoma. The ambiguous carcinomas exhibited glandular architecture, high nuclear grade, and overlapping features of endometrioid and serous carcinomas. All tumors overexpressed p53 and p16, and the majority of cases (12/13, 92%) were negative for ER. KRAS mutations were identified in 3 of 7 (42%) mixed carcinomas, including the 2 cases with a "low-grade" serous-like component. PIK3CA mutations occurred in 2 (2/13, 15%) ambiguous carcinomas and PTEN mutations in 1 (1/7, 14%) mixed and 1 (1/13, 8%) ambiguous carcinoma. POLE exonuclease domain mutations were encountered in a case of mixed undifferentiated and well-differentiated (dedifferentiated) carcinoma. Two of the 7 (29%) mixed endometrial carcinomas and 5 of the 13 (38%) ambiguous carcinomas had extended beyond the pelvis (stages III and IV). Two of the 7 (29%) patients with mixed endometrial carcinoma and 6 of 12 (50%) patients with ambiguous endometrial carcinoma were alive with disease or had died of tumor. Our results show that, biologically, many so-called mixed carcinomas represent serous carcinomas with ambiguous morphology. Our series include 2 true mixed endometrial carcinomas with a "low-grade serous"-like component, microcystic, elongated, or fragmented features, KRAS mutations, and aggressive behavior.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
10.
Clin Cancer Res ; 21(15): 3501-11, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25896974

RESUMO

PURPOSE: Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. EXPERIMENTAL DESIGN: Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes. RESULTS: We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies. CONCLUSIONS: We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach.


Assuntos
Biomarcadores Tumorais/biossíntese , Leiomiossarcoma/genética , Proteínas de Neoplasias/biossíntese , Prognóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomiossarcoma/classificação , Leiomiossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Análise Serial de Tecidos
11.
Int J Gynecol Pathol ; 34(3): 257-65, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25844549

RESUMO

Breast carcinomas rarely metastasize to the ovary and are even more rarely present clinically as primary ovarian tumors. However, patients with breast cancer not infrequently develop independent primary ovarian carcinomas. In these cases, distinction between independent primaries and metastatic tumors is crucial. Several comparative immunohistochemical studies have been reported, but few included significant clinicopathologic data and none investigated cases of ovarian and breast carcinomas from the same patients. In this study, we compared 18 cases of patients with bona fide independent breast and ovarian carcinomas (15 high-grade serous and 3 clear cell carcinomas), with 9 cases of patients with known mammary carcinomas (7 lobular and 2 ductal carcinomas) metastatic to the ovary. Immunohistochemical stains for Pax-8, WT-1, and GATA3 were carried out on tissue microarrays (TMA). Most primary ovarian carcinomas were larger than the metastatic tumors (P=0.001) and were diagnosed at an advanced stage. All primary ovarian tumors showed marked nuclear pleomorphism, whereas only 2 metastatic breast carcinomas had Grade 3 nuclei (P=0.000). The vast majority of ovarian metastases (7/9) showed the typical pattern of lobular breast carcinoma. Pax-8 and WT-1 expression were found in 16 of 18 (88%) and 13 of 18 (72%) primary ovarian carcinomas, respectively. In contrast, all primary ovarian carcinomas were negative for GATA3. The 2 Pax-8-negative ovarian carcinomas were also negative for WT-1. With the exception of 3 triple-negative carcinomas, all primary breast carcinomas were positive for GATA3. All metastatic breast carcinomas were positive for GATA3 and negative for Pax-8. WT-1 expression was seen in only 1 of 9 metastatic breast carcinomas (11%). Patients with ovarian metastases had worse prognosis than patients with independent breast and ovarian carcinomas (P=0.000). Pax-8, WT-1, and GATA3 immunoreactions are useful in the distinction between independent primaries and metastatic mammary carcinomas to the ovary in the light of clinicopathologic findings.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Metástase Neoplásica/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/análise , Fator de Transcrição GATA3/biossíntese , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados/análise , Fatores de Transcrição Box Pareados/biossíntese , Análise Serial de Tecidos , Proteínas WT1/análise , Proteínas WT1/biossíntese
12.
Hum Pathol ; 45(5): 942-51, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24746199

RESUMO

Micro-RNA (miRNA) signatures influence the prognosis of cancer, but little is known about their role in myometrial invasion in endometrioid endometrial adenocarcinoma (EEC). We studied miRNA expression signatures in noninvasive and invasive EEC focusing on the alteration of miR-27 and its main target, FOXO1 as well as their relationship with the clinicopathological parameters and other genetic alterations such as PIK3CA mutations. In 25 tumors and 5 normal endometria, unsupervised hierarchical clustering analysis showed that normal endometria and noninvasive EEC were grouped together and separately from invasive and advanced stage tumors. Of the 20 miRNAs differentially expressed in noninvasive (stage IA) and myoinvasive adenocarcinomas (stage IB and IC), miR27 was overexpressed in invasive adenocarcinomas, and its expression increased linearly according to stage. Results were validated by quantitative real-time reverse transcription polymerase chain reaction in an independent series of 44 EEC. By in situ hybridization, miR-27 expression was limited to the stroma. Using quantitative real-time reverse transcription polymerase chain reaction, the expression of proapoptotic transcription factor FOXO1 was down-regulated in invasive compared with noninvasive tumors. Furthermore, we found that the expression of active caspase 3 was higher in noninvasive than invasive EEC. When stratified by PIK3CA mutations, all invasive tumors down-regulated FOXO1, but only nonmutated adenocarcinomas showed miR-27 overexpression. In conclusion, we propose that the miR27-FOXO1 tandem inhibits apoptosis and represents an alternative pathway for tumor cell survival in PIK3CA-nonmutated EEC.


Assuntos
Carcinoma Endometrioide/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição Forkhead/fisiologia , MicroRNAs/genética , Invasividade Neoplásica/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Caspase 3/biossíntese , Classe I de Fosfatidilinositol 3-Quinases , Regulação para Baixo , Neoplasias do Endométrio/patologia , Feminino , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/biossíntese , Humanos , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética
13.
Histopathology ; 65(1): 119-31, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24467224

RESUMO

AIMS: Focal adhesions have been associated with poor prognosis in multiple cancer types, but their prognostic value in diffuse large B-cell lymphoma (DLBCL) has not been evaluated. The aim of this study was to investigate the expression patterns and the prognostic value of the focal adhesion proteins FAK, Pyk2, p130Cas and HEF1 in DLBCL. METHODS AND RESULTS: Focal adhesion protein expression was examined using immunohistochemistry in normal lymphoid tissues and in 60 DLBCL patient samples. Kaplan-Meier survival and Cox regression analysis were performed to evaluate the correlation of focal adhesion protein expression with patient prognosis. FAK, Pyk2, p130Cas and HEF1 expression was mostly found in the germinal centres of normal human lymphoid tissues. When assessed in DLBCL samples, FAK, Pyk2, p130Cas and HEF1 were highly expressed in 45%, 34%, 42% and 45% of the samples, respectively. Multivariate Cox analysis revealed that decreased FAK expression was a significant independent predictor of poorer disease outcome. CONCLUSIONS: FAK expression is an independent prognostic factor in DLBCL. Our results suggest that the addition of FAK immunostaining to the current immunohistochemical algorithms may facilitate risk stratification of DLBCL patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Biomarcadores Tumorais/análise , Proteína Substrato Associada a Crk/biossíntese , Proteína-Tirosina Quinases de Adesão Focal/biossíntese , Linfoma Difuso de Grandes Células B/patologia , Fosfoproteínas/biossíntese , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise Serial de Tecidos
14.
Mod Pathol ; 27(4): 631-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24263966

RESUMO

The pattern of myometrial invasion in endometrioid endometrial carcinomas varies considerably; ie, from widely scattered glands and cell nests, often associated with a fibromyxoid stromal reaction (desmoplasia) and/or a lymphocytic infiltrate, to invasive glands with little or no stromal response. Recently, two distinct stromal signatures derived from a macrophage response (colony-stimulating factor 1, CSF1) and a fibroblastic response (desmoid-type fibromatosis, DTF) were identified in breast carcinomas and correlated with clinicopathologic features including outcome. In this study, we explored whether these stromal signatures also apply to endometrioid carcinomas and how their expression patterns correlated with morphologic changes. We studied the stromal signatures both by immunohistochemistry and in situ hybridization in 98 primary endometrioid carcinomas with (87 cases) and without (11 cases) myometrial invasion as well as in the corresponding regional lymph nodes metatases of 9 myoinvasive tumors. Desmoplasia correlated positively with the DTF expression signature. Likewise, mononuclear infiltrates were found in the stroma of tumors expressing CSF1. Twenty-four out of eighty-seven (27%) myoinvasive endometrioid carcinomas were positive for the macrophage signature and thirteen out of eighty-seven (15%) expressed the fibroblast signature. Eleven additional cases were positive for both DTF and CSF1 signatures (11/87; 13%). However, over half of the cases (39/87; 45%) and the majority of the non-myoinvasive tumors (8/11; 73%) failed to express any of the two stromal signatures. The macrophage response (CSF1) was associated with higher tumor grade, lymphovascular invasion, and PIK3CA mutations (P<0.05). There was a concordance in the expression of the CSF1 signature in the primary tumors and their corresponding lymph node metastases. This study is the first characterization of stromal signatures in endometrioid carcinomas. Our findings shed new light on the relationship between genetically different endometrioid carcinomas and various stromal responses. Preservation of the CSF1 macrophage stromal response in the metastases leds support to targeting the CSF1 pathway in endometrioid endometrial carcinomas.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Neoplasias do Endométrio/química , Fibroblastos/química , Macrófagos/química , Células Estromais/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/secundário , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/patologia , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Valor Preditivo dos Testes , Células Estromais/patologia , Microambiente Tumoral
15.
Hum Pathol ; 44(10): 1973-81, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23845467

RESUMO

This review article describes the main features of epithelial-to-mesenchymal transition (EMT) and its possible role in understanding myometrial invasion in endometrial carcinoma (EC), as well as the development of malignant mixed Müllerian tumor (MMMT). Moreover, the article discusses the possible role of somatic (SSC) and cancer stem cells (CSC) in EC. Different transcriptional repressors of E-cadherin have been identified in EMT, including Snail and Slug, ZEB1 and ZEB2, and E47 and Twist. The expression of some of these genes is increased at the myoinvasive front and correlates inversely with E-cadherin inmunoreactivity. Whereas the transient occurrence of the EMT phenomenon is important for myometrial invasion in conventional EC, MMMT shows permanent expression of EMT leading to repression of E-cadherin and increased expression of mesenchymal markers including proteins involved in skeletal muscle development. An SSC population, identified as a side population, assessed by the Hoechst dye exclusion test has been identified in human endometrium. CSCs have been defined in analogy to SSC as cancer cells that have the capacity to self-renew, which means undergoing divisions that allow the generation of more identical CSCs and give rise to the variety of more differentiated cells found in the malignancy. Although published data show that CD133(+) cells retain the characteristics of CSC, there is no conclusive evidence showing that CD133 is the universal marker for EC stem cells. Finally, a possible role for endometrial stem cells in the development of ovarian endometriosis and ovarian endometrioid carcinoma is commented.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Transição Epitelial-Mesenquimal , Tumor Mulleriano Misto/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Tumor Mulleriano Misto/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
16.
Clin Cancer Res ; 19(18): 5127-35, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23804424

RESUMO

PURPOSE: We have previously characterized a tumor stroma expression signature in a subset of breast tumors that correlates with better clinical outcome. The purpose of this study is to determine whether this stromal signature, termed the "DTF fibroblast" (desmoid-type fibromatosis) signature, is specific to breast cancer or is a common stromal response found in different types of cancer. EXPERIMENTAL DESIGNS: The DTF fibroblast signature was applied to gene expression profiles from five ovarian, five lung, two colon, and three prostate cancer expression microarray datasets. In addition, two different tissue microarrays of 204 ovarian tumors and 140 colon tumors were examined for the expression of previously characterized protein markers of DTF fibroblast signature. The DTF fibroblast stromal response was then correlated with clinicopathologic features. RESULTS: The DTF fibroblast signature is robustly present in ovarian, lung, and colon carcinomas. Both expression microarray data and immunohistochemistry show that the subset of ovarian tumors with strong DTF fibroblast signature expression has statistically significant, worse survival outcomes. No reproducible survival differences were found in either the lung or the colon cancers. The prostate cancers failed to show a DTF fibroblast signature. Multivariant analysis showed that DTF fibroblast signature was significantly more prognostic than the proliferation status in ovarian carcinomas. CONCLUSIONS: Our results suggest that the DTF fibroblast signature is a common tumor stroma signature in different types of cancer, including ovarian, lung, and colon carcinomas. Our findings provide further insight into the DTF fibroblast stromal responses across different types of carcinomas and their potential as prognostic and therapeutic targets.


Assuntos
Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Fibroblastos/patologia , Perfilação da Expressão Gênica , Neoplasias Ovarianas/patologia , Neoplasias da Próstata/patologia , Células Estromais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proliferação de Células , Estudos de Coortes , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Feminino , Fibroblastos/metabolismo , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Células Estromais/metabolismo , Taxa de Sobrevida
17.
Haematologica ; 98(10): 1554-62, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23716551

RESUMO

MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.


Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/biossíntese , Taxa de Sobrevida/tendências , Resultado do Tratamento , Adulto Jovem
18.
Histopathology ; 62(4): 632-41, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23379820

RESUMO

AIMS: Expression of tissue inhibitor of metalloproteinases-3 (TIMP-3) has been found to be decreased in several types of cancer by promoter gene hypermethylation. However, little is known regarding the silencing effect of TIMP3 promoter hypermethylation on gene and protein expression in endometrial carcinomas and its prognostic significance. METHODS AND RESULTS: TIMP3 promoter hypermethylation and gene copy number variations were evaluated using a methylation-specific multiplex ligation-dependent probe amplification approach in 60 cases of endometrioid endometrial carcinomas. TIMP3 expression was also evaluated at the transcript and protein levels. Loss of TIMP-3 protein expression was found in 44 (73%) of 60 carcinomas. Promoter hypermethylation was identified in 25% (15 of 60); was more frequent in stages II-IV (55%, six of 11) than in stage I (18%, nine of 49; P = 0.021); and was found more commonly in tumours with deep myometrial invasion. MLH1 and TIMP3 promoters were hypermethylated simultaneously in the same group of tumours (P < 0.001). A correlation between TIMP3 methylation and microsatellite instability (MSI) was found (P = 0.005). TIMP3 copy number changes were frequently a loss (35%), whereas a gain was detected in only 5%. CONCLUSIONS: TIMP3 promoter hypermethylation was associated with high stage endometrioid endometrial tumours with extrauterine spread. Nevertheless, promoter hypermethylation and loss of heterozygosity are not the only mechanisms for TIMP3 inactivation.


Assuntos
Carcinoma Endometrioide/genética , Metilação de DNA , Regulação para Baixo , Neoplasias do Endométrio/genética , Regiões Promotoras Genéticas , Inibidor Tecidual de Metaloproteinase-3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , DNA de Neoplasias/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Inativação Gênica , Humanos , Pessoa de Meia-Idade
19.
Am J Surg Pathol ; 37(4): 514-21, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23211293

RESUMO

Endometrial stromal tumors may pose diagnostic challenges particularly when they exhibit variant histologic appearances, involve extrauterine sites, or present as metastatic disease. In such cases, use of immunohistochemical markers and identification of specific nonrandom chromosomal rearrangements may be helpful. Over the last decade, fluorescence in situ hybridization (FISH) has been progressively incorporated as a diagnostic tool for the evaluation of endometrial stromal tumors. The purpose of this study was to review a series of these tumors and compare the results of FISH analysis with the clinicopathologic characteristics. Three endometrial stromal nodules (ESNs), 13 endometrial stromal sarcomas (ESSs), and 7 undifferentiated endometrial sarcomas (UESs) were reviewed. Three metastases from 1 of the ESS cases were also analyzed. Nine of these tumors (1 ESN, 8 ESSs, and 1 UES) exhibited unusual histologic features, including smooth muscle (3), sex cord (7), epithelioid (1), fibromyxoid (1), and skeletal muscle (2) differentiation. A tissue microarray was prepared, and FISH analysis was performed using break-apart and fusion probes for JAZF1, SUZ12, EPC1, and PHF1 genes. FISH was successful in 22 cases, and rearrangements involving JAZF1, SUZ12, EPC1, and PHF1 genes were detected in 10 of the 22 (45%) uterine tumors, including 2 of the 3 ESNs and 8 of 12 ESSs. Genetic rearrangements were found neither in the 3 metastases of the ESS nor in any of the UESs. It is noteworthy that a correlation between sex cord differentiation and PHF1 rearrangement was encountered in ESSs (P=0.008). In our series, all ESSs showing sex cords had PHF1 genetic rearrangement, suggesting that such rearrangements may induce sex cord differentiation.


Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Rearranjo Gênico , Sarcoma do Estroma Endometrial/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica , Terapia Combinada , DNA de Neoplasias/análise , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Hibridização in Situ Fluorescente , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas do Grupo Polycomb , Sarcoma do Estroma Endometrial/secundário , Sarcoma do Estroma Endometrial/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia
20.
Virchows Arch ; 461(2): 117-22, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22744289

RESUMO

Desmoid-type fibromatosis (DTF) is a rare soft tissue tumor with fibroblastic features affecting two to four individuals per million population per year. Despite its bland microscopic appearance, the tumor behaves aggressively. Although unable to metastasize, DTF tends to recur and local recurrences in anatomically critical sites can be fatal. Tumor-associated macrophages (TAM) play an important role in tumor development through the activation of angiogenesis, particularly in cases of epithelial malignancies. The aim of this study is to investigate the prognostic significance of TAMs and the number of microvessels in DTF. Tumor macrophages (CD163), microvessel density (CD31), and beta-catenin were investigated on 69 primary DTF cases with follow-up information. CTNNB1 mutations were also studied. High density of tumor macrophages and high number of microvessels were associated with a significantly worse recurrence-free survival (P = 0.03 and P = 0.007, respectively). There was a significant correlation between microvessel density and CD163 macrophages (P = 0.02). Furthermore, combination of high number of tumor macrophages and high microvessel density greatly improved the statistical significance (P = 0.000005). Macrophages and microvessels may play an important role in the biologic behavior of DTF. This finding could help in the clinical management of patients with DTF.


Assuntos
Fibromatose Agressiva/patologia , Macrófagos/patologia , Neovascularização Patológica/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fibromatose Agressiva/genética , Fibromatose Agressiva/mortalidade , Genótipo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Análise Serial de Tecidos , Adulto Jovem , beta Catenina/genética
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