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Except for 4 cases, all branchiomas described in the literature were benign. Recently, <jats:italic>HRAS<\/jats:italic> mutation was detected in one case, but still little is known about the molecular genetic background of this rare entity. We herein report the histological, immunohistochemical, and molecular genetic analysis of a branchioma with a nested\/organoid (neuroendocrine-like) morphology in a 78-year-old man. Histology revealed classical branchioma areas merging with nested\/organoid cellular component lacking conventional features of malignancy. Immunohistochemistry was positive for high-molecular-weight cytokeratins. CD34 was expressed in the spindle cell component. Moreover, the tumor cells showed near-complete loss of retinoblastoma (RB1) expression (&lt;1% of cells positive). All neuroendocrine markers (synaptophysin, chromogranin, and INSM1) were negative. Next-generation sequencing (TSO500 Panel) revealed 5 pathogenic\/likely pathogenic mutations including 1 mutation in <jats:italic>KRAS<\/jats:italic> and 2 different mutations in each of <jats:italic>MSH6<\/jats:italic> and <jats:italic>PTEN.<\/jats:italic> FISH and DNA sequencing were negative for <jats:italic>RB1<\/jats:italic> gene alterations. To our knowledge, this is the first report of a branchioma showing misleading nested\/organoid morphology and the first report on Rb1 immunodeficiency in this entity, in addition to multiple gene mutations revealed by NGS.<\/jats:p>","DOI":"10.1007\/s00428-023-03592-9","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T13:05:00Z","timestamp":1688994300000},"page":"541-548","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Branchioma with a nested\/organoid morphology: molecular profiling of a distinctive potentially misleading variant and reappraisal of potential relationship to CD34-positive\/Rb1-deficient tumors of the neck"],"prefix":"10.1007","volume":"483","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-5572","authenticated-orcid":false,"given":"Martina","family":"Ban\u011b\u010dkov\u00e1","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Michal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Van\u011b\u010dek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitar Had\u017ei","family":"Nikolov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radek","family":"V\u010del\u00e1k","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radim","family":"\u017dalud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Michal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abbas","family":"Agaimy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"3592_CR1","first-page":"11776","volume":"8","author":"H Jing","year":"2015","unstructured":"Jing H, Wang J, Wei H et al (2015) Ectopic hamartomatous thymoma: report of a case and review of literature Int J. 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