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Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs

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Abstract

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.

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Data availability statement: all data are available upon request to the corresponding author.

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Authors and Affiliations

  1. Pathology Unit, Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy

    Silvia Uccella

  2. Pathology Service, Humanitas Clinical and Research Center - IRCCS, Via Manzoni 56, 20089, Rozzano, Milan, Italy

    Silvia Uccella

  3. Pathology Service, ASST Valle Olona, Busto Arsizio, Varese, Italy

    Eleonora Leoni

  4. Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

    Simon Kaiser & Dario Diviani

  5. Pathology Unit, Department of Oncology, ASST Sette Laghi, Varese, Italy

    Roberta Maragliano & Stefano La Rosa

  6. Microbiology Laboratory, ASST Sette Laghi, Varese, Italy

    Alessandro Valerio

  7. Pathology Unit, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy

    Laura Libera & Stefano La Rosa

  8. Endocrinology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy

    Maria Laura Tanda

  9. Department of Oncology, University of Turin, Orbassano, Italy

    Marco Volante

Authors
  1. Silvia Uccella
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  2. Eleonora Leoni
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  8. Marco Volante
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Contributions

SU designed and coordinated the study, interpreted the results, and drafted the manuscript; EL designed the study, performed and interpreted the experiments, and revised the manuscript; SK, RM, AV, and LL performed and interpreted the experiments and revised the manuscript; MLT provided clinical data about the patients and revised the manuscript; MV and DD interpreted the results and revised the manuscript; SLR designed the study, interpreted the results, and revised the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Silvia Uccella.

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Ethical approval

This study was performed according to the clinical standards of the 1975 and 1983 Declaration of Helsinki and was approved by the Ethical Committee of the ASST dei Sette Laghi, Varese, Italy.

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The authors declare no competing interests.

The authors declare that the submitted work is original and has not been published or submitted elsewhere in any form or language (partially or in full).

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Uccella, S., Leoni, E., Kaiser, S. et al. Heterogeneity of TPIT expression in ACTH-secreting extra-pituitary neuroendocrine tumors (NETs) supports the existence of different cellular programs in pancreatic and pulmonary NETs. Virchows Arch 483, 635–643 (2023). https://doi.org/10.1007/s00428-023-03642-2

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