Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: a Comprehensive Analysis of the Literature
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Review Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature Authors Ramazan Sari1, 8, Meric A. Altinoz2 , Eylem Burcu Kahraman Ozlu1, Aydin Sav3, Ayca Ersen Danyeli4, Ozdil Baskan5, Ozlem Er6, Ilhan Elmaci1, 7 Affiliations AbsTraCT 1 Department of Neurosurgery, Acibadem Hospital, Despite most of the prolactinomas can be treated with endo- Maslak, Istanbul, Turkey crine therapy and/or surgery, a significant percentage of these 2 Department of Biochemistry, Acibadem University, tumors can be resistant to endocrine treatments and/or recur Istanbul, Turkey with prominent invasion into the surrounding anatomical 3 Department of Pathology, Yeditepe University, Istanbul, structures. Hence, clinical, pathological, and molecular defini- Turkey tions of aggressive prolactinomas are important to guide for 4 Department of Pathology, Acibadem Mehmet Ali classical and novel treatment modalities. In this review, we Aydinlar University, School of Medicine, Istanbul, Turkey aimed to define molecular endocrinological features of dopa- 5 Department of Radiology, Memorial Hospital, Istanbul, mine agonist-resistant and aggressive prolactinomas for de- Turkey signing future multimodality treatments. Besides surgery, te- 6 Department of Medical Oncology, Acibadem Mehmet Ali mozolomide chemotherapy and radiotherapy, peptide receptor Aydinlar University, School of Medicine, Istanbul, Turkey radionuclide therapy, estrogen pathway modulators, proges- 7 Department of Neurosurgery, Acibadem Mehmet Ali terone antagonists or agonists, mTOR/akt inhibitors, pasireo- Aydinlar University, School of Medicine, Istanbul, Turkey tide, gefitinib/lapatinib, everolimus, and metformin are tested 8 Avrasya University, Health Sciences Faculty, Trabzon, in preclinical models, anecdotal cases, and in small case series. Turkey Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future tar- Key words gets for managing aggressive prolactinomas. Lastly, we dis- prolactinoma, aggressive, invasive, malignant, molecular cussed our management of a unique prolactinoma case by endocrinology asking which tumors’ proliferative index (Ki67) increased from 5–6 % to 26 % in two subsequent surgeries performed in a received 27.01.2021 2-year period, exerted massive invasive growth, and secreted accepted after revision 27.05.2021 huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood. Bibliography Horm Metab Res 2021; 53: 413–424 DOI 10.1055/a-1525-2131 ISSN 0018-5043 © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG, Rüdigerstraße 14, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 70469 Stuttgart, Germany Correspondence Professor Ilhan Elmaci M.D. Acibadem Maslak Hospital Sariyer Istanbul Turkey Tel.: + 90 536 2018327, Fax: + 90 536 2018327 [email protected] Sari R et al. Aggressive and Invasive Prolactinomas … Horm Metab Res 2021; 53: 413–424 | © 2021. Thieme. All rights reserved. 413 Review Introduction are meager, and even if resected, larger prolactinomas tend to Approximately 10–15 % of all manifest intracranial tumors origi- recur [2]. Here, data regarding molecular endocrinology of treat- nate from the hypophysis (pituitary gland) [1]. Prolactinomas are ment resistant and aggressive prolactinomas are reviewed. Prol- benign neoplasms (adenoma) that produce prolactin [2]. Prolactin actinomas developing at a young age are correlated to higher pro- can be secreted by various pituitary neuroendocrine tumors deriv- liferation and invasion. Other features, including the expression of ing either from somatotrophs or mammo-somatotroph cells be- growth factors such as VEGF (vascular endothelial growth factor) sides the lactotroph cells [3]. Similarly, densely or sparsely granu- and EGF (epidermal growth factor), adhesion molecules (E-cadher- lated lactotroph tumors, poorly differentiated Pit1-lineage tumors in), the genes regulating proliferation, invasion and differentiation, and acidophil stem cell tumors can also cause hyperprolactinemia matrix metalloproteinase 9, and chromosome abnormalities (chro- [3]. Prolactinomas – originating from lactotroph cells – are the mosomes 1, 11, and 19) also correlate with aggressiveness [4]. most frequently hormone-secreting pituitary tumors (approxi- mately 30–40 % of all pituitary tumors), and its prevalence is about 94 per 100 000 inhabitants [2]. Prolactinomas are much more fre- Evidence Acquisition and Synthesis quently diagnosed in female population with a sex ratio around To obtain data on the pathogenesis and treatment of aggressive 10:1 before the fifth decade, but after this age, the prolactinoma prolactinomas, the following keywords were searched in PubMed frequency is about the same in both gender [3]. This shows that fe- database: prolactinoma AND (invasive OR aggressive OR malig- male hormones may propagate prolactinoma growth; and indeed, nant) AND (chemotherapy OR radiotherapy OR molecular OR gene there exist substantial evidence supporting this hypothesis, which OR genetic), which yielded 2288 results (Last Check: 11th May, will be discussed below. But seemingly paradoxical at the first 2021). Based on the obtained results from PubMed data search, we glance, prolactinomas appearing in boys, at a young age ( < 20 mostly focused on molecular endocrinological features of these tu- years), and/or with accompaniment of a genetic predisposition mors since they are clinically targetable. The role of conventional have worse prognosis [4]. The most frequent clinical signs of pro- treatments including temozolomide chemotherapy and radiother- lactinomas are gonadal and sexual dysfunction and subsequent in- apy is also analyzed. At first, we will define the entities of “invasive”, fertility in both sexes [2]. Dopamine agonists, such as bromocrip- “aggressive” and “malignant” prolactinomas and pituitary carci- tine and cabergoline, are employed for treatment in prolactinomas nomas, their anatomical spread mechanisms and conventional since prolactinomas express high levels of dopamine receptors treatment modalities. Then, we will discuss molecular endocrino- (D2R) [2]. When the patients cannot tolerate dopamine agonists logical features of these tumors as potential treatment targets. or are refractory to medical therapy, they undergo surgical treat- ment and/or radiotherapy [5, 6]. Ten to 15 % of patients are resist- Are the Invasive Prolactinomas, Aggressive ant to medical treatment. Twenty-five percent of the patients re- Prolactinomas, Malignant Prolactinomas, and ceiving bromocriptine treatment fail to normalize prolactin where- Pituitary Carcinomas Different Entities? Anatomy as it is only 10–15 % in those receiving cabergoline [6]. Almost half and Immunohistopathology of tumor volume reduction is encountered in 33 % percent of those Invasive prolactinomas are prolactin secreting tumors invading ad- receiving bromocriptine and 10–15 % of those treated with caber- jacent anatomical structures, while aggressivity determines not goline [6]. Resistance to cabergoline is defined by the absence of only the invasion but also medical treatment-resistance and high prolactin normalization or lack of the tumor to reduce in size by tendency for recurrence. It is recommended the term “aggressive” 50 %, and these refractory prolactinomas tend to exert higher an- should not be used synonymously with “invasive” as aggressivity giogenesis, cell proliferation and atypia and invasiveness [5]. Quina- encompasses a broader biologically ominious behavior including golide is a non-ergot-derived D2R-selective agonist, which could drug resistance and occasionally atypical histology besides inva- provide significant reduction in tumor size and prolactin levels in siveness [5]. In general, invasiveness is mostly a radiological and around 90 % of patients [3]. Quinagolide is usually given at the av- aggressiveness a clinical definition [7]. Invasive prolactinomas are erage dose of 150 – 300 μg/day and compared to bromocriptine, tumors with proven invasion into adjacent structures, including more prominent reduction in dizziness, nausea, vomiting, and cavernous and sphenoid sinuses and bony structures, which can be This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. drowsiness is generally witnessed [3]. defined radiologically with preoperative MR investigations, during Most patients who respond well to dopamine agonists with re- operation, or with histopathological demonstration of tumor duction of prolactin levels exert evident decreases in tumor vol- spread to the bone, dura, or nasal mucosa [7]. A relatively recent umes, but not all do. On the contrary, some patients may experi- study demonstrated that prolactinomas constitute most invasive ence almost total reductions in tumor volumes unaccompanied pituitary tumors [7]. In our index case, which will be discussed with normalizing prolactin levels [6]. Resistance mechanisms in- below, extensive cavernous sinus, prepontine area and pontocer- clude lowered D2R (dopamine receptor D2) gene transcription, ebellar edge invasion and encasement of internal carotid artery, lowered receptor activity which regulate D2R expression, and low- CV, CVII, and CVIII nerves were detected. According to World ered inhibitory G protein-expression which couples the D2R to ade- Health Organization’s (WHO) recent criteria (2016), increased mi- nylyl cyclase [5, 6]. Prolactinomas are