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Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry.
Am J Surg Pathol. 2016 Feb; 40(2):155-65.AJ

Abstract

Expanded testing for Lynch syndrome (LS) is increasingly recommended for patients with endometrial carcinomas, and immunohistochemistry (IHC) for tumor loss of mismatch-repair (MMR) protein expression is the most common primary screen. This has led to the recognition of MMR-IHC-deficient cases without identifiable mutations on directed germline sequencing. The clinical implications of such "Lynch-like" (LL) cancers are unclear. We here report the clinicopathologic features of putative familial endometrial carcinoma identified on universal MMR-IHC screening with attention to cases with discordant IHC and germline results. The files of the University of Virginia Pathology Department were retrospectively searched for all MMR-deficient endometrial carcinomas identified on screening. Cases were categorized as likely sporadic (MLH1/PMS2 loss, evidence of MLH1 promoter hypermethylation) or putative LS (PLS) (loss of MSH2/MSH6, MSH6, or PMS2). PLS cases were further subdivided into LS and LL groups on the basis of the presence or absence of a confirmatory mutation by germline testing, and the clinicopathologic features of these cases were compared. A deficiency of ≥1 MMR protein was observed in 31.4% (66/210) of endometrial carcinomas, including 26 PLS cases, 15 of which had germline testing. Directed germline sequencing confirmed LS in 46.7% (7/15); the remaining cases were classified as LL. High-grade and/or biphasic morphology was seen in 42.9% (3/7) of LS and 62.5% (5/8) of LL cases; the remaining cases showed low-grade, conventional endometrioid morphology. High level microsatellite instability was observed in 71.4% (5/7) of LL cases. The majority of cases from both groups (LS: 85.7% [6/7]; LL: 87.5% [7/8]) were low-stage (T1a/T1b). Endometrial carcinoma was the presenting malignancy in 85.7% (6/7) of LS patients and 87.5% (7/8) of LL patients. Family history was suggestive of LS in 28.5% (2/7) of LS patients and 12.5% (1/8) of LL patients. Screening algorithms based on age and cancer history would have failed to identify LS patients in 57.1% (4/7) of cases. Although universal MMR-IHC identifies endometrial carcinoma patients with LS who would have been missed using targeted screening algorithms, it also identifies cancers with discordant IHC and germline results for which the somatic versus germline origin of the MMR defect is unclear. Further study of this LL group is required before drawing definitive conclusions about their familial cancer risk.

Authors+Show Affiliations

Departments of *Pathology‡Gynecologic Oncology†Emily Couric Cancer Center, University of Virginia, Charlottesville, VA.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

26523542

Citation

Mills, Anne M., et al. "Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified On Universal Screening Using Mismatch Repair Protein Immunohistochemistry." The American Journal of Surgical Pathology, vol. 40, no. 2, 2016, pp. 155-65.
Mills AM, Sloan EA, Thomas M, et al. Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry. Am J Surg Pathol. 2016;40(2):155-65.
Mills, A. M., Sloan, E. A., Thomas, M., Modesitt, S. C., Stoler, M. H., Atkins, K. A., & Moskaluk, C. A. (2016). Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry. The American Journal of Surgical Pathology, 40(2), 155-65. https://doi.org/10.1097/PAS.0000000000000544
Mills AM, et al. Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified On Universal Screening Using Mismatch Repair Protein Immunohistochemistry. Am J Surg Pathol. 2016;40(2):155-65. PubMed PMID: 26523542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinicopathologic Comparison of Lynch Syndrome-associated and "Lynch-like" Endometrial Carcinomas Identified on Universal Screening Using Mismatch Repair Protein Immunohistochemistry. AU - Mills,Anne M, AU - Sloan,Emily A, AU - Thomas,Martha, AU - Modesitt,Susan C, AU - Stoler,Mark H, AU - Atkins,Kristen A, AU - Moskaluk,Christopher A, PY - 2015/11/3/entrez PY - 2015/11/3/pubmed PY - 2016/5/18/medline SP - 155 EP - 65 JF - The American journal of surgical pathology JO - Am J Surg Pathol VL - 40 IS - 2 N2 - Expanded testing for Lynch syndrome (LS) is increasingly recommended for patients with endometrial carcinomas, and immunohistochemistry (IHC) for tumor loss of mismatch-repair (MMR) protein expression is the most common primary screen. This has led to the recognition of MMR-IHC-deficient cases without identifiable mutations on directed germline sequencing. The clinical implications of such "Lynch-like" (LL) cancers are unclear. We here report the clinicopathologic features of putative familial endometrial carcinoma identified on universal MMR-IHC screening with attention to cases with discordant IHC and germline results. The files of the University of Virginia Pathology Department were retrospectively searched for all MMR-deficient endometrial carcinomas identified on screening. Cases were categorized as likely sporadic (MLH1/PMS2 loss, evidence of MLH1 promoter hypermethylation) or putative LS (PLS) (loss of MSH2/MSH6, MSH6, or PMS2). PLS cases were further subdivided into LS and LL groups on the basis of the presence or absence of a confirmatory mutation by germline testing, and the clinicopathologic features of these cases were compared. A deficiency of ≥1 MMR protein was observed in 31.4% (66/210) of endometrial carcinomas, including 26 PLS cases, 15 of which had germline testing. Directed germline sequencing confirmed LS in 46.7% (7/15); the remaining cases were classified as LL. High-grade and/or biphasic morphology was seen in 42.9% (3/7) of LS and 62.5% (5/8) of LL cases; the remaining cases showed low-grade, conventional endometrioid morphology. High level microsatellite instability was observed in 71.4% (5/7) of LL cases. The majority of cases from both groups (LS: 85.7% [6/7]; LL: 87.5% [7/8]) were low-stage (T1a/T1b). Endometrial carcinoma was the presenting malignancy in 85.7% (6/7) of LS patients and 87.5% (7/8) of LL patients. Family history was suggestive of LS in 28.5% (2/7) of LS patients and 12.5% (1/8) of LL patients. Screening algorithms based on age and cancer history would have failed to identify LS patients in 57.1% (4/7) of cases. Although universal MMR-IHC identifies endometrial carcinoma patients with LS who would have been missed using targeted screening algorithms, it also identifies cancers with discordant IHC and germline results for which the somatic versus germline origin of the MMR defect is unclear. Further study of this LL group is required before drawing definitive conclusions about their familial cancer risk. SN - 1532-0979 UR - https://www.unboundmedicine.com/medline/citation/26523542/Clinicopathologic_Comparison_of_Lynch_Syndrome_associated_and_"Lynch_like"_Endometrial_Carcinomas_Identified_on_Universal_Screening_Using_Mismatch_Repair_Protein_Immunohistochemistry_ L2 - https://doi.org/10.1097/PAS.0000000000000544 DB - PRIME DP - Unbound Medicine ER -