Histopathological and molecular features of adrenal Cushing
| Primary adrenocortical hyperplasia | ||||||
|---|---|---|---|---|---|---|
| Macronodular hyperplasia | Micronodular hyperplasia | |||||
| Adenoma | Carcinoma | BMAH | c-BMAH | PPNAD | MAD | |
| Morphological features | Well-circumscribed tumour composed of pale lipid-rich and compact cells, with uniform nuclei | Often invasive tumour composed of cells with increased mitosis | Non-pigmented macronodules (>1 cm) composed of pale lipid-rich cells with admixed compact cells | Micronodules (<1 cm) composed of compact eosinophilic cells; pigment seen typically in PPNAD is secondary to lipofuscin storage | ||
| Pathogenesis | Excess cAMP/PKA and Wnt/β-catenin signalling; GPCRs* | Excess Wnt/β-catenin, growth factor (IGF2) and p53/Rb signalling; chromatin remodelling alterations | GPCRs, tumour suppressor gene(s), intra-adrenal ACTH; excess cAMP/PKA and Wnt/β-catenin signalling | Excess cAMP/PKA signalling | Excess cAMP/PKA signalling | Excess cAMP/PKA signalling |
| Associated somatic alterations | PRKACA, GNAS1, CTNBB1, PRKAR1A†, PDE8B†, GPCRs* | CTNBB1, ZNRF3, IGF2, TP53, RB1†, CDKN2A†, MEN1† DAXX†, MED12†, TERT†, INHA†, PRKAR1A† | GPCRs*, MC2R† | GNAS1 (postzygotic mutation in MAS) | Not defined | PDE11A‡, PDE8B‡ |
| Associated germline alterations | MEN1, APC, FH† | TP53, IGF2, MEN1, APC, NF1†, MMR† | ARMC5, MEN1, APC, FH†,GPCRs†, PDE11A‡ | Not defined | PRKAR1A, CNC2 locus PDE11A‡, PDE8B‡, 2p12-p16; 5q | PDE11A‡, PDE8B‡ |
| Associated genetic syndromes | MEN1, FAP, MAS, CNC†, Carney triad†, HLRCS† | LFS, BWS, MEN1, FAP, CNC†, NF1†, Lynch syndrome†, RTS* | MEN1, FAP, HLRCS† | MAS | CNC | Not defined |
*Indicates unclear causative gene.
†Indicates rare occurrence.
‡Evidence indicates unclear inheritance pattern in some reports.
ACTH, plasma corticotropin concentration; BMAH, bilateral macronodular adrenocortical hyperplasia; BWS, Beckwith-Wiedemann syndrome; c-BMAH, childhood BMAH; CNC, Carney complex; FAP, familial adenomatous polyposis syndrome; GPCRs, aberrant G-protein-coupled receptors; HLRCS, hereditary leiomyomatosis and renal cancer syndrome; IGF2, insulin-like growth factor 2; LFS, Li-Fraumeni syndrome; MAD, non-pigmented micronodular adrenocortical disease; MAS, McCune-Alright syndrome; MEN1, multiple endocrine neoplasia type 1 syndrome; NF1, neurofibromatosis type I; PKA, protein kinase A; PPNAD, primary pigmented nodular adrenocortical disease; Rb, retinoblastoma; RTS, Rubinstein-Taybi syndrome.