{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:13:15Z","timestamp":1785402795474,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Introduction: The ecto-endodermal boundary in the human oral cavity remains debated. Rather than a distinct line, this transition forms a complex interface, especially in the developing mouth and pharynx. This ambiguity is clinically relevant, as, for example, HPV-induced tumors often arise where ecto- and endoderm meet. The boundary is generally placed at the posterior third of the tongue and behind the uvula, though its developmental basis remains unclear. This review summarizes the literature on the embryological development of the mouth and pharynx to trace origins and interactions of ectodermal and endodermal derivatives and identify potential tumor initiation regions. Methods: PubMed articles on oral structures were reviewed to approximate the ecto-endodermal border. Results: Teeth originate from ectoderm. The origin of salivary glands and papillae depends on their location. No study reports were found for the tonsils, incisive papilla, tubarial glands, and faucial pillars. Conclusions: A clear educational image of the origin of the structures of the human mouth is made to help identify regions of risk for oral cancer.<\/jats:p>","DOI":"10.3390\/life16081258","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:09:42Z","timestamp":1785398982000},"page":"1258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Ecto-Endodermal Boundary in the Oral and Pharyngeal Mucosa: A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2297-699X","authenticated-orcid":false,"given":"Rogier","family":"Schipperheijn","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5265-3722","authenticated-orcid":false,"given":"Frederik G.","family":"Dikkers","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Amsterdam UMC Location University of Amsterdam, 1007 MB Amsterdam, The Netherlands"},{"name":"Department of Otorhinolaryngology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0758-4064","authenticated-orcid":false,"given":"Bernadette S.","family":"de Bakker","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Reproduction and Development Research Institute, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Pediatric Surgery, University Medical Center Rotterdam, Erasmus MC\u2014Sophia Children\u2019s Hospital, 3000 CB Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (2026, January 01). Cancers Caused by HPV, Available online: https:\/\/www.cdc.gov\/hpv\/parents\/cancer.html."},{"key":"ref_2","first-page":"285","article-title":"Anal canal development in the embryonic and early foetal period","volume":"62","author":"Kromer","year":"2003","journal-title":"Folio Morphol."},{"key":"ref_3","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1097\/CCO.0b013e32832a68ca","article-title":"Recent changes in the epidemiology of head and neck cancer","volume":"21","author":"Curado","year":"2009","journal-title":"Curr. Opin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.canep.2015.04.007","article-title":"Oral Cavity and Oropharyngeal Cancer Incidence Trends and Disparities in the United States: 2000\u20132010","volume":"39","author":"Weatherspoon","year":"2015","journal-title":"Cancer Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40880-016-0078-2","article-title":"Epidemiologic characteristics of oral cancer: Single-center analysis of 4097 patients from the Sun Yat-sen University Cancer Center","volume":"35","author":"Zhang","year":"2016","journal-title":"Chin. J. Cancer"},{"key":"ref_7","first-page":"439","article-title":"Oral Cancer: Epidemiology, Clinical Features, and Survival Rates in the United States","volume":"12","author":"Williams","year":"2024","journal-title":"J. Oral Hyg. Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1001\/jama.2025.21733","article-title":"Head and Neck Cancer: A Review","volume":"335","author":"Dunn","year":"2026","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.anorl.2019.04.002","article-title":"Head and neck carcinoma of unknown primary","volume":"136","author":"Kennel","year":"2019","journal-title":"Eur. Ann. Otorhinolaryngol. Head. Neck Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1469-7580.2012.01540.x","article-title":"Development and evolution of the vertebrate primary mouth","volume":"222","author":"Soukup","year":"2013","journal-title":"J. Anat."},{"key":"ref_11","unstructured":"O\u2019Rahilly, R., and M\u00fcller, F. (1987). Developmental Stages in Human Embryos, Carnegie Institution."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1002\/dvdy.23804","article-title":"Lineage tracing of the endoderm during oral development","volume":"241","author":"Rothova","year":"2012","journal-title":"Dev. Dyn."},{"key":"ref_13","first-page":"6315","article-title":"An interactive three-dimensional digital atlas and quantitative database of human development","volume":"354","author":"Hagoort","year":"2016","journal-title":"Science"},{"key":"ref_14","unstructured":"Carlson, B.M. (2018). Establishment of the Basic Embryonic Body Plan. Human Embryology and Developmental Biology, Elsevier."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1002\/ca.23889","article-title":"A three-dimensional analysis of the development of cranial nerves in human embryos","volume":"35","author":"Smit","year":"2022","journal-title":"Clin. Anat."},{"key":"ref_16","unstructured":"Sadler, T.W. (2023). Langman\u2019s Medical Embryology, Wolters Kluwer."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1002\/lary.26987","article-title":"The development of the human hyoid-larynx complex revisited","volume":"128","author":"Dikkers","year":"2018","journal-title":"Laryngoscope"},{"key":"ref_18","unstructured":"Cochard, L.R. (2012). Netter\u2019s Atlas of Human Embryology, Elsevier."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/j.1600-0722.1998.tb02148.x","article-title":"Contribution of foregut endoderm to tooth initiation of mandibular incisor in rat embryos","volume":"106","author":"Imai","year":"1998","journal-title":"Eur. J. Oral Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/dvg.20634","article-title":"Ectoderm, endoderm, and the evolution of heterodont dentitions","volume":"48","author":"Ohazama","year":"2010","journal-title":"Genesis"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Soukup, V., Tazaki, A., Yamazaki, Y., Pospisilova, A., Epperlein, H.-H., Tanaka, E.M., and Cerny, R. (2021). Oral and Palatal Dentition of Axolotl Arises From a Common Tooth-Competent Zone Along the Ecto-Endodermal Boundary. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.622308"},{"key":"ref_22","unstructured":"Ghannam, M.G., and Singh, P. (2023). Anatomy, Head and Neck, Salivary Glands. StatPearls, StatPearls Publishing."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0039-6109(05)70405-9","article-title":"THE SALIVARY GLANDS: Embryology, Anatomy, and Surgical Applications","volume":"80","author":"Carlson","year":"2000","journal-title":"Surg. Clin. N. Am."},{"key":"ref_24","unstructured":"Grewal, J.S., Jamal, Z., and Ryan, J. (2022). Anatomy, Head and Neck, Submandibular Gland. StatPearls, StatPearls Publishing."},{"key":"ref_25","first-page":"8739","article-title":"Embryology and development of salivary gland","volume":"7","author":"Anitha","year":"2020","journal-title":"Eur. J. Mol. Clin. Med."},{"key":"ref_26","unstructured":"Grewal, J.S., Bordoni, B., Shah, J., and Ryan, J. (2023). Anatomy, Head and Neck, Sublingual Gland. StatPearls, StatPearls Publishing."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.radonc.2020.09.034","article-title":"The tubarial salivary glands: A potential new organ at risk for radiotherapy","volume":"154","author":"Valstar","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109845","DOI":"10.1016\/j.radonc.2023.109845","article-title":"Immunohistological profiling confirms salivary gland-like nature of the tubarial glands and suggests closest resemblance to the palatal salivary glands","volume":"187","author":"Pringle","year":"2023","journal-title":"Radiother. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.radonc.2020.12.001","article-title":"The tubarial glands paper: A starting point. A reply to comments","volume":"154","author":"Valstar","year":"2021","journal-title":"Radiother. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1093\/chemse\/19.6.715","article-title":"Analysis of the embryonic lineage of vertebrate taste buds","volume":"19","author":"Barlow","year":"1994","journal-title":"Chem. Senses"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1073\/pnas.92.6.1916","article-title":"Taste receptor cells arise from local epithelium, not neurogenic ectoderm","volume":"92","author":"Stone","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.mod.2004.07.002","article-title":"Pax9 is required for filiform papilla development and suppresses skin-specific differentiation of the mammalian tongue epithelium","volume":"121","author":"Jonker","year":"2004","journal-title":"Mech. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103556","DOI":"10.1016\/j.mod.2019.103556","article-title":"Single origin of the epithelium of the human middle ear","volume":"158","author":"Ebbens","year":"2019","journal-title":"Mech. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1002\/ar.25561","article-title":"A comprehensive analysis of the tubarial glands","volume":"308","author":"Ebrahim","year":"2024","journal-title":"Anat. Rec."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1097\/PAP.0b013e3181f895c1","article-title":"Human Papillomavirus Detection in Head and Neck Squamous Cell Carcinomas","volume":"17","author":"Snow","year":"2010","journal-title":"Adv. Anat. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/s41586-023-06604-5","article-title":"Complete human day 14 post-implantation embryo models from naive ES cells","volume":"622","author":"Oldak","year":"2023","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0002-9440(10)63871-0","article-title":"Expression of p16 Protein Identifies a Distinct Entity of Tonsillar Carcinomas Associated with Human Papillomavirus","volume":"162","author":"Klussmann","year":"2003","journal-title":"Am. J. Pathol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1258\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T08:30:05Z","timestamp":1785400205000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["life16081258"],"URL":"https:\/\/doi.org\/10.3390\/life16081258","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}