RESUMO
Enteritis cystica profunda (ECP) is an uncommon benign condition arising after mucosal damage. We describe 2 cases of small intestinal adenocarcinomas associated with ECP at the distal ileum, one in a background of active Crohn ileitis (case 1), the other 22 years after pelvic radiation therapy (case 2). Both patients presented with small bowel obstruction and received ileocectomy. Macroscopic examination identified an indurated/strictured area in the distal ileum. Histologically, both cases showed a low-grade tubuloglandular adenocarcinoma arising in a background of chronic ischemic stricture and ECP lined by flat cuboidal cells with mild cytologic atypia resembling pancreatobiliary-type epithelium. There was no conventional dysplasia in the surface or adjacent mucosa. Immunohistochemically, both ECP with metaplasia and invasive carcinomas were diffusely positive for CK7 and CK19, while focally positive for CDX2 or CK20. Both cases showed normal wild-type p53 expression. Case 2 was also mismatch repair protein proficient, with membranous ß-catenin staining, and retained nuclear SMAD4 expression. In summary, the 2 cases uniquely exhibits "enteritis-metaplasia-carcinoma" sequence, which has not been reported before. This process appears to bypass conventional dysplasia, be slow and indolent, independent of p53, APC/ß-catenin, and SMAD4/TGFß signaling pathways.
Assuntos
Adenocarcinoma , Enterite , Neoplasias do Íleo , Mucosa Intestinal , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Adenocarcinoma/etiologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Enterite/complicações , Enterite/metabolismo , Enterite/patologia , Feminino , Humanos , Neoplasias do Íleo/etiologia , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases. METHODS: We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens. RESULTS: SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %. CONCLUSIONS: SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.
Assuntos
Regulação para Baixo , Neoplasias do Íleo/metabolismo , Neoplasias Hepáticas/secundário , Fígado/metabolismo , Proteínas de Neoplasias/metabolismo , Tumores Neuroendócrinos/metabolismo , Succinato Desidrogenase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Humanos , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/patologia , Íleo/metabolismo , Íleo/patologia , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/secundário , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.
Assuntos
Neoplasias do Sistema Digestório/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/metabolismo , Tumores Neuroendócrinos/metabolismo , Adulto , Idoso , Biópsia por Agulha Fina , Biópsia com Agulha de Grande Calibre , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias do Sistema Digestório/patologia , Neoplasias do Sistema Digestório/cirurgia , Feminino , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Neoplasias do Íleo/cirurgia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaAssuntos
Neoplasias do Íleo/terapia , Íleo/patologia , Linfoma Difuso de Grandes Células B/terapia , Bexiga Urinária/patologia , Derivação Urinária , Idoso , Evolução Fatal , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Íleo/cirurgia , Antígeno Ki-1/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Falha de Tratamento , Bexiga Urinária/cirurgiaRESUMO
Gastro-intestinal neuroendocrine tumors (GI-NETs) are rare neoplasms, frequently metastatic, raising difficult clinical and therapeutic challenges due to a poor knowledge of their biology. As neuroendocrine cells express both epithelial and neural cell markers, we studied the possible involvement in GI-NETs of axon guidance molecules, which have been shown to decrease tumor cell proliferation and metastatic dissemination in several tumor types. We focused on the role of Semaphorin 3F (SEMA3F) in ileal NETs, one of the most frequent subtypes of GI-NETs.SEMA3F expression was detected in normal neuroendocrine cells but was lost in most of human primary tumors and all their metastases. SEMA3F loss of expression was associated with promoter gene methylation. After increasing endogenous SEMA3F levels through stable transfection, enteroendocrine cell lines STC-1 and GluTag showed a reduced proliferation rate in vitro. In two different xenograft mouse models, SEMA3F-overexpressing cells exhibited a reduced ability to form tumors and a hampered liver dissemination potential in vivo. This resulted, at least in part, from the inhibition of mTOR and MAPK signaling pathways.This study demonstrates an anti-tumoral role of SEMA3F in ileal NETs. We thus suggest that SEMA3F and/or its cellular signaling pathway could represent a target for ileal NET therapy.
Assuntos
Orientação de Axônios/fisiologia , Neoplasias do Íleo/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tumores Neuroendócrinos/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Neoplasias do Íleo/genética , Neoplasias do Íleo/patologia , Proteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Transdução de SinaisRESUMO
Metastatic malignancies of the hand are rare and metastases to the skeletal muscle from the gastrointestinal system are even much rare. Here we present a case of metastatic ileocecal adenocarcinoma to the thenar muscle, which is the first report of thenar muscle metastasis from ileocecal adenocarcinoma with P53 mutation. To date, only two other cases of thenar muscle metastasis have been documented, one is from squamous cell carcinoma of the lung and the other is from rectal carcinoma. The present 67-year-old Chinese man of poorly differentiated adenocarcinoma of the ileocecal region developed metastatic carcinoma in the right thenar eminence, which presented with swelling and pain. Magnetic resonance imaging of the right hand revealed a well-defined enhanced mass in the right thenar muscle. It was proved to be metastatic adenocarcinoma using core needle biopsy, which was supported to be gastrointestinal origination by positive immunoreaction with CDX2. Positive immunoreaction with P53 protein indicated the poor prognosis of the patient. Further systemic evaluation including computerized tomography scans revealed extensive metastases to liver, right kidney, right abdominal wall, left axillary and right subclavicular lymph nodes, and skin of the right thigh. Treatment was given with palliative systemic chemotherapy. After 8 cycles of chemotherapy, the swelling and pain of the right thenar were ameliorated, and the patient regained full use of his right hand and his quality of life was improved. The patient died of liver metastasis 9 months after the diagnosis of the right thenar metastasis. In conclusion, here we display a case of thenar skeletal muscle metastasis from P53 mutated ileocecal adenocarcinoma, who survived 9 months after diagnosis of the rare metastasis. If an oncological patient presents an intramuscular mass, muscle metastasis must be included in the differential diagnosis. Metastatic hand tumors generally indicate systemic spread, so the treatment is usually palliative and the prognosis is poor. The primary objective of treatment is improvement of the patient's quality of life.
Assuntos
Adenocarcinoma/secundário , Neoplasias do Íleo/patologia , Neoplasias Hepáticas/secundário , Neoplasias Musculares/secundário , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma/metabolismo , Idoso , Evolução Fatal , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Neoplasias Musculares/metabolismo , Músculo Esquelético/patologiaRESUMO
BACKGROUND: Neuroendocrine tumors (NETs) of the ileum are sporadic tumors derived from submucosal gastrointestinal stem cells. They often show clinical symptoms only after hepatic metastasation when curative therapy is limited or impossible. In this study, we analyzed the expression of the candidate genes mammalian target of rapamycin (mTOR), alpha thalassemia/mental retardation syndrome X-linked (ATRX), and death domain-associated protein (DAXX) to investigate the specific oncogenetics and potential therapeutic options for ileal NETs. METHODS: In a prospective database, all patients who underwent surgical removal of a NET of the ileum between 2001 and 2011 were specified. Expression analysis was performed for mTOR, ATRX, and DAXX by immunohistochemistry of paraffin-embedded tumor samples. To evaluate the results the immunoreactive score was applied. Normal tissue and tumor tissue were analyzed for the comparison of gene expression levels using quantitative-real-time polymerase chain reaction for ATRX and mTOR genes. Results were correlated under pathologic and clinical aspects. RESULTS: A total of 69 patients were admitted to the study. Positive cytosolic expression of the potential oncogene mTOR was immunohistochemically detected in 76.2% of the human probes. A loss of nuclear ATRX expression was detected in 13.0% of the samples. A nonexpression of the DAXX-protein in cell nuclei was not found (0%). Gene transcript levels did not show a significant alteration in ileal NETs in comparison with normal tissue. CONCLUSIONS: mTOR is overexpressed in ileal NETs. Additionally, the loss of ATRX expression was registered, thus underlying a tumorigenic role in a subgroup of these tumors. To enable potential therapeutic application of mTOR inhibitors, further trials with larger study groups are needed.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , DNA Helicases/metabolismo , Neoplasias do Íleo/metabolismo , Complexos Multiproteicos/metabolismo , Tumores Neuroendócrinos/metabolismo , Proteínas Nucleares/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Biomarcadores Tumorais/genética , Proteínas Correpressoras , DNA Helicases/genética , Feminino , Humanos , Neoplasias do Íleo/genética , Neoplasias do Íleo/patologia , Íleo/patologia , Imuno-Histoquímica , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Pessoa de Meia-Idade , Chaperonas Moleculares , Terapia de Alvo Molecular , Complexos Multiproteicos/genética , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinases TOR/genética , Proteína Nuclear Ligada ao XRESUMO
AIMS: Primary Ewing sarcoma of the ileum has rarely been documented. Little is known about its pathogenesis and clinical implications, and it would be helpful to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in Ewing sarcoma, as FEV expression is restricted to prostate, brain and serotonin neuroendocrine cells (NE) and related tumours. METHODS AND RESULTS: Paraffin sections or snap-frozen material were used in this investigation. Tumours were investigated by means of immunohistochemistry, RT-PCR (EWSR1-FLI1, EWSR1-ERG and EWSR1-FEV transcripts), FISH analysis (EWSR1 break-apart and specific EWSR1-FEV translocation) and spectral karyotyping (SKY). Ten ileal neuroendocrine tumours (INET) made up the control group for EWSR1-FEV translocation. Among 445 Ewing sarcomas cases spanning a period of 20 years, seven (1.6%) arose in the ileum. All tumours were immunoreactive for synaptophysin, CD99, FLI1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumour showing the uncommon EWSR1-FEV rearrangement, with SKY, RT-PCR and FISH confirmation. The mean survival of EWSR1-FLI1 patients was 14 months, whereas the EWSR1-FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation. CONCLUSIONS: Most primary Ewing sarcomas of the ileum show the common EWSR1-FLI1 translocation, but EWSR1-FEV could be specific for tumours arising in the ileum and showing better prognosis.
Assuntos
Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Íleo/patologia , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Sarcoma de Ewing/patologia , Adolescente , Adulto , Feminino , Humanos , Neoplasias do Íleo/genética , Neoplasias do Íleo/metabolismo , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteína EWS de Ligação a RNA , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Fatores de Transcrição , Translocação Genética , Adulto JovemRESUMO
There is need to determine tissue-specific robust controls for normalization of microRNA expression to avoid false results and misinterpretation. The aim of this study was to evaluate the expression of different small RNAs in neuroendocrine tumors (NETs) and their suitability as normalizers in miRNA real-time PCR experiments. We investigated the expression of the nine small RNAs miR-93, miR-191, SNORD48, SNORD61, SNORD68, SNORD72, SNORD95, SNORD96a, and RNU6-2 in formalin-fixed, paraffin-embedded tissue samples of 25 ileal NETs by real-time PCR determining the most stable controls for expression normalization using four different algorithms. This analysis was expended to ten pancreatic NETs. Finally, five small RNAs were further tested as normalizers for miRNA-133a expression, which is known to be downregulated in metastases of ileal NETs, in ten matched pairs of ileal NETs and their metastases. Ranking of the expression results revealed the following order of stability from high to low: SNORD61 < SNORD95 < SNORD72 < SNORD96a < SNORD68 < miR-191 < miR-93 < RNU6-2 < SNORD48 for ileal NETs and SNORD95 < miR-93 < SNORD96a < SNORD61 < SNORD68 < SNORD72 < RNU6-2 < miR-191 < SNORD48 for pancreatic NETs. The determination of SNORD61 and SNORD95 for ileal NETs and SNORD95 and miR-93 for pancreatic NETs as good normalizers presents a useful tool for experiments involving the analysis of miRNA expression.
Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias do Íleo/genética , MicroRNAs/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , MicroRNAs/metabolismo , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Primary small bowel adenocarcinoma is rare. Although generally similar to colonic adenocarcinoma, some small bowel adenocarcinomas exhibit unique morphologic features, particularly those arising in association with Crohn disease. In this study, 15 sporadic small bowel adenocarcinomas and 11 Crohn enteritis-associated small bowel adenocarcinomas were examined for histology and immunohistochemical profile including cytokeratins (CK) 7 and 20, intestinal markers CDX2 and MUC2, and gastric epithelial markers MUC5AC and MUC6. We found that Crohn enteritis-associated small bowel adenocarcinomas frequently resemble gastric tubular adenocarcinoma histologically. In addition, when compared to sporadic small bowel adenocarcinoma, the former expressed MUC5AC and MUC6 with much higher frequency (82% vs. 7% and 73% vs. 0%, respectively). Ten of 11 Crohn enteritis-associated small bowel adenocarcinomas (91%) were positive for at least one gastric-type marker (MUC5AC or MUC6). Expression of CK7 was also more frequent in Crohn enteritis-associated small bowel adenocarcinoma (73% versus 27%) while expression of CK20 was less frequent (64% vs. 100%). There was no difference between sporadic and Crohn enteritis-associated small bowel adenocarcinoma in expression of CDX2 (100% vs. 91%) and MUC2 (93% vs. 73%). These observations suggest that there is a difference in the morphologic and immunohistochemical characteristics of sporadic versus Crohn enteritis-associated small bowel adenocarcinoma, particularly in their expression of gastric-type mucin. The findings also suggest that gastric differentiation in Crohn enteritis-associated small bowel adenocarcinoma is related to gastric metaplasia, a common phenomenon in Crohn disease.
Assuntos
Adenocarcinoma/etiologia , Doença de Crohn/complicações , Neoplasias Duodenais/etiologia , Neoplasias do Íleo/etiologia , Neoplasias do Jejuno/etiologia , Neoplasias Gástricas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Duodenais/metabolismo , Neoplasias Duodenais/patologia , Feminino , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Neoplasias do Jejuno/metabolismo , Neoplasias do Jejuno/patologia , Queratinas/metabolismo , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Mucinas/metabolismoRESUMO
The adenomatous polyposis coli gene is a key tumor suppressor gene. Alterations in this gene have been found in most sporadic colon cancers; associated with familial adenomatous polyposis; and found in neoplasms of other organs, such as the liver, stomach, lung, breast, and cerebellar medulloblastoma. In the heterogeneous group of neuroendocrine neoplasms of the gastrointestinal tract, the involvement of adenomatous polyposis coli is debated, and only occasional reports found adenomatous polyposis coli alterations in foregut and midgut neuroendocrine neoplasms, with adenomatous polyposis coli mutations only in the latter. To elucidate the penetrance of adenomatous polyposis coli alterations in ileal neuroendocrine neoplasms, we performed DNA fragment analysis (loss of heterozygosity for 5q22-23 and 5q23) and sequencing on the mutation cluster region of the adenomatous polyposis coli gene on 30 ileal enterochromaffin cell neuroendocrine neoplasms. Adenomatous polyposis coli gene mutations were detected in 23% of cases (7/30); in particular, 57% were missense and 14%, nonsense/frameshift, all novel and different from those reported in colorectal or other cancers. Loss of heterozygosity analysis demonstrated a deletion frequency of 15% (4/27). No association was found with features of tumor progression. Our observations support the involvement of somatic adenomatous polyposis coli alterations in tumorigenesis of ileal enterochromaffin cell neuroendocrine neoplasms; the mechanisms of adenomatous polyposis coli gene inactivation appear to be different from those reported in other tumor types.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Células Enterocromafins/metabolismo , Genes APC , Neoplasias do Íleo/genética , Tumores Neuroendócrinos/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Células Enterocromafins/patologia , Feminino , Humanos , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Transdução de Sinais , beta Catenina/metabolismoRESUMO
A 25-year-old, female rhesus macaque (Macaca mulatta) presented with a history of weight loss despite a normal appetite and supportive care. The animal was humanely destroyed due to poor prognosis. Post-mortem examination revealed a focally extensive, firm, white annular constriction at the ileocaecal junction and an incidental finding of a pale white nodule approximately 0.8 cm in diameter in the left renal pelvis. Based on the microscopical findings, ileocaecal adenocarcinoma and renal pelvis transitional cell carcinoma (TCC) were diagnosed. The use of cytokeratin (CK)-7 and -20 and uroplakin III as potential renal TCC markers was evaluated. The neoplastic cells were labelled intensely with antibodies to uroplakin III, but not to CK-7 or -20. Spontaneous intestinal adenocarcinoma has been documented in the rhesus macaque, but concurrent renal pelvis TCC is highly unusual.
Assuntos
Adenocarcinoma/veterinária , Carcinoma de Células de Transição/veterinária , Neoplasias do Íleo/veterinária , Neoplasias Renais/veterinária , Doenças dos Macacos/patologia , Neoplasias Primárias Múltiplas/veterinária , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/patologia , Feminino , Neoplasias do Íleo/metabolismo , Neoplasias do Íleo/patologia , Valva Ileocecal/patologia , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Pelve Renal/patologia , Macaca mulatta , Doenças dos Macacos/metabolismo , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/patologiaRESUMO
BACKGROUND: Neuroendocrine tumors (NETs) of the ileum are rare submucosal tumors that are often diagnosed at advanced stages with metastatic spread to the liver causing a carcinoid syndrome. They present as solitary or multiple tumors. In NETs, loss of sequences on chromosomes 11, 16, 18 and 22 or gain of sequences on chromosomes 17 and 19 has been described. In this study we explored the expression of two novel candidate genes, CDX2 and Oct4, in NETs of the ileum and analyzed whether the molecular expression pattern correlates with the clinical phenotype (solitary/multiple tumors). METHODS: Data from all patients who underwent surgery for a NET of the ileum between 2000 and 2010 were retrieved from a prospective database. For each patient, frozen normal and tumor tissue was used for the comparison of gene expression levels of two putative cancer stem cell markers, CDX2 and Oct4, using real-time PCR (rtPCR). Serial slides from paraffin blocks were used for immunohistochemistry. Gene expression was compared between normal and tumor tissue as well as between solitary and multiple tumors. RESULTS: 78 patients were identified. In rtPCR, a statistically significant higher expression of CDX2 in tumor tissue (p < 0.001) compared to normal tissue was found. The expression of Oct4 was elevated in the tumors, but did not reach the level of significance (p = 0.155). The expression of both candidate genes was confirmed immunohistochemically and showed a nuclear expression pattern. There was no difference in expression between solitary and multiple tumors or between tumors that had already spread to the liver. CONCLUSION: CDX2 is overexpressed in ileum NETs, thus playing a role in the tumorigenesis of these rare tumors. Since expression does not correlate with clinical stage or phenotype, it might be an early event in tumor development.
Assuntos
Proteínas de Homeodomínio/fisiologia , Neoplasias do Íleo/etiologia , Tumores Neuroendócrinos/etiologia , Fator 3 de Transcrição de Octâmero/fisiologia , Adulto , Idoso , Fator de Transcrição CDX2 , Feminino , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Humanos , Neoplasias do Íleo/metabolismo , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Fator 3 de Transcrição de Octâmero/análise , Fator 3 de Transcrição de Octâmero/genética , Projetos Piloto , Reação em Cadeia da Polimerase em Tempo RealRESUMO
A 72-year-old Japanese woman was admitted because of vomiting and abdominal pain. An enhanced computed tomography scan showed a small intestinal obstruction due to ileal wall thickening and multiple liver metastases. Her serum alpha-fetoprotein (AFP) level was high at 1671.9ng/ml. An ileocecal resection was performed. The histological diagnosis was AFP-producing small intestinal cancer resembling the primitive gut epithelium of a fetus. The present case suggested that even intestinal cancer could produce AFP.
Assuntos
Neoplasias do Íleo/metabolismo , alfa-Fetoproteínas/biossíntese , Idoso , Epitélio/patologia , Feminino , Feto , Humanos , Neoplasias do Íleo/patologia , Metástase NeoplásicaRESUMO
MALT lymphoma of the ileum is extremely rare: only several cases have been reported. A 34-year-old woman presented abdominal pain and melena. Colorectal and small intestinal endoscopes revealed multiple tumors and ulcers of the entire ileum. Biopsy was taken. Histologically, the biopsy consisted of 6 tissue specimens taken from the various sites of the ileum. All the tissue specimens showed infiltration of small atypical cells resembling centrocyte-like cells (CLC). Immunoblastic cells were scattered, though the number was scant. Monocytoid, plasma cell differentiation, and germinal centers were seen. Lymphoepithelial lesions (LEL) were scattered. Some small atypical lymphocyte were destructive the vessels and stromal tissues. Giemsa and Gram stains demonstrated no Helicobacter pylori and any bacteria. Immunohistochemically, the atypical small lymphocytes were positive for vimentin, but negative for various kinds of cytokeratins (CKs), EMA, CEA and CA19-9. The CK highlighted the LEL. They were positive for CD45, and B-cell markers (CD20, CD79a, CD10, CD23, bcl-2). CD138-positive plasma cells were seen in large number. CD68-positive macrophages were scattered. CD30- and CD15-positive immunoblastic cells were scattered. Most of the lymphoid cells were negative for T-cell markers (CD3, CD4, CD5, CD45RO, and CD43) and negative for NK cell markers (CD56 and CD57). The lymphoid cells were positive for κ-chain but negative for λ-chain; thus the light chain restriction was seen. TdT and cyclin D1 were negative. P53 was positive and Ki-67 labeling index was 67%. The lymphoid cells were negative for neuroendocrine markers (NCAM, NSE, chromogranin, and synaptophysin). The pathological diagnosis was MALT lymphoma of the ileum. Post-biopsy imaging techniques including CT, MRI, PET endoscope and gallium scintigraphy identified no tumors and no lymphadenopathy in the body except the ileum. The stomach was free from MALT lymphoma. She was treated by low dose chemotherapy and strictly followed up.
Assuntos
Neoplasias do Íleo/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Adulto , Antineoplásicos/uso terapêutico , Povo Asiático , Biomarcadores Tumorais/análise , Feminino , Humanos , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Íleo/metabolismo , Imuno-Histoquímica , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/metabolismoRESUMO
BACKGROUND: Extracellular ATP is an endogenous signaling molecule released by various cell types and under different stimuli. High concentrations of ATP released into the extracellular medium activate the P2X7 receptor in most inflammatory conditions. Here, we seek to characterize the effects of ATP in human intestinal epithelial cells and to evaluate morphological changes in these cells in the presence of ATP. METHODS: We treated human intestinal epithelial cells with ATP and evaluated the effects of this nucleotide by scanning and transmission electron microscopy analysis and calcium measurements. We used flow cytometry to evaluate apoptosis. We collected human intestinal explants for immunohistochemistry, apoptosis by the TUNEL approach and caspase-3 activity using flow cytometry analyses. We also evaluated the ROS production by flow cytometry and NO secretion by the Griess technique. RESULTS: ATP treatment induced changes characteristic of cell death by apoptosis and autophagy but not necrosis in the HCT8 cell line. ATP induced apoptosis in human intestinal explants that showed TUNEL-positive cells in the epithelium and in the lamina propria. The explants exhibited a significant increase of caspase-3 activity when the colonic epithelial cells were incubated with IFN-gamma followed by ATP as compared to control cells. In addition, it was found that antioxidants were able to inhibit both the ROS production and the apoptosis induced by ATP in epithelial cells. GENERAL SIGNIFICANCE: The activation of P2X7 receptors by ATP induces apoptosis and autophagy in human epithelial cells, possibly via ROS production, and this effect might have implications for gut inflammatory conditions.
Assuntos
Adenocarcinoma/patologia , Trifosfato de Adenosina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Colo/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Neoplasias do Íleo/patologia , Adenocarcinoma/metabolismo , Western Blotting , Cálcio/metabolismo , Caspase 3/metabolismo , Células Cultivadas , Colo/citologia , Colo/metabolismo , Células Epiteliais/metabolismo , Citometria de Fluxo , Imunofluorescência , Humanos , Neoplasias do Íleo/metabolismo , L-Lactato Desidrogenase/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Necrose , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
The synthesis and preclinical evaluation of [(99m)Tc]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N(4)-chelator to neuromedin C (human GRP(18-27)), which, after (99m)Tc-labeling, afforded [(99m)Tc]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC(50) in nM: GRPR, 1.4 ± 0.2; NMBR, 106 ± 18; and BB(3)R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca(2+) release in PC-3 cells (EC(50) = 1.3 nM). [(99m)Tc]Demomedin C rapidly and specifically internalized at 37 °C in PC-3 cells and was stable in mouse plasma. [(99m)Tc]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 ± 0.81%ID/g at 1 h pi; 6.36 ± 0.85%ID/g at 4 h pi, and 0.41 ± 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [(99m)Tc]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features--e.g. higher GRPR-selectivity--vs their frog-homologues.
Assuntos
Bombesina/síntese química , Oligopeptídeos/síntese química , Compostos de Organotecnécio/síntese química , Fragmentos de Peptídeos/síntese química , Compostos Radiofarmacêuticos/síntese química , Receptores da Bombesina/metabolismo , Tecnécio , Sequência de Aminoácidos , Animais , Anuros , Autorradiografia , Ligação Competitiva , Bombesina/química , Bombesina/farmacocinética , Neoplasias Brônquicas/diagnóstico por imagem , Neoplasias Brônquicas/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias do Íleo/diagnóstico por imagem , Neoplasias do Íleo/metabolismo , Ligantes , Masculino , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Transplante de Neoplasias , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Compostos de Organotecnécio/química , Compostos de Organotecnécio/farmacocinética , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Cintilografia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Receptores da Bombesina/agonistas , Especificidade da Espécie , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante HeterólogoRESUMO
Gastrointestinal and pancreatic neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells, expressing general and specific neuroendocrine markers. The World Health Organization 2010 classification of NETs is based on grading them according to the proliferation index (PI), which is determined by immunohistochemical staining of the nuclear antigen Ki-67. The classification introduces Ki-67 as the most important criterion for tumor grading, influencing patients' prognoses and the choice of treatment. The aim of this study was to evaluate the assessment of PI value in NETs and its influence on tumor grading. The tumor material consisted of 51 NETs from the pancreas (n=31) and ileum (n=20). The slides were stained with the Ki-67 antibody and visualized using a polymer kit. PI was assessed visually by microscope oculars and using a public domain image analysis software, ImmunoRatio. The PI was measured from the most proliferative areas of the tumor. The PI values and tumor grade by ImmunoRatio were highly reproducible as compared with conventional assessment, which suffered from variation especially if ascertained by different observers. Computer-aided assessments had almost perfect correlation (r=0.985, r=0.987, and r=0.995) (P=0.000) and reproducibility (κ=0.886, κ=0.886, and κ=1.000) (P=0.000) in PI values and tumor grades, respectively. The PI values and tumor grade between conventional and ImmunoRatio assessments by a qualified observer were in good agreement. ImmunoRatio is a qualified diagnostic aid to more objectively analyze Ki-67 PI-based tumor grade in NETs.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Íleo/patologia , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Proliferação de Células , Humanos , Neoplasias do Íleo/classificação , Neoplasias do Íleo/metabolismo , Processamento de Imagem Assistida por Computador , Gradação de Tumores , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/metabolismo , Reprodutibilidade dos TestesRESUMO
We report a case of adenocarcinoma of the small intestine responding to XELOX chemotherapy, leading to a partial metabolic response(PMR). The patient was a 58-year-old male with multiple peritoneal dissemination of adenocarcinoma of the small intestine. Chemotherapy with XELOX(L-OHP 130 mg/m² on day 1 , and capecitabine 1,000 mg/m2 on days 1-14)was performed. After 4 courses, a significant tumor reduction was obtained. This case suggests that chemotherapy with XELOX is a potential regimen for small intestinal adenocarcinoma.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Íleo/tratamento farmacológico , Adenocarcinoma/metabolismo , Capecitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Neoplasias do Íleo/metabolismo , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Oxaloacetatos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
Diffuse ganglioneuromatosis of the digestive tract is a rare condition, especially in children. It is frequently associated with multiple endocrine neoplasia type 2b and less commonly with neurofibromatosis type 1 (NF1). We report the case of an 8-month-old baby presenting with vasoactive intestinal polypeptide (VIP)-secreting diffuse ganglioneuromatosis affecting the small intestine and the colon and responsible for severe hydric diarrhea. Postoperatively the infant's symptoms resolved and the serum VIP level was normal. NF1 was clinically suspected and then confirmed through genetic testing. Two years later, the child developed an optic pathway glioma, another tumor frequently associated with NF1.