Table 3

 Histopathological and molecular features of adrenal Cushing

Primary adrenocortical hyperplasia
Macronodular hyperplasiaMicronodular hyperplasia
Morphological featuresWell-circumscribed tumour composed of pale lipid-rich and compact cells, with uniform nucleiOften invasive tumour composed of cells with increased mitosisNon-pigmented macronodules (>1 cm) composed of pale lipid-rich cells with admixed compact cellsMicronodules (<1 cm) composed of compact eosinophilic cells; pigment seen typically in PPNAD is secondary to lipofuscin storage
PathogenesisExcess cAMP/PKA and Wnt/β-catenin signalling; GPCRs*Excess Wnt/β-catenin, growth factor (IGF2) and p53/Rb signalling; chromatin remodelling alterationsGPCRs, tumour suppressor gene(s), intra-adrenal ACTH; excess cAMP/PKA and Wnt/β-catenin signallingExcess cAMP/PKA signallingExcess cAMP/PKA signallingExcess cAMP/PKA signalling
Associated somatic alterationsPRKACA, GNAS1, CTNBB1, PRKAR1A, PDE8B, GPCRs*CTNBB1, ZNRF3, IGF2, TP53, RB1, CDKN2A, MEN1DAXX, MED12, TERT, INHA, PRKAR1AGPCRs*, MC2RGNAS1 (postzygotic mutation in MAS)Not definedPDE11A, PDE8B
Associated germline alterationsMEN1, APC, FHTP53, IGF2, MEN1, APC, NF1, MMRARMC5, MEN1, APC, FH,GPCRs, PDE11ANot definedPRKAR1A, CNC2 locus PDE11A, PDE8B, 2p12-p16; 5qPDE11A, PDE8B
Associated genetic syndromesMEN1, FAP, MAS, CNC†, Carney triad†, HLRCS†LFS, BWS, MEN1, FAP, CNC†, NF1†, Lynch syndrome†, RTS*MEN1, FAP, HLRCS†MASCNCNot 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.