Paneth Cell in Adenomas of the Distal Colorectum Is Inversely Associated with Synchronous Advanced Adenoma and Carcinoma

Abstract

Recent studies have linked appearance of Paneth cells in colorectal adenomas to adenoma burden and male gender. However, the clinical importance of Paneth cells' associations with synchronous advanced adenoma (AA) and colorectal carcinoma (CRC) is currently unclear. We performed a comprehensive case-control study using 1,900 colorectal adenomas including 785 from females, and 1,115 from males. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths among both men and women in the United States 1 . Colonoscopy guidelines recommend that individuals should start having a colonoscopy at the age of 50 years, and a potential follow-up colonoscopy depending on the endoscopic findings, particularly the polyp number and characteristics 2,3 . Certain adenoma characteristics have been associated with an increased CRC risk, including polyp size greater than or equal to 1 cm, villous histology and high-grade dysplasia 2-8 . An adenoma with one or more of the 3 characteristics is considered as advanced adenoma (AA, also known as advanced neoplasia) and should be followed up within 3 years, according to the recent update of the U.S. Multi-society Task Force on Colorectal Cancer 2 . Identification of markers for AA may help with the prevention, early identification and treatment of CRC.Paneth cells are normally present in the small intestine, proximal colon and transverse colon, and contribute to mucosal innate immunity by exerting a number of anti-microbial effects 9-11 . Genetic studies have indicated that Paneth cells upregulate the production of lysozymes, phospholipase A2, the Apc/beta-catenin/Tcf pathway, WNT, and CD166, during colonic tumorigenesis [11][12][13][14][15][16][17] . Paneth cells are also critical for intestinal stem cell homeostasis, as shown by our and others' works [18][19][20] . Recently, more attentions have been focused on the role of Paneth cells in CRC development and diagnosis 9 .

Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation

“…Furthermore, the frequency of observing Paneth cells was found to be lowest in gallbladder cancer tissues compared to non-neoplastic mucosa, suggesting an inverse correlation of PCM to gallbladder cancer (Yamamoto et al, 1989). This observation was consistent with a recent comprehensive case-control study of 1,900 colorectal adenomas showing metaplastic Paneth cells in distal colorectal adenomas were inversely associated with synchronous advanced adenoma and carcinoma (Mahon et al, 2016). Sakaki et al (2000) observed a case of gallbladder adenocarcinoma with extensive PCM.…”

“…The detection of Paneth cells in colorectal adenomas was reported as early as 1967 (Gibbs, 1967) and the reported frequencies of such detection varied from 0.2 to 39% in different studies (Bansal et al, 1984;Wada et al, 1994Wada et al, , 2005Joo et al, 2009;Pai et al, 2013;Mahon et al, 2016). Furthermore, Paneth cells not only produce antimicrobial components but also constitute an important epithelial niche for small intestinal stem cells by producing epithelial growth factor (EGF), transforming growth factor (TGF-α), Wnt3, and Notch ligands (Sato et al, 2011).…”

“…In contrast, abnormal appearance of Paneth cells in other parts of the gastrointestinal and extra-gastrointestinal region is referred to as Paneth cell metaplasia (PCM). Abundant appearance of Paneth cells in the human distal colons have been extensively documented in literatures published on ulcerative colitis (Tanaka et al, 2001;Bedini et al, 2014;Simmonds et al, 2014), Crohn's disease (Tanaka et al, 2001;Simmonds et al, 2014), and colonic tubular adenoma (Symonds, 1974;Wada et al, 2005;Shi, 2007;Wehkamp and Stange, 2010;Wang et al, 2011a;Mahon et al, 2016). Although these Paneth cell alterations are frequently associated with chronic inflammation, the molecular mechanism and significance of Paneth cell-related pathologies are poorly understood.…”

Two-photon microscopy of Paneth cells in the small intestine of live mice

“…Moxifloxacin-based TPM would be useful for studying the interplay of small intestinal Paneth cells and mucosal immune defense system in health 3 , 41 – 43 , inflammatory bowel disease (IBD) pathogenesis 33 , 44 – 48 , and metabolic syndrome 49 . Perhaps, it could also be developed as a diagnostic or prognostic method including endoscopy to examine the abnormalities of Paneth cell granules in IBD animal models and human patients in vivo 33 , 45 , 46 . Therefore, TPM with moxifloxacin labeling might be useful to study Paneth cell functions and related diseases in preclinical animal models.…”

Extensive Paneth cell metaplasia in an ovarian Krukenberg tumor: report of an unusual case and literature review

“…Some authorities have found that PCM affects the prognosis of certain pre-neoplastic conditions and tumors. Furthermore, it was found by some investigators that the presence of PCM in distal colorectal adenoma is inversely associated with synchronous severely dysplastic adenoma or adenocarcinoma [ 9 ]. Chen et al [ 10 ] also found that the presence of PCM in cases of Barrett’s esophagitis is associated with a higher risk for disease progression.…”