TSAs were classified into two phenotypes according to their molecular characteristics: microvesicular serrated subtypes with BRAF mutations (SA-1 and -2 lesions) and subtypes containing tubulo-serrated/conventional adenoma with K/NRAS mutations (SA-3 and -4 lesions).
Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei.
In conclusion, BRAF-V600E mutation is associated with proximal localisation and CIMP-H status in both SSA and TSA, with size <10 mm only in TSA, and with expression of MUC5A5 and MUC6 and endoscopic pit pattern II-O at least in SSA.
SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019).
A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation.
The unique molecular spectrum of these tumors suggests a stepwise neoplastic progression from sessile serrated adenoma to traditional serrated adenoma and BRAF-mutated/microsatellite-stable colorectal carcinoma, which should be recognized as the traditional serrated pathway to distinguish from the sessile serrated pathway.
Despite sharing a serrated morphology, we found that SSAs and TSAs differed considerably with respect to anatomical location, expression of EPHB2 and PTCH1, presence of the V600EBRAF mutation and MSI status.
Awareness that many TSAs, particularly BRAF-mutated TSAs, arise in precursor microvesicular hyperplastic polyps and sessile serrated adenomas can aid in making this diagnosis and should not be confused with a sessile serrated adenoma with dysplasia.
Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma.
Traditional serrated adenoma with serrated dysplasia had a significantly higher frequency of BRAF mutation than traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature (P=0.006), whereas traditional serrated adenoma with conventional adenomatous dysplasia and tubulovillous adenoma with serrated feature had higher frequencies of KRAS mutation than traditional serrated adenoma with serrated dysplasia (P<0.0001).
Single morphological criteria for sessile serrated adenomas showed significant correlation with BRAF mutation (all p ≤ 0.001), and those for classical adenomas or traditional serrated adenoma correlated significantly with KRAS mutation (all p < 0.001).
We analyzed immunoreactivity of these proteins, methylation of PTCH and EphB2, and mutation of BRAF and Kras in sessile SAs (SSAs; n = 32), traditional SAs (n = 28), hyperplastic polyps (HPs; n = 24), and conventional adenomas (ADs; n = 21).
BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%).
The BRAFV600E mutation was detected in 36.3% of SCa and 26.7% of TSA patients, but it was not detected in TA and Ca patients; MSI-H was noticed in 23% of SCa, 33.3% of TSA, 5.3% of Ca and 0% of TA patients, respectively (P<0.05).