POORLY DIFFERENTIATED COLONIC ADENOCARCINOMA, MEDULLARY TYPE - CLINICAL, PHENOTYPIC, AND MOLECULAR CHARACTERISTICS

Clinicopathological evidence has accumulated that colorectal adenocarc inoma with minimal or no glandular differentiation constitutes two ent ities with different prognosis. In a series of 20 predominantly nongla ndular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatelli te instability were analyzed and correlated to the biology of the tumo rs. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated b y nested polymerase chain reaction. Histologically, 13 tumors showed s mall uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly and expansive growth patte rn (68.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltr ate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpar t, solid or medullary carcinoma. These tumors showed less frequent lym ph node as well as hematogeneous metastases than pleomorphic carcinoma s. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.0 5) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0 .05). No significant difference between the medullary and the pleomorp hic tumor type was found with respect to bcl2 expression and the occur rence of Ki-ras mutations at codon 12. In contrast, microsatellite ins tability was almost totally restricted to poorly differentiated adenoc arcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finall y, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, wh ich was, however, restricted to the peritumor lymphoid infiltrate as s hown by in situ hybridization. Correlation with the biology of the tum ors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months ), which was the case in five of the seven patients with the pleomorph ic-type carcinoma (P < 0.025). Our results clearly indicate that the p oorly differentiated colonic carcinoma with minimal or no glandular st ructures constitute two different entities, a medullary and a pleomorp hic variant, which markedly differ in their phenotype, genotype, and p rognosis.