Int J Colorectal Dis (2010) 25:1231–1242 DOI 10.1007/s00384-010-0986-6 ORIGINAL ARTICLE New insights into the development and differentiation of the human anorectal epithelia. Are there clinical consequences? Helga Fritsch & Sarah Zehm & Romana Illig & Patrizia Moser & Felix Aigner Accepted: 4 June 2010 / Published online: 20 June 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Purpose The epithelial lining of the anorectum still raises discussions concerning the levels of transition between the various zones and leads to an incomplete understanding of the immmunoprofile of rectal carcinoma. Since the expres- sion of cytokeratins depends on the epithelial cell-type and the parahox-gene CDX2 is important for the development of the colorectal epithelium, we investigated different cytokeratins and CDX2 in the anorectum of human prenatal stages and in adult normal and neoplastic anorecta. Materials and Methods The differentiation and spatiotem- poral distribution of the epithelial zones were examined in 33 human embryos and fetuses, in a 2-year-old child and four adults. In comparison, 17 specimens of ultralow rectal adenocarcinoma and 4 specimens of anal carcinoma were investigated. Monoclonal antibodies were directed against cytokeratin (CK) 18, 20, 7 and 14 and CDX2. H. Fritsch (*) : R. Illig Division of Clinical and Functional Anatomy, Department of Anatomy, Histology and Embryology, Innsbruck Medical University, Muellerstr. 59, A 6020 Innsbruck, Austria e-mail: helga.fritsch@i-med.ac.at S. Zehm Clinic of Vascular Surgery, Innsbruck Medical University, Innsbruck, Austria P. Moser Institute of Pathology, Innsbruck Medical University, Innsbruck, Austria F. Aigner Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria Results Due to the cytokeratin profile and to CDX2 expression, the different anorectal zones could already be differentiated in human prenatal life. We showed that anorectal epithelial differentiation including the squamous epithelia ran in a craniocaudal direction, and that the anorectal zone was a transitional zone between rectal zone and anal transitional zone where CK 7, 18, 20 and CDX2 are simultaneously expressed. All cases of rectal adenocar- cinoma showed positivity for CK 18, 20 and CDX2, and three also labelled for CK 7, whereas CK 14 was only expressed in the cases of anal carcinoma. Conclusions Our results elucidate the connection between the prenatal pattern and the origin of the different types of anorectal carcinoma. Keywords Human rectum . Epithelial differentiation . Anorectal tumours . Cytokeratins . CDX2 Introduction The epithelial boundaries of the anorectum are of high clinical relevance, as the exact location of pathological processes, especially carcinomas, in relation to these boundaries is crucial for prognosis and therapy [1–3]. The different epithelial zones of the human anorectum have caused numerous discussions concerning their embryonic origin, levels of transition and nomenclature [4]. Whereas it seems to be clear that the upper part of the anorectum belongs to the large intestine and is derived from the entoderm, the lower part is supposed to originate from the ectoderm. In 1914, Johnson [5] postulated that an exact histological determination of the border between entoderm and ectoderm is impossible. Only 10 years ago, O`Rahilly et Müller [6] pointed out that, as a result of developmental