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The issue is central to reconciling their shared phenotypic resemblance and protracted behavior with current pathologic classification. We conducted a transcriptomic analysis on a cohort of both pathologic forms and correlated the findings with the clinicopathologic features using RNA extracted from fresh frozen samples of 25 salivary basal tumors (five BCAs and 20 BCACs) and eight instances of metastatic basal cell carcinomas (BCCs) to parotid glands. Unsupervised analysis revealed shared and intertumoral transcriptome differences within and between BCA and BCAC and distinct segregation from metastatic dermal BCC. Transcriptomic profiling delineated two intermixed subgroups of salivary basal cell neoplasms (SBNs); SBN\u2010I group enriched with adverse pathologic features and SBN\u2010II that lacked any of these features except for a single case. The category with the most instances of adverse pathologic features (SBN\u2010I) manifested upregulations of transcriptional factors linked to cell proliferation pathways (<jats:italic>HOXB13<\/jats:italic>, <jats:italic>SOX21<\/jats:italic>, <jats:italic>MYB<\/jats:italic>, and <jats:italic>EN1<\/jats:italic> genes), while those lacking adverse pathologic features (SBN\u2010II) demonstrated a high expression of the <jats:italic>TFAP2B<\/jats:italic> transcription\u2010 and differentiation\u2010related pathways. Our transcriptomic findings support common neoplastic evolution and intertumoral heterogeneity of both pathologic forms of basal cell neoplasms and identify molecular pathways of potential biological and clinical significance. We therefore propose a nondeterministic designation of \u2018basal cell salivary neoplasms, noninvasive (adenoma)\/invasive (adenocarcinoma)\u2019 as a platform that integrates conventional phenotypic classification and transcriptomic characteristics pending a classification consensus. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6424","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T10:38:47Z","timestamp":1745491127000},"page":"258-267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative transcriptomics of salivary basal cell adenoma and adenocarcinoma sustain linear neoplastic evolution and intertumor heterogeneity: classification and biological implications"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8661-4702","authenticated-orcid":false,"given":"Yoshitsugu","family":"Mitani","sequence":"first","affiliation":[{"name":"Department of Pathology The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haneen","family":"Al\u2010Maghrabi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine King Faisal Specialist Hospital and Research Center  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana V","family":"Karpinets","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raissa T","family":"Relator","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Hilder","sequence":"additional","affiliation":[{"name":"Department of Pathology The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-2111","authenticated-orcid":false,"given":"Irene Y","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan P","family":"Goepfert","sequence":"additional","affiliation":[{"name":"Department of Head and Neck Surgery The University of Texas M.D. Anderson Cancer Center  Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Bell","sequence":"additional","affiliation":[{"name":"Department 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