Introduction

Non-functioning pituitary adenomas (NFPA) comprise a heterogeneous group of lesions, most of gonadotroph origin [1], characterized by the absence of clinical or biochemical evidence of tumor-related hormone excess. NFPA include some silent tumors, which synthesize hormones but do not secrete them, the most prevalent of which are those expressing ACTH [2]. In null cell adenomas, specific lineage of origin can be traced by antibodies to transcription factors [3, 4].

Primary treatment: surgery

NFPA usually present with symptoms secondary to mass effect on surrounding tissues, including headaches, visual dysfunction, cranial nerve palsy, and hypopituitarism [5]. In such cases, surgery is the treatment of choice as it rapidly achieves decompression and symptom amelioration [6–10]. Most NFPA are invasive macroadenomas, such that full resection is often challenging. The reported surgical outcomes are highly variable, with gross total removal ranging from 18 [11] to 83 % [12].

Surgery may not be needed for the increasing number of asymptomatic patients in whom NFPA are incidentally detected on brain imaging [13]. Patients’ age, comorbidities, tumor size, and proximity to the optic chiasm must be considered. Microadenomas or small macroadenomas whose propensity to grow is low (3.2–12.5 %) [14–16] may be safely observed. Still, symptomatic enlargement is reported in up to 50 % of asymptomatic patients harboring macroadenomas [15–17], suggesting that active treatment is warranted for these patients.

Post-surgical management

The therapeutic strategies for the management of NFPA after surgery, i.e., watchful waiting, irradiation, or medical therapy have not been compared in randomized controlled studies (RCT). Slow re-growth is common, but the natural history of untreated tumors is variable [6, 7, 18–21]. Radiation is highly effective in preventing residual tumor growth [22], but has serious long-term side effects [23]. On the other hand, conservative follow-up is associated with progression rates of over 40 % [5]. Finally, no medications are currently approved for the treatment of NFPA. Thus, risk stratification may help identify high-risk patients suitable for active intervention.

Risk stratification

Young age [6], presence of cavernous sinus invasion [24], size and extension of residual tumor [11, 18], follow-up duration [7], and pathological features [25] are all reportedly linked to a higher risk for tumor growth after surgery.

The completeness of surgical resection is particularly important as recurrence rates of 12 % and 46 % respectively, were compiled for patients without or with post-operative residual tumors in a recent metaanalysis [26]. Extrasellar extension was also associated with increased progression rate (52.3–66.7 %) relative to intrasellar remnants (30–33.3 %) [11, 18, 21].

Silent corticotroph adenomas [27] and silent type 3 adenomas (now recognized as a form of plurihormonal adenoma) [28] have been associated with a more aggressive biological behavior. Indeed, plurihormonal adenomas had a significantly higher rate of tumor progression (80 %) in comparison with gonadotropinomas (34 %) [25].

The Ki-67 labeling index (LI) is the most extensively studied proliferative marker used as a prognostic factor for tumor recurrence/progression [29–35]. A high Ki-67 LI has a high predictive value for tumor progression, as exemplified in a study in which all tumors with a Ki-67 LI higher than 1.5 % progressed [36]. On the other hand, a low index has a low-negative predictive value, as 36 % of tumors with a KI-67 LI lower than 0.5 % also progressed [37].

Radiation therapy

Conventional radiotherapy is highly effective in the post-operative treatment of residual pituitary tumors, achieving 10-year progression-free survival of over 90 % [22, 23]. Complication rate is, however, high and includes hypopituitarism [38], visual compromise [23], secondary brain tumors [39], and stroke [40].

Modern stereotactic radiotherapy appears as effective as conventional radiotherapy, but its long-term safety record remains less clear [41]. Larger residual volume is an independent predictor of tumor progression after stereotactic irradiation [40] and is associated with a higher complication risk [42].

Medical treatment

Older small series and case reports suggested that DA can induce tumor shrinkage in NFPA, [43, 44], but the effects were lesser than those seen in prolactinomas, possibly reflecting the lower expression of dopamine receptors [45]. We have introduced the concept that in the absence of mass effects, the treatment goal for NFPA should be tumor stabilization and growth prevention, not tumor shrinkage [46]. Using bromocriptine, tumor control was achieved in 78.8 % of patients, in comparison to 33.3 % in the untreated patients (mean follow-up 40 months) [46]. Furthermore, the control rate was 90 % when treatment was initiated upon detection of residual tumor on post-operative MRI, in comparison with 61.5 % for patients in whom DA therapy was started subsequently, when tumor remnant growth became evident during the course of routine follow-up. Although these data suggest that treatment should be initiated shortly after surgery, it can be occasionally difficult to distinguish between tumor tissue and post-operative changes, in which case conservative follow-up would be appropriate. The combined outcome of several small subsequent studies with the more potent dopamine agonist (DA) cabergoline [47–50] reinforced this concept: tumor shrinkage/stabilization was observed in 82 % of the patients, and tumor growth in only 18 % (Table 1). This approach appears attractive particularly since earlier concerns regarding cabergoline-induced valvular heart disease [51] have not been reported with the lower doses used in endocrine disorders [52]. Encouraging as they are, the available data are based on a limited number of patients and short follow-up periods for the cabergoline-treated patients (Table 1). Large scale studies, preferably in the form of a RCT, are required for final confirmation of this approach.

Table 1 Studies on cabergoline treatment of NFPA
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At the present time, reported experience with somatostatin analogs is limited to small patient numbers with short follow-up duration [44]. Pasireotide may be particularly interesting to test as it binds to SSTR3 [53], the most prevalent somatostatin receptor in NFPA [54].

The alkylating agent temozolomide has been increasingly used in the management of pituitary carcinomas and atypical pituitary adenomas [55]. The experience with this agent in treating non-functioning tumors is restricted to 14 invasive adenomas and carcinomas [56–58]: partial response, stable, and progressive disease were noted in five, four, and five tumors, respectively.

Overall strategy (Fig. 1)

Transsphenoidal surgery remains the treatment of choice for large tumors and symptomatic patients. Patients with significant post-operative residual tumors should be stratified according to risk factors for tumor progression. Tumors with aggressive biological behavior should be considered for radiation therapy, whereas low-risk patients could be offered DA therapy for prevention of tumor progression. In case of substantial tumor growth under surveillance (on or off medical treatment), radiation therapy is recommended. Surgical debulking should be considered before radiotherapy if there is imminent threat or actual visual impairment. Temozolomide is reserved for aggressive tumors unresponsive to the previously administered treatment modalities.

Fig. 1
figure 1

Proposed treatment strategy

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