Aggressive prolactinoma (APRL) is a subgroup of aggressive pituitary tumors (APTs) which represent a relatively new concept defined by three main features: tumor invasion based on radiological and/or histological features; a higher proliferation profile than usual pituitary adenomas (also called typical adenomas) and aggressive behavior such as rapidly developing resistance to standard medication/protocols and increased risk of early recurrence after surgical removal or after achieving transitory control under traditional medical therapy (1). APTs, representing around 10% of all pituitary tumors, require a complex multidisciplinary multimodal approach that may include: neurosurgery (numerous repeated procedures), radiotherapy, peptide receptor radionuclide therapy, combined medical therapy depending on secretory profile (such as cabergoline, pasireotide), but also uncommon medication as temozolomide (an alkylating agent) if standard regimes are inefficient (2).

Diagnosis of pituitary carcinoma (PC) is positive only if distant or cerebrospinal fluid metastases are identified (3). APTs and PC represents an atypical subcategory of pituitary tumors which otherwise usually display a more favorable profile, thus requiring a particular approach as pointed by 2018 ESE (European Society of Endocrinology) guideline (4).

Generally, prolactinoma is a subgroup of functioning pituitary adenomas (a category that also includes corticotropinoma, somatotropinoma, gonadotropinoma, and thyrotropinoma), knowing that the most frequent abnormal pituitary secretion is prolactin (between 47 and 66% of all secretor pituitary adenomas, depending on the studies) (5). Functioning and non-functioning hypophyseal adenomas represent 15% of all intra-cranial tumors, being considered one of the most frequent intra-cranial neoplasia (6). Their associated co-morbidities due to the tumor itself and due to hypersecretion/hyposecretion involve a relatively high rate of morbidity and mortality (7).

The clinical spectrum due to hyperprolactinemia of tumor origin varies from different manifestations of male/female hypogonadism, mammary anomalies such as galactorrhea up to osteoporosis and associated fractures and cardiovascular risk (8-10). In addition, prolactinomas of more than 1 cm in diameter up to giant prolactin-secreting tumors are associated with local mass effects as seen in other pituitary tumors, regardless of their secretor features (11). Some syndromic prolactinomas are synchronous or asynchronous with other non-pituitary tumors as seen in adrenal glands or parathyroids (12,13).

A total of 95% of all pituitary adenomas are sporadic, while germline mutations have been reported, for instance, multiple endocrine neoplasia type 1 (MEN1), aryl hydrocarbon receptor-interacting protein (AIP), and succinate dehydrogenase (SDHx) (14). AIP and MEN1 mutations are correlated with a diagnosis of patients younger than 30 years of age (or even 20 years); AIP mutation is mostly associated with gigantism and large tumors; Xq26.3 mutations are associated with pituitary tumors in very young children (15). Prolactinomas with underlying AIP mutations represent a small subset of tumors with a familial pattern which otherwise are typically growth hormone-producing tumors or non-functioning adenomas (16). Both AIP- and MEN1-related prolactinomas may be large and usually therapy resistant, especially AIP-associated prolactinomas, as similarly seen in somatotropinomas (17,18).

A complex multidisciplinary management may be require for pituitary adenomas since their first line of approach is surgical removal, except for prolactinomas which traditionally respond to medical therapy such as dopamine agonists (DAs) and also except for non-functioning microadenomas (usually named incidentalomas) that do not require a specific approach, only imaging follow-up (19-21).

We aimed to focus on APRL in terms of both presentation, but also management and associated prognostic factors (Fig. 1). This is a narrative review based on a PubMed search using key words, ‘aggressive prolactinoma’, ‘aggressive pituitary tumor’, and ‘pituitary carcinoma’. A number of 81 references are included from 2009 to 2021. Inclusion criteria included English language and full-length articles. Exclusion criteria included papers published before 2009.

Prolactinoma affects both females and males, having an incidence of 3-5 cases/100,000 individuals/year and a general prevalence of 50 cases/100,000 individuals which is higher in subjects with hypogonadism since increased prolactin levels induce central inhibition of gonadotropes through kisspeptin neurons (22). The detection of APRLs may not start from the clinical presentation itself, but the imaging detection of a large pituitary mass in addition to large mass-associated symptoms and signs and extremely elevated prolactin levels are important clues, further followed by a poor response to DA medication and need for neurosurgery/early relapse after hypophysectomy due to the unusual rapid growth (23). Generally, a patient with prolactinoma becomes a neurosurgery candidate in the event apoplexy or cystic transformation is present, neurological/ophthalmic deficit has been identified, and the patient develops DA resistance or intolerance (24).

Post-operative histological and immunohistochemistry reports provide additional elements of the aggressive profile in association with clinical outcome after removal. This can sometimes occur from the beginning even when the surgical procedure is for debulking purposes only (25).

Additional poor prognostic elements are represented by epigenetic data regarding APTs that demonstrate a high DNA methyltransferase overexpression, p53-related histone anomalies, and upregulation of citrullinating enzymes. Yet, currently research involving new predictive factors of aggressive behavior is still in progress (26). Sometimes the term ‘refractory’ pituitary adenoma is used as an open category of APT with high Ki-67, rapid growth and lack of response to a traditional guideline approach (25).

Overall, the cluster of elements used for evaluating the potential aggressive behavior starts with high prolactin levels at first admission and large diameter upon computed tomography or magnetic resonance imaging; yet these themselves do not necessarily indicate an APRL (27,28). If the patient is a male or there is an early age at diagnosis or a genetic predisposition is identified, the prognosis may be poor (27,29). Furthermore, the development of DA (mostly cabergoline) resistance represents another useful clue (27,30). Since the subject is referred to neurosurgery, the post-hypophysectomy histological report pointing out a mitotic count higher than 2 and a Ki-67 at least 3% is an indicator of increased proliferation risk. Yet, in the case that we analyze these characteristics apart from all other elements, these do not necessarily indicate an APRL (27,31). The evolution of prolactin levels and tumor size under multimodal therapy are also indicators of APRL (27,32).

Other indicators of poor prognosis may be provided by the assessment of E-cadherin, matrix metalloproteinase (MMP)-9, growth factors such as vascular endothelial growth factor (VEGF), and abnormal gene expression (AIP, MEN1, p53) or even breast cancer gene 1 (BRCA1) mutation has been described (27,33). At first glance, no single element of the features mentioned above is enough to reveal an APRL. This is a step by step process, while the clear difference between an adenoma and a carcinoma comes only with confirmation of metastases, not by just analyzing the pituitary tumor histology and immunohistochemistry (19,27).

Management of APRLs goes beyond the typical scenario of most prolactinoma cases that are not candidate to non-medical approach (34). In this particular situation, a complex team is eventually expected to be necessary, including approaches in neurosurgery, radiotherapy, and even oncology since the APRL profile is contoured step by step starting with the identification of a large invasive tumor and continuing to small changes in serum prolactin levels under DA (35). A total of 1-5% of prolactinomas are giant at presentation (a diameter larger than 4 cm), while most macro-prolactinomas have a diameter between 1 and 4 cm (36). DA is expected to induce tumor shrinkage and normalization of prolactin levels due to the abundant expression of type 2 dopamine receptors; yet 10-20% of prolactinomas are DA resistant (10% for cabergoline, respective 20-30% for bromocriptine; thus bromocriptine-resistance patients should be first switched to cabergoline with an 80% expected rate of response in most cases of prolactinomas) (37). APRLs are frequently resistant to traditional therapy with DA (mainly cabergoline); DA resistance is also seen in familial forms prolactinomas with underlying AIP or MEN1 mutations (38). In patients younger than 20 years, DA resistance is correlated with high serum levels of prolactin at first presentation and increased tumor diameter in addition to AIP/MEN1 mutations which represent an independent predictor factor for the poor rate of DA response, accounting for 14% of all cases with suboptimal evolution under DA (39). DA resistance is an essential feature of APRLs, but, on the other hand, not all DA-resistant prolactinomas are actually APRLs (40,41). According to current opinions, DA resistance means the lack of achieving normal prolactin levels and at least 30% reduction in the maximum diameter under high cabergoline doses (at least 3.5 mg/week) (40,41). The most useful clinical element of response is restoration of gonadal axe function. Usually lifelong administration of cabergoline is necessary in responsive cases since stopping the medication is associated with a 60-80% relapse rate (42).

Subjects with DA resistance become candidates for hypophysectomy and some experts consider that early recognition of patients who are DA non-responsive improves the success of the neurosurgical procedure due to tumor-associated fibrosis which is a direct contributor to incomplete resection (43-45). Retrospective post-surgery studies have shown that a value of Ki-67 of more than 3% is associated with a higher risk of resistance to medication and post-operatory relapse; however, Ki-67 is not the only useful indicator and this isolated value itself is subject to controversy regarding APRL prognosis (44,45). In cases with persistent or progressive disease after surgery or if only debulking surgery is feasible, DA should be re-considered in addition to irradiation therapy, preferable gamma knife (46).

Radiotherapy for pituitary tumors is useful if other medical and surgical procedures do not control the condition; the risk of hypopituitarism is high and in certain circumstances the risk of a secondary brain tumor should be taken into account (47). Some authors suggest that radiation therapy applied for invasive prolactinomas that are non-responsive to surgery and DA may be a promotor of distant metastases, thus subscribing to a PC profile, but this aspect is still a matter of debate (48).

Temozolomide, an active chemotherapy drug, represents a fourth-line therapy in prolactinomas after DA, transphenoidal selective hypophysectomy and radiotherapy (49). A specific time frame for its introduction into the patient regime varies, but prompt intervention is recommended (50). As pointed by the 2018 ESE guideline, temozolomide as a single medication is the first-line medical therapy after specific standard therapies have failed; 3 cycles are needed in order to decide if the patient is a responder, in which case therapy is prolonged for 6 months (4). However, following this article, controversies emerged at temozolomide withdrawn since an efficient fifth-line therapy (or second-line treatment) after temozolomide is still lacking and re-starting the same medication usually fails to achieve a relevant clinical and imaging response. Thus, the length of the therapy may go up to 12 cycles in many studies and even up to 14-59 cycles if it is well tolerated (a cycle means a daily oral dose of 50-200 mg/sqm, 5 out of 28 days) (51). Prolonged administration is under consideration in many cases despite guidelines based on an individual multidisciplinary decision (52).

Almalki et al described rates of response following temozolomide therapy as following: 76% of patients with tumor reduction, 75% with serum prolactin level reduction, 8% with normalization of prolactin, and a failure rate of 20.6% of subjects (53). It seems that APRLs had a higher rate of response to temozolomide than corticotropinomas (60%) and somatotropinomas (26.7%) (54). The assay of O(6)-methylguanine-DNA methyltransferase (MGMT) status may serve as a surrogate to anticipate the temozolomide response rate (50).

As mentioned, APRL is part of a syndromic combination similar to that seen in MEN1 syndrome, and in this particular circumstance the aggressive profile cannot be predicted by a specific gene mutation configuration itself but by a constellation of factors. However, the presence of other tumors such as associated neuroendocrine neoplasia of the pancreas or adrenals are direct contributors to a more severe overall prognosis (55,56).

Once temozolomide is inefficient or it is not tolerated by a patient with APRLs, the therapeutic options are extremely limited (57). A few cases of prolactinomas, respective corticotropinomas with very aggressive profile have been recently reported as candidates for new drugs such as checkpoint inhibitors (ipilimumab, nivolumab) after temozolomide has failed to control the APT (58). The ErbB pathway is newly detected as correlated with aggressive profile of prolactinoma and DA resistance in APRL; thus, therapy with lapatinib, an oral tyrosine kinase inhibitor (TKI) targeting ErbB1-epidermal growth factor receptor (EGFR) is under evaluation, already being included in Phase 2a clinical trials (59). Somatostatin analogue therapy for APRLs has demonstrated promising results, as well as its use in DA-resistant prolactinomas which are not APRLs (60-62). If a pituitary neuroendocrine tumor with prolactin production has somatostatin receptor (SSTR) expression, especially type 5 more than type 2, pasireotide long-acting release (LAR) (40 mg per month) may be beneficial (61,62).

Of course, a mixed secretion of both prolactin and growth hormone is associated with a better response to somatostatin analogues (63). In APRLs, cystic transformation and tumor necrosis have been reported under pasireotide LAR (64). Pasireotide, outside the fact that it represents a second-line medical therapy in acromegaly, is also used in Cushing disease and some pancreatic neuroendocrine neoplasia (65,66). In addition, isolated case reports have introduced pasireotide as an alternative to prolactinomas that are resistant to standard therapies, not necessarily APRLs (67). The use of SSTR immunostaining after neurosurgery may predict a potential response to this class of drugs, as currently being used in acromegaly treatment (68-70).

Moreover, estrogen modulators and metformin have been suggested for APRLs, but the findings still require statistical validation since the current level of evidence is low (60). The mammalian target of rapamycin (mTOR) inhibitor, everolimus, was applied as an off-label therapy in one case of APRL in combination with cabergoline and the results were encouraging (71). Generally, everolimus has been approved for pancreatic neuroendocrine neoplasia also in combination with somatostatin analogues including ocreotide or lanreotide (72,73). The mTOR pathway is involved in the development of tumors derived from pituitary cells through intervention of the pituitary tumor transforming gene (PTTG1) (74). The observation is consistent for GH-secreting tumors as well (75). Murine experiments suggest that inhibition of the mTOR pathway may increase the cytotoxicity induced by temozolomide (76). The use of temozolomide for APTs dates since 2006, and it is generally considered to be well tolerated (the most common side effects are nausea, fatigue, different types of cytopenia) (77). It is usually recommended for treating brain cancers such as glioblastoma (78,79).

APRLs represent a challenging condition that requires a multimodal approach; in addition to a standard three-line therapy, temozolomide medication is required.