RESUMO
Primary gastric chorioadenocarcinoma (PGC) constitutes less than 1% of all gastric cancers; it is more common in men. Approximately one third of patients already have metastatic disease at the time of diagnosis. We present the case of a 70-yearold male patient, diagnosed as gastric adenocarcinoma in anthropylorus, who underwent radical distal gastrectomy. The pathological diagnosis shows an adenocarcinoma, with 85% choriocarcinomatous differentiation, 10% with areas of tubular adenocarcinoma and the remaining 5% per component suggestive of yolk sac tumor. Our patient achieved a survival of 5 months after surgery, during this time he was followed up by oncology medicine with chemotherapy. This disease continues to have a gloomy prognosis; less than 6 months.
Assuntos
Adenocarcinoma , Coriocarcinoma , Neoplasias Gástricas , Adenocarcinoma/patologia , Idoso , Coriocarcinoma/diagnóstico , Coriocarcinoma/patologia , Feminino , Gastrectomia , Humanos , Masculino , Neoplasias Gástricas/patologiaRESUMO
Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17ß-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription.
Assuntos
Coriocarcinoma/patologia , Estrogênios/farmacologia , Leptina/metabolismo , NF-kappa B/metabolismo , Placenta/metabolismo , Neoplasias Uterinas/patologia , Núcleo Celular , Coriocarcinoma/genética , Coriocarcinoma/metabolismo , Feminino , Humanos , Leptina/genética , NF-kappa B/genética , Fosforilação , Placenta/efeitos dos fármacos , Gravidez , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismoRESUMO
OBJECTIVE: To investigate GTN lethality among Brazilian women comparing cases of death by GTN with those who survived, thereby identifying factors associated with GTN lethality. METHODS: We retrospectively reviewed medical records of women with GTN treated at ten Brazilian GTN Reference Centers, from January 1960 to December 2017. We evaluated factors associated with death from GTN and used Cox proportional hazards regression models to identify independent variables with significant influence on the risk of death. RESULTS: From 2186 patients with GTN included in this study, 2092 (95.7%) survived and 89 (4%) died due to GTN. When analyzing the relative risk (RR), adjusted for WHO/FIGO score, patients with low risk disease had a significantly higher risk of death if they had choriocarcinoma (RR: 12.40), metastatic disease (RR: 12.57), chemoresistance (RR: 3.18) or initial treatment outside the Reference Center (RR: 12.22). In relation to patients with high-risk GTN, these factors were significantly associated with death due to GTN: the time between the end of antecedent pregnancy and the initiation of chemotherapy (RR: 4.10), metastatic disease (RR: 14.66), especially in brain (RR: 8.73) and liver (RR: 5.76); absence of chemotherapy or initial treatment with single agent chemotherapy (RR: 10.58 and RR: 1.81, respectively), chemoresistance (RR: 3.20) and the initial treatment outside the Reference Center (RR: 28.30). CONCLUSION: The risk of mortality from low and high-risk GTN can be reduced by referral of these patients to a Reference Center or, if not possible, to involve clinicians in a Reference Center with consultation regarding management.
Assuntos
Doença Trofoblástica Gestacional/mortalidade , Adulto , Brasil/epidemiologia , Coriocarcinoma/mortalidade , Coriocarcinoma/patologia , Estudos de Coortes , Feminino , Doença Trofoblástica Gestacional/patologia , Humanos , Estadiamento de Neoplasias , Gravidez , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy. AIM: To explore the role of AREG in human choriocarcinoma cell proliferation. MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways. RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib. CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.
Assuntos
Anfirregulina/genética , Coriocarcinoma/genética , Receptor ErbB-2/genética , Anfirregulina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Oncogênica v-akt/genética , Receptor ErbB-2/antagonistas & inibidoresRESUMO
Primary gastric choriocarcinoma (PGC) is an extremely rare and highly invasive tumor with rapid hematogenous spread. We present the case of a 57-year-old female patient who started with hematemesis and progressive episodes of melena, weight loss and epigastralgia. It is derived from the National Institute of Neoplastic Diseases where gastroscopy and biopsy are performed. Histological analysis reported pattern suggestive of PGC; that was confirmed by immunohistochemical analysis for human chorionic gonadotrophin and fetal alpha protein. Subsequently, the patient underwent a radical D2 gastrectomy with splenic preservation and tail of the pancreas preservation. Unfortunately, her evolution was not favorable and died due to the progression of the disease.
Assuntos
Coriocarcinoma/patologia , Neoplasias Gástricas/patologia , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/análise , Coriocarcinoma/química , Coriocarcinoma/diagnóstico , Coriocarcinoma/cirurgia , Gonadotropina Coriônica/análise , Diagnóstico Diferencial , Evolução Fatal , Feminino , Gastrectomia/métodos , Gastroscopia , Hematemese/etiologia , Humanos , Melena/etiologia , Pessoa de Meia-Idade , Pólipos/diagnóstico , Pólipos/patologia , Neoplasias Gástricas/química , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia , Úlcera Gástrica/etiologia , Redução de Peso , alfa-Fetoproteínas/análiseRESUMO
El coriocarcinoma gástrico primario (CGP) es un tumor extremadamente raro, altamente invasivo y de rápida diseminación hematógena. Presentamos el caso de una paciente de 57 años que inicia con cuadro de hematemesis y, progresivamente, se le suman episodios de melena, baja de peso y epigastralgia. Es derivada al Instituto Nacional de Enfermedades Neoplásicas en donde se le realizan gastroscopía y biopsia. Así, el análisis histológico reportó patrón sugestivo para CGP; el cual se confirmó al realizarle a la paciente los estudios por imágenes necesarios y llevar a cabo el análisis inmunohistoquímico para gonadotrofina coriónica humana y alfa feto proteína. Posteriormente, a la paciente se le realiza una gastrectomía radical D2 con preservación esplénica y de cola de páncreas. Lamentablemente, su evolución no fue favorable y fallece por la progresión de la enfermedad.
Primary gastric choriocarcinoma (PGC) is an extremely rare and highly invasive tumor with rapid hematogenous spread. We present the case of a 57-year-old female patient who started with hematemesis and progressive episodes of melena, weight loss and epigastralgia. It is derived from the National Institute of Neoplastic Diseases where gastroscopy and biopsy are performed. Histological analysis reported pattern suggestive of PGC; that was confirmed by immunohistochemical analysis for human chorionic gonadotrophin and fetal alpha protein. Subsequently, the patient underwent a radical D2 gastrectomy with splenic preservation and tail of the pancreas preservation. Unfortunately, her evolution was not favorable and died due to the progression of the disease.
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia , Coriocarcinoma/patologia , Pólipos/diagnóstico , Pólipos/patologia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/química , Úlcera Gástrica/etiologia , Redução de Peso , Adenocarcinoma/diagnóstico , alfa-Fetoproteínas/análise , Coriocarcinoma/cirurgia , Coriocarcinoma/diagnóstico , Coriocarcinoma/química , Biomarcadores Tumorais/análise , Hematemese/etiologia , Melena/etiologia , Gastroscopia , Evolução Fatal , Diagnóstico Diferencial , Gastrectomia/métodos , Gonadotropina Coriônica/análiseRESUMO
The HLA-G 5'URR extending 1.4 kb from the ATG presents a unique set of regulatory elements among HLA genes. Several variable sites have been described that coincide with or are close to these elements, thus HLA-G 5'URR polymorphism might influence the HLA-G expression level. We cloned the ten most frequent HLA-G 5'URR haplotypes to evaluate their activity on a luciferase reporter gene in HLA-G+ cell lines (JEG-3/choriocarcinoma and FON+/melanoma). We also investigated associations between the plasma HLA-G (sHLA-G) levels and the HLA-G 5'URR variability in 157 healthy individuals. Cell lines were transfected with pGL3-Basic vector constructions containing HLA-G 5'URR sequences. The G010101a (in JEG-3) and G010101b (in FON+) haplotypes exhibited higher promoter activity, whereas the G010101d (in JEG-3) and G010102a (in FON+) haplotypes exhibited lower promoter activity. In the presence of HLA-G inducers (interferon-ß and progesterone) or repressors (cyclopamine) HLA-G promoter activity was modulated, but certain haplotypes exhibited differential responses. No strict association was observed between plasma sHLA-G levels and the 5'URR haplotypes or genotypes; however, the G010101b haplotype was underrepresented among HLA-G-negative plasmas. Therefore, the HLA-G 5'URR polymorphism may have an impact on the modulation of HLA-G gene expression, but alone provides a limited predictive value for sHLA-G levels in vivo.
Assuntos
Regiões 5' não Traduzidas/genética , Microambiente Celular , Antígenos HLA-G/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo , Adulto , Coriocarcinoma/genética , Coriocarcinoma/patologia , Feminino , Genótipo , Antígenos HLA-G/metabolismo , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Células Tumorais CultivadasRESUMO
Hyaluronan (HA) is the major glycosaminoglycan present in the extracellular matrix. It is produced by some tumours and promotes proliferation, differentiation and migration among others cellular processes. Gestational trophoblastic disease (GTD) is composed by non-tumour entities, such as hydatidiform mole (HM), which is the most common type of GTD and also malignant entities such as choriocarcinoma (CC) and placental site trophoblastic tumour (PSTT), being CC the most aggressive tumour. Although there is a growing understanding of GTD biology, the role of HA in the pathogenesis of this group of diseases remains largely unknown. The aim of this work was to study the role of HA in the pathogenesis of GTD by defining the expression pattern of HA and its receptors CD44 and RHAMM, as well as to determine if HA can modulate proliferation, differentiation and migration of CC cells. Receptors and signalling pathways involved were also analyzed. We demonstrated that HA and RHAMM are differently expressed among GTD entities and even among trophoblast subtypes. We also showed that HA is able to enhance the expression of extravillous trophoblast markers and also to induce migration of JEG-3 cells, the latter mediated by RHAMM as well as PI3K and MAPK pathways. These findings indicate a novel regulatory mechanism for CC cell biology and also contribute to the understanding of GTD pathophysiology.
Assuntos
Movimento Celular/efeitos dos fármacos , Coriocarcinoma/metabolismo , Coriocarcinoma/patologia , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peso Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
INTRODUCTION: Gestational (GC) (derived from the placenta) and non-gestational (NGC) choriocarcinomas are trophoblastic diseases originated from abnormal proliferation of trophoblastic cells. These rare tumors share similar morphology and pathological features and differ on chemotherapy response, genetic origin and prognosis. In this study, the genomic profile of choriocarcinomas was performed according to their origin (GC or NGC) aiming to better understand these poorly characterized diseases. METHODS: Thirteen patients were included in this study; 10 presented previous history of hydatidiform mole and six developed metastasis. Twelve polymorphic microsatellite markers (D15S659, APOC2, D5S816, BAT25, D3S1614, D3S1311, D1S1656, APC-D5S346, D3S1601, D18S70, D8S1110 and D11S1999) were investigated to distinguish GC from NGC. All choriocarcinomas were evaluated by copy number alterations using array CGH. RESULTS: Eight cases were classified as GC and five as NGC. Although potentially polymorphic, NGC exhibited significant gain of 21p11. Rare copy number alterations (CNA) were detected as a frequent event in GC including gains of 1p36.33-p36.32 (3 cases), 17q25.3 (4 cases), and losses of 9q33.1 (5 cases), 17q21.3 (3 cases) and 18q22.1 (4 cases) (varying from 724 to 3,053 Kb). DISCUSSION: Two tumor suppressor genes are candidates to be involved in GC: TRIM32 (9q33.1) and CDH19 (18q22.1). Gains of CBX2, CBX4 and CBX8 were frequently found in high risk prognostic score in GC. The in silico functional interaction analysis revealed the involvement of PTEN and PI3K-Akt signaling pathways. These data pointed out significant genomic alterations in GC, opening new avenues to better characterize the pathobiology of this disease.
Assuntos
Coriocarcinoma não Gestacional/genética , Coriocarcinoma/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Coriocarcinoma/patologia , Coriocarcinoma não Gestacional/patologia , Variações do Número de Cópias de DNA , Feminino , Genômica , Humanos , Pessoa de Meia-Idade , Gravidez , Transdução de Sinais/genética , Neoplasias Uterinas/patologia , Adulto JovemRESUMO
BACKGROUND: Testicular germ-cell carcinoma is the most frequent neoplasm in males aged 15 to 35 years old. It is bilateral in 2% to 3%, and synchronous in 20% to 25% of the cases. CLINICAL CASE: The case is presented of a 19 year-old male, with abdominal pain. Physical examination revealed abdominal mass in the umbilical region, and the computed tomography scan showed a retroperitoneal tumour, with α-fetoprotein, lactate dehydrogenase, and human chorionic gonadotropin above limits. Testicular ultrasound showed bilateral lesions. Exploratory laparotomy was performed, identifying an unresectable retroperitoneal tumour. Biopsies were taken, reporting mixed germ cell tumour composed of choriocarcinoma and embryonal carcinoma. Six cycles of chemotherapy were given, based on bleomycin, etoposide and cisplatin, with partial tumour response. Later on, the patient underwent bilateral radical orchiectomy, with pathology reporting a synchronous bilateral testicular teratoma. A second line of chemotherapy was given, based on vincristine, etoposide, ifosfamide and cisplatinum. Nevertheless, the disease progressed, with metastatic dissemination and the patient died. DISCUSSION: Germ cells tumours can present in primary extra-gonadal locations. It is difficult to distinguish a retroperitoneum primary germ cell tumour from metastatic disease of a clinically undetected gonadal tumour or one that has regressed, like the situation described in the case presented. CONCLUSIONS: Ninety percent of patients diagnosed with germ cell tumours can be cured. However, delay in diagnosis correlates with an advanced clinical stage and poor prognosis.