Expression of intestine‐specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas

Almeida, Raquel; Silva, Elisabete; Santos-Silva, Filipe; Silberg, Debra G.; Wang, Jiangfu; Bolós, Carme de; David, Leonor

doi:10.1002/path.1246

Cited by 260 publications

(275 citation statements)

References 27 publications

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“…7,13,[15][16][17][18]30 Our results are entirely consistent with these studies in that CDX2 staining was observed in only a subset of gastric cancers and significantly favored the intestinal-type tumors over the diffuse variants.…”

Section: Discussionsupporting

confidence: 91%

“…11,12 In humans, intestinal metaplasia of the stomach and esophagus is consistently accompanied by CDX2 expression. 6,[13][14][15][16] The relationship between CDX2 expression and intestinal differentiation suggests that CDX2 may serve as a specific marker for epithelial neoplasms of the gastrointestinal (GI) tract. This is supported by several recently published surveys in which selective staining of colorectal and duodenal adenocarcinomas has been observed using a commercially available monoclonal antibody to CDX2.…”

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confidence: 99%

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The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

et al. 2004

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CDX2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestines. Based on recent studies, CDX2 expression is immunohistochemically detectable in normal colonic enterocytes and is retained in most, but not all, colorectal adenocarcinomas. CDX2 expression has also been documented in a subset of adenocarcinomas arising in the stomach, esophagus and ovary. In this study, we examined CDX2 expression in a series of large tissue microarrays representing 4652 samples of normal and neoplastic tissues. Strong nuclear staining for CDX2 was observed in 97.9% of 140 colonic adenomas, 85.7% of 1109 colonic adenocarcinomas overall and 81.8% of 55 mucinous variants. There was no significant difference in the staining of well-differentiated (96%) and moderately differentiated tumors (90.8%, P ¼ 0.18), but poorly differentiated tumors showed reduced overall expression (56.0%, Po0.000001). Correspondingly, there was an inverse correlation between CDX2 expression and tumor stage, with a significant decrease in staining between pT2 and pT3 tumors (95.8 vs 89.0%, Po0.012), and between pT3 and pT4 tumors (89.0 vs 79.8%, Po0.016). Analysis of 140 locally advanced, CDX2-positive colorectal adenocarcinomas coarrayed with their matching lymph node metastases revealed that expression of this marker was retained in 82.1% of the metastases. Consistent with previous reports, CDX2 staining was observed in gastric adenocarcinomas (n ¼ 71), more commonly in the intestinal-type than the diffuse-type (28.9 vs 11.5%, Po0.05). Occasional ovarian carcinomas were positive for CDX2, including mucinous (10.5%), endometrioid (9.3%) and serous variants (2%), but expression was either very rare or absent in primary carcinomas of the lung, breast, thyroid, pancreas, liver, gallbladder, kidney, endometrium and urinary bladder. A low frequency of CDX2 expression in pancreatic and biliary carcinomas observed on the microarrays was pursued further by comparing these tumors with ampullary adenocarcinomas on conventional sections. Ampullary adenocarcinomas were more commonly positive for CDX2 (19/24, 79%) than cholangiocarcinomas (1/11, 9%) and pancreatic carcinomas (3/20, 15%). In summary, CDX2 is a sensitive and specific marker for colorectal adenocarcinoma, although its expression is decreased among higher grade and stage tumors, and it is not invariably present in metastases from positive primaries. CDX2 may also be helpful in distinguishing adenocarcinomas of the ampulla from those arising in the pancreas and biliary tree.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

et al. 2004

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“…31,46 CDX2 expression has also been reported in 54% of gastric carcinomas, often in conjunction with MUC2 expression. 47 In this milieu, CDX2 is associated with tumor progression, during which tumors undergo an immunophenotypic shift from gastric phenotype (MUC5AC and/or MUC6 positive) to intestinal phenotype. 30 Thus, intestinal-type differentiation can be seen in both pre-and postneoplastic transformation.…”

Section: Discussionmentioning

confidence: 99%

The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma

et al. 2011

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Adenocarcinoma of the distal esophagus and esophagogastric junction continues to rise in incidence. An intestinal metaplasia (Barrett esophagus)-dysplasia-carcinoma sequence induced by gastroesophageal reflux disease is well established. However, a significant number of adenocarcinomas in the vicinity of the esophagogastric junction are seen in the background of gastric/cardiac-type mucosa without intestinal metaplasia. Thus, the aim of this study was to investigate the role of Barrett esophagus (intestinal-type mucosa) in the classification and prognosis of tumors of the distal esophagus and esophagogastric junction. Clinicopathological and molecular characteristics were examined in 157 consecutively resected adenocarcinomas of the distal esophagus and esophagogastric junction and were compared between tumors arising in association with intestinal-type and cardiac-type mucosa. Intestinal-type mucosa-associated adenocarcinomas were more likely to be associated with younger age (P ¼ 0.0057), reflux symptoms (Po0.0001), proximal location (P ¼ 0.0009), lower T stage (Po0.0001), fewer nodal metastases (P ¼ 0.0001), absence of lymphatic (Po0.0001), venous (P ¼ 0.0060) or perineural (Po0.0001) invasion. Histologically, intestinal-type mucosa-associated tumors were more likely to be low-grade glandular tumors (P ¼ 0.0095) of intestinal or mixed immunophenotype (P ¼ 0.015) and express nuclear b-catenin (P ¼ 0.0080), whereas tumors arising in a background of cardiac-type mucosa were more frequently associated with EGFR amplification (P ¼ 0.0051). Five-year overall survival rate was significantly higher in patients with intestinal-type mucosa-associated tumors (28 vs 9%, P ¼ 0.0015), although no survival benefit was seen after adjusting for potential confounders. Our findings support the theory that multiple distinct pathways of tumorigenesis exist in the vicinity of the esophagogastric junction, including one in which tumors arise from dysplastic intestinal metaplasia (intestinal pathway), and one potentially involving dysplasia of the cardiac-type mucosa (non-intestinal pathway). Additional studies are warranted to further clarify their pathogenesis and the molecular mechanisms involved.

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“…22,24,27 In contrast, esophageal and gastric intestinal metaplastic cells are Cdx2 positive. 20,21,23,25,26 Further studies will help to confirm or refute Cdx2 as a sensitive and specific marker of intestinal differentiation.…”

mentioning

confidence: 99%

“…[15][16][17][18][19] The expression of Cdx2 in adult non-neoplastic tissues has been shown to be restricted to normal intestinal epithelium, normal pancreatic epithelial cells, and gastric and esophageal intestinal metaplasia. [20][21][22][23][24][25][26][27] In the gastrointestinal tract, Cdx2 is strongly and diffusely expressed in the nuclei of normal small and large intestinal epithelial cells, including absorptive, goblet, endocrine and Paneth cells; in the pancreatic epithelium its expression is focal and patchy. 22,24,27 Normal esophageal and gastric epithelial cells are Cdx2 negative.…”

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confidence: 99%

Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia

2004

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Barrett's esophagus is diagnosed when goblet cells are found in the lower esophageal mucosa. However, the distribution of these cells is patchy and they may not represent the earliest marker of intestinal metaplasia. Cdx2 is a transcription factor whose expression in normal tissues is restricted to intestinal-type epithelium. Its distribution in the columnar-lined esophagus with and without intestinal metaplasia has been seldom studied. We evaluated Cdx2 expression in lower esophageal biopsies from 90 patients with endoscopic diagnosis of short segment Barrett's esophagus, including 45 consecutive cases showing intestinal metaplasia (goblet cells present in hematoxylin eosin and/or Alcian blue stains) and 45 consecutive cases without goblet cells. 25 samples of cardiac-type mucosa without intestinal metaplasia biopsied from the stomach served as controls. All cases with intestinal metaplasia revealed Cdx2 reactivity in goblet cells and adjacent nongoblet columnar cells. Dysplastic foci, seen in five cases from this group, were Cdx2 positive. In the group without goblet cells, Cdx2 was focally expressed by columnar cells in 17 (38%) cases. All control cases were Cdx2 negative. Strips of Alcian blue-positive nongoblet columnar cells ('columnar blues') were observed in 11 (24%) of the cases without intestinal metaplasia. All these foci were Cdx2 negative. In conclusion, Cdx2 is a highly sensitive marker for Barrett's esophagus. It is also expressed in a significant minority of cases of columnar-lined esophagus without goblet cells, suggesting that it may detect intestinal phenotypic modifications in the absence of goblet cells. Accordingly, Cdx2 immunostaining could help identify patients with Barrett's metaplasia in cases where no goblet cells are visible in biopsies from the columnar-lined esophagus. Finally, lack of Cdx2 expression in the 'columnar blues' suggests that these cells are not diagnostic of intestinal metaplasia.

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Expression of intestine‐specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas

Cited by 260 publications

References 27 publications

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas

The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma

Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia

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