Loss of CDX2 Expression and Microsatellite Instability Are Prominent Features of Large Cell Minimally Differentiated Carcinomas of the Colon

Hinoi, Takao; Tani, Masachika; Lucas, Peter C.; Caca, Karel; Dunn, Rodney L.; Macrì, Ettore; Loda, Massimo; Appelman, Henry D.; Cho, Kathleen R.; Fearon, Eric R.

doi:10.1016/s0002-9440(10)63074-x

Cited by 206 publications

(172 citation statements)

References 29 publications

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“…This confirms a trend previously observed in much smaller studies by Hinoi et al and Ee et al, although Werling et al noted that '74 of 75 cases of colonic adenocarcinoma were CDX2-positive, independent of tumor grade. 7,28,29 It is unclear as to why our findings differed from those of Werling et al, but the decrease in CDX2 staining that we observed in higher grade tumors was paralleled by a significant decrease in the staining of higher stage tumors (pT1 and pT2 vs pT3 and pT4).…”

Section: Discussioncontrasting

confidence: 75%

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: Discussioncontrasting

confidence: 75%

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

et al. 2004

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“…These findings indicate that cytoplasmic accumulation of PPARd could be a sensitive marker of CRC cells with the potential for high malignancy. Recently, Hinoi et al showed that loss of CDX2 was a marker for large-cell minimally differentiated carcinomas of the colon (Hinoi et al, 2001), and we are not aware of other molecular markers tightly associated with CRC cell morphology.…”

Section: Discussionmentioning

confidence: 87%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

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Whether peroxisome proliferator-activated receptor (PPAR) d is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARd expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARd in CRC. Immunohistochemical analysis indicated that PPARd expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARd protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARd-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARd-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARd in CRC samples. Based on Western blot analysis and quantitative RT -PCR, high PPARd protein expression correlated with high PPARd mRNA levels. Peroxisome proliferator-activated receptor d may have a supporting role in tumorigenesis, and the close association between PPARd expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.

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“…33 CK20 negativity in colorectal cancer has been reported to range between 0 and 9%. 4,11,[51][52][53][54] Park et al 11 observed an association between CK20 loss, higher tumor grade and right-sided location and Hinoi et al 55 observed an association between loss of CDX2, microsatellite instability high status, right-sided tumor location and poor differentiation.…”

Section: Discussionmentioning

confidence: 99%

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

et al. 2008

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The differentiation of colorectal cancer from primary tumors at other sites can be challenging. Often a panel of immunohistochemical protein markers is needed to distinguish between these entities. Protein expression differs significantly in colorectal cancer depending on mismatch repair status and is also heterogeneous among mismatch repair-proficient or -deficient tumors. The aim of this study was to systematically analyze the diagnostic and prognostic role of the commonly used multi-marker phenotype CK20/CK7/CDX2 on a large series of colorectal cancers stratified by mismatch repair status. The immunohistochemical analysis of CK20, CK7 and CDX2 was performed on 1197 mismatch repair-proficient and 223 mismatch repair-deficient colorectal cancers using a tissue microarray. Multi-marker combinations of CK20/CK7/CDX2 were explored. Univariate and multivariable analysis of the markers was evaluated for their association with several clinico-pathological end points namely T stage, N stage, tumor grade, vascular invasion, intratumoral lymphocytes and survival. Multimarker phenotypes with CK20 and CDX2 negativity were more frequently found in mismatch repair-deficient than in mismatch repair-proficient colorectal cancer (19.3 vs 7.5% and 21.6 vs 6.7%, respectively; Po0.001). In both colorectal cancer subsets loss of CK20 was associated with higher tumor grade (Po0.001) and with presence of intratumoral lymphocytes (Po0.001 and P ¼ 0.02, respectively). In the proficient mismatch repair subset CK20 overexpression was an independent adverse prognostic factor (P ¼ 0.041) and CDX2 underexpression was linked to tumor progression. Loss of CDX2 and CK20 is more frequently encountered in mismatch repair-deficient colorectal cancer, which should be taken into consideration to differentiate between primary and metastatic colorectal cancer in daily practice. Although associated with lower tumor grade, CK20 overexpression is an independent adverse prognostic factor in mismatch repair-proficient colorectal cancer.

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Loss of CDX2 Expression and Microsatellite Instability Are Prominent Features of Large Cell Minimally Differentiated Carcinomas of the Colon

Cited by 206 publications

References 29 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

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

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