Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors

Lindor, Noralane M.; Burgart, Lawrence J.; Leontovich, Olga; Goldberg, Richard M.; Cunningham, Julie M.; Sargent, Daniel J.; Walsh-Vockley, Catherine; Petersen, Gloria M.; Walsh, Michael D.; Leggett, Barbara A.; Young, Joanne; Barker, Melissa; Jass, Jeremy R.; Hopper, John L.; Gallinger, Steve; Bapat, Bharati; Redston, Mark; Thibodeau, Stephen N.

doi:10.1200/jco.20.4.1043

Cited by 510 publications

(311 citation statements)

References 40 publications

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“…Molecular testing was not performed on this cohort of patients as the sensitivity for determining microsatellite instability status by immunohistochemistry alone is reported to exceed 90% and the predictive value of absence of expression of either MLH1 or MSH2 for predicting microsatellite instability high has previously been described at 100%. 40 Additionally, microsatellite instability testing is recognized as infeasible in standard pathology laboratories and is currently not recommended in routine practice. 41 One of the most obvious issues concerning the use of tissue microarrays is the extent of tumor heterogeneity, which may result from sampling of only one core of 0.6 mm in diameter.…”

Section: Discussionmentioning

confidence: 99%

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

et al. 2008

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The differentiation of colorectal cancer from primary tumors at other sites can be challenging. Often a panel of immunohistochemical protein markers is needed to distinguish between these entities. Protein expression differs significantly in colorectal cancer depending on mismatch repair status and is also heterogeneous among mismatch repair-proficient or -deficient tumors. The aim of this study was to systematically analyze the diagnostic and prognostic role of the commonly used multi-marker phenotype CK20/CK7/CDX2 on a large series of colorectal cancers stratified by mismatch repair status. The immunohistochemical analysis of CK20, CK7 and CDX2 was performed on 1197 mismatch repair-proficient and 223 mismatch repair-deficient colorectal cancers using a tissue microarray. Multi-marker combinations of CK20/CK7/CDX2 were explored. Univariate and multivariable analysis of the markers was evaluated for their association with several clinico-pathological end points namely T stage, N stage, tumor grade, vascular invasion, intratumoral lymphocytes and survival. Multimarker phenotypes with CK20 and CDX2 negativity were more frequently found in mismatch repair-deficient than in mismatch repair-proficient colorectal cancer (19.3 vs 7.5% and 21.6 vs 6.7%, respectively; Po0.001). In both colorectal cancer subsets loss of CK20 was associated with higher tumor grade (Po0.001) and with presence of intratumoral lymphocytes (Po0.001 and P ¼ 0.02, respectively). In the proficient mismatch repair subset CK20 overexpression was an independent adverse prognostic factor (P ¼ 0.041) and CDX2 underexpression was linked to tumor progression. Loss of CDX2 and CK20 is more frequently encountered in mismatch repair-deficient colorectal cancer, which should be taken into consideration to differentiate between primary and metastatic colorectal cancer in daily practice. Although associated with lower tumor grade, CK20 overexpression is an independent adverse prognostic factor in mismatch repair-proficient colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

et al. 2008

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“…19,20,[31][32][33][34][35][36] Clearly, mutation analysis cannot be applied at a large scale and should only be offered to patients with substantial risk of having a deleterious mutation. Also, microsatellite analysis and immunohistochemistry, which have been shown to allow effective enrichment of high-risk patients, are presently not recommended for all cases of colorectal tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI 5 18.3-23.0%) and 61.8% (95% CI 5 56.8-66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. ' 2005 Wiley-Liss, Inc.

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“…Since approximately 90% of medullary-type carcinomas showed an absence of hMLH1 protein expression together with microsatellite instability, immunohistochemistry for the detection of hMLH1 protein may be useful in predicting the tumor type. 12,32 However, immunohistochemistry cannot replace testing for microsatellite instability to identify microsatellite-unstable sporadic colorectal cancer, 33 and morphological prediction of microsatellite-unstable cancer has low sensitivity. 34 Thus, we emphasize that both hMLH1 immunohistochemistry and a histopathological evaluation can predict medullary-type carcinomas, but they may miss some cases.…”

Section: Discussionmentioning

confidence: 99%

“…34 Thus, we emphasize that both hMLH1 immunohistochemistry and a histopathological evaluation can predict medullary-type carcinomas, but they may miss some cases. 32,33 Molecular analysis is required for therapeutic decisions. 34 Colorectal adenocarcinoma are graded predominantly on the basis of the extent of glandular appearances.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

Arai

Esaki²,

Sawabe

et al. 2004

Modern Pathology

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To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, Po0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

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Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors

Abstract: I m m u n o h i s t o c h e m i s t r y V e r s u s M i c r o s a t e l l i t e I n s t a b i l i t y T e s t i n g i n P h e n o t y p i n g C o l o r e c t a l T u m o r s

Cited by 510 publications

References 40 publications

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

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