RESUMO
Histology is used to confirm the diagnosis of inflammatory bowel disease, exclude superimposed infections, and to evaluate for dysplasia. Histology has rarely been used to measure disease activity and guide therapy despite evidence that histologic measurements have value in predicting important clinical outcomes. More recently, there have been numerous studies supporting a role for histologic disease activity measurements in predicting a variety of outcomes including relapse, hospitalizations, steroid use, and dysplasia. The histologic assessment was superior to endoscopic measurements in many of these studies. This review will summarize the recent literature regarding histologic disease activity measurements in ulcerative colitis and Crohn disease. A detailed description of histologic scoring systems will also be provided to provide pathologists with the necessary tools to accurately measure disease activity.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Colite Ulcerativa/diagnóstico , Humanos , Doenças Inflamatórias Intestinais/diagnósticoRESUMO
SATB2 is a sensitive immunohistochemistry marker of colorectal carcinoma and non-neoplastic colorectal epithelium that is complementary to CDX2. However, its expression is affected by molecular alterations. Inflammatory bowel disease-associated neoplasia demonstrates molecular alterations that are different from those in sporadic colorectal neoplasia. Given these differences, we examined SATB2 expression in 73 cases of inflammatory bowel disease-associated neoplasia including 37 dysplasia cases and 36 carcinomas and compared the expression patterns with 50 cases of nondysplastic colorectal mucosa in patients with active inflammatory bowel disease, 40 sporadic colonic polyps (20 conventional adenomas and 20 sessile serrated lesions/polyps), and 343 sporadic colorectal adenocarcinomas to assess SATB2 immunohistochemistry as a biomarker of inflammatory bowel disease-associated neoplasia. Loss of SATB2 expression was only identified in colorectal dysplasia arising in inflammatory bowel disease (15/37, 41%) and was not seen in nondysplastic colorectal mucosa with active inflammatory bowel disease or sporadic colonic polyps (P<0.001). Loss of SATB2 expression was identified in both endoscopically visible dysplasia (11/28, 39%) and invisible (4/9, 44%) dysplasia. Loss of SATB2 expression was identified in 67% (24/36) of inflammatory bowel disease-associated carcinomas and was significantly more frequent compared with sporadic colorectal carcinomas (47/343, 14%, P<0.001). There was no difference in positive CDX2 expression between inflammatory bowel disease-associated colorectal carcinoma and sporadic colorectal carcinoma (89% vs. 85%, P=1.0). In conclusion, loss of SATB2 expression is common in inflammatory bowel disease-associated colorectal dysplasia and adenocarcinoma and may be a helpful ancillary biomarker when evaluating for inflammatory bowel disease-associated dysplasia.
Assuntos
Adenocarcinoma/química , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Doenças Inflamatórias Intestinais/complicações , Proteínas de Ligação à Região de Interação com a Matriz/análise , Fatores de Transcrição/análise , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise Serial de TecidosRESUMO
Signet ring cell carcinomas of the gastrointestinal (GI) tract are clinically aggressive neoplasms with frequent intra-abdominal metastases at initial presentation. Currently available immunohistochemistry (IHC) markers cannot distinguish signet ring cell carcinomas of the lower GI tract and upper GI tract, suggesting the need for more specific diagnostic markers. SATB2 is a novel, sensitive marker for colorectal carcinoma. We hypothesized that SATB2 IHC can reliably identify primary and metastatic signet ring cell carcinomas of lower GI tract origin. SATB2 and CDX2 IHC was performed on 159 primary (n=93) and metastatic (n=66) signet ring cell carcinomas of GI tract origin and 13 metastatic breast carcinomas with signet ring cell features. Positive SATB2 expression (SATB2) was identified in 82% (27/33) of appendiceal, 88% (43/49) of colorectal, 13% (7/54) of gastric, and 35% (8/23) of esophageal/esophagogastric junction signet ring cell carcinomas. Primary and metastatic signet ring cell carcinomas of lower GI tract origin were more frequently SATB2 than those from upper GI tract (70/82, 85% vs. 15/77, 19%, P<0.01). Compared with CDX2, SATB2 and dual-positive staining for SATB2 and CDX2 both had higher specificities for signet ring cell carcinomas from the lower GI tract (81% vs. 49% and 86% vs. 49%, respectively, P<0.01 for both). Two (15%) metastatic breast carcinoma were SATB2, but all 13 demonstrated negative CDX2 staining. In summary, our results show SATB2 is a relatively specific immunohistochemistry marker for both metastatic and primary signet ring cell carcinomas of lower GI tract origin.
Assuntos
Biomarcadores Tumorais/análise , Fator de Transcrição CDX2/análise , Carcinoma de Células em Anel de Sinete/química , Neoplasias Gastrointestinais/química , Proteínas de Ligação à Região de Interação com a Matriz/análise , Fatores de Transcrição/análise , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Carcinoma de Células em Anel de Sinete/secundário , Bases de Dados Factuais , Diagnóstico Diferencial , Feminino , Neoplasias Gastrointestinais/secundário , Humanos , Imuno-Histoquímica , Masculino , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.
Assuntos
Adenocarcinoma/química , Adenocarcinoma/genética , Biomarcadores Tumorais , Neoplasias Colorretais/química , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/análise , Proteínas de Ligação à Região de Interação com a Matriz/análise , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Fatores de Transcrição/análise , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Análise Serial de TecidosRESUMO
Background: Chronic idiopathic inflammatory bowel disease (IBD) is a significant risk factor for the development of intestinal adenocarcinoma. The underlying molecular alterations in IBD-associated intestinal adenocarcinoma remain largely unknown. Methods: We compared the clinicopathologic and molecular features of 35 patients with 47 IBD-associated intestinal adenocarcinomas with a consecutive series of 451 patients with sporadic colorectal carcinoma identified at our institution and published data on sporadic colorectal carcinoma. Results: c-MYC amplification was the most frequent molecular alteration identified in 33% of IBD-associated intestinal adenocarcinoma that is a significantly higher frequency than in sporadic colorectal carcinoma (8%) (P = 0.0001). Compared to sporadic colorectal carcinoma, IBD-associated intestinal adenocarcinomas more frequently demonstrated mucinous differentiation (60% vs 25%, P < 0.001) and signet ring cell differentiation (28% vs 4%, P < 0.001). Mucinous and signet ring cell differentiation were significantly associated with the presence of c-MYC amplification (both with P < 0.05). HER2 positivity (11%), KRAS exon 2 or 3 mutation (10%), and IDH1 mutation (7%) were less commonly observed in IBD-associated intestinal adenocarcinoma. There was an association between poor survival and HER2 status with 3 of 4 patients having HER2-positive adenocarcinoma dead of disease at last clinical follow-up; however, no statistically significant survival effect was identified for any of the molecular alterations identified. Conclusions: We demonstrate that IBD-associated intestinal adenocarcinomas have a high frequency of c-MYC amplification that is associated with mucinous and signet ring cell differentiation. Many of the identified molecular alterations have potential therapeutic relevance, including HER2 amplification, IDH1 mutation, and low frequency KRAS mutation.
Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma de Células em Anel de Sinete/genética , Neoplasias Colorretais/genética , Doenças Inflamatórias Intestinais/genética , Instabilidade de Microssatélites , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células em Anel de Sinete/patologia , Diferenciação Celular/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genéticaRESUMO
Recent literature indicates that adenocarcinomas of the cecum differ with respect to molecular alterations compared with noncecal proximal colon adenocarcinomas and that cecal tumor site may be a prognostically relevant variable. We compared molecular alterations, histopathologic features, and disease-specific survival in a series of 328 colonic adenocarcinomas identified over a 2-year period and stratified by tumor location (cecum, right colon, and left colon). Overall, cecal adenocarcinomas demonstrated the highest frequency of molecular abnormalities with 74% harboring either a KRAS exon 2 or 3 mutation, a BRAF mutation, or DNA mismatch repair protein deficiency. KRAS mutations were more frequently seen in the cecum compared with all other tumor sites (P=0.03). KRAS mutations were identified in 46% of cecal adenocarcinomas compared with only 25% of adenocarcinomas of the right colon (P=0.004). Cecal adenocarcinomas more frequently displayed adverse histopathologic features, in particular high tumor budding (31%), compared with tumors of the right colon (18%; P=0.04) and tumors of the left colon (17%; P=0.02). Overall stage was the most important independent predictor of disease-specific survival in the multivariable analysis; however, cecal tumor site and high tumor budding were also predictive of poor survival, particularly in patients with stage III or IV tumors. In conclusion, cecal adenocarcinomas are characterized by a high frequency of KRAS mutations compared with noncecal right colon tumors, frequently display high tumor budding, and may be a prognostically relevant variable, particularly in patients with stage III or IV disease.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Neoplasias do Ceco/genética , Neoplasias do Ceco/patologia , Movimento Celular , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ceco/mortalidade , Neoplasias do Ceco/cirurgia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estadiamento de Neoplasias , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
Most major professional medical organizations advocate universal screening for Lynch syndrome in colorectal carcinoma; however, some allow for a selective screening approach based on clinicopathologic factors including assessment of histologic features of mismatch repair protein deficiency (MMRD). We performed a prospective evaluation for histopathologic features of MMRD in colorectal carcinomas that underwent universal screening for Lynch syndrome to evaluate the ability of histology to predict MMRD. In total, 947 resected colorectal carcinomas over a 5-year period were prospectively analyzed for histologic features of MMRD and for DNA mismatch repair protein abnormalities. Histologic features of MMRD were reported as present in 281 of 947 (30%) tumors with only 109 (39%) cases demonstrating MMRD by immunohistochemistry. Histologic features of MMRD had a sensitivity of 74% [95% confidence interval (CI), 66%-80%], specificity of 78% (95% CI, 75%-81%), positive predictive value of 39% (95% CI, 32%-44%), and negative predictive value of 94% (95% CI, 92%-96%). Histologic features of MMRD in left colon/rectal tumors had a significantly lower sensitivity of 56% (95% CI, 41%-77%) compared with right colon tumors (P=0.02). Histologic rereview identified that tumor-infiltrating lymphocytes (TILs) were most likely to be incorrectly reported as absent, and 72% of cases incorrectly assessed as lacking TILs demonstrated MMRD by immunohistochemistry. We demonstrate that histologic features of MMRD do not reliably predict the presence of MMRD by immunohistochemistry. Interpretative errors in the assessment of histologic features of MMRD occur, particularly for TILs and in tumors of the left colon/rectum.
Assuntos
Neoplasias do Colo/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Neoplasias do Endométrio/diagnóstico , Linfócitos do Interstício Tumoral/patologia , Proteína 3 Homóloga a MutS/genética , Neoplasias Retais/diagnóstico , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Detecção Precoce de Câncer , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Proteína 3 Homóloga a MutS/metabolismo , Patologia Molecular , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Neoplasias Retais/patologia , Sensibilidade e EspecificidadeRESUMO
Universal screening for Lynch syndrome has been advocated for colorectal carcinoma but its utility in small bowel adenocarcinoma has not been reported. We analyzed a consecutive series of 71 small bowel adenocarcinomas identified over an 8-year period for DNA mismatch repair (MMR) protein expression to (1) compare the clinicopathologic features of small bowel adenocarcinoma stratified into MMR-deficient (MMRD) and MMR-proficient (MMRP) groups and (2) examine the patterns of MMR protein expression in small bowel adenocarcinoma compared with colorectal carcinoma. Six of 71 (8.5%) small bowel adenocarcinomas and 149 of 1291 (11.5%) colorectal carcinomas demonstrated MMRD. The 6 MMRD small bowel adenocarcinomas had the following expression pattern: 3 with concurrent loss of MSH2 and MSH6, 1 with isolated loss of MSH6, and 2 with concurrent loss of MLH1 and PMS2 in patients with a family history suggestive of genetic cancer susceptibility. Histopathology suggestive of MMR protein deficiency as proposed by the revised Bethesda guidelines was commonly seen in both MMRP (63%) and MMRD (67%) small bowel adenocarcinomas (P>0.05). MMRD small bowel adenocarcinoma more frequently demonstrated abnormalities of MSH2 and/or MSH6 (4/6, 67%) compared with MMRD colorectal carcinoma (23/149, 15%) (P=0.01). None of the MMRD small bowel adenocarcinomas harbored the BRAF V600E mutation, whereas 60% of MMRD colorectal carcinomas were positive for BRAF V600E with concurrent loss of MLH1 and PMS2 expression. Small bowel adenocarcinoma more frequently harbored Lynch syndrome-associated MMRD compared with colorectal carcinoma, providing support for screening of small bowel adenocarcinoma to identify patients at risk for Lynch syndrome. In contrast to colorectal carcinoma, sporadic MLH1 deficiency is not seen in small bowel adenocarcinoma. Clinicopathologic and histologic features do not distinguish between MMRP and MMRD small bowel adenocarcinoma indicating that universal screening in small bowel adenocarcinoma is necessary to detect patients at risk for Lynch syndrome.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Neoplasias Intestinais/genética , Intestino Delgado/patologia , Proteína 1 Homóloga a MutL/genética , Adenocarcinoma/patologia , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/patologia , Reação em Cadeia da PolimeraseRESUMO
Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular/tubulovillous adenomas.
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Neoplasias Colorretais/genética , Metilação de DNA , Proteína 1 Homóloga a MutL/deficiência , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/mortalidade , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Mutação , Regiões Promotoras GenéticasRESUMO
Lynch syndrome accounts for roughly 1 of every 35 patients with colorectal carcinoma, making it the most common hereditary form of colorectal carcinoma. Identifying patients at risk for Lynch syndrome is essential, as these patients can develop additional Lynch syndrome-related tumors, and patients and their relatives benefit from genetic counseling. The hallmark of Lynch syndrome-associated neoplasms is DNA mismatch repair protein deficiency. In most instances, the pathologist is the first to identify patients at risk for Lynch syndrome and is tasked with communicating these results to treating clinicians and genetics counselors. This review will attempt to provide the tools for pathologists to identify patients at risk for Lynch syndrome through evaluation of tumors of the gastrointestinal tract and provide up-to-date knowledge on evaluating mismatch repair protein deficiency in tumors of the gastrointestinal tract.