ABSTRACT

Pituitary adenomas comprise approximately 10-20% of intracranial tumors. Non-functioning pituitary adenomas (NFPAs) are benign adenohypophyseal tumors not associated with clinical evidence of hormonal hypersecretion. NFPAs comprise different histological subtypes, classified according to their immunostaining to different adenohypophyseal hormones and transcription factors. The silent gonadotroph adenoma is the most common subtype, followed by corticotroph, PIT1 (POU1F1) gene lineage, and null cell tumors. Patients with NFPAs usually come to medical attention as a result of “mass effects” symptoms such as headaches, visual disorders, and/or cranial nerve dysfunction caused by lesions large enough to damage surrounding structures. Hypopituitarism, caused by the compression of the normal anterior pituitary, and hyperprolactinemia due to pituitary stalk deviation can also be present. Some cases may be diagnosed incidentally through imaging studies performed for other purposes. Patients with NFPAs should undergo hormonal, clinical, and laboratory evaluation to rule out hyper and hypopituitarism. Assessment of prolactin and IGF-1 levels have been recommended in all patients whereas screening for cortisol excess is suggested in the presence of clinical symptoms. Impairment of pituitary function should be assessed by baseline hormonal measurements and/or stimulatory tests, if needed. Patients in whom the tumor abuts the optic chiasm should be submitted to visual field perimetry. Surgical resection is the primary treatment for symptomatic patients with NFPAs, i.e., those with neuro-ophthalmologic complaints and/or tumors affecting the optic pathway. Visual deficits and, less commonly, hormone deficiencies may improve following surgical treatment although new hormone deficiencies may also occasionally develop after a surgical approach. For patients with residual NFPAs following transsphenoidal surgery, a therapeutic attempt using cabergoline can be made according to clinical judgment in individual cases. Radiotherapy in the postoperative period is not consensual and is generally reserved for cases of tumors not completely resected by surgery, those cases that present progressive tumor growth during follow-up, or for patients who, at diagnosis, already have tumors with aggressive features. Highly aggressive tumors need special care during follow-up, including temozolomide with or without radiotherapy complementation or new potential emerging treatments. For patients with asymptomatic NFPAs a “watch and wait” option is reasonable. Follow up is individualized and should consider tumor size, prior treatments, and clinical symptoms. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Pituitary adenomas are common, predominantly indolent neoplasms comprising approximately 10-20% of intracranial tumors (1,2). Non-functioning pituitary adenomas (NFPAs) are benign neoplasms that originate from the adenohypophyseal cells and are not associated with clinical evidence of hormonal hypersecretion (3). They comprise a large and heterogeneous group, representing a sizeable proportion (22% to 54% in different series) of all pituitary adenomas (4-7). Malignant transformation in a non-functioning pituitary adenoma (pituitary carcinoma) is extremely rare and is characterized by craniospinal or systemic dissemination (8).

NFPAs can be further classified according to their pituitary hormone and transcription factor profile, as defined by the 2017 World Health Organization (WHO) classification for endocrine tumors (9). Tumors that express one or more anterior pituitary hormones or their transcription factors with immunohistochemistry (IHC) but do not secrete hormones at a clinically relevant level can be referred to as silent pituitary adenomas (SPAs) (10,11). As a consequence, the definition of “null cell adenoma” is now limited to an exceptionally rare primary adenohypophyseal tumor that shows immunonegativity for all adenohypophyseal hormones as well as for cell-type specific transcription factors (12) - Figure 1.

Figure 1

- Classification of non-functioning pituitary adenomas rely upon clinical features and histopathological data. Reprinted with permission from Drummond et al., 2019

The term “totally silent” has been proposed to be used when a patient with an NFPA presents basal and stimulated serum concentrations of the correspondent hormones within the normal range and there are no clinical signs or symptoms that can be attributed to hormone excess (13). The term “clinically silent” may be used when NFPAs secrete hormonal products that cause an elevation of the serum concentration but do not result in clinical signs or symptoms of hormonal hypersecretion (13). Some cases are referred to as “whispering” adenomas with borderline, mild, often overlooked, clinical symptoms and signs (14,15).

EPIDEMIOLOGY

The prevalence of NFPAs is variable and is often based upon autopsy or magnetic resonance imaging (MRI) series. Data from Europe, North and South America have estimated that the prevalence of clinically relevant NFPAs is 7–41.3 cases per 100,000 of population (16). This is likely an underestimate of the true prevalence, as many NFPAs go undiagnosed until they are large enough to cause mass effect or are accidentally discovered. Data are discordant about gender predominance and the peak occurrence is from the fourth to the eighth decade. A recent population-based study from South Korea showed an annual incidence of 3.5 cases/ 100,000 population for NFPAs, which is noticeably higher than the annual incidences previously reported in other countries, such as Sweden, Finland, and Argentina (17). These differences may be related to genetic and environmental factors in Asian populations or inter-study heterogeneity and may also reflect the good local access to diagnostic evaluations using magnetic resonance imaging and computed tomography.

CLINICAL PRESENTATION

The absence of clinical manifestations of hormonal hypersecretion usually results in significant diagnostic delay and therefore NFPAs may not be diagnosed until they cause mass effects to surrounding structures (3), causing symptoms such as headaches, visual disorders, and/or cranial nerve dysfunction. Other manifestations are hormone deficiencies or hyperprolactinemia due to pituitary stalk deviation and, less frequently, pituitary apoplexy (18,19). Additionally, some cases may be diagnosed incidentally through imaging studies performed for other purposes, the so-called pituitary incidentaloma.

HISTOPATHOLOGICAL CLASSIFICATION

The 2017 WHO classification for endocrine tumors (9) defines pituitary adenomas, including NFPAs, according to their pituitary hormone and transcription factor profile. It is noteworthy that in this classification system, IHC forms the basis of the new categorization, in which an adenohypophyseal cell lineage designation of the pituitary adenoma has replaced the concept of a “hormone-producing pituitary adenoma” (40) -Table 1.

Indeed, the prevalence of the different histological subtypes of NFPAs is dependent on the extent of the IHC profile. According to a large retrospective case series (11), the gonadotroph adenoma is the most common subtype, followed by corticotroph, PIT1 (GH/ Prolactin/TSH) lineage and null cell - Figure 2.

Figure 2

- Prevalence of silent pituitary adenoma subtypes according to immunochemistry for anterior pituitary hormones and transcription factors. Adapted from Nishioka et al., 2015

Pituitary hormones gene expression analysis using real-time quantitative PCR (RT-qPCR) has been shown to complement the IHC classification of pituitary tumors, according to a large observational, cross-sectional study evaluating 268 patients (41). Addition of RT-qPCR analysis reduced the proportion of null-cell subtype in this series from 36% to 19%. Lower specific adenohypophyseal hormone gene expression was observed in some SPA variants when compared with their secreting counterparts, including somatotroph, lactotroph, mixed somatotroph-lactotroph and plurihormonal adenomas, which could contribute to the absence of endocrine manifestations.

The European Pituitary Pathology Group has recently proposed a standardized report for the diagnosis of pituitary adenomas which includes a multi-step approach, comprising the summary of clinical and neuroimaging features, IHC for hormones and transcription factors, assessment of proliferation and, when indicated, the use of markers predictive of treatment response (42). This proposition highlights the role of the pituitary pathologist as part of a multidisciplinary pituitary team helping the clinician define the most appropriate post-operative strategy for each patient, including appropriate follow-up and early recognition and treatment of potentially aggressive tumors (43).

EVALUATION

According to current practice guidelines on incidentally discovered sellar masses, all patients, including those without symptoms, should undergo hormonal, clinical, and laboratory evaluation for hyper and hypopituitarism (69). The extent of the evaluation is still debatable and has commonly relied on clinical experience - assessment of prolactin and IGF-1 levels have been recommended, whereas screening for cortisol excess (i.e., overnight 1mg dexamethasone and/or late-evening salivary cortisol and/or urinary-free cortisol) is suggested in the presence of clinical symptoms, while measurement of ACTH levels is not routinely recommended. (69).

Patients with macroadenoma, especially those >3 cm and with normal or slightly elevated prolactin, must have their serum prolactin diluted in order to exclude the "hook effect" (70,71). This effect occurs when excessively high levels of this hormone interfere with the formation of the complex antibody-antigen-antibody sandwich, and a prolactinoma might be mistaken for a NFPA (72).

It is also suggested to check for pituitary hormone deficiencies in patients with non-functioning tumors, irrespective of symptoms. Macroadenomas can cause impairment of pituitary function by the involvement of the normal gland or pituitary stalk compression, and the risk of hypopituitarism is directly related to tumor volume. Microadenomas eventually lead to pituitary dysfunction, particularly if larger than 5mm (32,69). A large retrospective cohort of 218 patients with NFPAs found at least one pituitary deficiency at diagnosis in 33.3% of microadenomas (73) although other studies have failed to identify hormonal deficiencies in microadenomas. An interesting and cost-effective approach for microincidentalomas could be no hormonal evaluation for cystic and solid lesions smaller than 5 mm. For solid microadenomas (between 6-9 mm), it is suggested a simple investigation with measurements of PRL and IGF1 (74).

Concerning macroadenomas, current guidelines suggest that serum cortisol levels at 8-9 AM should be done as the first-line test for diagnosing central adrenal insufficiency (75). Despite well recognized limitations of most commercial cortisol immunoassays (76), baseline cortisol levels <3 µg/dL (83 nmol/L) are suggestive of central adrenal insufficiency, while baseline cortisol levels >15 µg/dL (414 nmol/L) likely exclude it, and levels between 3 and 15 µg/dL require a corticotropin/insulin stimulation test. Central hypothyroidism is assessed by measuring serum TSH and free T4 (fT4), and fT4 level below the laboratory reference range in conjunction with a low, normal, or mildly elevated TSH in the setting of pituitary disease usually confirms the diagnosis (75). Diagnosing GH deficiency (GHD) is relatively straightforward in patients with IGF1 concentration lower than the gender- and age-specific lower limit of normal and structural pituitary disease. Low IGF1 in patients with non-functioning tumors who have at least three pituitary hormone deficiencies is also suggestive of GHD (29). Nevertheless, some adults with suspected GHD may have normal IGF1, in such cases GH stimulation testing may be useful. Central hypogonadism in males, manifests with low serum testosterone, low or inappropriately normal FSH/LH and features of testosterone deficiency. For females, pre-menopausal women with oligomenorrhea or amenorrhea should be screened with serum E2, FSH, and LH. In postmenopausal women, if the patient is not in hormonal therapy, the absence of high serum FSH and LH is sufficient for a diagnosis of central hypogonadism (75).

Sellar MRI with gadolinium is the best imaging study for suspected adenomas because it provides images of high resolution of the mass as well as its relationship with surrounding structures. Pituitary adenomas usually appear hypo or isointense compared to normal pituitary tissue in T1 images on MRI. In addition, while the normal pituitary tissue enhances earlier with contrast, pituitary adenomas commonly present with delayed contrast uptake (77). Patients whose tumor abuts the optic chiasm should have visual field perimetry, preferably by the Goldmann method, to assess for visual deficits (69).

Functional (FDG- and/or SSTR- positron emission tomography (PET) imaging studies should only be considered in aggressive pituitary adenomas/carcinomas in the setting of site-specific symptoms (neck/back pain or neurological complaints), and/or where laboratory measures are discordant with known visible extent of disease (78). Recently, 37 patients diagnosed with NFPAs enrolled in a clinical trial underwent ⁶⁸Ga-DOTATATE PET/computed tomography (CT) of the head. ⁶⁸Ga-DOTATATE uptake was positive in 34/37 patients (92%), demonstrating in vivo SSTR expression in NFPAs and ultimately showing superior sensitivity of PET imaging when compared with ¹¹¹In-DTPA-octreotide scintigraphy (79).

The pre-operative differential diagnosis of NFPAs includes several additional primary non-hormonal-secreting lesions (80). This distinction is challenging in many cases because the clinical presentations and radiological aspects may be similar between adenomas and other pituitary lesions. The presence of diabetes insipidus (DI) is common in tumors of non-pituitary origin and indicates that the sellar mass is most likely not a pituitary adenoma (81). An increase in α subunit of the glycoprotein hormones (elevated in 30% of NFPA patients) can help in the differential diagnosis although normal values do not rule them out (82).

TREATMENT

In spite of current knowledge of definite NFPAs pathologic subtypes, initial treatment strategies are similar regardless of the subset. A small number of studies have reported treatment outcome results taking into consideration adenohypophyseal hormone immuno-profile (82-84) and, for the future, precise pathologic characterization utilizing adenohypophyseal hormones and transcription factors may potentially aid in predicting the response to specific adjunctive therapies.

Surgery

Surgical resection is the primary treatment for symptomatic patients with NFPAs (85), i.e., those with neuro-ophthalmologic complaints and/or tumors affecting the optic pathway. Surgery is also urgently indicated for patients with apoplexy who develop neuro-ophthalmologic complaints. In some experts’ opinion, tumors larger than 2cm should also be considered for surgery due to their propensity for growth (86). Treatment for hypopituitarism, primarily central adrenal insufficiency, and central hypothyroidism, should be commenced prior to surgical resection. Mortality rate is low (<1%) and reported surgical complication rates are acceptable. Postoperative complications such as CSF leakage, fistula, meningitis, vascular injury, persistent diabetes insipidus (DI), or new visual field defect occurred in ≤ 5% of patients, as reported by a systematic review and metanalysis (87). Accomplishment of total or near-total resection can be challenging and varies in different series, ranging from 20% to 80% (88,89). According to a recent large retrospective series evaluating 254 patients who underwent endoscopic endonasal surgery for a macroadenoma (including 72 patients with NFPAs), cavernous sinus invasion as assessed by the modified Knosp classification (90) effectively predicted surgical outcomes. Gross total resection was negatively correlated with tumor grade and success rates of gross-total resection were between 30% and 56% for tumors extending beyond the internal carotid artery and into the cavernous sinus compartments (grades 3A and 3B) (91).

A new “shape grading system” (Figure 3) has been recently proposed for predicting outcomes in patients with NFPAs operated by transsphenoidal surgery. In a retrospective single center study, 191 NFPAs were assessed according to different radiological growth patterns: spherical (Shape I), oval (Shape II), dumbbell (Shape III), mushroom (Shape IV), and polylobulated (Shape V) (92). Gross total resection was achieved in 53% of the patients, with decreasing likelihood of accomplishment in higher shape grades - shape I (82%), shape II (74%), shape III (24%), shape IV (17%) and shape 5 (0%). Furthermore, shape grades predicted resection rate better than Knosp grades. During a mean follow-up of 59 months, tumor recurrence or regrowth was observed in 6% and 12% of the patients, respectively. Higher shape grades also correlated with higher risk of tumor recurrence/regrowth as well as the need for reoperation and/or radiotherapy. Of note, SCAs more often grew as shape IV or V, while silent somatotroph adenomas were more often detected in the shape V group. Thus, the shape grading system seems to be a complimentary tool to better predict NFPA surgical outcomes, however, these findings need validation in other cohorts.

Figure 3

- The Shape grading system. Abbreviations: OC, optic chiasm; PS, pituitary stalk. From Berkaman et al Acta Neuropathologica 2021 (92)

Visual field deficits and, less commonly, hormone deficiencies may improve following surgical treatment although new hormone deficiencies may also occasionally develop after a surgical approach (87,93). The incidence of DI after endoscopic transsphenoidal surgery to remove NFPAs was recently investigated in 168 patients. Seventy-seven (45.8%) patients experienced postoperative DI and 10 (6.0%) patients suffered from permanent DI. A large cephalocaudal tumor diameter (cut off value-of 2.7 cm) was predictive of postoperative DI in such patients (94). Moreover, younger age and the absence or intrasellar location of the bright spot (as opposed to suprasellar location) on preoperative T1-weighted MRI were further factors predicting postoperative DI in a Japanese series of 333 patients with NFPAs undergoing transsphenoidal surgery (95).

Pituitary function should be reassessed one to three months after surgery and treatment of hypopituitarism introduced according to hormone deficiencies. Whether or not GH deficiency should be replaced requires a thoughtful and individualized evaluation of risks and benefits (96,97). Current data supports the absence of any stimulation of remnant or induction of recurrence by growth hormone replacement in patients with NFPAs solely treated by surgical removal (98). In a retrospective series, tumor regrowth occurred in 38/107 (36%) of non-GH treated subjects and in 8/23 (35%) of GH-treated subjects, followed up for a mean period of 6.8 years. The Cox regression analysis showed that after adjusting for sex and age at tumor diagnosis, cavernous sinus invasion at diagnosis, and type of tumor removal, GH treatment was not a significant independent predictor of recurrence.

A sellar MRI should be obtained three to six months after surgery to assess the extent of tumor resection. Also, as a significant number of patients with NFPAs may develop tumor re-growth, long-term imaging surveillance is recommended. In a retrospective analysis of 155 patients with NFPAs treated solely by surgery and followed-up for a mean period of six years (twenty-nine were followed up for more than 10 years), re-growth was reported in 34.8% of the cases, with 20% of relapse/re-growth occurring after 10 years (88). Likewise, in patients with NFPAs who present with classical apoplexy, tumor re-growth rate is not negligible. In a retrospective series of thirty-two patients with NFPAs who underwent surgery for pituitary apoplexy, tumor re-growth was reported in 11% of the cases at just over five years (99). Therefore, it is advisable that patients with NFPAs, particularly those with post-operative tumor remnants, be closely monitored following surgery, and follow-up surveillance needs to certainly be continued for more than 10 years.

Medical Therapy

Primary treatment of NFPAs with medical therapy is not currently recommended (15,85). Small series have demonstrated significant tumor volume stabilization under medical treatment in non-operated patients with NFPAs due to contraindications or refusal (110), whereas other studies have revealed tumor volume progression in the long term (111). The main medical agents that have been evaluated in NFPAs are dopamine agonists (DA) and somatostatin analogues (SAs), mainly in patients with residual tumor after transsphenoidal surgery. Figure 4 shows a suggested algorithm for the management of patients with NFPAs.

Figure 4

- Suggested algorithm for the management of patients with NFPAs. CBA: cabergoline; NFPA: non-functioning pituitary adenoma, MRI: magnetic resonance imaging; PRRT: peptide receptor radionuclide therapy RT: radiotherapy, *potential option, less evidenced-based approach; SSTR: somatostatin receptor

DOPAMINE AGONISTS

Dopamine receptor type 2 (D2R) expression has been demonstrated in patients with NFPAs. In a small series of 18 patients with hormone-negative NFPAs, two thirds of them (12/18) expressed D2R by real-time polymerase chain reaction. Patients who presented residual tumor (9/18) were treated with cabergoline up to 3mg per week. After 12 months of treatment, tumor shrinkage was observed in 56% of the patients and tumor reduction was significantly greater in those expressing D2R (112). A historical cohort analysis on the adjunctive role of DA in adult patients with GH and ACTH negative NFPAs showed favorable results (83). The treatment group consisted of patients who were either initiated on DA upon post-surgical residual tumor detection or when tumor growth was subsequently detected on follow-up, while the control group received no medication after surgical treatment. Tumor control was significantly superior in patients who were treated upon detection of post-operative residual tumor, compared to those who were treated after presenting tumor progression or the control group, 87% vs. 58% vs. 47%, respectively. The requirement for additional treatment (surgery and/or radiotherapy) during follow-up was significantly decreased from 47% to 16% with adjunctive DA therapy. In this series, there were no correlations between clinical response to DA and D2R expression, the isoform type or their expression levels.

A randomized open-label clinical trial was recently conducted aiming to compare cabergoline with non-intervention in 116 Brazilian patients with residual NFPA after transsphenoidal surgery followed-up for over two years. NFPAs were classified solely based on IHC for anterior pituitary hormones and included 59% hormone-negative adenomas and 34% silent gonadotroph adenomas. Silent corticotroph adenomas were excluded from this study. By the end of the study, residual tumor shrinkage was significantly more frequently observed in the medical-therapy group compared to patients in the control group (28.8% vs. 10.5%). Tumor response was not associated with D2R expression (113). Thus, although cabergoline has not been a consensual treatment for patients with NFPAs, a therapeutic attempt can be made according to clinical judgment in individual cases; particularly in patients with large extrasellar remnants after surgery and a high probability of tumor progression (114). On the other hand, most studies published so far included only patients with hormone-negative or silent gonadotroph adenomas, such that this proposition should not be extended to silent corticotroph adenomas or the other rarer silent tumors. It is also important to bear in mind the natural history of untreated NFPAs, which may show a spontaneous decrease in tumor volume in up to 30% of them (115).

Cabergoline doses are variable, but usually started at 0.5 mg weekly, increasing 0.5 mg each week until a maximum dose of 3.0 mg/week is reached. For these patients, tumor shrinkage is not the major target although it can occur in 38% of them; otherwise, prevention of tumor growth is the main treatment goal. Tumor progression can be assessed by a sellar MRI every six months for the first two years, and annually thereafter. Once stability is achieved without significant side effects, the drug can be maintained indefinitely, taking into account individual cost-benefits (82,116).

SOMATOSTATIN RECEPTOR LIGANDS

The finding of somatostatin receptors (SSTRs) expression by NFPAs has raised the possibility that the use of somatostatin receptor ligands (SRLs) could be an effective treatment strategy (117,118). The SRL octreotide which binds with high affinity to SSTR2 was not effective in controlling tumor size or improving visual field in a small group of patients with NFPAs (119). A case-control study evaluated the results of long-acting octreotide in patients harboring post-surgical NFPA residues and it demonstrated tumor remnant stabilization in 81% (21/26) of patients in the treated group compared to 47% (6/13) of patients in the control group after a mean follow-up of 37 months (120). However, neither visual field nor pituitary function changed in any of the groups. This cohort of 39 NFPAs consisted of a heterogeneous group as IHC revealed positivity for pituitary hormones in 28 cases (20 of those showing positivity for FSH and/or LH) whereas the remaining 11 cases were negative for adenohypophyseal hormones. SSTR5 was the predominant SSTR expressed (84%), followed by SSTR3 (61%), while SSTR2 was expressed in 46% of the cases.

The expression of SSTRs and zinc finger protein 1 (ZAC1), a protein regulating apoptosis and cell cycle arrest, were assessed in a group of NFPAs (SGAs and hormone-negative adenomas), active somatotroph adenomas, and normal pituitary. SSTR2 and ZAC1 expression was reduced whereas SSTR3 expression was increased in SGAs compared to active somatotroph adenomas and normal pituitary (121). Likewise, other studies have suggested that SSTR3 is the predominant SSTR expressed in most NFPAs, both by IHC studies (118,122) and mRNA levels (11,122). However, a few other studies have demonstrated higher SSTR2 expression than SSTR3 or SSTR5 expression in SGAs and hormone-negative adenomas (103,123). Regarding corticotroph pituitary tumors, SSTR5 expression was significantly less frequently found in SCAs as compared to their secreting counterparts (2/23 vs. 24/39) (124). Furthermore, amongst the 23 SCAs, somatic ubiquitin-specific protease 8 (USP8) mutation was detected in only two tumors, in line with previous reports showing a significantly lower prevalence of USP8 mutations in SCAs compared to functioning corticotroph tumors (125,126).

There is an ongoing multicenter, randomized, double-blind, placebo-controlled trial (GALANT study) evaluating the effectiveness of first generation SRLs in patients with NFPAs and suprasellar extension, either surgery-naive or with a postoperative remnant. Forty-four patients with positive results on 68Ga-DOTATATE PET are being randomized to treatment with either the SRL lanreotide or placebo (127).

Pasireotide is a universal SRL with action on SSTR1, SSTR2, SSTR3 and STR5 subtypes and, therefore, seems more attractive than first-generation SRLs as an alternative medical treatment for NFPAs. A head-to-head comparison of octreotide and pasireotide in MENX-affected rat harboring a mutation I the gene encoding p27, an in vivo model of NFPAs, was recently performed. Pasireotide showed superior anti-tumor effect vs. octreotide, especially in females, which also showed higher SSTR3 expression (128). There are two phase 2 clinical trials evaluating the safety and efficacy of pasireotide for the treatment of NFPAs. Both trials have been recently completed but the results are not yet available. Passion 1 (NCT01283542) is an open-label single arm study evaluating tumor volume response to pasireotide in naive patients with NFPAs >1cm. Another phase 2 clinical trial (NCT01620138) is currently comparing the response of patients with NFPAs and surgical remnants to cabergoline vs. pasireotide. Notwithstanding, until further data are available, the use of SSRLs is not currently recommended for the treatment of patients with NFPAs.

Treatment of NFPAs with dopastatin, i.e., chimeric compound with dopamine and somatostatin agonist activity, has also been under investigation. BIM-23A760, a compound with potent agonist activity both at D2R and SSTR2 effectively inhibited cell proliferation in primary cultures of NFPAs (129). Interestingly, TBR-760 (formerly BIM-23A760) was recently tested in a mouse model of aggressive NFPA and resulted in nearly complete inhibition of tumor growth (130). A one year, randomized, double-blind, placebo-controlled phase 2 study of TBR-760 in adult patients with residual NFPAs > 1cm after transsphenoidal surgery (NCT04335357) is being conducted and is expected to be completed by 2023.

TEMOZOLOMIDE

Temozolomide (TMZ) was the first alkylating chemotherapeutic drug to show significant response rates in aggressive pituitary tumors (131). Notwithstanding, TMZ seems to be less effective in NFPAs compared to their secreting counterparts as 45% of 110 clinically functioning pituitary tumors showed regression on first-line TMZ while only 17% of 47 NFPAs did (132).

Responsiveness to TMZ is probably dependent on the immuno-expression of O (6)-methylguanine DNA methyltransferase (MGMT), a DNA repair protein that acts by removing the alkyl group and therefore is associated with TMZ resistance (133). Low immuno-expression of MGMT by pituitary tumors has been associated with higher response rates to TMZ (131). MGMT immuno-expression was assessed in a group of 45 NFPAs and the degree of expression was correlated with tumor aggressiveness (133). Low MGMT expression was observed in 50% of the aggressive NFPAs compared to 24% of the non-aggressive NFPAs. These findings suggest that aggressive NFPAs with low MGMT expression could be potential candidates for treatment with TMZ.

Regarding dosing regimens and indications, current guidelines suggest using TMZ (150-200 mg/m²daily for 5/28 days) as an alternative treatment for patients with aggressive NFPAs presenting tumor progression despite radiotherapy and other therapeutic measures, and for exceptional cases of pituitary carcinomas (29,132). Furthermore, in the case of rapid tumor growth in patients who have not previously reached maximal doses of radiotherapy, the use of the STUPP protocol (six weeks of concomitant fractionated radiotherapy and TMZ 75 mg/m² daily, followed by TMZ alone 150-200 mg/m² daily for 5/28 days) has been suggested (132). Studies on long-term administration of TMZ are scarce but clinical observations indicate that TMZ should be continued for as long as it is effective and well tolerated. Some authors suggest continuing TMZ at standard dosage for two years and later reducing to half-dose (134). Patients receiving TMZ chemotherapy are at risk for hematologic toxicity, occurring in approximately 15-20% of the cases. The most common non-hematologic side effects of TMZ are nausea, anorexia, and fatigue (135).

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

In vivo SSTR expression by NFPAs has been previously demonstrated both by positive uptake on somatostatin receptor scintigraphy (120) and on 68Gallium DOTATATE PET/ CT (79) providing a rationale for the administration of PRRT in these patients. So far, PRRT has been studied in few patients with aggressive pituitary tumors (clinically functioning and NFPAs) with different response patterns (136,137). Among the six patients with nonfunctioning pituitary adenoma or carcinoma, three patients (not previously treated with TMZ) showed stable disease (138-140), two patients had progressive disease (138,141) and one patient died in the following months while information on tumor volume was lacking (142).

QUALITY OF LIFE AND LONG-TERM MORBIDITY AND MORTALITY

A substantial number of patients with NFPAs suffer from morbidities related to the tumor itself, as well as to the treatments offered. Standardized mortality ratios in these patients seem to be higher than that of the general population with deaths associated mainly with circulatory, respiratory, and infectious causes (143). Until now, there was no consensus on predictive factors of mortality but those most consistently described are older age at diagnosis (144,145) and high doses of glucocorticoid replacement therapy (146). A retrospective series of 546 patients operated on for a macro NFPA between 1963 and 2011 and followed up for a median period of 8 years reported a standardized mortality ratio of 3.6 (95% CI, 2.9–4.5) (144). After adjustment for factors proven to be significant in univariate analysis - radiotherapy, tumor regrowth, and untreated growth hormone deficiency - age at diagnosis was an independent predictor of mortality, with shorter survival observed in older patients.

Following NFPA treatment, patient-reported health-related quality of life (HR-QoL) substantially improves. Nevertheless, there are conflicting findings about HR-QoL normalization, which may also be related to the lack of a disease-specific HR-QoL questionnaire for NFPAs (147). Some studies have described a persistent decreased HR-QoL compared to healthy controls and reference data (148,149), while others have not (150). In the latest study, HR-QoL was evaluated in 193 consecutive patients with NFPAs followed up in a tertiary endocrine referral center (150). The overall health-related quality of life and perception of subjective health in patients with NFPAs was not compromised although specific groups, such as females, patients with tumor recurrences, and with visual defects, were shown to be affected in various dimensions. Altered sleep-wake rhythmicity has also been described in a cohort of 69 patients with NFPA in long term remission after transsphenoidal surgery on stable replacement treatment for hypopituitarism (151). NFPA patients reported severely impaired QoL, sleep quality, and increased daytime sleepiness. Preoperative visual field defects were associated with sleep-wake rhythm fragmentation and vasopressin deficiency was associated with decreased sleep efficiency, independent of age, hypopituitarism, or radiotherapy.

More recently, the use of the Wilson–Cleary model, a conceptual biopsychosocial model of HR-QoL, suggested that elements at each stage of this model could be contributing to the impairment in HR-QoL observed in patients with a NFPA (147). The authors concluded that currently available biomedical treatments, i.e., surgery, radiotherapy, and hormone replacement therapy, are clearly not sufficient for achievement of good HR-QoL in patients with a NFPA, and further improvement should be supported by a pituitary specific care trajectory, targeting not only biological and physiological variables, but also psychosocial care.

PROGNOSTIC FACTORS AND FUTURE PERSPECTIVES

There has been a search to identify reliable factors related to aggressiveness and the risk of recurrence in NFPAs. A single-center retrospective study which evaluated 108 surgically-resected NFPAs followed for up to 15 years (152) showed that 22% of the patients required further treatment, either second surgery or radiotherapy. Factors determining recurrence were the presence of residual tumor, tumor growth rate (>80 mm³/year), and suprasellar extension (152). According to another retrospective case series evaluating patients with NFPAs who presented tumor regrowth after primary treatment, the NFPA subtype, categorized by anterior pituitary hormone immunostaining, was not a predictive factor for the requirement of secondary treatment or tumor regrowth. Significant risk factors were female gender and treatment approach (monitoring vs. interventions); secondary progression was significantly higher in those patients who were followed conservatively (63%) as compared to those who received surgery (36%), radiotherapy (13%), and surgery/adjuvant radiotherapy (13%) (84). In patients with SGAs, ERα seems to be a prognostic factor for re-intervention (reoperation or radiation) in males - the combination of the absence of ERα expression and young age served as good predictive markers of aggressiveness (122).

The role of cellular markers, associated with cell proliferation and apoptosis, in predicting the recurrence of NFPAs has also been investigated (153). Proliferative indexes such as a high Ki-67 index, assessed by IHC, were significantly associated with a tumor size greater than 3 cm, as well as with tumor recurrence (103). Evaluation of tumor proliferation by using Ki-67 IHC is widely available and is recommended as part of the assessment of NFPAs (40). According to a large retrospective series evaluating 601 patients with surgically resected pituitary tumors, including approximately 30% NFPAs, the optimal cut-off points of the Ki-67 proliferation index that predicted recurrence was 2.5% with 84.6% sensitivity and 47.4% specificity (154). Moreover, a recent retrospective analysis of 120 patients operated on for an NFPA showed that invasive and proliferative tumors, i.e., grade 2b tumors. according to the clinicopathological classification of Trouillas et al. (155) showed an overall likelihood of recurrence that was approximately 9 times greater than those of grade 1a, i.e., non-invasive and non-proliferative tumors (156). Further risk factors associated with an increased risk of recurrence in this cohort were a younger age and the presence of residual tumor.

Minichromosome maintenance 7 (MCM7), a cell-cycle regulator protein, has been recently proposed as a marker of tumor progression in NFPAs. In a cohort study of 97 surgically treated NFPAs, the probability for reintervention within 6 years for patients harboring residual tumors with high MCM7 expression was 93% (157). Ki-67 expression >3%, age ≤55 years and mitotic index≥1, but not tumor subtype, were also associated with reintervention. Attempts to develop clinical nomograms to predict post-operative recurrence of NFPAs have recently been demonstrated based on age, tumor size, cavernous sinus invasion, sphenoid sinus invasion, and surgery extension. The nomogram model proposed by Lyu et al. (158) showed an area under the ROC curve of 0.953 and correlation analyses indicated that sphenoid sinus invasion, cavernous sinus invasion and tumor size could promote the recurrence of NFPA while advanced age and gross total resection could effectively inhibit it.

Genetic and epigenetic mechanisms underlying the development and aggressiveness of NFPAs have not been fully elucidated (159). The mutational landscape of a cohort of pituitary tumors including 37 NFPAs was recently published (160). Aside from demonstrating gonadotroph signatures in seven out of eight SCAs, retrieving the question whether a subset of SCAs arise from a specific pituitary lineage distinct from other corticotroph (161), this study showed that most NFPAs displayed no functional somatic variant and no chromosome alterations. Further characterization of these tumors with techniques such as whole genome sequencing coupled to chromatin structure analysis may disclose mutations in non-coding regions affecting chromatin opening and/or the binding of specific transcription factors. allowing for the development of novel therapeutic strategies.

An adverse pituitary adenoma phenotype is defined not only by the intrinsic activity of tumor cells but also by the infiltrated immune cells in the tumor microenvironment (162). The study of the immune profile of pituitary tumors for predicting immunotherapy responsiveness is an evolving field. Wang et al (163) have recently proposed classification of these tumors on three clusters based on tumor-infiltrating immune cells and the expression of immune checkpoint molecules This study cohort included 57 “unspecified“ NFPAs since they were not pathologically classified with pituitary transcription factors. The majority of them exhibited a “hot” immune microenvironment and were predicted to exhibit higher immunotherapy responsiveness.

CONCLUSION

NFPAs are frequent in endocrine practice. Clinically they range from being completely asymptomatic (incidental findings on head MRI or computed tomography scans) to causing significant hypothalamic/pituitary dysfunction and visual symptoms due to mass effect., For microadenomas and asymptomatic/relatively small macroadenomas (1–2 cm), a “watch and wait” option is reasonable. If tumor growth, development of visual field defects, or progressive pituitary dysfunction is detected during follow up, then surgery is indicated. It is now recommended that NFPAs are classified according to their pituitary hormone and transcription factor profiles along with proliferation markers such as Ki-67. This refined stratification may potentially aid in predicting disease course and in selecting adjunctive therapies. Radiotherapy is an effective treatment, although usually reserved for those patients with aggressive tumors and significant tumor remnant after pituitary surgery as considerable side effects may occur. Medical treatment with dopamine agonists stands as an alternative in selected cases, despite the lack of placebo-controlled trials. Highly aggressive tumors need special care during follow-up, including treatment with TMZ with or without RT complementation or new potential emerging treatments. Close collaboration of a multidisciplinary pituitary team is crucial to better serve this challenging group of patients.

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