The diagnostic value of prolactin adjustment in bilateral inferior petrosal sinus sampling for differentiating Cushing's disease from the ectopic ACTH syndrome: a systematic review and meta-analysis

Background Adrenocorticotropin (ACTH)-dependent Cushing's syndrome can arise from a pituitary tumour (Cushing's disease) or an ectopic ACTH-secreting tumour, making precise differentiation essential for effective treatment. Bilateral inferior petrosal sinus sampling (BIPSS) is the gold standard for this differentiation, but false-negative results can limit its accuracy. Adding prolactin (PRL) measurement to BIPSS has been proposed to improve diagnostic precision. This meta-analysis evaluates how correction for prolactin levels ('prolactin adjustment') affects the diagnostic value of BIPSS in distinguishing Cushing's disease from ectopic ACTH syndrome. Methods A systematic literature search was conducted in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar up to July 2024. Studies were included if they provided data on BIPSS with and without PRL adjustment for ACTH-dependent Cushing's syndrome. Data extraction and quality assessment were performed, and diagnostic accuracy metrics were analysed using bivariate generalised linear mixed modelling. Results A total of 10 studies with 310 participants were included. The pooled sensitivity and specificity of BIPSS with PRL adjustment were 0.96 (95% CI: 0.93-0.98) and 0.68 (95% CI: 0.52-0.81), respectively. The diagnostic odds ratio (DOR) was 48.0 (95% CI: 19.0-123.0), with a positive likelihood ratio (LR) of 3.00 (95% CI: 1.9-4.7) and a negative LR of 0.06 (95% CI: 0.03-0.12). The area under the summary receiver operating characteristic (SROC) curve was 0.95 (95% CI: 0.93-0.97). For BIPSS without PRL adjustment, the pooled sensitivity was 0.90 (95% CI: 0.86-0.93) and specificity was 0.74 (95% CI: 0.59-0.85), with a DOR of 27.0 (95% CI: 13.0-59.0). The SROC curve area was 0.92 (95% CI: 0.89-0.94). Prolactin adjustment improved sensitivity (P < 0.01) without a significant change in specificity (P = 0.13). Conclusions Prolactin adjustment in BIPSS slightly improves sensitivity for diagnosing Cushing's disease but does not enhance specificity for ectopic ACTH syndrome. This highlights the value of PRL measurement in improving diagnostic accuracy and reducing false negatives, while BIPSS remains crucial for ruling out EAS in clinical practice.