This is the first report to analyze REG Iα expression and crypt cell compartmentalization in serrated polyps. We show that REG Iα overexpression is a characteristic of SSA/Ps, as compared to (large) HPs. In analyses of ulcerative colitis-associated neoplasia, the expression of REG Iα gradually increased from regenerative mucosa through low-grade dysplasia to high-grade dysplasia; in this sequence, the distribution of proliferative cells increased similar to the REG Iα-positive region [12, 13]. In addition, REG Iα-positive pleomorphic adenoma of the salivary gland demonstrated a significantly higher Ki67 labeling score than those negative for REG Iα . In previous reports, SSA/Ps demonstrated high proliferative activity with asymmetric localization of proliferative cells [6–8]. This observation is in line with our results that aberration of crypt cell compartmentalization was more frequently identified in SSA/Ps (72%) than in HPs (18%). We also found a significant association between REG Iα overexpression and aberration of crypt cell compartmentalization in serrated polyps. In normal colonic crypts, endocrine cells and Paneth cells exist, in general, in proliferative and intermediate regions, and goblet cells are present only in the intermediate region ; however, in SSA/Ps, numerous goblet cells are identified at the base of the crypts (proliferative region) as well as in the intermediate region . In SSA/Ps, there are abnormalities in the location of the various compartments (previously referred to as abnormal proliferation or dysmaturation ), a feature that Torlakovic et al. designated as the aberration of crypt compartmentalization .
Interestingly, we found that REG Iα-expressing endocrine cells are increased in SSA/Ps. To our knowledge, endocrine cell hyperplasia has not been previously described in the context of SSA/Ps. In microvesicular-type HP, the number and/or size of endocrine cells are increased and they are mainly found in the intermediate region of the crypts . Recently, Naert et al. reported a case of large cell neuroendocrine carcinoma arising in an SSA . Corresponding to this case and our findings, REG Iα is thought to be associated with endocrine cell hyperplasia and the development of neuroendocrine tumors in SSA/Ps. Mutations in REG Iα were identified in patients with carcinoid tumors , suggesting a link between its gain-of-function mutation and endocrine cell hyperplasia.
In our ancillary study, REG Iα positivity was related to aberrant (non-membranous type) β-catenin expression in SSA/Ps. In conjunction with this finding, aberrant β-catenin expression was related to REG Iα positivity in pleomorphic adenoma . A link between REG Iα and β-catenin has been demonstrated in a study of liver cancer, in which β-catenin mutations induced REG Iα expression in liver cancer cells [15, 16]. Therefore, REG Iα may be a possible downstream target of the Wnt/β-catenin signaling pathway. Wu et al. found aberrant nuclear labeling for β-catenin in 9 of 22 cases of SSA/Ps (41%). In a recent study, widespread or focal nuclear accumulation of β-catenin (using an N-terminus antibody) was also identified in 14 of 35 right-sided SSA/Ps (40%). Consequently, REG Iα overexpression may contribute to the early activation of the Wnt/β-catenin signaling pathway in SSA/Ps.
In the present study, we found one case of inverted HP displaying REG Iα overexpression in the ascending colon with a maximum diameter of 15 mm. This is the only case of HP with REG Iα overexpression similar to SSA/Ps. Inverted HPs as first described by Sobin et al. are an unusual morphological variant of HPs that show epithelial misplacement into the submucosa . Inverted HPs are located in the rectum or sigmoid colon; their mean size is 5 mm . To date, a small number of cases of inverted HP associated with adenoma and adenocarcinoma have been reported [26–28]. An association of SSA/Ps with inverted HPs in addition to their ability of malignant progression remains unknown and an area of research and controversy.