Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs.
Humans
Cushing Syndrome
Neuroendocrine Tumors
Pro-Opiomelanocortin
/ genetics
Pheochromocytoma
Pituitary Neoplasms
/ pathology
Pituitary Diseases
Pituitary Gland
/ pathology
Lung Neoplasms
/ metabolism
Carcinoma, Neuroendocrine
Pancreas
/ pathology
Adrenal Gland Neoplasms
Adrenocorticotropic Hormone
/ metabolism
ACTH
ACTH-secreting neuroendocrine tumor
Ectopic ACTH secretion
Ectopic Cushing syndrome
Lung neuroendocrine tumor
Pancreatic neuroendocrine tumor
TPIT
Journal
Virchows Archiv : an international journal of pathology
ISSN: 1432-2307
Titre abrégé: Virchows Arch
Pays: Germany
ID NLM: 9423843
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
11
08
2023
accepted:
01
09
2023
revised:
30
08
2023
medline:
27
11
2023
pubmed:
20
9
2023
entrez:
19
9
2023
Statut:
ppublish
Résumé
Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data are currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. Forty-one extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs), and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs, and the two pheochromocytomas were CS-associated. For comparison, 6 NETs of the pituitary gland (PitNETs; 3 ACTH-secreting and 3 ACTH-negative) and 35 ACTH-negative extra-pituitary NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real-time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extra-pituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.
Identifiants
pubmed: 37726450
doi: 10.1007/s00428-023-03642-2
pii: 10.1007/s00428-023-03642-2
doi:
Substances chimiques
Pro-Opiomelanocortin
66796-54-1
Adrenocorticotropic Hormone
9002-60-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
635-643Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, Drouin J (2001) A pituitary cell-restricted T box factor, TPIT, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104:849–859. https://doi.org/10.1016/s0092-8674(01)00282-3
doi: 10.1016/s0092-8674(01)00282-3
pubmed: 11290323
Vallette-Kasic S, Figarella-Branger D, Grino M, Pulichino AM, Dufour H, Grisoli F, Enjalbert A, Drouin J, Brue T (2003) Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs. J Clin Endocrinol Metab 88:3050–3056. https://doi.org/10.1210/jc.2002-021934
doi: 10.1210/jc.2002-021934
pubmed: 12843142
Villa C, Vasiljevic A, Jaffrain-Rea ML, Ansorge O, Asioli S, Barresi V, Chinezu L, Gardiman MP, Lania A, Lapshina AM, Poliani L, Reiniger L, Righi A, Saeger W, Soukup J, Theodoropoulou M, Uccella S, Trouillas J, Roncaroli F (2019) A standardised diagnostic approach to pituitary neuroendocrine tumours (PitNETs): a European Pituitary Pathology Group (EPPG) proposal. Virchows Arch 475:687–692. https://doi.org/10.1007/s00428-019-02655-0 . (Epub 2019 Oct 2)
doi: 10.1007/s00428-019-02655-0
pubmed: 31578606
Asa SL, Mete O, Cusimano MD et al (2021) Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification. Mod Pathol 34:1634–1650. https://doi.org/10.1038/s41379-021-00820-y
doi: 10.1038/s41379-021-00820-y
pubmed: 34017065
Asa SL, Mete O, Perry A, Osamura RY (2022) Overview of the 2022 WHO classification of pituitary tumors. Endocr Pathol 33:6–26. https://doi.org/10.1007/s12022-022-09703-7
doi: 10.1007/s12022-022-09703-7
pubmed: 35291028
Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A (2020) Management of endocrine disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol 182:R29–R58. https://doi.org/10.1530/EJE-19-0877
doi: 10.1530/EJE-19-0877
pubmed: 31999619
Kasajima A, Pfarr N, von Werder A, Schwamborn K, Gschwend J, Din NU, Esposito I, Weichert W, Pavel M, Agaimy A, Klöppel G (2023) Renal neuroendocrine tumors: clinical and molecular pathology with an emphasis on frequent association with ectopic Cushing syndrome. Virchows Arch Jul 5. https://doi.org/10.1007/s00428-023-03596-5 . Epub ahead of print.
Drummond J, Roncaroli F, Grossman AB, Korbonits M (2019) Clinical and pathological aspects of silent pituitary adenomas. J Clin Endocrinol Metab 104:2473–2489. https://doi.org/10.1210/jc.2018-00688
doi: 10.1210/jc.2018-00688
pubmed: 30020466
La Rosa S, Volante M, Uccella S, Maragliano R, Rapa I, Rotolo N, Inzani F, Siciliani A, Granone P, Rindi G, Dominioni L, Capella C, Papotti M, Sessa F, Imperatori A (2019) ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature. Virchows Arch 475:587–597. https://doi.org/10.1007/s00428-019-02612-x
doi: 10.1007/s00428-019-02612-x
pubmed: 31264037
Araki T, Liu NA, Tone Y, Cuevas-Ramos D, Heltsley R, Tone M, Melmed S (2016) E2F1-mediated human POMC expression in ectopic Cushing’s syndrome. Endocr Relat Cancer 23:857–870. https://doi.org/10.1530/ERC-16-0206
doi: 10.1530/ERC-16-0206
pubmed: 27935805
pmcid: 5152695
Maragliano R, Vanoli A, Albarello L, Milione M, Basturk O, Klimstra DS, Wachtel A, Uccella S, Vicari E, Milesi M, Davì MV, Scarpa A, Sessa F, Capella C, La Rosa S (2015) ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol 39:374–382. https://doi.org/10.1097/PAS.0000000000000340
doi: 10.1097/PAS.0000000000000340
pubmed: 25353285
Ben-Shlomo A, Cooper O (2018) Silent corticotroph adenomas. Pituitary 21:183–193
doi: 10.1007/s11102-018-0864-8
pubmed: 29344907
Uccella S, Cerutti R, Vigetti D, Furlan D, Oldrini R, Carnevali I, Pelosi G, La Rosa S, Passi A, Capella C (2006) Histidine decarboxylase, DOPA decarboxylase, and vesicular monoamine transporter 2 expression in neuroendocrine tumors: immunohistochemical study and gene expression analysis. J Histochem Cytochem 54:863–875. https://doi.org/10.1369/jhc.5A6770.2006
doi: 10.1369/jhc.5A6770.2006
pubmed: 16517981
Araki T, Tone Y, Yamamoto M, Kameda H, Ben-Shlomo A, Yamada S, Takeshita A, Yamamoto M, Kawakami Y, Tone M, Melmed S (2021) Two distinctive POMC promoters modify gene expression in Cushing disease. J Clin Endocrinol Metab 106:e3346–e3363. https://doi.org/10.1210/clinem/dgab387
doi: 10.1210/clinem/dgab387
pubmed: 34061962
pmcid: 8372657
Araki T, Wang J, Lawrence R, Kawakami Y (2022) Aberrant nuclear translocation of E2F1 and its association in Cushing’s disease. Endocrinology 163:bqac086. https://doi.org/10.1210/endocr/bqac086
doi: 10.1210/endocr/bqac086
pubmed: 35678423
pmcid: 9246279
Agaimy A, Kasajima A, Stoehr R, Haller F, Schubart C, Tögel L, Pfarr N, von Werder A, Pavel ME, Sessa F, Uccella S, La Rosa S, Klöppel G (2023) Gene fusions are frequent in ACTH-secreting neuroendocrine neoplasms of the pancreas, but not in their non-pancreatic counterparts. Virchows Arch 482:507–516. https://doi.org/10.1007/s00428-022-03484-4
doi: 10.1007/s00428-022-03484-4
pubmed: 36690805
pmcid: 10033480
Elliott PF, Berhane T, Ragnarsson O, Falhammar H (2021) Ectopic ACTH- and/or CRH-producing pheochromocytomas. J Clin Endocrinol Metab 106:598–608. https://doi.org/10.1210/clinem/dgaa488
doi: 10.1210/clinem/dgaa488
pubmed: 32710791