ORIGINAL ARTICLE A Novel Logistic Model Based on Clinicopathological Features Predicts Microsatellite Instability in Colorectal Carcinomas Anna Colomer, PhD,* Nadina Erill, PhD,* August Vidal, MD,*† Miquel Calvo, PhD,‡ Ruth Roman, PhD,* Montse Verdu ´, PhD,† Carlos Cordon-Cardo, MD, PhD,*†§ and Xavier Puig, MD, PhD*† Abstract: High-frequency microsatellite instability has been reported to be associated with good prognosis in colorectal adenocarcinoma. However, methods to assess microsatellite instability (MIN) are based on genetic assays and are not ideally suited to most histopathology laboratories. The aim of the present study was to develop a model for prediction of MIN status in colorectal cancer based on phenotypic characteristics. Clinicopathological features of a cohort of 204 patients with primary colon cancer were retrospectively reviewed following predetermined criteria. Genetic assessment of MIN status was per- formed on DNA extracted from sections of formalin-fixed, paraffin- embedded specimens by testing a panel of 11 microsatellite markers. Logistic regression analysis generated a mathematical tool capable of identifying colorectal tumors displaying MIN status with a sensitivity of 77.8% and a specificity of 96.8%. Features associated with insta- bility included the proximal location of the lesions, occurrence of solid and/or mucinous differentiation, absence of cribriform struc- tures, presence of peritumoral Crohn-like reaction, expansive growth pattern, high Ki67 proliferative index, and p53-negative phenotype. This approach predicts microsatellite instability in colorectal car- cinoma with an overall assigned accuracy of 95.1% and a negative predictive value of 97.8%. Implementation of this tool to routine histopathological studies could improve the management of patients with colorectal cancer, especially those presenting with stage II and III of the disease. It will also assist in identifying a subset of patients likely to benefit from adjuvant chemotherapy. Key Words: hereditary nonpolyposis colorectal cancer, sporadic colorectal cancer, microsatellite instability, DNA replication errors, logistic model (Diagn Mol Pathol 2005;14:213–223) F amiliar and sporadic colorectal carcinomas arise through a multistep process from the transformation of normal colonic epithelial cells. Two main genetic pathways of tu- morigenesis have been distinguished, known as chromosomal instability (CIN) and microsatellite instability (MIN). 1 CIN is the most common, affecting approximately 85% of sporadic colorectal cancers, and shares genetic alterations characteristic of the familial adenomatous polyposis (FAP). 2 It involves mutations of critical genes, such as APC, K-RAS, and TP53; DNA hypermethylation; and chromosomal aberrations, in- cluding loss of heterozygosity at chromosomes 17p and 18q, leading to aneuploidy. 2–4 MIN tumors share their molecular mechanisms with hereditary nonpolyposis colorectal cancer (HNPCC). They are characterized by alterations of the mis- match repair (MMR) genes 5,6 and secondary mutations af- fecting genes involved in growth signaling (eg, TGFßRII, IGFRII) 7,8 and apoptosis (eg, BAX). 9 Because cells with alterations in MMR genes do not properly repair spontaneous errors occurring during DNA replication, they are prone to accumulate frame-shift mutations and base-pair substitutions at microsatellite sequences. Therefore, colorectal cancers that belong to this mutator phenotype display a characteristic mo- lecular pattern that has been termed ‘‘high-frequency micro- satellite instability’’ or MSI-H. 5,6,10 Clinical evidence let to the conclusion that patients carrying sporadic MIN colorectal cancers behave like those with HNPCC in terms of improved survival 10–12 and display a stage-by-stage better prognosis than those with sporadic CIN tumors. 13–16 Additional studies confirmed the good prognosis of stage II or III colorectal carcinoma patients with MSI-H. 13,14,16–18 Furthermore, it was reported that MSI-H tumors possessed greater chemosensitivity. 17–19 However, it was also found that 5-fluorouracil–based chemotherapy (5-FU) did not signifi- cantly increase overall and disease-free survival in patients with stage II or III MSI-H tumors. 20–22 Due to this different response to adjuvant chemotherapy, defining MIN status could assist in discriminating a subgroup of patients who may benefit from 5-FU regimens. A distinct histologic appearance has been attributed to colorectal cancers arising from the MIN pathway. These lesions are typically right sided, more likely to be poorly dif- ferentiated, and often display mucinous-type or signet-ring cells. 23,24 Additionally, these lesions frequently exhibit pronounced intraepithelial lymphocytic infiltration 25,26 and From *BIOPAT, Grup Assiste `ncia, Barcelona, Spain; †HISTOPAT Labo- ratoris, Barcelona, Spain; ‡Statistics Department of the Universitat de Barcelona, Barcelona, Spain; and §Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Reprints: Carlos Cordon-Cardo, Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (e-mail: cordon-c@mskcc.org). Copyright Ó 2005 by Lippincott Williams & Wilkins Diagn Mol Pathol  Volume 14, Number 4, December 2005 213