RESUMO
OBJECTIVES: The purposes of the study are to describe the incidence trend of malignant polyp of large bowel over a 25-year period in the District of Modena and to assess the effect of an organized colorectal cancer screening program. MATERIAL AND METHODS: Through the data of a specialized colorectal cancer Registry, we evaluate the clinical and pathological features of the polyps. Trend analysis was assessed with the Joinpoint Regression Program. RESULTS: A total of 172 patients with malignant polyps were diagnosed throughout the study (3.5% of 4.835 registered patients); their overall frequency during the registration period increased from zero cases in the initial years (1984-85) to 57 cases in the past 3 years (2006-2008). Crude incidence rate passed from 0.37 in 1986-89 to 10.2 in 2006. Joinpoint trend analysis of crude rates showed a significant increase of incidence during the study period, with percent of annual variation ranging between 38.6% (95% CI 12.5-70.7) and 7.3% (95% CI 2.6-12.1). During the screening period (2005-2008, the past 4 years of registration) there was a significant increase of sessile polyps (p < 0.001), while other clinical and morphological features, including the number of low- and high-risk malignant polyps, remained unchanged. The surgery (after polypectomy) tended to raise both in low- and high-risk subgroups. CONCLUSION: The incidence of malignant polyps increased significantly from the initial to the most recent periods of colorectal cancer registration. Screening was associated with changes in gross morphology of polyps and with an increased use of the surgery after endoscopic polypectomy.
Assuntos
Carcinoma/epidemiologia , Pólipos do Colo/epidemiologia , Pólipos do Colo/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Sistema de Registros , Idoso , Carcinoma/patologia , Colonoscopia , Feminino , Humanos , Incidência , Itália , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: The analysis of regional lymph nodes is particularly relevant in patients with stage II colorectal cancer, in whom the role of adjuvant chemotherapy remains unclear. The aim of this study was to assess the relationship between number of examined lymph nodes and survival in patients with stage IIA (pT3N0M0) colorectal cancer, and to determine the optimal number of lymph nodes that should be examined. METHODS: The study group included all the surgically-treated colorectal cancer patients in stage IIA (n = 657) who were identified through the population-based Cancer Registry of the Province of Modena (Northern Italy), during the period 2002-2006. RESULTS: The median number of harvested lymph nodes was 19 (range 1-68). Considering, as a reference point, patients with 12 or less lymph nodes, subjects with n ≥ 20 lymph nodes examined showed, in univariate analysis, a significantly higher cancer specific (p = 0.01) and relapse-free survival (p = 0.003). The results were confirmed by multivariate analysis (Cox model). CONCLUSION: The result suggests that colorectal cancer patients in stage IIA with n ≥ 20 lymph nodes examined exhibit better survival when compared with subjects in whom fewer lymph nodes were examined. The number of 20 lymph nodes is the essential requirement for an oncologic resection of the large bowel.
Assuntos
Adenocarcinoma Mucinoso/patologia , Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adenocarcinoma Mucinoso/epidemiologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Taxa de SobrevidaRESUMO
OBJECTIVE: Stage I colorectal carcinomas display a highly variable behavior which is not accurately predicted by the available prognostic markers. CD133 is considered a useful marker to identify the so-called cancer stem cells in colorectal cancers (CRCs) and its expression has been shown to have prognostic significance in CRC patients. This study aimed to verify whether immunohistochemical evaluation of CD133 might correlate with the progression risk of stage I CRC patients. MATERIAL AND METHODS: Expression levels of the CD133 molecule were analyzed and compared in two series of stage I surgically resected CRC patients showing disease progression and death for the disease and patients with no evidence of disease progression after at least 6 years after surgery. RESULTS: A positive staining for CD133 was detected in 52% of the cases with poor prognosis and only in 9% of the group with good prognosis, and this difference was highly significant (p < 0.001). A significant correlation was detected between CD133 expression and histological parameters, such as tumor budding, vascular invasion, and presence of lymph node micrometastases but not tumor grading, gender, and age. Disease-free survival and cancer-specific survival of CD133 negative tumors were significantly longer compared to positive cases. In multivariate analyses, CD133 staining confirmed to be a predictor of shorter survival independent from vascular invasion but not from lymph nodes micrometastases. CONCLUSIONS: These findings demonstrate that CD133 immunostaining is a useful predictor of high risk progression in stage I CRC patients and might help to identify patients eligible for adjuvant chemotherapy.
Assuntos
Adenocarcinoma/secundário , Antígenos CD , Biomarcadores Tumorais , Neoplasias Colorretais , Glicoproteínas , Células-Tronco Neoplásicas/metabolismo , Peptídeos , Antígeno AC133 , Idoso , Antígenos CD/análise , Antígenos CD/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glicoproteínas/análise , Glicoproteínas/metabolismo , Humanos , Imuno-Histoquímica/métodos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Seleção de Pacientes , Peptídeos/análise , Peptídeos/metabolismo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodosRESUMO
BACKGROUND: In patients with Lynch syndrome, germline mutations in DNA mismatch repair (MMR) genes cause a high risk of developing a broad spectrum of cancers. To date, the management of patients with Lynch syndrome has represented a major challenge because of large variations in age at cancer onset. Several factors, including genetic anticipation, have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Telomere shortening is a common event in tumorigenesis and also has been observed in different familial cancers. In this study, the authors investigated the possibility of a relation between telomere length and cancer onset in patients with Lynch syndrome. METHODS: The mean telomere length was measured using quantitative polymerase chain reaction in peripheral blood samples from a control group of 50 individuals, from 31 unaffected mutation carriers, and from 43 affected patients, and the results were correlated with both gene mutation and cancer occurrence. In affected patients, telomere attrition was correlated with age at cancer onset. In all patients, a t test was used to assess the linearity of the regression. RESULTS: A significant correlation between telomere length and age was observed in both affected and unaffected mutation carriers (P = .0016 and P = .004, respectively) and in mutS homolog 2 (MSH2) mutation carriers (P = .0002) but not in mutL homolog 1 (MLH1) mutation carriers. Telomere attrition was correlated significantly with age at onset in MSH2 carriers (P = .004), whereas an opposite trend toward longer telomeres in patients with delayed onset was observed in MLH1 carriers. CONCLUSIONS: The current data suggested that telomere dynamics differ between MLH1 and MSH2 mutation carriers. It is possible that subtle, gene-specific mechanisms can be linked to cancer onset and anticipation in patients with Lynch syndrome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Telômero/patologia , Adulto , Idade de Início , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Mutação , LinhagemRESUMO
OBJECTIVE: Although patients with Stage I colorectal cancer show an excellent prognosis, a few of them die of metastatic disease. In this subgroup of individuals, the search of occult metastasis might reveal that early dissemination of tumor cells could be the cause of cancer progression. MATERIAL AND METHODS: Through a Cancer Registry, we selected all patients with Stage I disease who died of metastatic tumor; a total of 32 patients were identified and in 25 of them paraffin-embedded material was available. The group was matched to 70 Stage I patients with favorable prognosis (controls). In cases and controls resected lymph nodes were cut, and micrometastases were searched using pan-cytokeratin antibodies. RESULTS: Micrometastases were detected in 18 of 25 (72%) Stage I patients who died of the disease, while they were almost absent among controls (1 of 70, p < 0.001 by χ(2) test). Vascular invasion and tumor budding were more frequent among Stage I patients with an unfavorable prognosis than in controls. By regression analyses, micrometastases (HR 12.3, CI 4.8-32) and vascular invasion (HR 3.5, CI 1.4-8.5) maintained an independent association with prognosis (cancer-specific survival). CONCLUSION: Micrometastasis in the lymph nodes can be revealed in the majority of patients with early colorectal cancer who die of tumor progression, while they appear extremely rare in Stage I individuals with good prognosis. The selection of patients through histology (vascular invasion) and search of occult metastatic cells might represent a way to identify individuals who might benefit from adjuvant chemotherapy.
Assuntos
Vasos Sanguíneos/patologia , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Idoso , Carcinoma/secundário , Estudos de Casos e Controles , Feminino , Humanos , Queratinas/metabolismo , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de RegressãoRESUMO
OBJECTIVE: The study reviews the endoscopic and histological features of human cytomegalovirus (HCMV) infections of the upper gastrointestinal (UGI) tract. MATERIALS AND METHODS: Clinical histories, endoscopic findings and bioptic specimens of 30 cases of HCMV infection of the UGI tract, diagnosed in a University Hospital in a 10-year period, were reviewed. In all cases, viral inclusion bodies were detected in routine histopathological sections and the diagnosis was confirmed with immunohistochemistry. RESULTS: Six patients were HIV+, whereas four had received organ transplantations, one was affected by common variable immunodeficiency and four had a recent history of malignancy. No other pathologic condition was evidenced in the remaining 15 cases. Mucosal alterations were endoscopically observed in the stomach (19 cases), esophagus (9), cardias (6) and duodenum (1), and multiple organs being synchronously affected in five patients (3 HIV+, 2 with history of malignancy). The antropyloric area was the most frequently affected site. Single ulcers were detected in 11 cases and multiple ulcers in 8, whereas mucosal thickenings (in the form of localized thickenings, polyps or rugal hypertrophy) were present in 13 patients. Thickenings of the mucosa were detected only in the stomach. At histology, necrotic material and granulation tissue were associated with moderate or marked lympho-plasmacytic infiltrate and foveolar hyperplasia in ulcerative lesions, whereas lesions labeled as mucosal thickenings showed mild or moderate chronic inflammatory infiltrate and foveolar hyperplasia. CONCLUSIONS: Endoscopic manifestations of UGI tract involvement in HCMV infection are not specific, varying from erythematous mucosa to ulcers to mucosal thickenings.
Assuntos
Infecções por Citomegalovirus/patologia , Citomegalovirus , Duodenopatias/patologia , Doenças do Esôfago/patologia , Gastropatias/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Imunodeficiência de Variável Comum/complicações , Citomegalovirus/imunologia , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Neoplasias do Sistema Digestório/complicações , Duodenopatias/virologia , Endoscopia Gastrointestinal , Doenças do Esôfago/virologia , Feminino , Soropositividade para HIV/complicações , Humanos , Hospedeiro Imunocomprometido , Transplante de Rim/imunologia , Transplante de Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Gastropatias/virologiaRESUMO
AIMS: Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups. METHODS AND RESULTS: Bronchial rings from 10 non-smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid-Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5-31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5-17.5%); P < 0.05] and non-smoking subjects [2% (0.4-6.2%); P < 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25-92%) epithelial area] compared with non-smoking subjects [15% (2.7-32%); P < 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack-years. CONCLUSIONS: COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.
Assuntos
Brônquios/metabolismo , Mucina-5AC/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Mucosa Respiratória/metabolismo , Idoso , Azul Alciano , Brônquios/patologia , Feminino , Humanos , Masculino , Mucina-5B/metabolismo , Mucinas/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Fumar/efeitos adversos , Coloração e RotulagemRESUMO
OBJECTIVE: Familial adenomatous polyposis (FAP) is an interesting model for the study of colorectal tumour. Two genes contribute to the FAP phenotype - APC and MUTYH - but their relative role is still undefined. The objective of this study was to evaluate the contribution of the two genes to the pathogenesis of FAP by means of a series of FAP families. MATERIAL AND METHODS: Sixty-one unrelated families with a diagnosis of FAP and a total of 187 affected individuals were evaluated. After extracting DNA, APC and MUTYH genes were sequenced. RESULTS: In the whole series of patients, colectomy with ileorectal anastomosis was the most frequent surgery, although the number of patients treated by total proctocolectomy and ileoanal anastomosis was increasing. Duodenal and jejunal-ileal adenomas were present in more than half of the patients. Constitutional mutations were detected in 37 of the 45 families (82.2%); there were 33 families with APC and 4 with MUTYH alterations. Age at onset of polyposis and age at surgery were 10-15 years delayed for carriers of MUTYH mutations; cancer at diagnosis was frequent, and extracolonic manifestations were diagnosed in the majority of MUTYH-positive families. MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations). CONCLUSIONS: At least two genes are associated with the FAP phenotype. APC mutations account for the majority of cases, while MUTYH mutations can be observed in 10% of patients. There are few but definite differences between APC- and MUTYH-associated FAP, such as age at diagnosis and pattern of transmission.
Assuntos
DNA Glicosilases/genética , Genes APC , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Adulto , Idade de Início , Distribuição de Qui-Quadrado , Feminino , Predisposição Genética para Doença , Humanos , Itália , Masculino , Mutação , Linhagem , Fenótipo , Fatores de Risco , Estatísticas não ParamétricasRESUMO
BACKGROUND AND AIMS: A general improvement of colorectal cancer prognosis has been observed. Reasons of this more favourable trend are diffusion of screening, advancements in molecular biology, new developments in chemotherapy and surgical techniques. Through the data of a colorectal cancer registry, we purposed to evaluate changes in surgical procedures for colorectal neoplasms and to analyse trends of perioperative mortality. PATIENTS AND METHODS: Patients with colorectal cancer were registered from 1984 to 2004. The main surgical procedures were recorded and classified. Perioperative mortality was defined as death of patients within 1 month since the operation. RESULTS: Regression analysis showed an increase over time of right and left hemicolectomy. Both colectomy and endoscopic polypectomy showed significant rise over time. In contrast, abdominoperineal operations dropped during the study period. A similar decrease was observed for palliative surgery. Perioperative mortality declined from 7-11% to 3-6% of all operations; main factors associated with perioperative mortality were presence of comorbidities, increasing age and advanced stage. CONCLUSION: The better prognosis of patients with colorectal cancer was associated with changes of surgical techniques, with a tendency to prefer large operations over limited resections. Perioperative mortality showed a gradual decrease and is at present in the order of 3% to 6% of all operations.
Assuntos
Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Assistência Perioperatória , Sistema de Registros , Adulto , Causas de Morte , Colectomia , Feminino , Humanos , Itália , Masculino , Cuidados Paliativos , Análise de SobrevidaRESUMO
Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.
Assuntos
Neoplasias Colorretais/enzimologia , Peroxidase/metabolismo , Lesões Pré-Cancerosas/genética , Adenoma/enzimologia , Adenoma/patologia , Análise de Variância , Biomarcadores Tumorais/metabolismo , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Doenças Inflamatórias Intestinais/enzimologia , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
Epigenetic alterations have been reported in colorectal neoplasia which can either complement or in some cases be predisposed to genetic alterations such as K-ras mutations. We examined the promoter methylation status of the CDKN2A and O6-methylguanine-DNA methyltransferase (MGMT) genes, after sodium bisulfite conversion and DNA amplification with methylation specific PCR. Moreover, we searched for G to A transitions in codons 12 and 13 of the K-ras oncogene in normal colorectal mucosae, aberrant crypt foci (ACF, early premalignant lesions) and carcinomas. CDKN2A hypermethylation was an infrequent event in ACF (2 of 26, 7.7%). On the contrary, MGMT hypermethylation was found in the normal mucosae (3 of the 12 samples, 25%), in 14 of the 26 ACF (53.8%) and in 7 of the 9 (77.8%) carcinomas examined. K-ras mutations were evident in 6 ACF (23%) and in 3 carcinomas (33.3%), mostly associated with MGMT promoter hypermethylation. These findings strongly support the hypothesis that epigenetic mechanisms play an important role in the early steps of colorectal carcinogenesis.
Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , O(6)-Metilguanina-DNA Metiltransferase/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Feminino , Genes ras/genética , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Sulfitos/químicaRESUMO
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal-dominant disorder characterized by predisposition to colorectal cancer and extracolonic malignancies, frequent multiple primary tumors in the same patient, and early age of cancer onset. A main clinical variant of Lynch syndrome, Muir-Torre syndrome (MTS) is characterized by the association between one or more visceral malignancies, with at least one sebaceous skin tumor or keratoacanthoma. In our study, we have screened a cohort of 538 HNPCC patients, related to 57 HNPCC families, to detect sebaceous skin tumors and keratoacanthomas and the role of mismatch repair (MMR) genes, MLH1, MSH2, and MSH6, in their pathogenesis. Among the 57 HNPCC families, we have identified four MTS families and one suspected MTS family, in which sebaceous carcinoma was found in one HNPCC mutation carrier subject who did not show visceral malignancy. In four of these families, linked to two MLH1 mutations and to two MSH2 mutations, biomolecular characterization showed concordance among immunohistochemistry analysis and gene mutations. The evidences of our investigations show that MLH1 and MSH2 gene mutations have an equivalent etiopathological role both for Lynch syndrome and for MTS; hence, we propose a broadened clinical criteria for definition of Lynch syndrome that will include sebaceous adenoma, carcinoma, and keratoacanthoma.
Assuntos
Proteínas de Transporte/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Ceratoacantoma/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Neoplasias das Glândulas Sebáceas/genética , Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Colorretais Hereditárias sem Polipose/etiologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Instabilidade Genômica , Humanos , Ceratoacantoma/patologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Fenótipo , Neoplasias das Glândulas Sebáceas/patologiaRESUMO
BACKGROUND: The assessment of microsatellite instability (MSI) is not included yet in the routine evaluation of patients with gastric cancer, as controversial data exist regarding its prognostic value. METHODS: We determined the clinical significance of MSI in 510 sporadic gastric cancers, using the mononucleotide markers BAT25 and BAT26. The results were compared with the immunohistochemical expression of the mismatch repair proteins Mlh1 and Msh2. RESULTS: MSI was present in 83 (16%) cancers and correlated with better survival (P < .001). Multivariate analysis showed that the MSI phenotype was an independent factor (P = .005) and added prognostic information to TNM stage, location, and age. The relative risk of death for MSI cancer patients was 0.6 (95% confidence interval [CI], 0.4-0.8). Moreover, when grouped according to stage, only stage II cancers showed a significant effect of MSI status on survival (P = .011; hazard ratio = 0.3; 95% CI, 0.1-0.8). MSI also correlated with older age (P = .002), female gender (P < .001), intestinal histotype (P = .011), lower T stage (P = .018), and less lymph node involvement (P < .001). Finally, comparison of the results of immunohistochemical expression of the mismatch repair proteins Mlh1 and Msh2 with microsatellite analysis showed concordant results in 95% of neoplasms, with a sensitivity of 82% and specificity of 98%. CONCLUSIONS: Microsatellite analysis of gastric cancer has clinical utility in determination of prognosis, but should be determined in only stage II neoplasms in a routine clinical setting. Immunohistochemistry may be considered sufficient, although microsatellite analysis is preferable.
Assuntos
Instabilidade Genômica , Repetições de Microssatélites , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
PURPOSE: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. EXPERIMENTAL DESIGN: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. RESULTS: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year-specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non-polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. CONCLUSIONS: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non-polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.
Assuntos
Neoplasias Colorretais/genética , Instabilidade Genômica , Repetições de Microssatélites/genética , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Proteínas de Transporte/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The main purpose of this study was to examine the expression of mucins and mismatch repair proteins in colorectal carcinomas. The immunohistochemical distribution of apomucins MUC2, MUC5AC, and the expression of MLH1 and MSH2 proteins were examined in 76 mucinous and 60 non-mucinous colorectal carcinomas. MUC2 was noted in all mucinous carcinomas, whereas MUC5AC was present in 41 cases only (54%). In non-mucinous carcinomas, MUC2 was expressed in 61.7% of the tumors; by contrast, MUC5AC was present in 20% of the cases. The expression level of apomucins was significantly different in mucinous and non-mucinous lesions (p<0.001). Twenty-seven (35.5%) of the mucinous carcinomas showed no MLH1 expression, whereas 11 (18.3%) of the non-mucinous tumors did. This difference was statistically significant (p<0.005). Altered expression of MSH2 protein was never observed. The lack of MLH1 expression was considerably more frequent in carcinomas with secretion of MUC5AC (p<0.005). Our study has demonstrated this close relationship by immunohistochemical methods. In summary, our data show: (1) differences in the expression of mucins between mucinous and non-mucinous tumors; (2) a high frequency of altered MLH1 protein expression (35.5%) in mucinous carcinomas; (3) a significant relationship between the presence of MUC5AC and the altered expression of MLH1 protein in colorectal carcinomas.
Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias Colorretais/patologia , Mucinas/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Proteínas de Transporte , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mucina-5AC , Mucina-2 , Proteína 1 Homóloga a MutL , Proteínas NuclearesRESUMO
We report the clinical case of a patient who showed an "accelerated" form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family-already described in 2001-featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient.
Assuntos
Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Genes APC , Idade de Início , Criança , Pré-Escolar , Feminino , Hepatoblastoma/epidemiologia , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The aim of the present study was to determine whether BCL6 is expressed during malignant transformation of the large bowel and to assess whether, and to what extent, immunoreactivity is related to the different stages of neoplastic progression. Samples of normal colorectal mucosa (n=22), microadenomas (n=22) and colorectal cancer (n=22), were analyzed by immunohistochemistry, immunofluorescence coupled with confocal microscopy and western blotting. Our results clearly outlined the marked increase occurring in both intensity and density of BCL6 protein expression in the normal mucosa-microadenoma-carcinoma sequence. Immunohistochemistry and immunofluorescence analyses showed that BCL6 is expressed at low levels in normal mucosa and increases in microadenoma and in cancer with statistical significance. These results were confirmed by western blotting data. The increasing expression of BCL6 in human colorectal cancer development suggests the involvement of BCL6 in tumor progression, from the earliest stages of carcinogenesis with significant increase in cancer. The enhanced understanding of the biological role of BCL6, previously shown to exert a key role in lymphomagenesis, may lead to a re-evaluation of this protein and may highlight the importance of performing further studies in order to identify novel therapeutic targets for colorectal cancer.
Assuntos
Adenoma/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/biossíntese , Mucosa Intestinal/patologia , Intestino Grosso/patologia , Adenoma/imunologia , Biomarcadores Tumorais/biossíntese , Neoplasias Colorretais/imunologia , Proteínas de Ligação a DNA/imunologia , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/imunologia , Intestino Grosso/metabolismo , Microscopia Confocal , Proteínas Proto-Oncogênicas c-bcl-6RESUMO
Some histological features of malignant polyps have been used to classify patients into low- and high-risk groups. This study proposed to evaluate the impact of this classification on the clinical outcome of patients with malignant polyps. Through the Colorectal Cancer Registry, 105 patients with endoscopically removed malignant polyps were selected. The presence of one of the following histological features defined malignant polyps as high-risk: infiltrated resection-margin, poorly differentiated carcinoma, lymphatic/vascular invasion and tumour budding and depth of submucosal invasion. Available literature was reviewed by applying a similar classification. Most of the malignant polyps were pedunculated and were localized in the left colon. Fifty-five malignant polyps were classified as low-risk lesions and 50 as high-risk. None of the patients at low-risk died of colorectal cancer. Of the patients at high-risk, three died of cancer; all three cases showed lymphatic/vascular invasion. Review of the literature reveals that an unfavourable clinical outcome is significantly more prevalent in the high-risk compared with the low-risk group (p > 0.005). Moreover, all histological risk factors show a specific predictive value of clinical adverse outcome. Our study and the pooled data analysis confirmed the usefulness of the subdivision into low- and high-risk malignant polyps for management of patients with endoscopically removed colorectal carcinoma.
Assuntos
Neoplasias Colorretais/patologia , Pólipos Intestinais/patologia , Idoso , Pólipos do Colo/patologia , Pólipos do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Pólipos Intestinais/cirurgia , Masculino , Estudos Prospectivos , Doenças Retais/patologia , Doenças Retais/cirurgia , Medição de Risco , Resultado do TratamentoRESUMO
Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Mutations in MSH2 cause concomitant loss of hMSH6, whereas MLH1 mutations lead to concurrent loss of PMS2. Much less frequent mutations in MSH6 or PMS2 are associated with the isolated loss of the corresponding proteins. We here demonstrate the causative role of the first germline mutation of MSH2, c.1249-1251 dupGTT (p.417V-418I dupV), associated with normal hMSH2 expression and lack of hMSH6 protein despite a normal MSH6 gene sequence. hMSH6 protein was completely lost only in advanced cancer stages due to 2 different "second hits": a whole MSH2 gene deletion and a frame-shifting insertion in the MSH6 (C)8 repeat in the coding sequence.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Sequência de Bases , Western Blotting , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Imunoprecipitação , Masculino , Reação em Cadeia da Polimerase Multiplex , Proteína 2 Homóloga a MutS/metabolismo , Linhagem , Reação em Cadeia da Polimerase , Ligação ProteicaRESUMO
BACKGROUND: Prognostic factors for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) are still a matter of debate. The absence of viable tumor in the native liver, due to effectiveness of pre-LT locoregional treatment or liver resection, is an intriguing prognostic factor that had never been evaluated. METHODS: Between November 2000 and December 2011, 210 LTs were performed in patients with evidence of HCC and cirrhosis. RESULTS: Fifty-three (25.2%) patients did not show any evidence of active residual HCC in the native liver (Group NVH), whereas 157 (74.8%) patients showed viable HCC (Group VH). All patients in Group NVH were treated before LT with a multimodal approach combining transarterial chemoembolization, liver resection, radiofrequency ablation, percutaneous ethanol injection, or sorafenib, whereas, in Group VH, 110 of the 157 (70.1%) patients received bridging therapy (P<0.001). HCC recurrence occurred in none of the patients in Group NVH (0%) and in 25 (15.9%) patients in Group VH (P=0.003). Liver resection was the most effective treatment in obtaining absence of HCC on liver explantation. The results of multivariate analysis showed that existence of pathologic HCC findings outside of the University of California-San Francisco criteria (P=0.001; odds ratio, 4; confidence interval, 1.7-9.2) and the presence of viable HCC (P=0.003; odds ratio, 5.9; confidence interval, 1.5-17.6) were independently associated with HCC recurrence. CONCLUSIONS: The histologic absence of viable HCC in the native liver after LT and morphologic criteria, due to the high effectiveness of pre-LT bridging treatments, is a highly positive prognostic factor against HCC recurrence after LT.