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From the Department of Pathology,*
Division of
Gastrointestinal-Liver Pathology, The Johns Hopkins University School
of Medicine and Hospital, Baltimore, Maryland; the Department of
Pathology,
Division of Pathology and
Laboratory Medicine, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas; and the Eastern Cooperative Oncology
Group,
Brookline, Massachusettes
Cancer with high levels of microsatellite instability (MSI-H) is
the hallmark of hereditary nonpolyposis colorectal cancer
syndrome, and MSI-H occurs in 
15% of sporadic colorectal
carcinomas that have improved prognosis. We examined the utility of
histopathology for the identification of MSI-H cancers by evaluating
the features of 323 sporadic carcinomas using specified criteria and
comparing the results to MSI-H status. Coded hematoxylin and eosin
sections were evaluated for tumor features (signet ring cells; mucinous
histology; cribriforming, poor differentiation, and
medullary-type pattern; sponge-like mucinous growth; pushing invasive
margin) and features of host immune response (Crohn’s-like lymphoid
reaction, intratumoral lymphocytic infiltrate, and
intraepithelial T cells by immunohistochemistry for CD3 with
morphometry). Interobserver variation among five pathologists was
determined. Subjective interpretation of histopathology as an
indication for MSI testing was recorded. We found that medullary
carcinoma, intraepithelial lymphocytosis, and poor
differentiation were the best discriminators between MSI-H and
microsatellite-stable cancers (odds ratio: 37.8, 9.8,
and 4.0, respectively; P = 0.000003 to
<0.000001) with high specificity (99 to 87%). The
sensitivities, however, were very low (14 to
38%), and interobserver agreement was good only for evaluation
of poor differentiation (kappa, 0.69). Mucinous
histopathological type and presence of signet ring cells had low odds
ratios of 3.3 and 2.7 (P = 0.005 and
P = 0.02) with specificities of 95% but
sensitivities of only 15 and 13%. Subjective interpretation of the
overall histopathology as suggesting MSI-H performed better than any
individual feature; the odds ratio was 7.5 (P <
0.000001) with sensitivity of 49%, specificity of
89%, and moderate interobserver agreement (kappa,
0.52). Forty intraepithelial CD3-positive lymphocytes/0.94
mm2, as established by receiver operating
characteristic curve analysis, resulted in an odds ratio of 6.0
(P < 0.000001) with sensitivity of 75% and
specificity of 67%. Our findings indicate that histopathological
evaluation can be used to prioritize sporadic colon cancers for MSI
studies, but morphological prediction of MSI-H has low
sensitivity, requiring molecular analysis for therapeutic
decisions.
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