Loss of CDX2 in colorectal cancer is associated with histopathologic subtypes and microsatellite instability but is prognostically inferior to hematoxylin–eosin-based morphologic parameters from the WHO classification

Abstract

Background Immunohistochemical loss of CDX2 has been proposed as a biomarker of dismal survival in colorectal carcinoma (CRC), especially in UICC Stage II/III. However, it remains unclear, how CDX2 expression is related to central hematoxylin–eosin (HE)-based morphologic parameters defined by 2019 WHO classification and how its prognostic relevance is compared to these parameters. Methods We evaluated CDX2 expression in 1003 CRCs and explored its prognostic relevance compared to CRC subtypes, tumour budding and WHO grade in the overall cohort and in specific subgroups. Results CDX2-low/absent CRCs were enriched in specific morphologic subtypes, right-sided and microsatellite-instable (MSI-H) CRCs (P < 0.001) and showed worse survival characteristics in the overall cohort/UICC Stage II/III (e.g. DFS: P = 0.005) and in microsatellite stable and left-sided CRCs, but not in MSI-H or right-sided CRCs. Compared with CDX2, all HE-based markers showed a significantly better prognostic discrimination in all scenarios. In multivariate analyses including all morphologic parameters, CDX2 was not an independent prognostic factor. Conclusion CDX2 loss has some prognostic impact in univariate analyses, but its prognostic relevance is considerably lower compared to central HE-based morphologic parameters defined by the WHO classification and vanishes in multivariate analyses incorporating these factors.

Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups

“…In this study, we investigated the expression of Special AT-rich sequence-binding protein 2 (SATB2) in one thousand and thirty-nine resected CRCs, correlated the results with histomorphologic parameters (CRC subtypes, tumour budding activity, WHO grade) [ 17 ], expression of CDX2 [ 18 ] as well as clinicopathological parameters (pTNM/UICC staging, microsatellite status, localisation) and analysed the prognostic relevance of SATB2 in the overall cohort and in specific subcohorts.…”

“…As SATB2 has emerged as a considerable alternative to CDX2 to verify or rule out colorectal differentiation, another aim of our study was to compare the incidence and overlap of SATB2 loss with loss of CDX2 and also to compare the prognostic relevance of these two markers with one another [ 18 ]. The findings of these aspects of our study are also particularly interesting, because they highlight possible strengths and weaknesses of the most commonly used colorectal markers.…”

“…Clinicopathological characteristics as well as survival data were extracted from hospital records or from the Munich Cancer Registry. Definitions of survival parameters, survival endpoints and general treatment modalities were defined as described previously [ 18 , 19 ]. The local ethic committee of the Technical University of Munich approved this study (reference number: 252/16 s).…”

“…The parameters were available from a previous study on the same cohort regarding the distribution and the prevalence of the essential morphologic criteria given in the 2019 WHO classification of colorectal carcinoma, from which also the microsatellite status was extracted [ 17 ] (cohort details; Table 1 ). Furthermore, SATB2 expression was correlated with CDX2 expression, which was analysed in a previous study [ 18 ], where a similar methodology regarding the finding of an optimised cutoff for CDX2 expression groups was used [ 21 ]. The cases from 2019 that were recently added to the collective ( n = 36) were classified regarding the aforementioned parameters (histomorphology, CDX2 expression) as described previously [ 17 , 18 ].…”

“…Furthermore, SATB2 expression was correlated with CDX2 expression, which was analysed in a previous study [ 18 ], where a similar methodology regarding the finding of an optimised cutoff for CDX2 expression groups was used [ 21 ]. The cases from 2019 that were recently added to the collective ( n = 36) were classified regarding the aforementioned parameters (histomorphology, CDX2 expression) as described previously [ 17 , 18 ].…”