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Impact of Morphology in the Genotype and Phenotype Correlation of Bilateral Macronodular Adrenocortical Disease (BMAD): A Series of Clinicopathologically Well-Characterized 35 Cases

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Abstract

Bilateral macronodular adrenocortical disease (BMAD) is characterized by the development of adrenal macronodules resulting in a pituitary-ACTH independent Cushing’s syndrome. Although there are important similarities observed between the rare microscopic descriptions of this disease, the small series published are not representative of the molecular and genetic heterogenicity recently described in BMAD. We analyzed the pathological features in a series of BMAD and determined if there is correlation between these criteria and the characteristics of the patients. Two pathologists reviewed the slides of 35 patients who underwent surgery for suspicion of BMAD in our center between 1998 and 2021. An unsupervised multiple factor analysis based on microscopic characteristics divided the cases into 4 subtypes according to the architecture of the macronodules (containing or not round fibrous septa) and the proportion of the different cell types: clear, eosinophilic compact, and oncocytic cells. The correlation study with genetic revealed subtype 1 and subtype 2 are associated with the presence of ARMC5 and KDM1A pathogenic variants, respectively. By immunohistochemistry, all cell types expressed CYP11B1 and HSD3B1. HSD3B2 staining was predominantly expressed by clear cells whereas CYP17A1 staining was predominant on compact eosinophilic cells. This partial expression of steroidogenic enzymes may explain the low efficiency of cortisol production in BMAD. In subtype 1, trabeculae of eosinophilic cylindrical cells expressed DAB2 but not CYP11B2. In subtype 2, KDM1A expression was weaker in nodule cells than in normal adrenal cells; alpha inhibin expression was strong in compact cells. This first microscopic description of a series of 35 BMAD reveals the existence of 4 histopathological subtypes, 2 of which are strongly correlated with the presence of known germline genetic alterations. This classification emphasizes that BMAD has heterogeneous pathological characteristics that correlate with some genetic alterations identified in patients.

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Acknowledgements

The authors would like to thank all the members of the department of pathology, Cochin Hospital, Paris, France, for their precious technical support.

Funding

This work was supported by the Fondation pour la Recherche Médicale (EQU201903007854) and by the Agence Nationale de la Recherche (18-CE14-0008–01). FV and LB received a fellowship from ARC (association de recherche contre le cancer) foundation and from the CARPEM (Cancer research for personalized medicine). FV received a fellowship from FIRENDO (Filière maladies rares endocriniennes).

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  1. Université Paris-Cité, Institut Cochin, CNRS UMR8104, Inserm U1016, Paris, France

    Florian Violon, Lucas Bouys, Annabel Berthon, Bruno Ragazzon, Maxime Barat, Karine Perlemoine, Jérôme Bertherat & Mathilde Sibony

  2. Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

    Lucas Bouys, Laurence Guignat & Jérôme Bertherat

  3. Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France

    Florian Violon, Benoit Terris & Mathilde Sibony

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F.V. and M.S. wrote the main manuscript text. F.V. L.B. M.B. and M.S. collected the data. All authors reviewed the manuscript.

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Correspondence to Jérôme Bertherat or Mathilde Sibony.

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All patients gave their written consent for research purposes including genetic analysis in the national COMETE network. This project was approved as a monocentric retrospective study by the data protection office (bureau de la protection des données, registre d’enregistrement AP-HP) (number 20220221155734) and the CLEP, (comité local d’éthique des publications de l’hôpital Cochin) (number AAA-2022–08019). It complies with the principles of the declaration of Helsinki.

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Violon, F., Bouys, L., Berthon, A. et al. Impact of Morphology in the Genotype and Phenotype Correlation of Bilateral Macronodular Adrenocortical Disease (BMAD): A Series of Clinicopathologically Well-Characterized 35 Cases. Endocr Pathol 34, 179–199 (2023). https://doi.org/10.1007/s12022-023-09751-7

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  • DOI: https://doi.org/10.1007/s12022-023-09751-7

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