RESUMO
INTRODUCTION: We evaluated immunohistochemical staining for thyroid peroxidase (TPO), a glycoprotein found in the apical plasma membrane of thyroid follicular cells, as a marker for metastatic PTC in FNA samples and compared results with thyroglobulin (Tg) and thyroid transcription factor 1 (TTF1) staining. METHODS: Cell block sections prepared from 100 FNA specimens were stained with a rabbit monoclonal antibody to TPO (EP159). The FNAs included 64 metastatic malignancies from non-thyroid primary sites, including 18 lung, and 36 cases of thyroid tumours (29 PTC, six cases of medullary thyroid carcinoma and one thyroid anaplastic carcinoma). Thyroid tumours were stained with TTF1 and Tg in addition to TPO. All cases of metastatic lung carcinoma also had TTF-1 staining results. RESULTS: TPO staining was negative in all non-thyroid malignancies. Ninety percent (26/29) of PTC were positive. All positive cases showed strong cytoplasmic staining, although 54% (14/26) showed positivity in less than half of the cells. By comparison, Tg staining of TPC cases was present in 62% and TTF-1 in 100%. In addition to showing higher sensitivity, interpretation of staining results with TPO was generally easier with than Tg. All metastatic lung adenocarcinomas were positive for TTF-1 and TPO negative. The six medullary cancers showed positivity in 17%, 0% and 83% with TPO, Tg and TTF-1, respectively. CONCLUSIONS: TPO (mAb EP159) may be a useful addition to immunohistochemical panels for FNA specimens where metastatic PTC is a consideration, particularly in cases where metastatic lung carcinoma features in the differential diagnosis.
Assuntos
Metástase Neoplásica/patologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Autoantígenos/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina/métodos , Proteínas de Ligação a DNA/metabolismo , Humanos , Imuno-Histoquímica/métodos , Iodeto Peroxidase/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Tireoglobulina/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismoAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina Trifosfatases/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Análise Mutacional de DNA/métodos , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Imuno-Histoquímica , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteínas Nucleares/metabolismo , Polimorfismo Genético , Sistema de RegistrosRESUMO
A 66-year-old man with a history of repeated surgery, external radiation and brachytherapy for ameloblastoma presented with a recurrence of the tumor with sinus, intraorbital and skull base infiltration. Histopathologic examination of the resected orbital and sinus tissue confirmed the diagnosis of ameloblastoma. Immunohistochemical staining for CD56 was strongly positive in the tumor cells. Although ameloblastoma is usually a low-grade malignant tumor, it can be locally aggressive with invasion of the surrounding tissue. Maxillary ameloblastomas are more likely to infiltrate the orbit.
Assuntos
Ameloblastoma/patologia , Neoplasias Maxilares/patologia , Neoplasias Orbitárias/patologia , Idoso , Humanos , Masculino , Invasividade Neoplásica/patologiaRESUMO
Genes have been identified for which germline mutations are associated with high lifetime risks of breast, colorectal and other cancers. Identification of mutation carriers through genetic testing is important as it could help lower cancer incidence and mortality. The translation of genetic information into better health outcomes is expensive because of the costs of genetic counselling as well as laboratory testing. Approaches to triage for mutation screening of known genes which rely on cancer family history are not necessarily sensitive and specific or the most cost-effective. Recent population-based research has shown that the cancers and precancerous lesions arising in mutation carriers have specific molecular and morphological characteristics. People with colorectal cancer, especially those diagnosed at a young age, whose tumours exhibit microsatellite instability and some specific pathology and immunohistochemically-defined features are more likely to carry a germline mutation in one of four mismatch repair genes. Some morphological and immunohistochemically-defined features are associated with breast cancers arising in women who carry BRCA1 or BRCA2 germline mutations, especially if at a young age. Screening paradigms based on molecular and morphological features that predict mutation status, especially if focused on early-onset disease, have the potential to identify mutation carriers with greater sensitivity and specificity, and in a more cost-effective way, than those based on family history alone. Genetic testing results could help inform treatment if those affected are tested soon after diagnosis using pathology-led selection strategies to identify cases most likely to carry germline mutations. We propose how this new approach could be undertaken by having genetic testing and counselling prioritised to those with the greatest probability of carrying a germline mutation in these known cancer predisposition genes.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Predisposição Genética para Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , MasculinoRESUMO
BACKGROUND AND AIMS: Reduced ileal Paneth cell alpha-defensin expression has been reported to be associated with Crohn's disease, especially in patients carrying NOD2 mutations. The aim of this study was to independently assess whether NOD2, alpha-defensins and Crohn's disease are linked. METHODS: Using quantitative real-time polymerase chain reaction (RT-PCR), we measured the mRNA expression levels of key Paneth cell antimicrobial peptides (DEFA5, DEFA6, LYZ, PLA2G2A), inflammatory cytokines [interkelukin 6 (IL6) and IL8], and a marker of epithelial cell content, villin (VIL1) in 106 samples from both affected ileum (inflamed Crohn's disease cases, n = 44) and unaffected ileum (non-inflamed; Crohn's disease cases, n = 51 and controls, n = 11). Anti-human defensin 5 (HD-5) and haematoxylin/eosin immunohistochemical staining was performed on parallel sections from NOD2 wild-type and NOD2 mutant ileal Crohn's disease tissue. RESULTS: In Crohn's disease patients, DEFA5 and DEFA6 mRNA expression levels were 1.9- and 2.2-fold lower, respectively, in histologically confirmed inflamed ileal mucosa after adjustment for confounders (DEFA5, p<0.001; DEFA6, p = 0.001). In contrast to previous studies, we found no significant association between alpha-defensin expression and NOD2 genotype. HD-5 protein data supports these RNA findings. The reduction in HD-5 protein expression appears due to surface epithelial cell loss and reduced Paneth cell numbers as a consequence of tissue damage. CONCLUSIONS: Reduction in alpha-defensin expression is independent of NOD2 status and is due to loss of surface epithelium as a consequence of inflammatory changes rather than being the inciting event prior to inflammation in ileal Crohn's disease.
Assuntos
Doença de Crohn/metabolismo , Íleo/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , alfa-Defensinas/metabolismo , Adulto , Idoso , Doença de Crohn/genética , Doença de Crohn/imunologia , Feminino , Expressão Gênica , Genótipo , Fosfolipases A2 do Grupo II/genética , Fosfolipases A2 do Grupo II/metabolismo , Humanos , Técnicas Imunoenzimáticas , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Muramidase/genética , Muramidase/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Celulas de Paneth/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , alfa-Defensinas/genéticaRESUMO
BACKGROUND: When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences. METHODS: Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis. RESULTS: We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency <0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120). CONCLUSION: Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.
Assuntos
Adenosina Trifosfatases/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura/genética , Adulto , Idoso , Sequência de Bases , Análise Mutacional de DNA , DNA de Neoplasias/genética , Feminino , Testes Genéticos , Genoma Humano/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Dados de Sequência MolecularRESUMO
The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with MSS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (p = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, MSS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions.
Assuntos
Colite Ulcerativa/imunologia , Neoplasias Colorretais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Idoso , Apoptose , Antígenos CD2/imunologia , Antígenos CD8/imunologia , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Colite Ulcerativa/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Células Epiteliais/patologia , Feminino , Granzimas , Humanos , Imuno-Histoquímica/métodos , Linfócitos do Interstício Tumoral/enzimologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Serina Endopeptidases/análiseRESUMO
Mesh material affects complications following hernia repair. Medical device reports on the use of surgical mesh for hernia repair were reviewed from the Food and Drug Administration's (FDA) Manufacturer User Facility Device Experience Database from January 1996 to September 2004. We analyzed 252 adverse event reports related to the use of surgical mesh for hernia repair. Adverse events included infection (42%, 107 reports), mechanical failure (18%, 46), pain (9%, 23), reaction (8%, 20), intestinal complications (7%, 18), adhesions (6%, 14), seroma (4%, 9), erosion (2%, 6), and other (4%, 9). Compared to all other mesh types, Sepra/polypropylene mesh had more mechanical failures (80 vs 14%, p < 0.05), biomaterial mesh had more reactions (57 vs 7%, p < 0.05), polytetrafluoroethylene (PTFE)/polypropylene mesh had more intestinal complications (14 vs 7%, p < 0.05), and PTFE mesh tended to have more infections (75 vs 41% all other, p = 0.07). Death occurred in 2% (5). We conclude that specific mesh materials are related to specific complications.
Assuntos
Vigilância de Produtos Comercializados , Telas Cirúrgicas/efeitos adversos , United States Food and Drug Administration , Humanos , Estados UnidosRESUMO
BACKGROUND: Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently located in the proximal colon and share features such as circumscribed tumour margins and tumour-infiltrating lymphocytes. However, significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC. AIMS: In this study, we sought to determine whether the presence of widespread promoter hypermethylation and BRAF mutations would exclude HNPCC. MATERIALS AND METHODS: We investigated the methylation status of four methylated in tumour markers (MINTs 1,2,12 and 31), and the promoter regions of 5 genes hMLH1, HPP1, MGMT, p16INK4A and p14ARF, in 21 sporadic MSI-H colorectal cancers and compared these with 18 cancers from HNPCC patients. The methylation status of CpG islands were determined by either methylation specific PCR (MSP) or combined bisulfite restricton analysis (COBRA). In addition we considered the BRAF mutation status of 18 HNPCC tumours and 19 sporadic MSI-H cancers which had been previously determined by RFLP analysis and confirmatory sequencing. RESULTS: Methylation of the promoter regions in target genes occurred less frequently within the HNPCC tumours (27% of analyses), compared with the sporadic MSI-H tumours (59% of analyses) (P < 0.001). Methylation of MINTs 1, 2, 12 and 31 occurred in 4% of analyses for HNPCC tumours contrasted with 73% for sporadic MSI-H tumours (P < 0.001). BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC cancers tested. CONCLUSIONS: The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.
Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA , Repetições de Microssatélites , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Polipose Intestinal/genética , Proteínas Proto-Oncogênicas c-raf/genética , Adenoma/genética , Adenoma/patologia , Idoso , Pólipos do Colo/genética , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Ilhas de CpG/genética , Feminino , Genes ras/genética , Humanos , Polipose Intestinal/patologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação , Fenótipo , Proteínas Proto-Oncogênicas B-rafRESUMO
AIM: Hyperplastic polyps (HP) of the colorectum have traditionally been regarded as non-neoplastic lesions. Recent data implicate HP in the pathogenesis of colorectal cancers (CRC) characterised by extensive DNA methylation and microsatellite instability. The aim of this study was to identify morphological and molecular features that may characterise subtypes of HP with potential for neoplastic progression. MATERIALS AND METHODS: HP (22) clustering around distal CRC (group I) were compared with HP (58) in subjects with hyperplastic polyposis (group II). DNA methylation was tested in methylated in tumour (MINT) loci (1, 2, 12, 31) and genes HPP1, MGMT, p14ARF, p16INK4a, and hMLH1. RESULTS: Group II HP showed significantly more methylation than group I HP at all loci except MINT1 and MGMT. Group I showed the lowest frequency of DNA methylation but the highest frequency of K-ras mutation. Group II HP (termed HP variant) had the morphological features of the recently described "sessile serrated adenomas". Methylation of hMLH1 was found most frequently in group II polyps that included foci of dysplasia (7/10) and in no group I lesions. CONCLUSION: The findings support the existence of morphological and molecular heterogeneity among HP and highlight a subset that is likely to have significant malignant potential.
Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais/genética , Metilação de DNA , DNA de Neoplasias/genética , Lesões Pré-Cancerosas/genética , Idoso , Colo/patologia , Pólipos do Colo/patologia , Progressão da Doença , Feminino , Genes ras , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Lesões Pré-Cancerosas/patologiaRESUMO
AIM: To determine the frequency of tumour budding and somatic APC mutation in a series of colorectal cancers stratified according to DNA microsatellite instability (MSI) status. MATERIAL/METHODS: Ninety five colorectal cancers were genotyped for APC mutation in the mutation cluster region (exon 15) and scored for the presence of tumour budding at the invasive margin in haematoxylin and eosin stained sections. A subset was immunostained for beta catenin and p16. RESULTS: The frequency of both somatic APC mutation and tumour budding increased pari passu in cancers stratified as sporadic MSI high (MSI-H), hereditary non-polyposis colorectal cancer (HNPCC), MSI low (MSI-L), and microsatellite stable (MSS). Both budding and APC mutation were significantly less frequent in sporadic MSI-H cancers than in MSI-L or MSS cancers. Tumour buds were characterised by increased immunostaining for both beta catenin and p16. CONCLUSION: Tumour budding is associated with an adverse prognosis. The lack of budding in MSI-H colorectal cancer may account for the improved prognosis of this subset and may be explained by an intact WNT signalling pathway and/or inactivated p16(INK4a).
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genes APC , Mutação , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais Hereditárias sem Polipose/química , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Proteínas do Citoesqueleto/análise , DNA de Neoplasias/genética , Humanos , Técnicas Imunoenzimáticas , Repetições de Microssatélites/genética , Invasividade Neoplásica , Proteínas de Neoplasias/análise , Prognóstico , Transativadores/análise , beta CateninaRESUMO
While mutations of CDKN2A are associated with melanoma predisposition, the precise role of its gene product p16 in the development of sporadic melanoma is less clearly understood. We sought to determine the prevalence of p16 expression using immunohistochemical analysis in a population-based sample of melanoma tumours, and also to identify histological, phenotypic and environmental factors associated with the presence or absence of p16 expression. We conducted face-to-face interviews with 108 patients newly diagnosed with melanoma to ascertain their history of sun exposure, and recorded various phenotypic parameters. Paraffin sections of tumours from these patients were stained with an anti-p16 monoclonal antibody following antigen retrieval. Overall, 52 (48%) tumours expressed p16; nodular melanomas had significantly lower levels of p16 immunoreactivity than superficial spreading melanomas (P = 0.015). While no association was found between p16 expression and host phenotype, loss of p16 staining was associated with thicker lesions (p = 0.084) and a high mitotic index (P = 0.013). Taken together, these findings are consistent with loss of p16 being a late event in the progression of sporadic primary melanomas, being associated with tumours of a more aggressive nature.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Índice Mitótico , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fatores de Risco , Neoplasias Cutâneas/genéticaRESUMO
Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together. Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients. The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Axila , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Genes erbB-2 , Genes p53 , Humanos , Metástase Linfática , Prognóstico , Receptores de Estrogênio/análise , Análise de SobrevidaRESUMO
Attempts to classify colorectal cancer into subtypes based upon molecular characterisation are overshadowed by the classical stepwise model in which the adenoma-carcinoma sequence serves as the morphological counterpart. Clarity is achieved when cancers showing DNA microsatellite instability (MSI) are distinguished as sporadic MSI-low (MSI-L), sporadic MSI-high (MSI-H) and hereditary non-polyposis colorectal cancer (HNPCC). Divergence of the 'methylator' pathway into MSI-L and MSI-H is at least partly determined by the respective silencing of MGMT and hMLH1. Multiple differences can be demonstrated between sporadic and familial (HNPCC) MSI-H colorectal cancer with respect to early mechanisms, evolution, molecular characterisation, demographics and morphology. By acknowledging the existence of multiple pathways, rapid advances in the fields of basic and translational research will occur and this will lead to improved strategies for the prevention, early detection and treatment of colorectal cancer.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Repetições de Microssatélites , Pareamento Incorreto de Bases , Neoplasias Colorretais Hereditárias sem Polipose/classificação , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Mutação em Linhagem Germinativa/genética , Humanos , Perda de HeterozigosidadeRESUMO
High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA , Repetições de Microssatélites/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte , Cromossomos Humanos Par 5/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Metilação de DNA , Feminino , Genes ras/genética , Humanos , Imuno-Histoquímica , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Mutação , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/genética , Proteínas Nucleares , Regiões Promotoras Genéticas/genética , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/análise , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Supressora de Tumor p53/análiseRESUMO
Sporadic colorectal cancer (CRC) characterized by high-level DNA microsatellite instability (MSI-H) has a favorable prognosis. The reason for this MSI-H survival advantage is not known. The aim of this study was to correlate proliferation, apoptosis, and prognosis in CRC stratified by MSI status. The proliferative index (PI) was measured by immunohistochemical staining with the Ki-67 antibody in a selected series of 100 sporadic colorectal cancers classified according to the level of MSI as 31 MSI-H, 29 MSI-Low (MSI-L), and 40 microsatellite stable (MSS). The Ki-67 index was significantly higher in MSI-H cancers (P < 0.0001) in which the PI was 90.1 +/- 1.2% (mean +/- SE) compared with 69.5 +/- 3.1% and 69.5 +/- 2.3% in MSI-L and MSS subgroups, respectively. There was a positive linear correlation between the apoptotic index (AI) and PI (r = 0.51; P < 0.001), with MSI-H cancers demonstrating an increased AI:PI ratio indicative of a lower index of cell production. A high PI showed a trend toward predicting improved survival within MSI-H cancers (P = 0.09) but did not predict survival in MSI-L or MSS cancers. The AI was not associated with survival in any MSI subgroup. In conclusion, this is the first study to show that sporadic MSI-H cancers are characterized by a higher AI:PI ratio and increased proliferative activity compared with MSI-L and MSS cancers, and that an elevated PI may confer a survival advantage within the MSI-H subset.
Assuntos
Apoptose , Divisão Celular , Neoplasias Colorretais/patologia , Repetições de Microssatélites/genética , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Análise de SobrevidaRESUMO
The majority of small-cell lung cancers (SCLCs) express p16 but not pRb. Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC and MCC, we wished to determine if this was also the case in MCC. Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and 1 on 9q. No loss of heterozygosity (LOH) was seen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p. Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined. Half of all informative cases had LOH at D9S168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168. A second region (IFNA-D9S126) showed LOH in 10 (44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all 11 tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p14(ARF) antibody. These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus.
Assuntos
Carcinoma de Célula de Merkel/genética , Cromossomos Humanos Par 9/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Deleção de Genes , Neoplasias Cutâneas/genética , Western Blotting , Aberrações Cromossômicas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Heterozigoto , Homozigoto , Humanos , Técnicas Imunoenzimáticas , Perda de Heterozigosidade , Repetições de Microssatélites , Mutação , Proteínas/genética , Proteínas/metabolismo , Proteína Supressora de Tumor p14ARFRESUMO
BACKGROUND: A previous study showed the effectiveness of a clinical pathway for infrainguinal bypass surgery in reducing postoperative length of stay (LOS) in an acute care setting. Most of the deviations from the pathway were due to patient factors (50%) and/or external disposition problems (30%), but 20% were related to physician or system problems that could potentially be modified. The current study examined those factors influencing LOS following infrainguinal bypass surgery and the impact of daily rounds by a nurse case manager--a vascular nurse specialist--on LOS and pathway deviations. METHODS: Data were collected through detailed chart review and prospective tracking of pathway deviations. LOS was compared in 58 patients on the modified pathway (with the nurse case manager) to 69 patients on the original pathway and 67 prepathway controls. Multivariate analysis was used to identify factors influencing postoperative LOS and to compare LOS among the three groups. RESULTS: Use of a nurse case manager significantly reduced physician-related deviations, from the pathway from 10% to 0% (p = .015), and reduced system-related deviations from 3% to 0%. Median postoperative LOS was 7 days before the pathway was begun, 6 days with the original pathway, and 5 days after the introduction of a vascular nurse specialist (p = .0001). There were no differences in rates of complications, rates of readmission, or mortality. CONCLUSIONS: Intervention by a nurse case manager facilitated implementation of a critical pathway for patients undergoing infrainguinal bypass surgery, especially by preventing patient deviations due to intrainstitutional factors.