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Despite most of the prolactinomas can be treated with endocrine therapyand/or surgery, a significant percentage of these tumors can beresistant to endocrine treatments and/or recur with prominent invasioninto the surrounding anatomical structures. Hence, clinical, pathological, andmolecular definitions of aggressive prolactinomas are important to guide forclassical and novel treatment modalities. In this review, we aimed to definemolecular endocrinological features of dopamine agonist-resistant and aggressiveprolactinomas for designing future multimodality treatments. Besides surgery,temozolomide chemotherapy and radiotherapy, peptide receptor radionuclidetherapy, estrogen pathway modulators, progesterone antagonists or agonists,mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib,everolimus, and metformin are tested in preclinical models, anecdotal cases, andin small case series. Moreover, chorionic gonadotropin, gonadotropin releasinghormone, TGFβ and PRDM2 may seem like possible future targets formanaging aggressive prolactinomas. Lastly, we discussed our management of aunique prolactinoma case by asking which tumors’ proliferative index(Ki67) increased from 5–6% to 26% in two subsequentsurgeries performed in a 2-year period, exerted massive invasive growth, andsecreted huge levels of prolactin leading up to levels of 1 605671 ng/dl in blood.

Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature