Prolactinoma

ContextThe improved remission and complication rates of current transsphenoidal surgery warrant reappraisal of the position of surgery as a viable alternative to dopamine agonists in the treatment algorithm of prolactinomas.ObjectiveTo compare clinical outcomes after dopamine agonist withdrawal and transsphenoidal surgery in prolactinoma patients.MethodsEight databases were searched up to July 13, 2018. Primary outcome was disease remission after drug withdrawal or surgery. Secondary outcomes were biochemical control and side effects during dopamine agonist treatment and postoperative complications. Fixed- or random-effects meta-analysis was performed to estimate pooled proportions. Robustness of results was assessed by sensitivity analyses.ResultsA total of 1469 articles were screened: 55 (10 low risk of bias) on medical treatment (n = 3564 patients) and 25 (12 low risk of bias) on transsphenoidal surgery (n = 1836 patients). Long-term disease remission after dopamine agonist withdrawal was 34% (95% confidence interval [CI], 26-46) and 67% (95% CI, 60-74) after surgery. Subgroup analysis of microprolactinomas showed 36% (95% CI, 21-52) disease remission after dopamine agonist withdrawal, and 83% (95% CI, 76-90) after surgery. Biochemical control was achieved in 81% (95% CI, 75-87) of patients during dopamine agonists with side effects in 26% (95% CI, 13-41). Transsphenoidal surgery resulted in 0% mortality, 2% (95% CI, 0-5) permanent diabetes insipidus, and 3% (95% CI, 2-5) cerebrospinal fluid leakage. Multiple sensitivity analyses yielded similar results.ConclusionsIn the majority of prolactinoma patients, disease remission can be achieved through surgery, with low risks of long-term surgical complications, and disease remission is less often achieved with dopamine agonists.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.

PurposeAs consensus regarding outcome sets for prolactinoma treatment evaluation is lacking, this study evaluated outcome parameters reported in the literature, and objective, clinically relevant outcome sets were proposed.MethodsA systematic review of studies up to February 2, 2024. Reported biochemical and radiological parameters; clinician-reported findings; patient-reported outcomes (PROs); and definitions of disease remission, control, and recurrence were extracted and placed into a clinical context. Subsequently, objective and clinically relevant definitions of clinical outcomes were proposed based on the findings, with comprehensive outcome sets to evaluate treatment success.ResultsOne hundred thirty-seven articles were included. Albeit ill-defined or subjective, 23 unique prolactin parameters and 73 unique radiological parameters were reported. Seventy articles included clinician-reported findings, and none reported PROs. Ultimately, 27 unique definitions of remission, 3 unique definitions of disease control, and 20 unique definitions of recurrence were reported. We propose 2 separate definitions for biochemical and clinical remission/recurrence-either evaluating prolactin levels only or including symptomology, gonadal function, and radiology. Integrated outcome quadrants were illustrated to objectively categorize treatment success by combining achievement of treatment goals with the occurrence of adverse effects. A 3-tier outcome set based on the Value-Based Healthcare principles is provided.ConclusionHeterogeneity in reported outcome parameters using varying definitions hampers the comparison of prolactinoma treatment outcomes. This study proposes objective, easily applicable, and clinically relevant definitions of clinical outcomes and offers a comprehensive outcome set. These parameters enable comparison of outcomes across treatment modalities and medical centers to gain insight into this rare disease and improve prolactinoma care.