Pathologic predictors of microsatellite instability in colorectal cancer

Abstract

Identification of microsatellite unstable (MSI-H) colorectal cancers (CRCs) is important not only for the identification of hereditary nonpolyposis colorectal cancer syndrome but also because MSI-H CRCs have a better prognosis and may respond differently to 5-fluorouracil-based chemotherapy. We present 2 nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on the review of 1649 CRCs from patients of all ages collected in a population-based case control study in northern Israel. One hundred ninety-eight of these 1649 tumors demonstrated a high degree of microsatellite instability (12%). Multivariate analysis found that >2 tumor-infiltrating lymphocyte (TIL) cells per high-powered field, the lack of dirty necrosis, the presence of a Crohn-like reaction, right-sided location, any mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age less than 50 were all independent predictors of MSI-H. We developed 2 logistic regression models that differ only by the statistical approach used to analyze the number of TIL cells per high-powered field, where the slightly more accurate (and complex) model uses the log of the total number of TIL cells. The simpler clinical model uses a cut-off of 2>TIL cells per high-powered field. The accuracy of both models is high, with an 85.4% versus 85.0% probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score (Table 4 and Fig. 1) from simple histologic and clinical data available during sign-out. Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (<3%) of being MSI-H. Although this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.

Figure 1

Histologic features of microsatellite unstable tumors. A. Low-power view of the advancing edge of an MSI-H CRC showing a crohn’s-like reaction and focal mucinous differentiation. B. Another example of focal mucinous differentiation in a well-differentiated CRC. C. High-power view of a well-differentiated CRC with large numbers of TIL cells. D. High-power view of a poorly differentiated (medullary type) CRC with large numbers of TIL cells.

Figure 2

This map shows the MSI probability score (sum of coefficients from table 4) along the top and the percent likelihood of microsatellite instability on the bottom. Hence a tumor with a MSI probability score of 0 would have a 1% chance of being MSI-H while a tumor with a MSI probability score of 4.5 would have a 50% chance of being MSI-H.

Figure 3

This histogram shows the number of colorectal cancers for each MSI probability score. Cases that are MSI-H are depicted in purple, while cases that are MSS are light blue. Note that more than 42% of cases have a score of 1 or less and that very few of these cases are MSI-H.

Figure 4

This receiver operator characteristic curve shows an area under the curve of 0.850. The sensitivity and specificity for a given MSI probability score is listed. Note that for a MSI probability score of 1, the sensitivity is 92% and the specificity is 46%.