Update: Clinically nonfunctioning pituitary adenoma (CNFPA)

Clinically nonfunctioning pituitary adenoma (CNFPA)

J. Sales-Llopis; J.Abarca-Olivas

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain

Clinically nonfunctioning pituitary adenoma (CNFPA) is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrheagalactorrhea in the context of prolactinomas, acromegalyCushing’s disease or hyperthyroidism secondary to TSH secreting pituitary adenoma).

Epidemiology

Non-functioning pituitary adenomas are the most common pituitary adenomas in adults with a prevalence of 7-22/100,000 people, and constitute over one-third of all pituitary adenomas 1) 2)3).

Despite being the most frequent pituitary tumors, NFPAs are the least studied 4).

Types

Non-functioning adenomas are mainly gonadotroph, but may also be “silent”.

Silent, or clinically nonfunctioning, pituitary adenomas can arise from any anterior pituitary cell type.

Some are “clinically silent” in that they result in a supranormal serum concentration of the hormonal product of the cell type from which the adenoma arose but do not cause the clinical manifestations typical of excessive levels of that hormone.

Others are “totally silent” in that they result in neither hormonal excess nor clinical manifestations. Gonadotroph and null cell adenomas are the most prevalent types and are typically silent.

25 to 30 percent of pituitary adenomas are clinically nonfunctioning or “silent”; 80 to 90 percent of these are gonadotroph adenomas, making them the most common type of pituitary macroadenoma.

By immunocytochemistry, the large majority of these tumors are glycoprotein producing and less commonly they are non-functioning somatotroph, lactotroph or corticotoph adenomas. In contrast to the immunocytochemistry results, only a minority of these tumors actively secrete intact gonadotrophs or glycoprotein subunits 5).

see nonfunctioning pituitary macroadenoma

Classification

Clinical features

They do not produce any hormonal hypersecretion syndrome but rather present with symptoms and signs related to the mass effect of the pituitary tumor such as headaches and visual disturbances, due to mass effects, while others may be completely asymptomatic and be first detected on an imaging study done for reasons other than pituitary symptoms or disease, and is known as pituitary incidentaloma.

Somatotroph and corticotroph adenomas typically cause clinical syndromes but occasionally are clinically or totally silent.

Those that are silent are usually larger and grow more aggressively than those that cause clinical syndromes. Silent adenomas may become, rarely, clinically apparent over time.

Visual disurbances

They may lead to blindness and causes visual impairment in 58% of cases and, more rarely, ocular motor disorder. Patients are slow to become aware of their visual dysfunction, vision in one eye compensating the deficit in the other. Assessment of visual function, comprising visual acuity and visual field evaluation and fundus examination, should be performed regularly according to the severity of impairment. Optic nerve optical coherence tomography (OCT) can quantify optic atrophy reproducibly, and is of prognostic value for postoperative visual recovery. Diplopia most often involves decompensation of heterophoria, visual field fusion being hampered by the visual field defect; such diplopia without ocular motor deficit is known as “hemifield slide”. Diplopia associated with ocular motor palsy is caused by tumoral invasion of the cavernous sinus (IIIrd, IVth or VIth nerve palsy); in large impairment, restricted eye movement is easily observed; milder palsies require neuro-ophthalmologic assessment and/or Lancaster test. Pituitary apoplexy induces ocular motor impairment in 70% of cases, strongly guiding diagnosis. Visual impairment is associated in 75% of cases. The degree of neuro-ophthalmologic (visual and ocular motor) impairment is one of the main criteria guiding treatment of pituitary apoplexy (conservative medical and/or surgical treatment) and follow-up 6).

Scores

Diagnosis

Detection of a sellar mass by MRI. Biochemical testing can identify the adenoma cell type in those that are clinically silent.

Immunohistochemical evaluation

Immunohistochemical evaluation has revealed that most of these lesions are of gonadotroph differentiation, as they usually immunostain for the beta subunit of LH and/or FSH, as well as for the common alpha subunit of these glycoproteic hormones; a small proportion of these patients have tumors that immunostain for ACTH, GH, and TSH, the so-called “silent corticotroph, somatotroph, and thyrotroph adenomas,” respectively 7) 8).

Treatment

The management of Non-Functioning Pituitary Adenoma (NFPA) invading the cavernous sinus (CS) is currently a balancing act between the surgical decompression of neural structures, radiotherapy and a wait-and-see policy.

Those tumors that require treatment are generally macroadenomas.

Therapy is directed at eliminating mass effect and correcting hypopituitarism. There are anecdotal reports of tumor shrinkage during therapy with either dopamine agonists or somatostatin agonists; however tumor response to medical treatment is not reliable.

Silent adenomas that cause neurologic deficits require transsphenoidal surgery, but those that do not can be followed by MRI. Residual or recurrent disease is treated by radiation therapy, which is usually effective in preventing further growth but results in hormonal deficiencies in about half of patients. Dopamine agonists and somatostatin analogs are usually ineffective, but occasionally have been associated with reduced adenoma size 9).

Surgery

Therapy is directed at eliminating mass effect and correcting hypopituitarism.

For most patients, transphenoidal resection of the tumor is the preferable primary treatment.

Surgery improves visual defects in the majority of patients and a lesser number will recover pituitary function. In the past, pituitary radiation was commonly administered following pituitary surgery; however the need for routine radiation has recently been reevaluated. Although tumor recurrence at 10 years post surgery may be as high as 50%, few patients with recurrence will have clinical symptoms. Close follow-up with surveillance pituitary scans should be performed after surgery and radiation therapy reserved for patients having significant tumor recurrence 10).

The management of NFPA invading the cavernous sinus (CS) is a balancing act between the surgical decompression of neural structures, radiotherapy and a wait-and-see policy.

Endoscopic endonasal management EEA is a minimally-invasive, safe and effective procedure for the management of NFPA invading the CS. The extent of CS involvement was the main factor limiting the degree of tumor resection. The EEA was able to resolve the mass effect, preserving or restoring visual function, and obtaining adequate long-term tumor control 11).

Gamma Knife radiosurgery

Gamma Knife radiosurgery (GKRS) is an alternative therapeutic strategy for patients whose comorbidities substantially increase the risks of resection. In

Lee et al, evaluated the efficacy and safety of initial GKRS for NFAs.

An international group of three academic Gamma Knife centers retrospectively reviewed outcome data in 569 patients with NFAs.

Forty-one patients (7.2%) underwent GKRS as primary management for their NFAs because of an advanced age, multiple comorbidities, or patient preference. The median age at the time of radiosurgery was 69 years. Thirty-seven percent of the patients had hypopituitarism before GKRS. Patients received a median tumor margin dose of 12 Gy (range 6.2-25.0 Gy) at a median isodose of 50%. The overall tumor control rate was 92.7%, and the actuarial tumor control rate was 94% and 85% at 5 and 10 years postradiosurgery, respectively. Three patients with tumor growth or symptom progression underwent resection at 3, 3, and 96 months after GKRS, respectively. New or worsened hypopituitarism developed in 10 patients (24%) at a median interval of 37 months after GKRS. One patient suffered new-onset cranial nerve palsy. No other radiosurgical complications were noted. Delayed hypopituitarism was observed more often in patients who had received a tumor margin dose > 18 Gy (p = 0.038) and a maximum dose > 36 Gy (p = 0.025).

GKRS resulted in long-term control of NFAs in 85% of patients at 10 years. This experience suggests that GKRS provides long-term tumor control with an acceptable risk profile. This approach may be especially valuable in older patients, those with multiple comorbidities, and those who have endocrine-inactive tumors without visual compromise due to mass effect of the adenoma 12).

Postoperative treatment

Post-surgical surveillance of non-functioning pituitary adenoma (NFPA) is based on magnetic resonance imaging (MRI) at 3 or 6 months then 1 year. When there is no adenomatous residue, annual surveillance is recommended for 5 years and then at 7, 10 and 15 years. In case of residue or doubtful MRI, prolonged annual surveillance monitors any progression. Reintervention is indicated if complete residue resection is feasible, or for symptomatic optic pathway compression, to create a safety margin between the tumor and the optic pathways ahead of complementary radiation therapy (RT), or in case of post-RT progression. In case of residue, unless the tumor displays elevated growth potential, it is usually recommended to postpone RT until progression is manifest, as efficacy is comparable whether treatment is immediate or postponed. The efficacy of the various RT techniques in terms of tumor volume control is likewise comparable. RT-induced hypopituitarism is frequent, whatever the technique. The choice thus depends basically on residue characteristics: size, delineation, and proximity to neighboring radiation-sensitive structures. Reduced rates of vascular complications and secondary brain tumor can be hoped for with one-dose or hypofractionated stereotactic RT, but there has been insufficient follow-up to provide evidence. Somatostatin analogs and dopaminergic agonists have yet to demonstrate sufficient efficacy. Temozolomide is an option in aggressive NFPA resistant to surgery and RT 13).

Outcome

They cause significant morbidity unless adequately treated.

Although tumor recurrence at 10 years post surgery may be as high as 50%, few patients with recurrence will have clinical symptoms. Close follow-up with surveillance pituitary scans should be performed after surgery and radiation therapy reserved for patients having significant tumor recurrence 14).

Case series

2015

546 patients operated for a macroNFA between 1963 and 2011 were studied. Mortality data were retrieved through the National Health Service Central Register and hospital records and recorded as standardized mortality ratio (SMR). Mortality was estimated for the total and various subgroups with clinical follow-up data.

Median follow-up was 8 years (range 1 month-48.5 years). SMR was 3.6 [95% confidence interval (CI), 2.9-4.5], for those operated before 1990, 4.7 (95% CI, 2.7-7.6) and for those after 1990, 3.5 (95% CI, 2.8-4.4). Main causes of death were cardio/cerebrovascular (33.7%), infections (30.1%) and malignancy (28.9%). Cox regression analysis demonstrated that only age at diagnosis remained an independent predictor of mortality (Hazard Ratio 1.10; 95% CI, 1.07-1.13, p<0.001) whereas sex, presentation with acute apoplexy, extent of tumour removal, radiotherapy, recurrence, untreated GH deficiency, FSH/LH deficiency, ACTH deficiency, TSH deficiency and treatment with desmopressin had no impact.

Despite the improvement of treatments over the last three decades, the mortality of patients with NFAs in our series remains high. Apart from age, factors related with the management/outcome of the tumour are not independent predictors, and pituitary hormone deficits managed with the currently-used substitution protocols do not adversely affect mortality15).


A HRQoL questionnaire (15D) was sent to all patients (n=161) having undergone transsphenoidal surgery for NFPA in the years 2000 to 2010 at the Helsinki University Hospital. The 15D score and dimension scores of the study population (n=137) were compared with those of a large (n=4967) gender- and age-standardised control population. Possible independent predictors of HRQoL in the patients were estimated with multivariate regression analysis.

Postoperatively, 56.9% of the patients had normal visual function. After a mean follow-up of 7.4 ± 3.2 years (mean ± SD), 62% suffered from hypopituitarism. Overall HRQoL was near-normal in patients compared to controls (15D scores 0.885 ± 0.114 vs. 0.903 ± 0.093, respectively, p=0.07). On single dimensions, patients had impaired vision and sexual activity (both p<0.0005), more depression and distress (both p<0.005) and less discomfort and symptoms (p<0.05). Age, body mass index, diabetes, depression and reoperation were independent predictors of impaired HRQoL (all p< 0.05). Thyroxine substitution was associated with impaired and hydrocortisone and testosterone substitution (males only) with better HRQoL (all p< 0.05).

This recent series of NFPA patients demonstrates that overall HRQoL is near-normal after medium term follow-up; the most impaired dimensions were in vision and sexual activity. Comorbidities are strong predictors of impaired HRQoL 16).


160 patients operated via pure endoscopic endonasally. Presenting symptoms, results of neurological and visual examination, levels of pituitary hormones, results of radiological examinations, adenoma sizes, rates of resection, results of postoperative visual examination, and pituitary hormone levels at follow-up were recorded to establish the appropriate approach, operative criteria, and outcomes of patients with non-functioning pituitary adenoma.

Headache was the presenting symptom in 87.5% of the patients. Thirty-three percent had visual loss and visual examination carried out in the whole study population revealed a visual field defect in 47.5% of the subjects. While only 16.25% of the patients presented with endocrinological symptoms, 52.5% had abnormal anterior pituitary hormone levels. Regarding the adenoma size56 patients had macroadenoma (35%), 84 (52.5%) had mesoadenoma and 20 patients had giant adenoma. The grosstotal resection was achieved in majority (90%) of the patients and in the remaining group subtotal resection could be done. The rate of total resection was lower in giant adenomas and recurrences. Visual symptoms and anterior pituitary hormone levels improved in 27 and 42 patients, respectively following the operation.

Non-functioning pituitary adenomas present frequently as meso- and giant-adenomas. Patients harboring these tumors may have subclinical visual or hormonal deficits at the time of diagnosis. An early and effective surgical treatment is essential for rapid recovery of visual and/or hormonal deficits, particularly in symptomatic cases 17).


56 cases of NFPA with CS invasion treated through an endoscopic endonasal approach (EEA) between 2000 and 2010. The Knosp classification was adopted to describe CS involvement using information from preoperative MRI and intraoperative findings. Extent of resection and surgical outcomes were evaluated on the basis of postoperative contrast-enhanced MRI. Endocrinological improvement and visual outcomes were assessed according to the most recent consensus criteria.

EEA was performed using direct para-septal, trans-ethmoidal-sphenoidal or trans-ethmoidal-pterygoidal-sphenoidal ap- proach. Visual outcomes improved in 30 (81%) patients. Normalization or at least improvement of previous hypopituitarism was obtained in 55% of cases. A gross total resection was achieved in 30.3% of cases. The recurrence-free survival was 87.5%, with a mean follow-up of 61 months (range, 36-166 months). No major intraoperative or postoperative complications occurred.

EEA is a minimally-invasive, safe and effective procedure for the management of NFPA invading the CS. The extent of CS involvement was the main factor limiting the degree of tumor resection. The EEA was able to resolve the mass effect, preser- ving or restoring visual function, and obtaining adequate long-term tumor control 18).


84 patients with presumed NFPA were studied retrospectively. Patients were enrolled based on the following criteria: imaging suggestive of pituitary adenoma, absence of any biochemical/clinical evidence of hormonal excess, exclusion of prolactinomas and at least one sequential imaging during the follow-up. Repeated assessment of the pituitary function, visual fields and imaging was performed at regular intervals. The follow-up duration was evaluated from the first and last imaging dates.

In group F (follow-up without surgery, 33 patients), the macroadenomas showed a 15 % probability of tumor growth and reduction. Similar tumor size alterations were observed also for the microadenomas. In group S (surgery, 51 patients), both residual tumors (>1 and <1 cm) following initial surgical resection remain mainly stable until the last imaging.

Based on the given lack of approved medical treatment and the possible risks of surgical intervention in presence of significant comorbidities, the study proposes a conservative approach with a careful follow-up in patients with NFPAs without visual or neurological abnormalities 19).


In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and post-treatment MRI scans in patients treated with (n=47) or without RT.

The median MRI follow-up time for RT patients was 10 (range 1-22) years and 5 (range 1-21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25-0.97, p=.042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups.

Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients 20).


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