Gastric adenocarcinoma with enteroblastic differentiation (GAED) has been recognized as a variant of alpha-fetoprotein (AFP)-producing gastric carcinoma, although its clinicopathologic and immunohistochemical features have not been fully elucidated. To elucidate the clinicopathologic and immunohistochemical features of GAED, we analyzed 29 cases of GAED, including ten early and 19 advanced lesions, and compared these cases with 100 cases of conventional gastric adenocarcinoma (CGA). Immunohistochemistry for AFP, glypican 3, SALL4, and p53 was performed, and the phenotypic expression of the tumors was evaluated by immunostaining with antibodies against MUC5AC, MUC6, MUC2, CD10, and caudal-type homeobox 2 (CDX2). Lymphatic and venous invasion was more frequent in GAED (76 and 72 %) than in CGA (41 and 31 %; P ≤ 0.001). Lymph node metastasis was more frequently observed in GAED (69 %) than in CGA (38 %; P = 0.005), as were synchronous or metachronous liver metastases (GAED, 31 %; CGA, 6 %; P ≤ 0.001). Immunohistochemically, all GAED were positive for at least one of three enteroblastic linage markers (AFP, glypican 3, and SALL4). Glypican 3 was the most sensitive marker (83 %) for GAED, followed by SALL4 (72 %) and AFP (45 %), whereas no CGA was positive. Furthermore, the rate of positive p53 staining was 59 % in GAED. Regarding the mucin phenotype, CD10 and CDX2 were diffusely or focally expressed in all GAED cases. Invasive areas with hepatoid or enteroblastic differentiation were negative for CD10 and CDX2. Clinicopathologic features of GAED differ from those of CGA. GAED shows aggressive biological behavior, and is characteristically immunoreactive to AFP, glypican 3, or SALL4.

Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF‐mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to “interval cancers” and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.

Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma

Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.