{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:25:12Z","timestamp":1793157912991,"version":"4.5.0"},"reference-count":30,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Pituitary neuroendocrine tumour (PitNET)\/adenoma classification is based on cell lineage and requires immunopositivity for adenohypophysial hormones and\/or transcription factors (TFs) steroidogenic factor 1 (SF1), T\u2010box transcription factor TBX19 (TPIT) or pituitary\u2010specific positive transcription factor 1 (PIT1). PitNET\/adenomas lacking lineage affiliation are termed \u2018null cell\u2019 tumours (NCTs). NCT diagnosis may be afflicted by methodological limitations and inconsistent diagnostic approaches. Previous studies have questioned the existence of true NCTs. In this study, we explore the epigenomic identities of PitNET\/adenomas lacking clear TF immunopositivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Seventy\u2010four hormone\u2010negative PitNET\/adenomas were immunostained and scored for SF1, TPIT and PIT1 expression. All tumours were classified as gonadotroph, corticotroph, PIT1\u2010positive or \u2018null cell\u2019. NCTs were subjected to global DNA methylation analysis. Epigenomic profiles of NCTs were compared to reference tumours using Uniform Manifold Approximation and Projection (UMAP) plotting and methylation\u2010based classification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TF immunostaining revealed definite lineage identity in 59 of 74 (79.7%) hormone\u2010negative PitNET\/adenomas. Of the remaining 15 NCTs, 13 demonstrated minimal and inconclusive nuclear SF1 or TPIT expression (5 and 8, respectively). Two NCTs were entirely immunonegative. UMAP plotting and methylation\u2010based classification demonstrated that the epigenomes of NCTs with minimal SF1 or TPIT expression were adequately affiliated with gonadotroph or corticotroph lineages, respectively. The two immunonegative NCTs were located near the corticotroph PitNET\/adenomas via UMAP, whereas the methylation classifier could not match these two cases to predefined tumour classes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Epigenomic analyses substantiate lineage identification based on minimal TF immunopositivity in PitNET\/adenomas. This strategy dramatically decreases the incidence of NCTs and further challenges the legitimacy of NCTs as a distinct PitNET\/adenoma subtype. Our study may be useful for guiding diagnostic efforts and future considerations of PitNET\/adenoma classification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.12870","type":"journal-article","created":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T05:13:47Z","timestamp":1671254027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Unveiling the identities of null cell tumours: Epigenomics corroborate subtle histological cues in pituitary neuroendocrine tumour\/adenoma classification"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9769-7080","authenticated-orcid":false,"given":"Matthias","family":"Dottermusch","sequence":"first","affiliation":[{"name":"Institute of Neuropathology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-1121","authenticated-orcid":false,"given":"Ulrich","family":"Sch\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Department of Pediatric Hematology and Oncology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Research Institute Children's Cancer Center Hamburg  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hagel","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Saeger","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"Institute of Pathology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010017\u20101769\u20108"},{"key":"e_1_2_12_3_1","volume-title":"Endocrine and neuroendocrine tumours [internet]. 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