From Resistant to Aggressive and Malignant Prolactinomas: A Translational Approach

Review Article

J Endocr Disord. 2014;1(3): 1012.

From Resistant to Aggressive and Malignant Prolactinomas: A Translational Approach

Jaffrain-Rea ML*

Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli and Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Italy

*Corresponding author: Jaffrain-Rea ML, Neuroendocrinology, Neuromed Institute, IRCCS, ViaAtinense 18, 86077 Pozzilli, Italy

Received: September 08, 2014; Accepted: October 08, 2014; Published: October 10, 2014


Prolactinomas are the most frequent pituitary adenomas. Most are successfully treated with Dopamine-Agonists (DA) and Cabergoline (CAB) is recommended as a first line therapeutic option. However, up to 20% may present primary or secondary DA/CAB resistance. Primary resistance is more frequent in macro- and/or invasive prolactinomas, in males and in the presence of inherited genetic predisposition to pituitary adenomas. Secondary resistance develops during follow-up, possibly indicating a change in tumour behaviour. Whereas partial resistance can be frequently overcome by increasing the weekly CAB dose above the labelled dose, severe resistance is typically associated with more aggressive features, often requiring a multimodal approach. Surgery may be indicated to improve neurological symptoms, before pregnancy, or to reduce pharmacological requirement. Because highly aggressive and malignant prolactinomas are life-threatening diseases, a panel of clinical, pathological and molecular features may be considered in order to achieve an early diagnosis and plan an adeguate follow-up and treatment. In addition to surgery and/or radiotherapy, Temozolomide (TMZ) currently represents the best option for highly aggressive/malignant prolactinomas. However, up to 30-40% of these tumours may not respond satisfactorily to TMZ and require innovative and personalized therapeutic approaches, such as molecular or radionuclide therapies targeted upon further characterization of the tumour. Increasing knowledge about the pathways involved in severe DA resistance and the aggressive behaviour of prolactinomas should help improve the clinical outcome of such patients.

Keywords: Prolactinoma; Dopamine-Agonists; Pharmacological resistance; Pituitary carcinoma; Target therapy


Prolactinomas are the most frequent Pituitary Adenomas (PA) and a large majority are successfully treated with Dopamine-Agonists (DA), in particular Cabergoline (CAB), which has become the first line drug due its excellent efficacy and tolerability [1]. However, a minority develop aggressive features, which may be present at diagnosis or develop during follow-up. Resistance to DA is more frequent in invasive prolactinomas. Aggressive prolactinomas represent an ill-defined group of invasive tumours characterized by uncontrolled growth/recurrences and increasing Prolactin (PRL) secretion despite increasing doses of DA, often requiring repeated surgery and/or radiotherapy. Malignant prolactinomas are defined by the presence of metastasis and are typically resistant to high dose DA. The large majority of them arise from invasive macroprolactinomas and, until the last decade, their outcome was poor despite multimodal approaches including conventional chemotherapy [2,3]. The introduction of Temozolomide (TMZ) has greatly improved the treatment of aggressive and malignant prolactinomas, rapidly becoming the first line chemotherapy in these patients [1,4,5]. Based on increasing knowledge about abnormal pathways involved the pathogenesis of aggressive/malignant prolactinomas, molecular target therapies represent promising additional tools [4,5]. The aim of this review is to summarize current knowledge and prospective views on this challenging topic, with special reference to the frequent relationship obseved between DA resistance and aggressive behaviour in prolactinomas.

Definition and Epidemiology

The prevalence of prolactinomas has been variably appreciated in the literature, due to variations in diagnostic criteria and recruitement bias. Since 2006, case-finding studies have reported an overall clinical prevalence of PA around 1/1000 inhabitants, with prolactinomas accounting for 57-66% [6-8]. Among these, about 20% were macroprolactinomas (maximal diameter > 10 mm). A minority of prolactinomas (1-4%) are giant (> 40 mm) [9,10]. Athough prolactinomas are particularly frequent in young females, the male-to-female ratio increases with age (1:1 after the age of 50). Macro- and giant prolactinomas are more frequent in males, regardless of patient’s age [11]. Prolactinomas should not be missed in the perimenopausal age as they can present later as large tumours [12-14]. Because of the relationship between tumour volume and PRL secretion in prolactinomas [11], huge tumours are typically associated with very high PRL levels, which may be missed in sandwich immunometric assays unless the serum is appropriately diluted (e.g. 1:100). This so-called “hook effect” [15] should be considered in all patients with large pituitary tumours, regardless of age and gender, in order to avoid unappropriate surgical approaches.

The prevalence of aggressive prolactinomas has not been specifically adressed, probably due to the absence of specific diagnostic criteria and the frequent need for a sufficient follow-up to disclose tumour aggressiveness. For example, giant prolactinomas have reached a sufficiently aggressive potential at diagnosis to grow outside the sella and invade surrounding structures. However, most of them are slowly growing and will respond to DA, with PRL normalization in 60-80% and significant tumour shrinkage since the first weeks/monthsof treatment [9,10]. These latter cases may therefore exit the subgroup of clinically aggressive/challenging prolactinomas. In contrast, a subset of prolactinomas will show an aggressive, uncontrolled growth despite increasing doses of DA/ CAB and seldom evolve towards malignancy. The large majority of them present as macroprolactinomas. We found 77/92 prolactinomas resistant to standard doses of CAB to be macroadenomas at diagnosis (83.7%), out of which 15 were giant [16]. Overall, 7.6% developed highly aggressive or malignant features, 4.8% died from neurological complications or metastasis [16]. Thus, in clinical practice, resistance to DA may be a stronger negative prognostic factor than initial macroscopic characteristics and severe DA resistance is a serious concern.

Pathological and molecular markers are being searched for in order to optimize the early identification and treatment of aggressive prolactinomas, hopefully reducing in the future the risk of uncontrolled growth or malignant evolution. The WHO 2004 classification defined as “atypical adenomas” a subset of PA characterized by active proliferation (Ki67 >3%, high mitotic activity), p53 immunoreactivity and cellular atypia [17]. Atypical prolactinomas may represent 2.9- 11% of surgically treated cases [18,19]. The prognostic value of this classification was recently investigated [20], confirming a higher rate of recurrence in atypical PA. However, atypical PA are largely represented by invasive macroadenomas [19,20], which are the most likely to recur. A recent classification also takes into account the presence of invasive characteristics, defined by pre- and intra-operative criteria [21]. With a mean post-operative follow-up of 8 years, this model showed that in prolactinomas, the presence of invasive features dramatically increased the risk of recurrence, with proliferative characteristics alone being associated with a mild increase only [21]. Limits in the use of Ki67 and p53 consist of tumour heterogeneity and methodological issues which may contribute to apparently conflicting data on their clinical significance. However, high Ki67 values with convincing p53 immunostaining are sufficiently negative prognostic factors to deserve special clinical attention [4,5,22]. An unresolved issue remains the impact of pre-operative DA, which induces significant morphological changes in prolactinomas [23], on such parameters. Due to the anti-proliferative effects of DA, lower Ki67 values can be observed in treated patients [24,25], thoughthis has not been unequivocally reported [18,25]. This may reflect differences in DA sensitivity, since higher Ki67 values were found in bromocriptine-resistant tumours [26]. Therefore, a medium/high proliferative activity is likely to have a stronger negative prognostic value in prolactinomas treated with DA before surgery than in untreated cases.

Pituitary carcinomas are defined by the presence of histologically proven metastatic dissemination in the Central Nervous Sytem (CNS) or outside the CNS and represent< 0.4% of pituitary tumours [2-4]. No pathological feature is specific of pituitary carcinomas at the primary site [2-5]. More than 30% of pituitary carcinomas are PRL-secreting [2], with a mean time interval between the diagnosis of prolactinoma and metastasis around 7 years and large individual variations (1 month-20 years) [27]. Up to 40% of malignant prolactinomas initially present as atypical adenomas, but active proliferation and pleomorphism are inconstant even in metastatic tissues [27]. Metastasis may be suspected in the presence of unexplained raising PRL levels or local compression symptoms, in particular for cranio-spinal localisations [2-4,27], or be revealed by incidental imaging or at autopsy. Diagnostic pitfalls are mainly represented by co-existing solid tumours of extra-pituitary origin. Although pituitary carcinomas are increasingly reported, it is likely that in the absence of a gold standard technique for advanced functional imaging, able to detect metastases at an early stage, their prevalence remains underestimated. Scintigraphywith isotopic ligands of the dopamine receptor D2R such as 123I-IBZM and 123I-epidepride, can be used [27-29], although it may not be sensitive enough in the presence of poor D2R expression [29,30]. Alternatively, somatostatin receptor imaging [31] and Positron Emission Tomography (PET) for D2R (11C-raclopride) and markers of metabolic activity (11C-L-methionine, 18F-fluorodeoxyglucose/FGD) [32] may be proposed. Except for 18F-FDG, these techniques are poorly available and there is limited experience in malignant prolactinomas [27,33].


The pathogenesis of PA is a complex multistep and multifactorial process, which includes early initiating events, growth promotion by a variety of extracellular growth factors, abnormal transduction and proliferative pathways [34,35]. Genetic and epigenetic events may be involved in the initiation of PA and contribute to tumour progression, invasiveness and exceptionally metastasis. These include gene promoter methylation, histone modifications and an anbormal expression of non-coding RNAs, in particular microRNAs [34,35].

Most prolactinomas are believed to arise from the sparsely granulated PRL-secreting cells, which actively release PRL, rather than from the densely granulated cells, considered as resting storage cells [36]. Indeed, densely granulated prolactinomas are rare [18,37]. A minority may also arise from GH/PRL-secreting cells [36,37], which is clinically relevant since it may impact tumour treatment and patient management. Hence, mixed GH/PRL-secreting adenomas should be recognized even in the absence of typical signs and symptoms of GH/IGF1 hypersecretion, especially in macroadenomas. Elucidating the molecular mechanisms of tumorigenesis in prolactinomas is hampered by their first line pharmacological approach, which not only limits the amount of samples available for molecular studies but potentially represents a con founding factor. Nonetheless, a subset of somatic alterations and abnormal signalling have long been reported in prolactinomas [36,38,39]. The development of powerful methodological approaches (genomics/epigenomics/ transcriptomics), able to explore hundred of genes simultaneously, has become an essential tool for the identification of new players in prolactinoma pathogenesis [40-44]. Because these studies are performed on a limited number of cases (including single tumours or pooled samples), results must then be validated by studies of gene/ protein expression on larger series. Elucidating the biological role of candidate genes/proteins may be challenging. Prolactinomas are characterized by a very low rate of progression from microadenomas (< 10 mm) to macroadenomas, suggesting the presence of differential molecular mechanisms since an early stage of tumour development. Recent evidence for a pituitary niche of stem cells in the adult pituitary raises the possibility of tumour formation from incompletely differentiated cells, with a a more aggressive potential than tumour arising from mature cells [45]. This would also explain considerable overlap between pathways involved in tumour aggressiveness and in DA resistance. Interestingly, some developmental signaling molecules are overexpressed in prolactinomas (e.g.BMP4, Notch3) [Table 1], Alternatively, progressive tumour de-dedifferentiation may occur. Most prolactinomas are believed to be monoclonal in origin but somatic initiating events are poorly understood. Animal models represent essential tools to unravel the capacity of single gene abnormalities to drive prolactinoma pathogenesis [46,47]. In human prolactinomas, multiple somatic abnormalities have been reported, none of which being identified as an initiating event. Among cytogenetic abnormalities, trisomies involving chromosome 5,8 and 12 have been observed [48] and their molecular implications are being increasingly unravelled. For example, polysomy of chromosome 12, as well as rearrangements in 12q14-15, contribute to the frequent overexpression of the HMGA2 oncogene in prolactinomas [47] which may in turn be responsible for Pit-1 upregulation [36,43,49]. Among the several abnormalities in chromosome 11 reported in PA, allelic loss in 11p and in 11q were observed in aggressive and malignant prolactinomas, respectively, with transcriptomic and proteomic analysis identifying a subgroup of dysregulated genes in 11p [50]. Allelic loss of the whole chromosome 11 was reported in aggressive and malignant prolactinomas [33]. In contrast, classical somatic mutations of oncogenes and inactivating mutations of Tumor Suppressor Genes (TSGs) are rare [36,38,39]. Recently, H-Ras and PIK3CA mutations have been reported in invasive prolactinomas [51] and an activating GNAS1 mutation (Gsp)was found in an aggressive prolactinoma shifting to a mixed GH/PRL-secreting tumour [52]. Rather, overexpression of oncogenic proteins and/or downregulation of TSGs occur [Table 1], with accumulating evidence for underlying epigenetic changes [34,35]. This may translate into the identification of immunohistochemical markers of aggressiveness, as proposed for nuclear PTTG [42] or strong galectin-3immunostaining [53]. A set of prognostic biomarkers have been proposed [54], though they may not invariably apply to all functional phenotypes. Increased apoptosis has been reported in invasive/aggressive and especially in malignant prolactinomas [54,55].

Citation: Jaffrain-Rea ML. From Resistant to Aggressive and Malignant Prolactinomas: A Translational Approach. J Endocr Disord. 2014;1(3): 1012. ISSN:2376-0133