{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T17:01:22Z","timestamp":1774976482899,"version":"3.50.1"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T00:00:00Z","timestamp":1614902400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T00:00:00Z","timestamp":1614902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100007195","name":"Universit\u00e0 degli Studi di Napoli Federico II","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007195","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The nature of endometrial morular metaplasia (MorM) is still unknown. The nuclear \u03b2-catenin accumulation and the not rare ghost cell keratinization suggest a similarity with hard keratin-producing odontogenic and hair matrix tumors rather than with squamous differentiation. We aimed to compare MorM to hard keratin-producing tumors. Forty-one hard keratin-producing tumors, including 26 hair matrix tumors (20 pilomatrixomas and 6 pilomatrix carcinomas) and 15 odontogenic tumors (adamantinomatous craniopharyngiomas), were compared to 15 endometrioid carcinomas with MorM with or without squamous\/keratinizing features. Immunohistochemistry for \u03b2-catenin, CD10, CDX2, ki67, p63, CK5\/6, CK7, CK8\/18, CK19, and pan-hard keratin was performed; 10 cases of endometrioid carcinomas with conventional squamous differentiation were used as controls. In adamantinomatous craniopharyngiomas, the \u03b2-catenin-accumulating cell clusters (whorl-like structures) were morphologically similar to MorM (round syncytial aggregates of bland cells with round-to-spindled nuclei and profuse cytoplasm), with overlapping squamous\/keratinizing features (clear cells with prominent membrane, rounded squamous formations, ghost cells). Both MorM and whorl-like structures consistently showed positivity for CD10 and CDX2, with low ki67; cytokeratins pattern was also overlapping, although more variable. Hard keratin was focally\/multifocally positive in 8 MorM cases and focally in one conventional squamous differentiation case. Hair matrix tumors showed no morphological or immunophenotypical overlap with MorM. MorM shows wide morphological and immunophenotypical overlap with the whorl-like structures of adamantinomatous craniopharyngiomas, which are analogous to enamel knots of tooth development. This suggests that MorM might be an aberrant mimic of odontogenic differentiation.<\/jats:p>","DOI":"10.1007\/s00428-021-03060-2","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T08:03:30Z","timestamp":1614931410000},"page":"607-616","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Does endometrial morular metaplasia represent odontogenic differentiation?"],"prefix":"10.1007","volume":"479","author":[{"given":"Antonio","family":"Travaglino","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5443-2333","authenticated-orcid":false,"given":"Antonio","family":"Raffone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Russo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elia","family":"Guadagno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Pignatiello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Moretta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulvio","family":"Zullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marialaura","family":"Del Basso De Caro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Insabato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Mascolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"issue":"2","key":"3060_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1136\/jcp.2010.085555","volume":"64","author":"A Nicolae","year":"2011","unstructured":"Nicolae A, Preda O, Nogales FF (2011) Endometrial metaplasias and reactive changes: a spectrum of altered differentiation. J Clin Pathol 64(2):97\u2013106","journal-title":"J Clin Pathol"},{"issue":"10","key":"3060_CR2","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1097\/01.pas.0000171001.87599.e2","volume":"29","author":"EF Brachtel","year":"2005","unstructured":"Brachtel EF, S\u00e1nchez-Estevez C, Moreno-Bueno G, Prat J, Palacios J, Oliva E (2005) Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules). Am J Surg Pathol 29(10):1322\u20131329","journal-title":"Am J Surg Pathol"},{"issue":"4","key":"3060_CR3","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1002\/(SICI)1096-9896(199708)182:4<429::AID-PATH872>3.0.CO;2-Z","volume":"182","author":"M Saegusa","year":"1997","unstructured":"Saegusa M, Okayasu I (1997) Down-regulation of bcl-2 expression is closely related to squamous differentiation and progesterone therapy in endometrial carcinomas. J Pathol 182(4):429\u2013436","journal-title":"J Pathol"},{"issue":"6","key":"3060_CR4","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1038\/labinvest.3700273","volume":"85","author":"M Saegusa","year":"2005","unstructured":"Saegusa M, Hashimura M, Kuwata T, Hamano M, Okayasu I (2005) Upregulation of TCF4 expression as a transcriptional target of beta-catenin\/p300 complexes during trans-differentiation of endometrial carcinoma cells. Lab Investig 85(6):768\u2013779","journal-title":"Lab Investig"},{"issue":"3","key":"3060_CR5","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1097\/PGP.0b013e31826129e1","volume":"32","author":"LZ Blanco Jr","year":"2013","unstructured":"Blanco LZ Jr, Heagley DE, Lee JC, Gown AM, Gattuso P, Rotmensch J, Guirguis A, Dewdney S, Bitterman P (2013 May) Immunohistochemical characterization of squamous differentiation and morular metaplasia in uterine endometrioid adenocarcinoma. Int J Gynecol Pathol 32(3):283\u2013292","journal-title":"Int J Gynecol Pathol"},{"issue":"5","key":"3060_CR6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1159\/000089421","volume":"72","author":"T Ueo","year":"2005","unstructured":"Ueo T, Kashima K, Daa T, Kondo Y, Sasaki A, Yokoyama S (2005) Immunohistochemical analysis of morules in colonic neoplasms: morules are morphologically and qualitatively different from squamous metaplasia. Pathobiology. 72(5):269\u2013278","journal-title":"Pathobiology."},{"issue":"9","key":"3060_CR7","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1136\/jcp.2004.017996","volume":"57","author":"K Chinen","year":"2004","unstructured":"Chinen K, Kamiyama K, Kinjo T, Arasaki A, Ihama Y, Hamada T, Iwamasa T (2004) Morules in endometrial carcinoma and benign endometrial lesions differ from squamous differentiation tissue and are not infected with human papillomavirus. J Clin Pathol 57(9):918\u2013926","journal-title":"J Clin Pathol"},{"issue":"5","key":"3060_CR8","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1097\/PGP.0000000000000544","volume":"38","author":"WG McCluggage","year":"2019","unstructured":"McCluggage WG, Van de Vijver K (2019) SATB2 is consistently expressed in squamous morules associated with endometrioid proliferative lesions and in the stroma of atypical polypoid adenomyoma. Int J Gynecol Pathol 38(5):397\u2013403","journal-title":"Int J Gynecol Pathol"},{"key":"3060_CR9","doi-asserted-by":"publisher","first-page":"153307","DOI":"10.1016\/j.prp.2020.153307","volume":"217","author":"A Travaglino","year":"2020","unstructured":"Travaglino A, Raffone A, Gencarelli A, Raimondo D, Moretta P, Pignatiello S, Granata M, Seracchioli R, Zullo F, Insabato L (2020) Relationship between morular metaplasia and squamous differentiation in endometrial carcinoma. Pathol Res Pract 217:153307. https:\/\/doi.org\/10.1016\/j.prp.2020.153307","journal-title":"Pathol Res Pract"},{"issue":"10","key":"3060_CR10","first-page":"13120","volume":"8","author":"T Nakamura","year":"2015","unstructured":"Nakamura T (2015) Shadow cell differentiation from squamoid morule in endometrial adenoacanthoma. Int J Clin Exp Pathol 8(10):13120\u201313124","journal-title":"Int J Clin Exp Pathol"},{"issue":"3","key":"3060_CR11","first-page":"123","volume":"51","author":"M Z\u00e1me\u010dn\u00edk","year":"2015","unstructured":"Z\u00e1me\u010dn\u00edk M, Barto\u0161 P, Ka\u0161\u010d\u00e1k P (2015) Shadow cell differentiation in endometrioid carcinomas of the uterus. Its frequent occurrence and beta-catenin expression. Cesk Patol 51(3):123\u2013126","journal-title":"Cesk Patol"},{"issue":"2","key":"3060_CR12","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1111\/j.1365-2559.2008.03083.x","volume":"53","author":"O Houghton","year":"2008","unstructured":"Houghton O, Connolly LE, McCluggage WG (2008) Morules in endometrioid proliferations of the uterus and ovary consistently express the intestinal transcription factor CDX2. Histopathology. 53(2):156\u2013165","journal-title":"Histopathology."},{"issue":"14 Pt 1","key":"3060_CR13","doi-asserted-by":"publisher","first-page":"4251","DOI":"10.1158\/1078-0432.CCR-06-0398","volume":"12","author":"S Chiarelli","year":"2006","unstructured":"Chiarelli S, Buritic\u00e1 C, Litta P, Ciani S, Guarch R, Nogales FF (2006) An immunohistochemical study of morules in endometrioid lesions of the female genital tract: CD10 is a characteristic marker of morular metaplasia. Clin Cancer Res 12(14 Pt 1):4251\u20134256","journal-title":"Clin Cancer Res"},{"issue":"2","key":"3060_CR14","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/modpathol.2008.146","volume":"22","author":"MC Lin","year":"2009","unstructured":"Lin MC, Lomo L, Baak JP et al (2009) Squamous morules are functionally inert elements of premalignant endometrial neoplasia. Mod Pathol 22(2):167\u2013174","journal-title":"Mod Pathol"},{"key":"3060_CR15","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1097\/PAI.0000000000000780","volume":"28","author":"A Travaglino","year":"2019","unstructured":"Travaglino A, Raffone A, Saccone G, Fuggi M, de Placido G, Mascolo M, Mollo A, Insabato L, Zullo F (2019) Immunophenotype of atypical polypoid adenomyoma of the uterus: diagnostic value and insight on pathogenesis. Appl Immunohistochem Mol Morphol 28:646\u2013653. https:\/\/doi.org\/10.1097\/PAI.0000000000000780","journal-title":"Appl Immunohistochem Mol Morphol"},{"issue":"5","key":"3060_CR16","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1309\/EALEG7LD6W7167PX","volume":"120","author":"AM Hassanein","year":"2003","unstructured":"Hassanein AM, Glanz SM, Kessler HP, Eskin TA, Liu C (2003) beta-Catenin is expressed aberrantly in tumors expressing shadow cells. Pilomatricoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol 120(5):732\u2013736","journal-title":"Am J Clin Pathol"},{"issue":"3","key":"3060_CR17","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1309\/WVTRR1DXYMC8PBMK","volume":"123","author":"K Kusama","year":"2005","unstructured":"Kusama K, Katayama Y, Oba K, Ishige T, Kebusa Y, Okazawa J, Fukushima T, Yoshino A (2005) Expression of hard alpha-keratins in pilomatrixoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol 123(3):376\u2013381","journal-title":"Am J Clin Pathol"},{"issue":"6","key":"3060_CR18","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1111\/j.1365-2559.2004.02029.x","volume":"45","author":"S Sekine","year":"2004","unstructured":"Sekine S, Takata T, Shibata T, Mori M, Morishita Y, Noguchi M, Uchida T, Kanai Y, Hirohashi S (2004) Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation. Histopathology. 45(6):573\u2013579","journal-title":"Histopathology."},{"issue":"5","key":"3060_CR19","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s00401-018-1830-2","volume":"135","author":"JR Apps","year":"2018","unstructured":"Apps JR, Carreno G, Gonzalez-Meljem JM, Haston S, Guiho R, Cooper JE, Manshaei S, Jani N, H\u00f6lsken A, Pettorini B, Beynon RJ, Simpson DM, Fraser HC, Hong Y, Hallang S, Stone TJ, Virasami A, Donson AM, Jones D, Aquilina K, Spoudeas H, Joshi AR, Grundy R, Storer LCD, Korbonits M, Hilton DA, Tossell K, Thavaraj S, Ungless MA, Gil J, Buslei R, Hankinson T, Hargrave D, Goding C, Andoniadou CL, Brogan P, Jacques TS, Williams HJ, Martinez-Barbera JP (2018) Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK\/ERK pathway as a novel therapeutic target. Acta Neuropathol 135(5):757\u2013777","journal-title":"Acta Neuropathol"},{"issue":"1","key":"3060_CR20","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s13046-017-0562-9","volume":"36","author":"E Guadagno","year":"2017","unstructured":"Guadagno E, de Divitiis O, Solari D, Borrelli G, Bracale UM, di Somma A, Cappabianca P, del Basso de Caro M (2017) Can recurrences be predicted in craniopharyngiomas? \u03b2-catenin coexisting with stem cells markers and p-ATM in a clinicopathologic study of 45cases. J Exp Clin Cancer Res 36(1):95","journal-title":"J Exp Clin Cancer Res"},{"issue":"3","key":"3060_CR21","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/j.1365-2559.2007.02911.x","volume":"52","author":"J Cameselle-Teijeiro","year":"2008","unstructured":"Cameselle-Teijeiro J, Alberte-Lista L, Chiarelli S, Buritic\u00e1 C, Gon\u00e7alves L, Gonz\u00e1lez-C\u00e1mpora R, Nogales FF (2008) CD10 is a characteristic marker of tumours forming morules with biotin-rich, optically clear nuclei that occur in different organs. Histopathology. 52(3):389\u2013392","journal-title":"Histopathology."},{"issue":"4","key":"3060_CR22","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1111\/jop.12234","volume":"44","author":"A Rumayor","year":"2015","unstructured":"Rumayor A, Carlos R, Kirsch HM, de Andrade BA, Roma\u00f1ach MJ, de Almeida OP (2015) Ghost cells in pilomatrixoma, craniopharyngioma, and calcifying cystic odontogenic tumor: histological, immunohistochemical, and ultrastructural study. J Oral Pathol Med 44(4):284\u2013290","journal-title":"J Oral Pathol Med"},{"issue":"2","key":"3060_CR23","first-page":"75","volume":"48","author":"J Schittenhelm","year":"2010","unstructured":"Schittenhelm J, Psaras T, Meyermann R, Honegger J, Beschorner R (2010) Pituitary adenomas and craniopharyngiomas are CDX2 negative neoplasms. Folia Neuropathol 48(2):75\u201380","journal-title":"Folia Neuropathol"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-021-03060-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-021-03060-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-021-03060-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T01:24:23Z","timestamp":1631928263000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-021-03060-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,5]]},"references-count":23,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["3060"],"URL":"https:\/\/doi.org\/10.1007\/s00428-021-03060-2","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,5]]},"assertion":[{"value":"24 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 January 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 February 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 March 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was based on retrospective analyses of routine archival formalin-fixed, paraffin-embedded tissue. All patients provided a routine written consent for the use of their biological specimen for research purpose at the time of surgery, in agreement with the Declaration of Helsinki and the indications of Italian Legislative Decrees no. 196\/03 and 101\/18 (Codex on Privacy). All data were anonymized.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}