Peripheral leukocyte profiles in different clinical forms of hypercortisolism and nonfunctioning adrenal tumors: a retrospective cross-sectional study

Chronic cortisol excess exerts well-characterized immunomodulatory effects on peripheral leukocyte populations. Whether mild autonomous cortisol secretion (MACS) induces measurable hematological alterations comparable to overt Cushing syndrome (CS) remains incompletely understood. This single-center retrospective cross-sectional study included 252 patients: 132 with overt CS (75 Cushing disease, 57 adrenal CS), 68 with MACS, and 52 with nonfunctioning adrenal tumor (NFAT). We compared white blood cell (WBC)-derived parameters across groups, including neutrophil, monocyte, lymphocyte, eosinophil, and basophil counts; neutrophil-to-lymphocyte ratio (NLR); and monocyte-to-lymphocyte ratio (MLR). Exploratory linear discriminant analysis (LDA) was performed to characterize multivariate leukocyte profiles across CD, adrenal CS, MACS, and NFAT. Total WBC, neutrophil count, monocyte count, and MLR were significantly higher in overt CS than in both MACS and NFAT (all p ≤ 0.002), whereas NLR was significantly higher only compared with MACS after Bonferroni correction. Conversely, no significant differences were observed between MACS and NFAT on individual parameters (all p > 0.05); effect sizes were uniformly small (Cohen’s d = 0.02–0.17), suggesting that any difference between MACS and NFAT is likely small, although subtle effects cannot be excluded. Neutrophil count, monocyte count, NLR, and MLR correlated positively with multiple biochemical cortisol markers. Exploratory LDA showed basophil count as the parameter with the highest normalized loading on the primary discriminant axis, but this finding may partly reflect a scale-related statistical artifact rather than a biological signal. Overt CS was associated with a myeloid expansion profile that correlated with biochemical markers of cortisol excess and was not observed in MACS or NFAT. Exploratory multivariate profiling showed modest, non-validated classification performance; these findings are hypothesis-generating and should not be interpreted as evidence of a validated diagnostic tool or a pathophysiological continuum.