title: BRAF-mutated microsatellite stable colorectal carcinoma: an aggressive adenocarcinoma with reduced CDX2 and increased cytokeratin 7 immunohistochemical expression.
abstract: Reduced CDX2 and cytokeratin 20 (CK20) expression in colorectal carcinoma with BRAF mutation and high-level microsatellite instability (MSI-H) has been well documented. The immunophenotype of BRAF-mutated microsatellite stable (MSS) colorectal carcinoma has not been reported. We analyzed 205 colorectal carcinomas including 28 BRAF-mutated MSS, 53 BRAF-mutated MSI-H, and 124 BRAF wild-type MSS tumors for CDX2, cytokeratin 7 (CK7), and CK20 immunohistochemical expression. CDX2 was scored semiquantitatively for both staining intensity and percent of tumor cells staining and a modified CDX2 H-score was calculated. Patients with BRAF-mutated MSS colorectal carcinomas were more frequently stage IV at presentation compared to patients with BRAF-mutated MSI-H colorectal carcinomas and BRAF wild-type MSS colorectal carcinomas (32% versus 8% versus 15%, P < .001). BRAF-mutated MSS colorectal carcinoma displayed reduced CDX2 expression compared to BRAF wild-type MSS colorectal carcinoma (75% versus 94%; mean CDX2 H-score 98 versus 150, P < .001). CK7 expression was more often identified in BRAF-mutated MSS colorectal carcinoma compared to both BRAF-mutated MSI-H colorectal carcinoma and BRAF wild-type MSS colorectal carcinoma (39% versus 6% versus 6%, P = .0001). BRAF-mutated MSI-H colorectal carcinomas were less often CK20 positive compared to BRAF-mutated MSS and BRAF wild-type MSS tumors (70% versus 93% versus 90%, P = 0.001). In summary, BRAF-mutated MSS colorectal carcinoma often displays reduced CDX2 and increased CK7 expression. Knowledge of this altered immunophenotype is important as patients with BRAF-mutated MSS colorectal carcinoma often present with metastatic disease and the altered tumor immunophenotype may lead to the erroneous assumption that origin from the colon/rectum is unlikely.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Landau
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Shih-Fan
authors.initials: SF
authors.lastname: Kuan
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Simon
authors.initials: S
authors.lastname: Chiosea
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Electronic address: pair@upmc.edu.
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071616:CDX2 Transcription Factor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053554:Keratin-20 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism*; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D053554:Keratin-20; D053552:Keratin-7; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; CDX2; CK7; Colorectal carcinoma; Immunohistochemistry; MSI