Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon

Abstract

Most large bowel cancers are moderately to well-differentiated adenocarcinomas comprised chiefly or entirely of glands lined by tall columnar cells. We have identified a subset of poorly differentiated colon carcinomas with a distinctive histopathological appearance that we term large cell minimally differentiated carcinomas (LCMDCs). These tumors likely include a group of poorly differentiated carcinomas previously described by others as medullary adenocarcinomas. To better understand the pathogenesis of these uncommon neoplasms, we compared molecular features of 15 LCMDCs to those present in 25 differentiated adenocarcinomas (DACs) of the colon. Tumors were examined for alterations commonly seen in typical colorectal carcinomas, including increased p53 and beta-catenin immunoreactivity, K-ras gene mutations, microsatellite instability, and loss of heterozygosity of markers on chromosomes 5q, 17p, and 18q. In addition, tumors were evaluated by immunohistochemistry for CDX2, a homeobox protein whose expression in normal adult tissues is restricted to intestinal and colonic epithelium. Markedly reduced or absent CDX2 expression was noted in 13 of 15 (87%) LCMDCs, whereas only 1 of the 25 (4%) DACs showed reduced CDX2 expression (P < 0.001). Nine of 15 (60%) LCMDCs had the high-frequency microsatellite instability phenotype, but only 2 of 25 (8%) DACs had the high-frequency microsatellite instability phenotype (P = 0.002). Our findings provide support for the hypothesis that the molecular pathogenesis of LCMDCs is distinct from that of most DACs. CDX2 alterations and DNA mismatch repair defects have particularly prominent roles in the development of LCMDCs.

Figure 1.

Histological appearance and CDX2 and p53 expression in representative LCMDCs and DACs. A and B: H&E-stained LCMDC and DAC, respectively. C and D: LCMDC stained with anti-CDX2 antibody showing reactivity only in normal epithelium (C; arrows indicate neoplastic cells) and reactivity in both neoplastic cells (2+ scoring) and normal glands (D). E and F: LCMDC stained with anti-p53 antibody showing strong (3+ reactivity) in E and no reactivity in F. G and H: DACs stained with anti-CDX2 antibody showing moderate (2+ scoring) reactivity in G and weak (1+ scoring) staining in H. I and J: DACs stained with anti-p53 antibody with strong (3+ scoring) staining in I and no reactivity in J. Note that cancers often had variable, albeit weak, cytoplasmic staining of CDX2. Hence, only the levels of nuclear CDX2 staining were scored.

Figure 2.

β-catenin, MLH1, and MSH2 staining in representative LCMDCs and DACs. A and B: Staining of LCMDC and DAC cases, respectively, with anti-β-catenin antibody showing strong cytosolic and nuclear staining. C and D: LCMDCs stained with anti-MLH1 antibody showing strong nuclear staining in C (MSS case), but not in D (MSI-H case). E and F: DACs stained with anti-MLH1 antibody with strong nuclear staining in E (MSS case), but not in F (MSI-H case). G and H: Staining of LCMDC and DAC cases, respectively, with anti-MSH2 antibody, with both cases showing strong nuclear reactivity.