Clinicopathologic and Genetic Characterization of Traditional Serrated Adenomas of the Colon

Fu, Baojin; Yachida, Shinichi; Morgan, Richard A.; Zhong, Yi; Montgomery, Elizabeth A.; Iacobuzio‐Donahue, Christine A.

doi:10.1309/ajcpvt7lc4crpzsk

Cited by 61 publications

(76 citation statements)

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“…Our clinicopathological data are in agreement with recent publications, [14][15][16][17] although in our series, precursor polyps were limited to microvesicular hyperplastic polyps and sessile serrated adenomas and were exclusively associated with BRAF mutation. BRAF mutant traditional serrated adenomas were also more likely to be proximal than KRAS or BRAF/KRAS wild-type traditional serrated adenomas.…”

Section: Discussionsupporting

confidence: 93%

“…Cytological features included increased nuclear size, frequent and atypical mitoses, nuclear crowding, complete loss of polarity, and pseudo-stratification with nuclei extending into the upper half of the neoplastic cell. 11,14,15 Architectural features were crowding of glands, cribriform glands, and intraluminal necrosis. Carcinoma was recognized by breach of the muscularis mucosae by cytologically dysplastic cells in concert with desmoplastic stroma.…”

Section: Diagnosis Of Advanced Traditional Serrated Adenomamentioning

confidence: 99%

“…Loss of membrane staining and cytoplasmic staining were not considered positive. 14,23 Positive p53 required nuclear staining with a score of Z6 in any compartment. 14 Positive P16 required either cytoplasmic or nuclear staining with a score of Z3 in any compartment.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…11,13 Moreover, a subset of traditional serrated adenomas develop discrete areas of morphologically overt dysplasia. [14][15][16] How to classify these advanced traditional serrated adenomas and how to separate them from ordinary traditional serrated adenomas in routine practice has been inadequately addressed. The origin of the traditional serrated adenomas is also unclear.…”

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confidence: 99%

“…The frequency of BRAF and KRAS mutation and CpG island methylator phenotype high versus CpG island methylator phenotype low or negative is variable in the literature, unusual for a polyp that, above issues aside, is morphologically fairly uniform. 14,16,17,19,20 The reasons for, and the significance of, this heterogeneity have not been investigated. Finally, the pathways by which traditional serrated adenomas progress to carcinoma have not been extensively studied.…”

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confidence: 99%

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A clinicopathological and molecular analysis of 200 traditional serrated adenomas

et al. 2015

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The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, b-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; Pr0.0001), were exclusively associated with a precursor polyp (57% versus 0%; Pr0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; Pr0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear b-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wildtype traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma. The serrated neoplasia pathway accounts for 15 to 35% of colorectal carcinoma. 1-3 Well-established molecular drivers of this pathway are MAP kinase pathway activation, a critical early event resulting from either activating BRAF or KRAS mutation, 4 and the CpG island methylator phenotype, a coordinate methylation of CpG islands in the promoter regions of many genes that results in gene silencing. [4][5][6] The CpG island methylator phenotype is particularly relevant to carcinogenesis when affecting tumorsuppressor genes. 5 MLH1 is the best known of these, with silencing leading to microsatellite instability. This is frequently observed in the malignant transformation of sessile serrated adenomas. However, MLH1 methylation and microsatellite instability are not prerequisites of serrated neoplasia.

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Section: Discussionsupporting

confidence: 93%

Section: Diagnosis Of Advanced Traditional Serrated Adenomamentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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