Introduction: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome. It is characterized by the development of supracentimetric nodules resulting in increased adrenal volume and weight. Its presentation is clinically, radiologically and biologically heterogeneous. Morphological descriptions of PBMAH are rare. Although the initial description highlights that multinodular hyperplastic adrenal glands are made of a majority of spongiocytic cells with some eosinophilic cell isles, later descriptions based on a few cases only, did not mention any morphological variation. The identification of inactivating pathogenic variants of ARMC5 in 2013 and of KDM1A in 2021, argues for a genetic heterogeneity. This work aimed to describe the microscopic characteristics of a series of PBMAH and determine if morphological heterogeneity might correlate with the genetic profile.
Methods: 35 PBMAH patients operated by adrenalectomy at Cochin Hospital between 1998 and 2021 whose genetic status was known. All slides were reviewed by two independent pathologists, without knowledge of the patients genetics. Immunohistochemistry included DAB2, HSD3, Cyp17 and inhibin. DNA sequencing on multiple nodules from 25 of these patients was performed by Illumina NGS.
Results: Four morphological subtypes are identified: two subtypes with nodular architecture (with nodules within macronodules) referred as subtype 1 and 2, and two subtypes with few nodules: subtype 3 and 4. Subtype 1 consists of a majority of spongiocytic cells and eosinophilic cells (1030%) that forms isles or bands. Subtype 2 has a higher proportion of eosinophilic cells (>30%), mixed with spongiocytic cells. Subtype 3 is composed mostly of spongiocytic cells with less than 10% eosinophilic cells. Subtype 4 is composed of numerous (>40%) oncocytic cells. Their immunohistochemical profile is also heterogeneous. NGS identifies somatic events in ARMC5 and KDM1A mutated patients. The study of correlations between morphological data and genetic status showed that 14 out of the 17 patients classified in subtype 1 are harboring pathogenic variant in ARMC5gene whereas the subtype 2 is exclusively composed of 4 KDM1A mutated tissues. Subtypes 3 and 4 are seen in patients without known mutation. These correlations are statistically significant: P < 0.0001 (Fisher test).
Conclusion: The study of this series allowed us to propose four different morphological groups, in favor of a histopathological heterogeneity. Two of these subtypes correlated with the presence of specific germline mutations. The anatomopathological examination of PBMAH based on architectural analysis and cell quantification represents an advance in the classification of adult nodular adrenal hyperplasia.
21 May 2022 - 24 May 2022