Genetic and Molecular Insights into Aggressive Prolactinomas: A Literature Review

Introduction: Prolactinomas are the most prevalent subtype of pituitary adenomas, accounting for approximately 50% of all PA cases. While generally considered benign, a subset of prolactinomas exhibit atypical characteristics such as rapid growth, invasiveness, and resistance to standard treatment. Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening mass effect complications. The complexity of APRLs necessitates the development of new patient-tailored precision therapies. This approach requires a deep understanding of the underlying molecular abnormalities for accurate diagnosis, prognosis, and treatment. The aim of this study is to provide a comprehensive review of molecular abnormalities of APRLs, and corroborating tissue analysis findings with patients’ response to targeted therapies.

Methods: A total of 268 articles were obtained through a literature search conducted using PubMed and Cochrane Central Register of Controlled Trials libraries. We included case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs. Studies that lacked molecular characterization of the tumors were excluded. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as “aggressive” or “atypical.” The review was conducted according to the PRISMA guidelines.

Results: Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors(SSTR5) and EGFR were associated with increased invasiveness and higher proliferation activity. Regarding treatment, APRL showed limited responsiveness to dopamine agonist(DA) therapy. Moreover, APRL tends to recur even after surgical resection and demonstrates resistance to conventional radiotherapy approaches. Temozolomide has displayed promise as a pharmacological agent for treating APRL patients, particularly in tumors with low levels of MGMT expression. Studies have highlighted the effectiveness of SSTR5 ligands in achieving favorable response in APRL treatment, with patients experiencing a progression-free periods of up to 7 years. Concerning tyrosine kinase inhibitors (TKI), some cases of APRL with overexpressed human EGFR2 have led to receptor blockade trials, which have shown varying degrees of effectiveness. Given the relatively high expression of VEGF in APRL, anti-VEGF TKI have been explored as potential options for APRL. Subsequently, studies have established a connection between DA resistance and increased VEGF expression. Finally, immunotherapy has emerged as a promising avenue for APRL treatment. Both preclinical and clinical research has demonstrated that PD-1/PD-L1 blockade can enhance T cell antitumor responses. However, the direct impact of PD-L1 blockade on the progression of aggressive pituitary tumors remains a subject of ongoing debate.

Conclusion: APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
05 February 2024