RESUMO
Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.
Assuntos
Adenocarcinoma Mucinoso , Neoplasias das Tubas Uterinas , Tubas Uterinas , Metaplasia , Proteína Supressora de Tumor p53 , Humanos , Feminino , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/metabolismo , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/metabolismo , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Tubas Uterinas/patologia , Idoso de 80 Anos ou mais , Proteína Supressora de Tumor p53/metabolismo , Metaplasia/patologia , Queratina-7/metabolismo , Fator de Transcrição CDX2/metabolismo , Fator de Transcrição CDX2/genética , Mucina-6/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma in Situ/patologia , Imuno-HistoquímicaRESUMO
Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of pseudocarcinomatous hyperplasia of the fallopian tubes. Methods: Sixteen cases of pseudocarcinomatous hyperplasia of the fallopian tubes diagnosed at Obstetrics and Gynecology Hospital of Fudan University from January 2011 to January 2024 were collected.The pathological sections were reviewed, the clinical and pathological data were consulted, and immunohistochemical examination was conducted along with follow-up. Results: The patients were aged from 19 to 57 years, with an average age of 41 and a median age of 38. Among the 16 cases, 4 were located in the right fallopian tubes, 6 in the left fallopian tubes, while the remaining cases presented bilaterally. The general manifestations were tubal edema, crispness and purulent secretion in the lumen. Morphologically, the fallopian tube mucosa exhibited a significant infiltration of neutrophils, lymphocytes and plasma cells. The epithelial cells of the fallopian tube displayed evident proliferation, stratification and disorganized arrangement leading to formation of small glandular cavity with back-to-back, fissure-like and sieve-like structures. Immunohistochemical analysis revealed positivity for CK7 and WT1, along with wild-type p53 expression, Ki-67 index ranged from 5% to 20%. During the follow-up period ranging from 1 to 156 months, all the patients remained free of disease. Conclusions: Pseudocarcinomatous hyperplasia of the fallopian tube is a rare non-neoplastic lesion, which can lead to epithelial hyperplasia and atypical hyperplasia. The most important significance of recognizing this lesion lies in avoiding misdiagnosis of fallopian tube cancer during intraoperative and postoperative pathological examination. This ensures that clinicians can administer correct clinical interventions.
Assuntos
Tubas Uterinas , Hiperplasia , Humanos , Feminino , Adulto , Hiperplasia/patologia , Pessoa de Meia-Idade , Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Diagnóstico Diferencial , Proteína Supressora de Tumor p53/metabolismo , Queratina-7/metabolismo , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/cirurgia , Neoplasias das Tubas Uterinas/diagnóstico , Antígeno Ki-67/metabolismo , Proteínas WT1/metabolismo , Adulto Jovem , Células Epiteliais/patologia , Células Epiteliais/metabolismo , Imuno-Histoquímica , Doenças das Tubas Uterinas/patologia , Doenças das Tubas Uterinas/metabolismo , Doenças das Tubas Uterinas/diagnósticoRESUMO
Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.
Assuntos
Biomarcadores Tumorais , Claudinas , Neoplasias Ovarianas , Humanos , Feminino , Claudinas/análise , Claudinas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Biomarcadores Tumorais/análise , Imuno-Histoquímica , Pessoa de Meia-Idade , Idoso , Análise Serial de Tecidos , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/metabolismoRESUMO
Epithelial ovarian cancers (EOC) associated with germline or somatic BRCA pathogenetic variants have a significantly higher rate of TP53aberrations. The majority of TP53 mutations are detectable by immunohistochemistry and several studies demonstrated that an abnormal p53 pattern characterized high-grade EOCs. An abnormal p53 immunohistochemical staining in fallopian tube (serous tubal intraepithelial carcinoma (STIC) and "p53 signature" is considered as a precancerous lesion of high-grade EOCs and it is often found in fallopian tube tissues of BRCA germline mutated patients suggesting that STIC is an early lesion and the TP53 mutation is an early driver event of BRCA mutated high-grade EOCs. No relevant data are present in literature about the involvement of p53 abnormal pattern in EOC carcinogenesis of patients negative for germline BRCA variants. We describe TP53 mutation results in relationship to the immunohistochemical pattern of p53 expression in a series of EOCs negative for BRCA1 and BRCA2 germline mutations. In addition, we also investigated STIC presence and "p53 signature" in fallopian tube sampling of these EOCs. Our results demonstrate that TP53 alterations are frequent and early events in sporadic EOCs including also low-grade carcinomas. Also in this series, STIC is associated with an abnormal p53 pattern in fallopian tubes of high-grade EOCs. In summary, TP53 aberrations are the most frequent and early molecular events in EOC carcinogenesis independently from BRCA mutation status.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Proteína BRCA1/análise , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteína BRCA2/análise , Tubas Uterinas/química , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Cistadenocarcinoma Seroso/patologia , Mutação , Carcinogênese/patologia , Células Germinativas/patologiaRESUMO
Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin-like growth factor (IGF2) and hepatocyte growth factor (HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high-grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co-injection model, we observed that FF co-injection induced tumorigenesis of STIC-mimicking cells, FE25. Co-injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co-injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring-independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine-protein kinase Met (cMET)/mitogen-activated protein kinase and cMET/AKT pathways. Together with the previous finding that the FF-IGF2 could mediate clonogenicity and stemness activities via the IGF-1R/AKT/mammalian target of rapamycin and IGF-1R/AKT/NANOG pathways, respectively, this study demonstrated the cooperation of the FF-sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Feminino , Humanos , Camundongos , Animais , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Líquido Folicular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Ovarianas/patologia , Proteína Supressora de Tumor p53/genética , Células Epiteliais/metabolismo , Carcinogênese/patologia , Carcinoma Epitelial do Ovário/patologia , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Transformação Celular Neoplásica/patologia , Mamíferos/metabolismoRESUMO
Most ovarian high-grade serous carcinomas (HGSC) arise from Serous Tubal Intraepithelial Carcinoma (STIC) lesions in the distal end of the fallopian tube (FT). Formation of STIC lesions from FT secretory cells leads to seeding of the ovarian surface, with rapid tumor dissemination to other abdominal structures thereafter. It remains unclear how nascent malignant cells leave the FT to colonize the ovary. This report provides evidence that the L1 cell adhesion molecule (L1CAM) contributes to the ability of transformed FT secretory cells (FTSEC) to detach from the tube, survive under anchorage-independent conditions, and seed the ovarian surface. L1CAM was highly expressed on the apical cells of STIC lesions and contributed to ovarian colonization by upregulating integrins and fibronectin in malignant cells and activating the AKT and ERK pathways. These changes increased cell survival under ultra-low attachment conditions that mimic transit from the FT to the ovary. To study dissemination to the ovary, we developed a tumor-ovary co-culture model. We showed that L1CAM expression was important for FT cells to invade the ovary as a cohesive group. Our results indicate that in the early stages of HGSC development, transformed FTSECs disseminate from the FT to the ovary in a L1CAM-dependent manner.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Molécula L1 de Adesão de Célula Nervosa , Neoplasias Ovarianas , Feminino , Humanos , Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Cistadenocarcinoma Seroso/metabolismoRESUMO
Identification of serous tubal intraepithelial carcinomas (STIC) in the fallopian tubes of women who are carriers of germ line pathogenic variants in tubo-ovarian cancer predisposition genes (i.e., BRCA1 and BRCA2) has led to the hypothesis that many high-grade serous carcinomas (HGSC) arise from the fimbria of the fallopian tube. However, the primitive (stem and progenitor) tubal epithelial cells that give rise to STIC and HGSC have not been defined. Further, as putative HGSC precursors are discovered at salpingectomy, the natural history of such lesions is truncated at diagnosis. Thus, living cultures of human fallopian tubes suitable for experimental studies are needed to define and characterize the cellular origin of HGSCs and thereby advance the discovery of improved methods to assess risk, develop effective early detection tests and identify novel prevention approaches. Accordingly, patient-derived tissue-organoids and isolated epithelial stem cell derived-organoids generated from average and high-risk patients are vital resources to understand the developmental biology of aging fallopian tubes and pathogenesis of HGSCs. With a vision to boost HGSC prevention research, we have established state-of-the-art protocols for the collection, processing, storage, distribution, and management of fallopian tube tissues. Here we describe the protocol for preparing these organoids, with emphasis on the key steps that require meticulous attention to achieve success.
Assuntos
Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Células Epiteliais/metabolismo , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Feminino , Humanos , Organoides/metabolismo , Neoplasias Ovarianas/metabolismoRESUMO
The natural incidence of primary epithelial ovarian cancer (OVC) in adult female voles of some established strains of Microtus fortis is relatively high. M. fortis OVC has some pathological similarities to human epithelial OVC, therefore M. fortis represents the latest and most valuable animal model for studying human OVC. The lack of available genetic information for M. fortis limits the use of common immunological methods; thus, highthroughput sequencing technologies have been used to reveal the mechanisms of primary OVC in M. fortis. The individuals with cancer were diagnosed using histopathologic hematoxylin and eosin staining. The present study used RNAsequencing (RNAseq) technology to establish a de novo assembly of the M. fortis transcriptome produced 339,830 unigenes by the short reads assembly program Trinity. Comparisons were made between OVC and healthy ovarian tissue (OV) and between fallopian tube cancer (FTC) and healthy fallopian tube (FT) tissues using RNAseq analysis. A total of 3,434 differentially expressed genes (DEGs) were identified in OVC tissue compared with OV tissue using RNASeq by ExpectationMaximization software, including 1,950 significantly upregulated and 1,484 significantly downregulated genes. There were 2,817 DEGs identified in the FTC tissues compared with the FT tissue, including 1,762 significantly upregulated and 1,055 significantly downregulated genes. Pathway enrichment analysis revealed that upregulated transcripts in the OVC vs. OV groups were involved in cell growth and proliferationassociated pathways, whereas the downregulated DEGS in the OVC vs. OV groups were enriched in steroid biosynthesisrelated pathways. Furthermore, the tumor suppressor gene, p53, was downregulated in the FTC and OVC compared with the FT and OV groups, respectively; whereas, genes that promoted cell migration, such as Rasrelated protein Rap1b, Ras homolog family member A and RAC1, were upregulated. In summary, to the best of our knowledge, the present study characterized the M. fortis de novo transcriptome of OV and FT tissues and to perform RNAseq quantification to analyze the differences in healthy and cancerous OV and FT tissues. These results identified pathways that differed between cancerous and healthy M. fortis tissues. Analysis of these pathways may help to reveal the pathogenesis of primary OVC in M. fortis in future work.
Assuntos
Arvicolinae/genética , Arvicolinae/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Transcriptoma/genética , Animais , Carcinoma Epitelial do Ovário/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Análise de Sequência de RNAAssuntos
Antígeno CA-19-9/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/metabolismo , Neoplasias Ovarianas/metabolismo , Ovário/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Estudos RetrospectivosRESUMO
The fallopian tube fimbrial epithelium, which is exposed to the follicular fluid (FF) contents of ovulation, is regarded as the main origin of ovarian high-grade serous carcinoma. Previously, we found that growth factors in FF, such as IGF2, are responsible for the malignant transformation of fallopian tube epithelium. However, ovulation is a monthly transient event, whereas carcinogenesis requires continuous, long-term exposure. Here, we found the transformation activity of FF sustained for more than 30 days after drainage into the peritoneal fluid (PF). Hepatocyte growth factor (HGF), activated through the ovulation injury-tissue factor-thrombin-HGF activator (HGFA)-HGF cleavage cascade confers a sustained transformation activity to fallopian tube epithelium, high-grade serous carcinoma. Physiologically, the high reserve of the coagulation-HGF cascade sources a sustained level of HGF in PF, then to the blood circulation. This HGF axis promotes the growth of the corpus luteum and repair of tissue injury after ovulation.
Assuntos
Transformação Celular Neoplásica/patologia , Corpo Lúteo/fisiologia , Cistadenocarcinoma Seroso/patologia , Neoplasias das Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Ovulação , Peptídeo Hidrolases/metabolismo , Adulto , Animais , Apoptose , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Corpo Lúteo/lesões , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Feminino , Líquido Folicular/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/metabolismo , Prognóstico , Serina Endopeptidases/metabolismo , Trombina/metabolismo , Tromboplastina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pelvic high-grade serous carcinoma (HGSC) has been postulated to arise via a stepwise accumulation of (epi)genetic alterations from normal epithelium to secretory cell outgrowth (SCOUT), p53 signature, and serous tubal intraepithelial carcinoma (STIC) to invasive HGSC. The aim of this study is to investigate alterations in p53 and CD44v9 expression and the status of Ki-67 labeling index in a series of fallopian tube lesions of HGSC patients. A total of 45 specimens were analyzed in 16 patients with HGSC, and their lesions were categorized as follows: morphologically normal fallopian tube epithelium (FTE, n=6 samples), SCOUT (n=5), p53 signature (n=4), dormant STIC (n=8), active STIC (n=6), and HGSC (n=16). Morphologic features and immunohistochemical expression patterns of the p53 protein, CD44v9 protein, and Ki-67 antigen were blindly evaluated by 2 pathologists. Increased nuclear p53 protein accumulation was observed in p53 signature, dormant STIC, active STIC and HGSC compared with normal FTE and SCOUT (P<0.001). Immunohistochemistry scores of CD44v9 protein expression were significantly higher in normal FTE, SCOUT, and p53 signature than in dormant STIC, active STIC, and HGSC (P<0.001). Both active STIC and HGSC had significantly higher Ki-67 labeling indices than normal FTE, SCOUT, p53 signature and dormant STIC (P<0.001). CD44v9 loss contributes to the stepwise progression of p53 signature to dormant STIC. In conclusion, p53 mutation followed by CD44v9 loss may be involved in the evolution of STIC, which may confer positive clonal selection with a growth and survival advantage.
Assuntos
Cistadenocarcinoma Seroso/patologia , Neoplasias das Tubas Uterinas/patologia , Receptores de Hialuronatos/metabolismo , Antígeno Ki-67/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Carcinogênese , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/metabolismo , Epitélio/patologia , Neoplasias das Tubas Uterinas/diagnóstico , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , MutaçãoRESUMO
OBJECTIVES: To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer. METHODS: Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria. RESULTS: 26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months. CONCLUSIONS: The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/metabolismo , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Neoplasias Peritoneais/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/farmacocinéticaRESUMO
During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10-4) by Kaplan-Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10-4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10-4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.
Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Queratina-7/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Cistadenocarcinoma Seroso/mortalidade , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-19/metabolismo , Neoplasias Pulmonares/metabolismo , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Neoplasias Gástricas/metabolismo , Vimentina/metabolismoRESUMO
BACKGROUND: The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response. METHODS: We first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response. RESULTS: NNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51-3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02-2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31-0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn't benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48-1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect. CONCLUSIONS: In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.
Assuntos
Bevacizumab/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias das Tubas Uterinas/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Nicotinamida N-Metiltransferase/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/secundário , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Nicotinamida N-Metiltransferase/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de SobrevidaRESUMO
In the absence of a dominant driving mutation other than uniformly present TP53 mutations, deeper understanding of the biology driving ovarian high-grade serous cancer (HGSC) requires analysis at a functional level, including post-translational modifications. Comprehensive proteogenomic and phosphoproteomic characterization of 83 prospectively collected ovarian HGSC and appropriate normal precursor tissue samples (fallopian tube) under strict control of ischemia time reveals pathways that significantly differentiate between HGSC and relevant normal tissues in the context of homologous repair deficiency (HRD) status. In addition to confirming key features of HGSC from previous studies, including a potential survival-associated signature and histone acetylation as a marker of HRD, deep phosphoproteomics provides insights regarding the potential role of proliferation-induced replication stress in promoting the characteristic chromosomal instability of HGSC and suggests potential therapeutic targets for use in precision medicine trials.
Assuntos
Instabilidade Cromossômica/fisiologia , Cistadenocarcinoma Seroso , Replicação do DNA/genética , Neoplasias Ovarianas , Fosfotransferases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pontos de Checagem do Ciclo Celular/genética , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/mortalidade , Dano ao DNA , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Mitose/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Fosfotransferases/metabolismo , Proteogenômica , Transcriptoma , Proteína Supressora de Tumor p53/genéticaRESUMO
Steroid cell tumors occur usually in the ovaries with very few reported cases of extra-ovarian origin. Our patient was a fifteen year old female, complaining from secondary amenorrhea and voice deepening. Values of serum cortisol, DHEA, FSH & LH were normal. Serum Testosterone was elevated while ACTH-pm was markedly elevated. MRI described bilateral solid para-ovarian masses. Exploration revealed two bilateral tubal extraluminal cysts & a right broad ligament cyst which were all excised. Pathological examination led to the diagnosis of steroid cell tumor. Serum testosterone & ACTH returned to normal levels after surgery with subsequent regression of the virilizing symptoms. We can conclude that extra-ovarian steroid cell tumors are extremely rare. They are usually presented with virilizing symptoms and hormonal abnormalities. Surgery is the main line of treatment.
Assuntos
Síndrome de ACTH Ectópico/diagnóstico , Ligamento Largo/patologia , Neoplasias das Tubas Uterinas/diagnóstico , Neoplasias Pélvicas/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Síndrome de ACTH Ectópico/etiologia , Síndrome de ACTH Ectópico/metabolismo , Adolescente , Hormônio Adrenocorticotrópico/metabolismo , Ligamento Largo/metabolismo , Egito , Neoplasias das Tubas Uterinas/complicações , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Neoplasias Pélvicas/complicações , Neoplasias Pélvicas/metabolismo , Neoplasias Pélvicas/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/metabolismo , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Virilismo/diagnóstico , Virilismo/etiologia , Virilismo/metabolismoRESUMO
The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of â¼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of â¼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.
Assuntos
Células Epiteliais/patologia , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Epitélio/metabolismo , Epitélio/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Heterogeneidade Genética , Humanos , Neoplasias Ovarianas/metabolismoRESUMO
Carcinosarcomas are rare, highly aggressive neoplasms composed of a combination of carcinomatous and sarcomatous elements. These tumors represent a paradigmatic field for the study of intratumor heterogeneity. A series of 8 tubo-ovarian carcinosarcomas was characterized for the following: (i) immunohistochemical expression of MNF116, epithelial membrane antigen, vimentin, S100, chromogranin, synaptophysin, desmin, myogenin (MYF4), and p53; (ii) mutational profiling of KRAS, BRAF, PIK3CA, NRAS, TP53, and DICER1 genes. Heterologous differentiation was present in 6 of 8 tumors. Cytokeratin MNF116 and epithelial membrane antigen were positive in all the carcinomatous components and in 87.5% and 50.0% of the sarcomatous components, respectively. The sarcomatous components showed positive staining for vimentin in all cases. Two cases demonstrated positivity for neuroendocrine markers in their carcinomatous components. All rhabdomyosarcomas were positive for desmin and MYF-4. Chondrosarcomas were positive for S100. All but one tumor showed similar p53 immunoreactivity in both the carcinomatous and sarcomatous components, and one case showed cytoplasmic p53 expression. Three of 8 cases (37.5%) showed TP53 mutations, and, in 2 cases, the TP53 mutation was shared by both epithelial and mesenchymal components. DICER1 mutation was found in all components of one case. Mutations in KRAS, NRAS, BRAF, and PIK3CA genes were not found in the study cohort. Our results highlight the heterogeneity of ovarian carcinosarcomas at the phenotypic level. A common mutational signature was observed in both components in 3 of 4 informative tumors. More studies are required to dissect different levels of ovarian carcinosarcomas' heterogeneity in order to define the best therapeutic approaches to these aggressive neoplasms.
Assuntos
Biomarcadores Tumorais/genética , Carcinossarcoma/genética , RNA Helicases DEAD-box/genética , Neoplasias das Tubas Uterinas/genética , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Proteína Supressora de Tumor p53/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinossarcoma/metabolismo , Carcinossarcoma/patologia , Estudos de Coortes , RNA Helicases DEAD-box/metabolismo , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Feminino , Heterogeneidade Genética , Humanos , Imuno-Histoquímica , Imunofenotipagem , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Ribonuclease III/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
High-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.
Assuntos
Epitélio/patologia , Estrogênios/metabolismo , Neoplasias das Tubas Uterinas/patologia , Tubas Uterinas/patologia , Fator de Transcrição PAX2/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/metabolismo , Tubas Uterinas/efeitos dos fármacos , Tubas Uterinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Fator de Transcrição PAX2/genética , Fator de Transcrição PAX2/metabolismo , Receptores de Estrogênio/genética , Transdução de Sinais , Transcriptoma , Células Tumorais CultivadasRESUMO
A recent phase II clinical trial showed increased progression-free survival in patients with HER2-positive endometrial serous carcinoma receiving trastuzumab in addition to carboplatin-paclitaxel chemotherapy. Similar to endometrial serous carcinomas, carcinosarcomas of the female genital tract have a dismal prognosis and could potentially benefit from new targeted therapeutic approaches. We aimed to systematically evaluate the characteristics of HER2 expression/amplification in gynecologic carcinosarcomas using standardized staining methods and scoring criteria. Tumors from 80 patients (65 uterine, 15 tubo-ovarian) were included, containing a serous (60%), endometrioid (10%), clear cell (3%), undifferentiated (3%), neuroendocrine (1%), or mixed (24%) carcinoma, and either a homologous (46%), or a heterologous (54%) sarcoma component. HER2 scores were assigned to both components per the 2007 and 2013 ASCO/CAP breast scoring criteria. A total of 13 cases (12 uterine, 1 ovarian, 16%) were HER2 positive (either by immunohistochemistry or FISH) using the 2013 criteria, while only 10 cases (9 uterine, 1 ovarian, 13%) were HER2 positive per the 2007 criteria. Nine cases showed a change in their HER2 immunohistochemical score between the two scoring systems, including two cases with a change in the overall HER2 status from negative (2007) to positive (2013). Heterogeneity of HER2 protein expression was observed in 38% of HER2-positive tumors, and a lateral/basolateral membranous staining pattern was common. The sarcoma component showed 2+, equivocal HER2 expression in five cases, one of which also demonstrated HER2 amplification by FISH. All HER2-positive carcinosarcomas had either a serous or a mixed carcinoma component, and all but one HER2-positive tumors were of uterine primaries. Our study demonstrates that gynecologic carcinosarcomas share similarities in their HER2 expression/amplification profiles to endometrial serous carcinomas, which should be taken into account when assessing their HER2 status to ensure appropriate patient selection for potential targeted HER2-based therapies in the future.