Limited diagnostic value of microsatellite instability associated pathology features in colorectal cancer

Abstract

To determine the diagnostic test characteristics and inter-observer variation of pathology features for identifying high microsatellite instability (MSI-H) colorectal cancer (CRC). Six pathologists blindly evaluated 177 CRC for the presence of MSI-H associated pathology features. Inter-observer agreement was determined by using Kappa-statistics. In the first random 88/177 cases, mucinous carcinoma, tumor-infiltrating lymphocytes (TIL) and Crohns-like infiltrate (CLI) were the best discriminators between MSI-H and microsatellite stable CRC [OR 5.6 (95 % CI 1.7-19), 5.4 (1.8-17) and 3.5 (1.1-11), respectively], with high specificity (89-91 %). The sensitivities for MSI-H, however, were low (31-41 %). In addition, inter-observer agreement was moderate for TIL and CLI (κ 0.38 and 0.48, respectively), but very good for mucinous carcinoma (κ 0.86). Interpretation of overall histopathology as suggestive for MSI-H performed better than any individual feature; OR 15 (5.2-44), and area under the curve 0.79. However, inter-observer agreement was moderate (κ 0.53). In the second set, TIL and CLI were scored according to updated scoring systems. Although both remained the best individual discriminators, test characteristics and inter-observer agreement did not improve. MSI-H pathology features have moderate accuracy for identifying MSI-H CRC, and are identified with moderate inter-observer agreement. These findings highlight the limitations of clinical strategies, such as the revised Bethesda guidelines, which incorporate the MSI-H associated pathology features in their strategy to identify persons with lynch syndrome.

A Model for Predicting DNA Mismatch Repair-deficient Colorectal Cancer

“…Moreover, these models have not been widely used. In addition, findings characteristic of MSI-H, such as TILs and Crohn's-like reaction, are not specific in identifying MSI-H. Evaluations of these findings differ based on the pathologist, which seems to be the reason why these tests are not widely applied clinically (36). Fujiyoshi et al (15) have developed an MSI-H "prediction score model" for Japanese patients aged 50 years and older.…”

Lynch Syndrome Patients with Limited Family History Identified in a Laboratory Setting: A Descriptive Study

“…Proponents have advocated a variety of alternate screening strategies, including mathematical algorithms to predict MMR gene mutation carriers based on personal and family history [22] and broader, even universal, tumor mutation testing [14,19,23,24]. However, the inconsistency between pathologists in evaluating the histopathological features of MSI tumors [25,26,27,28] highlights the limitations of these clinical strategies. Furthermore, the use of MSI and IHC as screening tools for MMR genetic testing delays medical management decisions and excludes 7-23% of LS carriers, based on test sensitivity alone.…”

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer

“…TIL in the advancing margin were measured as previously described, 21 which has an acceptable interobserver agreement. 10,24,25 In brief, TIL were first identified at scanning magnification to select areas with the highest counts. Using a BX51 microscope (Olympus, Tokyo, Japan) with a standard 22-mm diameter eyepiece under an objective lens with a magnification of ×40 (specimen area, 0.238 mm 2 ), TIL were counted in five consecutive HPFs parallel to the invasive margin (Supplemental Figure 1).…”