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Gastrointestinal Pathology Our Data Support the Notion That Optimized IHC Identification of CMV May Serve As a Gold Standard for the Diagnosis of CMV Colitis

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Gastrointestinal Pathology Our Data Support the Notion That Optimized IHC Identification of CMV May Serve As a Gold Standard for the Diagnosis of CMV Colitis 144A ANNUAL MEETING ABSTRACTS As identification of CMV by histology/IHC rather than PCR has clinical implications, Gastrointestinal Pathology our data support the notion that optimized IHC identification of CMV may serve as a gold standard for the diagnosis of CMV colitis. 565 Unusual Immunohistochemistry Staining Patterns Encountered in Cancers Screened for Lynch Syndrome 567 Retrospective Study of Clinicopathologic Features and Patient Rocky Adams, Katherine Geiersbach, Sheryl Tripp, Wade Samowitz. University of Outcome of Primary Adenosquamous Carcinoma of the Esophagus Utah Health Sciences Center, ARUP Institute for Clinical & Experimental Pathology, Atin Agarwal, Dongfeng Tan, Susan Abraham, Melissa Taggart, Huamin Wang, Salt Lake City, UT; ARUP Institute for Clinical and Experimental Pathology, Salt Jeannelyn Estrella, Miao Zhang, Asif Rashid, Dipen Maru. Baylor College of Medicine, Lake City, UT. Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX. Background: Mismatch repair deficiency is associated with Lynch syndrome in a subset Background: Primary adenosquamous carcinoma (ASC) of the esophagus is an of colorectal and endometrial cancers, and universal screening is now recommended infrequent tumor with limited information on its biology and clinical behavior. for these tumors. Immunohistochemistry for four mismatch repair proteins (MLH1, Design: In a retrospective search of the institutional database (2001-2014) of MSH2, MSH6, and PMS2) is the most frequently used screening method. Although primary esophageal ASC, we identified 73 patients whose pathology was reviewed interpretation is usually straightforward for these stains, unusual patterns are encountered by a GI Pathologist. Forty-three of 73 patients with ASC diagnosed on pretreatment occasionally. Unusual staining patterns can lead to uncertainty about the possible biopsies were included in the study. Pretreatment clinical staging was confirmed by underlying gene defects. endoscopic ultrasound and/or CT/PET CT scans. The presence of Barrett’s esophagus Design: Retrospective review of 3,564 cases of cancer tested by immunohistochemistry was assessed either on esophagogastroduodenoscopy or pathology specimens. indicated that 727 (20%) were abnormal. The usual abnormal pattern was defined as loss Adenosquamous carcinoma was diagnosed based on presence of separate or admixed of both MLH1 and PMS2, loss of PMS2 alone, loss of both MSH2 and MSH6, or loss glandular and squamous component identified on H&E with or without mucicarmine of MSH6 alone in the entire tumor tested. Of the abnormal cases, a significant fraction or immunohistochemistry for keratin 5/6, p63, p40 and CDX-2. All patients with (93, almost 13%) showed unusual staining patterns. Unusual cases were stratified into advanced locoregional disease underwent chemoradiation with or without surgery. categories based on the staining pattern and histopathologic features. All stage IV patients underwent chemotherapy with or without palliative localized Results: The most common categories of unusual staining are indicated in Table 1. radiation. Esophagectomy specimens after preoperative chemoradiation were reviewed The patterns indicate different underlying mechanisms, both intrinsic to the biology of for presence of Barrett’s esophagus, amount of residual tumor and pathologic stage. the tumor (genetic heterogeneity or multiple gene defects) and extrinsic to the tumor Results: The patient population included 36 men and 7 women with an age range of 49- (chemoradiation and tissue preservation artifacts). 88 years. Tumor location was mid or distal esophagus in 25 (58%) and gastroesophageal Colorectal Endometrial Other junction in 18 (42%). Barrett’s esophagus was found in 13 (30%) patients. Two thirds Staining pattern Cancer Cancer Cancers Total (n=29) of patients presented with stage IV (n=28) or locally advanced unresectable (n = 57) (n = 31) (n = 5) disease (n=1). Six patients with locoregional disease demonstrated disease progression True heterogeneity (partial staining after preoperative chemoradiation. Five patients with locoregional disease had extensive of the tumor; absent staining in whole residual tumor in surgical resection specimens. Three patients with locoregional 22 20 2 44 regions of the tumor with retained disease demonstrated radiologic response to preoperative chemoradiation and were not internal control staining). operated due to high risk of operative morbidity. Only 3 of 41 (7%) patients survived Non-standard loss of staining indicating more than 3 years. 12* 3 1 16 a defect in more than one gene. Conclusions: Primary esophageal adenosquamous carcinoma has higher stage at presentation and poor response to preoperative chemoradiation. Unusual staining in the setting of prior 5 0 0 5 chemoradiation. 568 Prevalence and Clinical Significance of Microsatellite Instability Artifacts of tissue preservation and staining, preventing interpretation of 12 6 2 20 in Colorectal Cancers With Retained DNA Mismatch Repair Proteins By mismatch repair status in the tumor. Immunohistochemistry Agoston Agoston, Lynette Sholl, Neal Lindeman, Jason Hornick, Amitabh Srivastava. Unknown / other mechanisms. 7 2 0 9 Brigham & Women’s Hospital, Boston, MA. (*) 1 case showed two unusual staining patterns. Background: DNA mismatch repair (MMR) protein immunohistochemistry (IHC) is now used more often than microsatellite instability (MSI) testing by PCR to screen Conclusions: Multiple mechanisms can contribute to unusual staining patterns. These colorectal carcinomas (CRC) for Lynch Syndrome (LS). The rate of discordance reported unusual patterns are encountered infrequently overall but represent a significant in the literature between these two screening tests varies widely. The aim of our study proportion of abnormal cases (13% in our series). Better understanding of the was to determine the discordance rate between MMR IHC and MSI in a large series of mechanisms causing unusual immunohistochemistry staining patterns will enable CRC and to analyze its clinical significance. improved classification of tumors with mismatch repair deficiencies. Design: MMR IHC to screen for LS was performed in 2116 CRC between 1991-2014. MSI testing was also performed in 947/2116 cases, most commonly due to young age 566 Prognostic Implication of Optimized Detection of CMV By (<50 yrs) at CRC diagnosis. MMR IHC status was assessed using a four antibody panel Immunohistochemistry in CMV PCR-Positive Inflammatory Bowel Disease (MLH1, MSH2, MSH6, and PMS2) and scored as MMR deficient only when complete Patients loss of nuclear staining was seen in the tumor cells. Tumors were classified as MSI-high Kajsa Affolter, Jessica Johnson, John Valentine, Kathryn Peterson, Xinjian Chen. if >30% of tested loci showed instability. University School of Medicine, Salt Lake City, UT. Results: Mean age of the study group was 54 years and M:F ratio was 1:1.1. MMR Background: The significance of superimposed CMV infection in patients with IBD IHC was intact in 839/947 (89%) patients in whom both MMR IHC and MSI testing has been an issue of debate. Independent studies have reported a significantly higher was performed. Only 6/839 cases (0.7%) with intact MMR IHC were MSI-H, and incidence of colon CMV infection in patients with steroid-refractory IBD as compared represented 6% of the 106 MSI-H cases. Germline testing in two of these 6 patients (due to those with non-refractory disease, suggesting a contributory role of this virus in to young age, 35 and 46yrs, respectively, and strong family history of CRC) confirmed the disease process. Despite the relative high incidence, CMV was identified only in LS due to MLH1 point mutations in both cases. The results of genetic testing were not a small proportion (20 – 40%) of the steroid resistant patients. The reported lack of available in the remaining four patients but one had a family history suggestive of LS. colon CMV infection in the majority of these patients raises the question whether CMV Conversely, 8/841 (0.95%) patients with either microsatellite stable (MSS) tumors infection is truly not associated with the patients or the negative result is due to the low (n=738) or tumors with low level MSI (MSI-L) (n=103) showed abnormal results by sensitivity of the examination. MMR IHC . 3/8 discordant cases were MSI-L and two of these three were LS patients Design: To address this question, we identified 26 IBD patients whose intestinal biopsies (both MSH6 mutations) . The third MSI-L patient had loss of MLH1/PMS2 on IHC or resection specimens were CMV PCR positive, and performed CMV IHC on all the but no genetic testing was available and family history was not suggestive of LS. Of tissue blocks that were initially found to be CMV negative per H&E. the 5/8 discordant MSS cases (3 with MSH2/MSH6 loss, 2 with only MSH6 loss), 3 Results: Re-examination of 153 tissue blocks derived from 37 separate colonoscopy were negative for LS by genetic testing, and 2 did not have genetic testing and did not and colectomy specimens from 26 IBD patients (representing 28 separate clinical CMV have a family history suggestive of LS. infections) identified additional CMV inclusions in patients whom were diagnosed CMV Conclusions: Discordance between intact MMR IHC and MSI testing is rare (0.7%) negative by H&E or IHC performed only on selected blocks in the initial examination. in CRC, and there was no clear trend favoring either method. Performing MSI testing However, despite the enhanced sensitivity, IHC
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