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Morphological Harbingers of ARMC5-Pathogenic Variant-Related Bilateral Macronodular Adrenocortical Disease

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Abstract

Bilateral macronodular adrenocortical disease (BMAD) is a neoplastic disease associated with a high frequency of germline disease. Armadillo repeat containing 5 (ARMC5) pathogenic variants (PVs) have not been widely studied to determine the morphological and immunohistochemical characteristics of BMAD. We carried out a detailed morphologic review of 22 surgical specimens excised from patients with BMAD and compared them with PV of ARMC5 (PV + , n = 14) and those without (PV − , n = 8), and further comparing them with a control group of adrenals excised from patients with renal cancer (n = 11). No patients presented with a genetic syndrome related to BMAD. Overt Cushing’s syndrome was present in 12/22 patients, 10 PV + and 2 PV − (p = 0.074). We also evaluated the expression of Ki-67, BCL-2, BAX, p53, CYP11B1, and ARMC5 protein. The pseudo-glandular and trabecular architectural patterns were strongly associated with the PV + group (both p < 0.001), as well as capsular extrusion (p < 0.001). There was no predictive value in the distinction of ARMC5 variants in Hsiao subtyping. ARMC5 diffuse cytoplasmic staining was observed in all 11 control samples. The ARMC5 expression was significantly lower in BMAD than in the control group (p < 0.001). In all the specimens, expression of BCL-2 was identified only in the medulla, and expression of BAX was observed in adrenocortical cells. CYP11B1 diffuse immunoexpression was identified in all the specimens of BMAD and in the fasciculata zone in the control group. The mitotic count and Ki-67 proliferation index was very low in all three groups (controls, PV + , and PV − BMAD). None of the specimens stained positive for the p53 protein. Although our series is limited, the presence of pseudo-glandular and/or trabecular patterns and capsular extrusion indicated the presence of pathogenic variants of ARMC5 in BMAD. The gland enlargement does not seem to be related to the increase of mitotic count or a higher proliferation index (Ki-67).

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Acknowledgements

We thank Dr. Maria Candida Barisson Villares Fragoso for providing clinical data; Dr. Sheila Friedrich Faraj for providing the adrenal samples used as control group; and Mrs. Angela Batista Gomes dos Santos for technical assistance with the immunostainings.

Funding

Financial support for this study was provided by the Fundação de Apoio a Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation; Grant no.2017/11495–1 and 2015/50192–9).

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Authors and Affiliations

  1. Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

    Maria Luiza Anhaia de Arruda Botelho, Karina Braga Ribeiro & Maria Claudia Nogueira Zerbini

  2. Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, LIM/42, São Paulo, SP, Brazil

    Mirian Yumie Nishi

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  1. Maria Luiza Anhaia de Arruda Botelho
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Contributions

Maria Luiza Anhaia de Arruda Botelho: conceptualization, methodology, acquisition, and interpretation of data and drafting the article; Mirian Yumie Nishi: molecular data acquisition, analysis, and interpretation; Karina Braga Ribeiro: statistical analyses and interpretation of data; Maria Claudia Nogueira Zerbini: conceptualization, funding acquisition, design of the study, methodology, analysis and interpretation of data, and review of draft. All authors reviewed the manuscript.

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Correspondence to Maria Luiza Anhaia de Arruda Botelho.

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This study was approved by the local research ethics committee: “Comitê de Ética em Pesquisa do Hospital das Clinicas da FMUSP” (Reference no. 15747). Written informed consent was obtained from all participating patients.

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de Arruda Botelho, M.L.A., Nishi, M.Y., Ribeiro, K.B. et al. Morphological Harbingers of ARMC5-Pathogenic Variant-Related Bilateral Macronodular Adrenocortical Disease. Endocr Pathol 34, 200–212 (2023). https://doi.org/10.1007/s12022-023-09761-5

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