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In recent years, several studies have elucidated the mutational landscape of BCL, which may also serve as a complementary diagnostic tool. We have developed a custom next-generation sequencing panel for application in the routine diagnosis of BCL based on available literature and our diagnostic questions. We applied this panel to 160 cases of BCL or with this differential diagnosis (DD) in our routine workflow to gain further diagnostic support or on clinical request. Evaluable results were obtained in all but two cases of the entire cohort. Diagnostically informative molecular genetic profiles were identified in 72% of the evaluable cases. Focusing on 21 challenging cases with the DD of Burkitt lymphoma (BL) and the germinal center B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL), we detected at least one mutation in all cases, and in 18\/21 (86%) cases, panel sequencing provided significant decision guidance. In conclusion, although morphology and immunohistochemistry remain the backbone of diagnosis, panel sequencing provided substantial diagnostic assistance in many cases. It has been particularly useful in providing additional arguments to clarify the clinically important DD between BL and DLBCL in challenging cases.<\/jats:p>","DOI":"10.1007\/s00428-026-04428-y","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T02:52:51Z","timestamp":1770173571000},"page":"751-760","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted panel sequencing for refining B-cell lymphoma diagnosis: a real-life, reference center experience"],"prefix":"10.1007","volume":"488","author":[{"given":"Julia","family":"B\u00f6ck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Maurus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Doll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Br\u00e4ndlein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunpei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin S.","family":"Kurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"German","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Anagnostopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rosenwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Zam\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2134-2774","authenticated-orcid":false,"given":"Elena","family":"Gerhard-Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"4428_CR1","unstructured":"WHO (2024) Classification of Tumours Editorial Board. 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