Prolactinomas and Knosp grade: when is surgery the appropriate choice? A systematic review and meta-analysis

Prolactinomas are the most common type of pituitary adenoma. Historically, surgery was the primary treatment, but the introduction of dopaminergic agonists in the 1970s changed therapeutic practices. Recent guidelines (2023) from the Pituitary Society now recommend surgery as the first-line option for select prolactinomas, particularly those with certain grades as defined by the Knosp classification system. This systematic review and meta-analysis was performed to evaluate the safety of and the biochemical remission rates following resection of prolactinomas classified preoperatively by Knosp grade.

A comprehensive literature search was conducted across the MEDLINE (via PubMed), Scopus, Web of Science, LILACS (Latin American and Caribbean Literature on Health Sciences), and Cochrane CENTRAL (Central Register of Controlled Trials) databases from inception to February 2024. Eligible studies reported individual participant data on the biochemical remission and surgical outcomes of patients with prolactinomas stratified by Knosp grade. A random effects meta-analysis was performed to synthesize biochemical remission rates and relative risks, with results presented in forest plots. Subgroup analyses were conducted according to Knosp grade, heterogeneity was assessed using the I2 statistic, prediction intervals were reported, and publication bias was evaluated through funnel plots and Egger's test. This review was registered in the International Prospective Register of Systematic Reviews (registration no.: CRD42024602904) and followed the PRISMA guidelines.

Twelve studies involving 1010 patients with prolactinomas undergoing transsphenoidal surgery were included. Prolactinomas classified as Knosp grades 0-2 demonstrated significantly higher biochemical remission rates of 75% (95% CI 67%-82%, prediction interval 42%-96%, I2 = 81.5%, p < 0.0001) compared to 22% (95% CI 16%-31%, prediction interval 11%-38%, I2 = 17.2%, p = 0.57) for Knosp grades 3-4. Transsphenoidal surgery was associated with favorable outcomes characterized by low complication rates and no reported deaths.

Resection for Knosp grade 0-2 prolactinomas appears to be an effective first-line treatment option, resulting in favorable biochemical remission rates and low complication risks. These findings support considering surgery in appropriately selected patients, particularly at experienced medical centers. However, the high heterogeneity among and the observational design of most included studies limit the strength of the conclusions. Thus, further studies are needed to compare surgical and medical management strategies across Knosp grades and to refine patient selection.