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Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.
Am J Surg Pathol. 2014 Jun; 38(6):793-800.AJ

Abstract

Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.

Authors+Show Affiliations

Departments of *Pathology ‡Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco †Cancer Risk Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

24503759

Citation

Rabban, Joseph T., et al. "Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients: Implications for Universal Versus Selective Screening Strategies for Lynch Syndrome." The American Journal of Surgical Pathology, vol. 38, no. 6, 2014, pp. 793-800.
Rabban JT, Calkins SM, Karnezis AN, et al. Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome. Am J Surg Pathol. 2014;38(6):793-800.
Rabban, J. T., Calkins, S. M., Karnezis, A. N., Grenert, J. P., Blanco, A., Crawford, B., & Chen, L. M. (2014). Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome. The American Journal of Surgical Pathology, 38(6), 793-800. https://doi.org/10.1097/PAS.0000000000000177
Rabban JT, et al. Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients: Implications for Universal Versus Selective Screening Strategies for Lynch Syndrome. Am J Surg Pathol. 2014;38(6):793-800. PubMed PMID: 24503759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome. AU - Rabban,Joseph T, AU - Calkins,Sarah M, AU - Karnezis,Anthony N, AU - Grenert,James P, AU - Blanco,Amie, AU - Crawford,Beth, AU - Chen,Lee-May, PY - 2014/2/8/entrez PY - 2014/2/8/pubmed PY - 2014/6/27/medline SP - 793 EP - 800 JF - The American journal of surgical pathology JO - Am. J. Surg. Pathol. VL - 38 IS - 6 N2 - Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/24503759/Association_of_tumor_morphology_with_mismatch_repair_protein_status_in_older_endometrial_cancer_patients:_implications_for_universal_versus_selective_screening_strategies_for_Lynch_syndrome_ L2 - http://dx.doi.org/10.1097/PAS.0000000000000177 DB - PRIME DP - Unbound Medicine ER -